Perez & Brady's Principles and Practice of Radiation Oncology (Perez and Bradys Principles and Practice of Radiation Oncology), 6 Ed.

Chapter 13. Late Effects and QUANTEC

John P. Kirkpatrick, Michael T. Milano, Louis S. Constine, Zeljko Vujaskovic, and Lawrence B. Marks

The modern era of cancer therapy is predicated on the safe intensification of radiation, chemotherapy, and biologic adjuvants. This has resulted in a markedly increased survivorship, which now exceeds 64% overall, and for some malignancies, such as breast and prostate cancer, is much higher. Malignancies resistant to therapy may demand an aggressive treatment approach that often resides at the limit of, or even exceeds, normal tissue tolerance to some “acceptable” degree. Clearly, the potential to ameliorate or prevent such normal tissue damage, or to manage and rehabilitate affected patients, requires an understanding of tissue tolerance to therapy. Because “late effects” manifest months or years after cessation of treatment, therapeutic decisions intended to obviate such effects can be based only on the probability, not the certainty, that such effects will develop. In making such decisions, the balance between efficacy and potential for toxicity should be considered, as well as the influence of host, disease, and treatment-related risk factors.

Historically, radiation therapy fields and doses were selected empirically, based largely on physicians’ clinical experience and judgment. They understood that these empiric guidelines were imprecise and did not completely reflect the underlying anatomy, physiology, molecular biology, and dose distributions. The introduction of three-dimensional (3D) treatment planning offered the promise of quantitative correlates of doses/volumes with clinical outcomes. This promise was partly delivered. When 3D dosimetric information became widely available, guidelines were needed to help physicians predict the relative safety of proposed treatment plans, although only limited data were available.

In 1991, investigators pooled their clinical experience, judgment, and information regarding partial organ tolerance doses and produced the “Emami paper”.¹ As discussed later, this paper clearly stated the uncertainties and limitations in its recommendations, and it is rightly admired for addressing a critical clinical need. Over the past two decades, numerous studies have reported associations between dosimetric parameters and normal tissue outcomes. In 2007, a joint task force of physicists and physicians was formed, with the support of the American Society for Therapeutic Radiology and Oncology (ASTRO) and the American Association of Physicists in Medicine (AAPM), to summarize the available data in a format useful to clinicians and to update/refine the estimates provided by Emami et al.

The resulting QUANTEC reviews² (quantitative analysis of normal tissue effects in the clinic), published in a special issue of the International Journal of Radiation Oncology, Biology and Physics in March 2010, are summarized in this chapter.

FIGURE 13.1. Key events in the development of dose–volume and normal tissue toxicity relationships in radiation oncology.

 HISTORICAL BACKGROUND

The relationship between dose–volume parameters and outcome has been the focus of numerous investigators for decades. A brief summary of historical landmarks is provided to follow, along with our opinion regarding the key contributions and shortcomings of these reviews (Fig. 13.1 and Table 13.1).

 THE INCORPORATION OF 3D DOSE–VOLUME INFORMATION INTO CLINICAL GUIDELINES

The pre-Emami reports³ were novel in that there were no tools available (to either the authors or clinicians) to accurately quantify the fraction of various organs that were being irradiated. Thus, the dose/volume/outcome information presented consisted largely of estimates based on expert opinion. Similarly, clinicians needed to estimate the partial volumes of different organs that were being irradiated in their patients in order to apply the provided information.

In the late 1980s and early 1990s, 3D planning systems were providing clinicians with a plethora of information. However, systematic dose/volume/outcome data to guide clinical decisions based on this information were limited. There was an urgent need for clinicians to have some guidance in making clinical dose–volume decisions. The report by Emami et al.¹ met this critical need. This report was, and remains, a landmark summary of decades worth of data for a wide variety of organs, supplemented with expert opinion where data were lacking. This article remains a required reading for all trainees in our field.

During the 1990s and 2000s, a large number of studies related dose–volume data to clinical outcomes. The QUANTEC review was an attempt to refine the guidelines based on the available 3D dose/volume/outcome data.

 DOSE–VOLUME HISTOGRAMS AND ASSOCIATED FIGURES OF MERIT

Three-dimensional dose–volume data can be difficult for clinicians to readily digest. Visualizing isodose distributions is challenging, and comparing competing distributions is almost impossible. Therefore, dose–volume histograms (DVHs; essentially two-dimensional [2D] representations of the 3D data) were embraced as a rapid way to summarize the dose distribution. Note that DVHs discard information regarding the spatial character of dose as well as (usually) variations in fraction size. However, DVHs can also be challenging for clinicians to consider and compare. Therefore, it has become attractive to extract “figures of merit” from the DVH, such as the V_x (the percent of an organ receiving ≥ x Gy). Thus, DVHs and their associated figures of merit are necessary tools to enable clinicians to readily apply 3D information clinically. They are excellent tools but obviously have their shortcomings.

TABLE 13.1 HISTORICAL OVERVIEW OF SUMMARIES OF DOSE/VOLUME/OUTCOME INFORMATION

 MODEL-BASED ESTIMATES OF OUTCOMES

The Emami et al. report systematically used the same DVH-based construct across many organs, for example, the TD_5/5 and TD_50/5 for the uniform irradiation of one-third, two-thirds, and the whole volume of an organ. This uniform approach enabled the application of “single unifying models” of dose/volume/outcome across organs. For example, the dose/volume/outcome estimates from Emami et al. were used by Lyman et al.,⁴ Kutcher et al.,⁵ and Burman et al.⁶ to generate a set of organ-specific model parameters. Such a uniform approach is attractive to modelers and busy clinicians.

During the last two decades, many clinical dose/volume/outcome reports computed parameters for these “unifying models” (e.g., Ten Haken et al.^7–8,9). Other investigators have suggested alternative models that appeared to be better suited to specific organs (vide infra).

The dose/volume/outcome data available for the QUANTEC review were not of a uniform format. Outcomes across organs were correlated with a diverse array of dose–volume metrics (e.g., threshold volumes [V_x], threshold doses [D_x], mean doses). Therefore, the QUANTEC review included model-based parameters for just a few organs, and not always in a systematic fashion.

TABLE 13.2 COMPARISON OF THE CHARACTER/CONTENT OF EMAMI ET AL AND QUANTEC

 MAJOR DIFFERENCES BETWEEN THE QUANTEC AND EMAMI REVIEWS

Emami et al.¹ provided information for 26 organs, judged necessary to support protocols for “three dimensional treatment planning for high energy photons (RFP #NCI-CM-36716-21).” Conversely, the QUANTEC review was focused on organs for which the steering committee thought that there were meaningful dose/volume/outcome data (Table 13.2).

Emami et al. addressed a wide variety of clinical outcomes and thus provided the reader with a set of dose–volume parameters for essentially all clinical situations. Conversely, the QUANTEC review was focused on endpoints where there were dose/volume/outcome data. In this regard, the Emami tables are more complete. For example, consider the QUANTEC summary for the small bowel. A volume restriction is provided for the endpoint of acute grade ≥3 toxicity. No guidance is provided for late small bowel injury, as the authors did not believe that there was meaningful dose/volume/outcome data for late injury. This is a shortcoming of the QUANTEC review as it is not “complete.” When evaluating a proposed 3D treatment plan, one obviously must consider both acute and late injury.

Emami et al. presented information in a systematic/uniform manner, facilitating interorgan comparisons and model-based parameter estimates. The QUANTEC review presented dose/volume/outcome data in the diverse manner in which they were available in the literature.

 MOLECULAR MECHANISMS OF LATE RADIATION DAMAGE

The design of optimal radiation treatment plans and identification of therapeutic strategies to prevent radiation-induced damage would benefit from an understanding of the underlying late effects from ionizing radiation. Both of these issues are further complicated by the variability in sensitivity to radiation observed across disease types and between patients, as well as the current absence of identifiable factors that predict a propensity for radiation-induced toxicity.^10–13 While the initial damage done to the DNA, proteins, and membrane lipids of cells by exposure to ionizing radiation is well known, the mechanisms behind the sustained changes in gene expression and signaling pathways that contribute to latent and permanent tissue injury are less clear. This section will focus on the established mechanisms of radiation-induced tissue injury and identify areas in which further efforts are needed to determine the mechanisms driving tissue injury and prognostic markers for the development of radiation injury.

Early Cellular Effects of Radiation

Exposure to ionizing radiation causes direct DNA damage through linear energy transfer as well as indirect damage by radiolytic cleavage of water, yielding hydroxyl radicals capable of abstracting hydrogen from the backbone of DNA to cause double-stranded breaks.^14,15 This damage to genomic DNA causes cell death by apoptosis or mitotic catastrophe. While the ability of hydroxyl radicals to cause DNA damage is significant, the initial increase in hydroxyl radical and other reactive oxygen species (ROS) attributable to radiation exposure is negligible compared to the baseline presence of ROS in the cell.¹⁵ Within a few hours of radiation exposure, however, the cell responds by increasing ROS production, creating a cellular environment capable of exacerbating the initial injury by causing oxidative damage to proteins and lipids.¹⁶ This is thought to occur via ROS-mediated activation of mitochondria-dependent and -independent metabolic enzymes, including nitric oxide synthases (NOSs) and oxidoreductase enzymes.

Sources of Reactive Oxygen Species

NADPH Oxidases

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are a family of broadly distributed oxidoreductase enzymes. Membrane-associated NADPH oxidases are the primary source of ROS in nonphagocytic cells.¹⁷ Under normal conditions, NADPH oxidase–derived superoxide anion is a mediator of maintenance and smooth muscle tone of the vasculature.¹⁸ When these enzymes are induced to begin pathologic overproduction of ROS, however, they can contribute to the development of oxidative stress, resulting in cell damage and disruption of signaling pathways.¹⁹ Nox4, a hydrogen peroxide–producing isoform, is of particular interest, as overproduction of hydrogen peroxide by Nox4 has been shown to be a necessary element of tumor growth factor-β1 (TGF-β1)–mediated cell death.²⁰

Mitochondria

Under normal conditions, electrons from the electron transport chain can leak into the mitochondrial matrix and react with oxygen to form superoxide anion.²¹ Following radiation, Leach et al. observed that mitochondria in squamous carcinoma cells undergo a permeability transition, causing release of high levels of ROS into the cytoplasm.²² They further showed that inhibition of this transition not only attenuates the increase in cytoplasmic free radicals but also prevents radiation-induced activation of mitogen-activated protein (MAP) kinase, suggesting a causal link between mitochondrial ROS/reactive nitrogen species (RNS) generation and a large group of signal transduction pathways. The role of mitochondrial-generated ROS/RNS in radiation injury is further supported by the radioprotective effect of Mn porphyrin superoxide dismutase (SOD) mimetics, which accumulate preferentially within the mitochondria.²³

Augmentation of Reactive Oxygen Species from Other Sources

Superoxide anion from any source can react with nitric oxide to form peroxynitrite (ONOO–), itself a powerful oxidizing species capable of reacting with other molecules and cellular elements to perpetuate free radical overproduction and cause oxidative damage to the cell.²⁴

Free Radicals and the Tissue Response to Radiation

When the increase in ROS production exceeds the antioxidant capacity of the cell, the intracellular environment becomes strongly oxidizing. This change results in altered gene expression as a part of the response to oxidative damage to genomic DNA, modification of redox-sensitive protein activity, and membrane lipid oxidation.²⁵ All of these insults can affect the structure, function, and signaling capacity of the cell. Of particular importance to the radiation response is the persistent up-regulation of transcription factors, including hypoxia-inducible factor-1α (HIF-1α) and nuclear factor κB (NFκB), and cytokines, including TGF-β, which contributes to the development of radiation-induced tissue injury.^16,26 These molecules all contribute to the vascular changes, inflammation, and cell death observed in response to radiation, but their roles in complex signaling pathways suggest that early changes in the activity of these molecules may also contribute to the disease process of latent injury. The role of ROS in radiation-induced tissue injury has been confirmed by the finding that SOD overexpression and the use of SOD mimetics can mitigate tissue injury following ionizing radiation exposure.^{11,23,27–29,30}

The Role of Inflammation in the Response to Radiation

Although the manifestations of radiation injury can be divided into early and late effects, irradiated tissues show a dynamic population of different inflammatory cell types throughout the “latency” period, suggesting that, on a cellular level, radiation injury is an ongoing disease process.³¹ Localization of inflammatory cells is mediated by vascular adhesion markers, and preferentially blocking intercellular adhesion molecule-1 (ICAM-1) does indeed reduce the inflammatory response to radiation in the lungs of C57BL/6 mice.^32,33 The resulting reduction in inflammation was, however, not sufficient to suppress development of latent pulmonary damage, suggesting that there are other mechanisms at work during this latent period that contribute to disease processes.³² With the changing inflammatory cell populations come changes in cytokine activity, specifically interleukins, tumor necrosis factor-α (TNF-α), TGF-β, monocyte chemoattractant protein-1 (MCP-1), and keratinocyte chemoattractant (KC).^31,34,35 Expression of interleukin-1 (IL-1) messenger RNA (mRNA), together with a two-part up-regulation of TGF-β expression, is known to coincide with the development of fibrosis in C57BL/6J mice, suggesting that the inflammatory response does indeed contribute to the development of latent tissue injury.³⁶ This idea is further supported by the finding that early inhibition of TGF-β reduces radiation-induced pulmonary fibrosis and improves lung function.^37,38–39 Further studies indicate that administration of exogenous SOD following thoracic radiation reduced the early up-regulation of IL-1, TNF-α, and TGF-β and extended postradiation survival.⁴⁰ The apparent link between ROS, inflammatory signaling, and latent injury development suggests that early changes in ROS production do affect delayed tissue damage through ongoing perturbations of signaling pathways.

Radiation-Induced Vascular Changes

Exposure to ionizing radiation causes damage to endothelial cells and vascular structural elements, causing increased vascular permeability.⁴¹ This vascular dysfunction results in edema as well as decreased perfusion, which can lead to development of hypoxic regions within the affected tissues.⁴² Hypoxia exacerbates the initial injury by increasing recruitment of inflammatory cells that, in the process of undergoing the respiratory burst, produce ROS and increase tissue hypoxia by consuming the available oxygen.⁴³ Hypoxia also results in activation of HIFs. HIF-1α is an ROS-stabilized transcription factor that, under hypoxic conditions, forms a heterodimer with HIF-1β. This heterodimer is translocated to the nucleus where it binds the hypoxia response element (HRE), inducing transcription of genes involved in migration proliferation, apoptosis, and angiogenesis.⁴⁴ This element of the hypoxia response contributes to endothelial cell damage, increasing vascular permeability and, as a result, leakage of fibrin into the extracellular matrix.

Vascular endothelial growth factor (VEGF) is an HIF-mediated growth factor. Under hypoxic conditions, VEGF expression is increased, resulting in aberrant vascular network formation, which leads to irregular perfusion.⁴⁵ The resulting cycles of hypoperfusion and reperfusion contribute to oxidative stress, further damaging tissue.³⁸

Macrophage accumulation further contributes to the self-perpetuating nature of radiation-induced tissue injury. Accumulation of macrophages is known to occur in areas of low perfusion and inadequate supply of oxygen and is observed in tissues following radiation exposure.^46,47 When activated, these cells produce HIF-1α in order to initiate angiogenesis to correct low perfusion.⁴⁷ This response on the part of macrophages increases the level of oxidative stress, continuing the spread of damage through inappropriate continuation of wound-healing mechanisms.

Possible Metabolic Changes

Carbonic anhydrase-9 (CA-9) is commonly used as a hypoxia marker because CA-9 transcription is dependent on HIF-1α. Because carbonic anhydrases act to catalyze the conversion of metabolically produced carbon dioxide to bicarbonate,⁴⁸ this increase in CA-9 suggests that cells may also be undergoing a metabolic shift in response to their hypoxic environments. The observed changes in mitochondrial activity would support altered metabolism in postradiation cells, but further work is necessary to determine the nature of such a change.

Implications

Exposure to ionizing radiation disrupts DNA, causing cell death, but it also causes increased production of ROS in viable cells. The oxidizing environment that results from ROS production exceeding the antioxidant capacity of the cell causes further damage by disrupting cell function and signaling pathways. This disturbance results in changes in vascular integrity, an ongoing inflammatory response, and aberrant angiogenesis. Because overproduction of ROS is self-perpetuating, these effects are amplified, increasing the area and severity of damage.

Though many of the mechanisms through which ROS production affects the development of late radiation effects remain unclear, it is likely that these early changes initiate disease processes that progress over time to cause the observed late injury.

 SUMMARY BY ORGAN SYSTEM

To provide a consistent summary of the extensive information in the individual organ reviews, the following outline is utilized:

1. Clinical Significance

2. Endpoints

3. Challenges Defining Volumes

4. Dose/Volume/Toxicity Data

5. Factors Affecting Risk

6. Mathematic/Biologic Models

7. Special Situations

8. Recommended Dose–Volume Limits

9. Future Studies

10. Toxicity Scoring Criteria

Note that the brief summaries for each review do not substitute for reading and understanding the original papers and, as necessary, the underlying literature. In addition, the dose–volume limits described in the QUANTEC reviews are intended to supplement, not supplant, clinical judgment.

FIGURE 13.2. Incidence of radiation necrosis in brain irradiation from selected studies. Biological equivalent dose (BED) calculated from the linear-quadratic model with α/β = 3 Gy; n = patient numbers as shown. Solid line represents least-squares best fit of data to probit model; dotted lines represent 95% confidence limits. A: Once-daily fractions <2.5 Gy. B: Once-daily fractions ≥2.5 Gy (data too scattered to allow plotting of “best-fit” line). C: Twice-daily radiotherapy. (From Lawrence YR, et al. Radiation dose-volume effects in the brain. Int J Radiat Oncol Biol Phys 2010;76[3 Suppl]:S20–S27.)

 CENTRAL NERVOUS SYSTEM

Brain

Clinical Significance. The acute and late effects of radiotherapy on the brain are common and represent a significant source of morbidity.⁴⁹ In particular, patients with tumor-related neurocognitive dysfunction may exhibit exacerbated deficits after radiotherapy. In addition, the radiation fields used to treat the upper aerodigestive tract (e.g., sinuses and pharynx) often include a portion of the brain.

Endpoints. The acute side effects of radiation therapy (RT) to the brain include nausea, vomiting, and headache; seizures, visual disturbances, and vertigo are less common.⁴⁹ These symptoms are typically transient and generally respond well to medication. The endpoints for assessing long-term radiation-induced complications are typically radiation necrosis or asymptomatic radiologic changes as seen on serial magnetic resonance imaging (MRI) scans.⁴⁹Other measures have included steroid usage, preservation of performance status, and neurocognitive function.^50,51–52

Challenges Defining Volumes. Contouring the entire brain is straightforward, and with appropriate immobilization, there is little intra- or interfraction motion. However, delineation of subregions (e.g., the border between the brainstem and thalamus) and functional segments (e.g., Broca area) of the brain is challenging, and the utility of defining such areas has not yet been proven.⁴⁹

Dose/Volume/Toxicity Data. For fractionated radiotherapy to the brain, the relationship between dose and radiation necrosis for partial brain irradiation is shown in Figure 13.2 for various fractionation schemes.^53–60 Lawrence et al. compared different fractionation schemes by calculating the biologically effective dose (BED),⁶¹ with an α/β ratio of 3 Gy.⁴⁹ For standard fractionation, a dose–response relationship appears to exist, such that an incidence of side effects of 5% and 10% occur at a BED of 120 Gy₃ (range, 100 to 140) and 150 Gy₃ (range, 140 to 170), respectively (corresponding to 72 Gy [range 60 to 84] and 90 Gy [range, 84 to 102] in 2-Gy fractions). For twice-daily fractionation, a steep increase in toxicity is apparent when the BED exceeds 80 Gy. For daily large fraction sizes (>2.5 Gy), the incidence and severity of toxicity are unpredictable. Lawrence et al. caution against overinterpreting this analysis given the heterogeneity of the data pool (i.e., different target volumes, endpoints, sample sizes, and brain regions).

In children, whole-brain radiotherapy appears associated with neurocognitive decline. With central nervous system prophylaxis for acute lymphoblastic leukemia, the addition of 24-Gy radiation to the whole brain (to a chemotherapy regimen) is associated with a median 13-point intelligence quotient reduction at 5 years after radiotherapy, as well as poorer academic performance and greater psychological distress.⁶² Reported toxicities have been lower when 14 to 18 Gy was used.^63–65 In medulloblastoma, the post-RT intelligence quotients were 10 to 15 points higher for a total whole-brain dose of 23.4 Gy versus 36 Gy.^66,67 In adults, the neurocognitive effects of whole-brain irradiation are less clear.

In stereotactic radiosurgery (SRS) of brain lesions, normal tissue toxicity appears to be a function of dose, volume, and location in the brain. The Radiation Therapy Oncology Group (RTOG) conducted a dose-escalation study (RTOG 9005) of radiosurgery to recurrent brain metastases and primary tumors in patients who previously received whole- or partial-brain irradiation.⁶⁸ The goal of this study was to determine the maximal tolerated dose as a function of maximum diameter of the lesion. Unacceptable toxicity was defined as acute irreversible severe neurologic symptoms, requiring inpatient or outpatient medications, any life-threatening neurologic toxicity, or death. This study found a maximum tolerated prescription dose to the tumor margin of ≥24 Gy, 18 Gy, and 15 Gy for tumors with a maximal diameter of ≤2.0 cm, 2.1 to 3.0 cm, and 3.1 to 4.0 cm, respectively. The rates of acute and late unacceptable toxicities in patients treated at these doses were 0% and 10%, 0% and 14%, and 0% and 20%, respectively. The dose limits appear to be validated by the results of the RTOG 9508, a randomized study of SRS + whole-brain radiation therapy (WBRT) versus WBRT alone in 333 patients with brain metastases.⁵⁰ Using the dose constraints developed in RTOG 90-05, this study found a 3% and 6% rate of grade 3 and 4 acute and late toxicities, respectively, in the group of 167 patients receiving radiosurgery.

The results of dose–volume studies of the development of “radionecrosis” following single-fraction radiosurgery are shown in Table 13.3.^49,69–78 While a common element in many of these studies is the volume receiving a dose of 10 or 12 Gy or more (V₁₀ or V₁₂, respectively), there is a broad variation in the crude rate of radionecrosis as a function of volume irradiated. This is likely due to difference in the definition of radionecrosis, the location irradiated, the proximity to and sparing of critical structures, and the length and intensity of clinical follow-up.

TABLE 13.3 SELECTED STUDIES OF RADIONECROSIS IN PATIENTS RECEIVING BRAIN STEREOTACTIC RADIOSURGERY

These results suggest that the rate of complications increases rapidly as the V₁₂ increases beyond 5 to 10 cm³. Note, however, that V₁₂ will far exceed these limits for lesions 2 cm or greater in mean diameter when the RTOG guidelines are utilized. For example, assume that spherical lesions 1, 2, 3, and 4 cm in diameter are treated under the RTOG guidelines with single-fraction radiosurgery with the plans yielding V₁₂’s of six, five, four, and three times the lesion volume, respectively. Then, the calculated V₁₂’s are 3, 21, 57, and 101 cm³, respectively.

The location of the lesion is important as the severity of expressed damage is greater in the more eloquent parts of the brain. For example, for a V₁₂ of 10 cm³, Flickinger et al.⁷¹ found a <5% symptomatic postradiosurgery injury for arteriovenous malformations (AVMs) in the frontal, temporal, and parietal lobes versus >20% for AVMs in the brainstem, thalamus, and basal ganglia.

Factors Affecting Risk. Younger age is associated with a higher risk of neurocognitive decline in children undergoing cranial irradiation.^79,80 Other risk factors include female gender, neurofibromatosis-1 (NF-1) mutation, extent of surgical resection, hydrocephalus, concomitant chemotherapy (especially methotrexate), location, and volume of brain irradiated.⁸¹ No evidence has shown that children are at particular risk of radiation necrosis,^82,83 however.

Mathematic/Biologic Models. While the linear-quadratic model appears useful in comparing dose/fraction for conventionally fractioned radiotherapy schemes, its utility at high doses per fraction (≥8 Gy) is controversial. In general, quantitative dose/volume/clinical toxicity relationships have not been established for neurocognitive function in partial brain irradiation. The apparent increased risk of radionecrosis in twice-daily partial brain irradiation suggests that the time constant for repair of radiation-induced damage may be longer than the typical interfraction interval, but this has not been modeled for this specific system.

Special Situations. Reirradiation of the whole brain is frequently performed in the setting of recurrent, multiple brain metastases. A meta-analysis of whole-brain reirradiation (interval between courses, 3 to 55 months) found no cases of necrosis when the total radiation dose was <100 Gy (normalized to 2 Gy/fraction with an α/β ratio = 2 Gy).⁸⁴ In primary central nervous system lymphoma, whole-brain radiotherapy has been associated with an atypically high risk of cognitive decline, especially in those >60 years old.^85,86 The heightened sensitivity of this population to irradiation might be explained by the tumor’s highly diffuse, angiocentric growth pattern and that most patients receive high-dose methotrexate, a potent neurotoxin. As a result, up-front full-dose RT is now often avoided in elderly patients with this disease. A lower radiation dose of 23.4 Gy delivered in 1.8-Gy daily fractions appears to be associated with minimal cognitive toxicity, even in older patients.⁸⁷

Recommended Dose–Volume Limit.⁴⁹ For partial-brain irradiation at a conventional dose per fraction, there is a predicted 5% and 10% risk of symptomatic radiation necrosis at a BED of 120 Gy₃ (range, 100 to 140) and 150 Gy₃ (range, 140 to 170), respectively, which corresponds to 72 Gy (range 60 to 84 Gy) and 90 Gy (range 84 to 102 Gy) for 2-Gy daily fractions. This is a less conservative estimate than the 5% risk of radionecrosis for one-third of the brain irradiated to 60 Gy in the Emami paper.¹ The authors stress that for most cancers, there is no clinical indication for partial-brain dose above 60 Gy and that, in some scenarios, an incidence of 1% to 5% radiation necrosis at 5 years would be unacceptably high. The brain appears especially sensitive to fraction sizes >2 Gy and, surprisingly, twice-daily irradiation.

For radiosurgery, the available data suggest that it is prudent to minimize the volume of normal brain receiving >12 Gy in a single fraction and to consider both target diameter and anatomic location when prescribing dose. However, the QUANTEC authors admit that “the substantial variation between the reported treatment parameters and outcomes from different centers has prevented [more] precise toxicity risk predictions.”

Future Studies. Key questions that would benefit from systematic study include:

1. What is the dose/volume/location/clinical toxicity relationship for brain metastases and other common lesions treated with single-fraction SRS?

2. What is the rate of local and distant failure for the aforementioned sets of patients as a function of prescribed dose?

3. How does the gross tumor volume (GTV) to planning target volume (PTV) expansion influence the incidence of normal tissue toxicity and failure rates in single-fraction SRS?

4. How is the incidence of normal tissue toxicity affected by previous large-field irradiation to the brain, particularly the combination of WBRT and SRS in the treatment of brain metastases?

5. How do systemic treatments affect the incidence of normal tissue toxicity?

6. What is the time interval for repair of radiation-induced damage in the brain?

Toxicity Scoring Criteria. Studies of brain radiotherapy should report detailed dosimetric and outcome data, including neurocognitive and neurologic dysfunction (e.g., per the Common Terminology Criteria for Adverse Events, version 4.0 [CTCAE v. 4.088]), the prescription dose, dose/fraction, target volume, V₁₂, anatomic location treated, and clinical outcome data (e.g., adverse events, patterns of failure).

Optic Apparatus

Clinical Significance. The optic nerves and chiasm frequently receive a substantial dose during therapeutic irradiation of brain, base of skull, and head and neck targets, and the optic apparatus is frequently the dose-limiting structure in these cases. While rare, damage to the optic apparatus can produce devastating and, at present, irreversible visual deficits.⁸⁸

Endpoints. The primary endpoint for radiation-induced optic neuropathy (RION) is visual impairment, defined by visual acuity and the size/extent of visual fields.⁸⁹ Of course, damage to the lens (development of cataracts), retina (retinitis), and lacrimal apparatus and trigeminal nerve (dry eye syndrome) can also produce impaired vision.⁹⁰ While toxicity may be objectively scored using CTCAE version 4⁹¹ and late effects of normal tissues, subjective, objective, medical management and analytical evaluation of injury (LENT-SOMA) criteria,^92,93 it is important to obtain a comprehensive ophthalmologic examination of patients with suspected RION.

Challenges Defining Volumes. The optic nerve originates roughly at the posterior center of the globe and is bracketed by the rectus muscles as it tracks posteriorly through the orbit to pass through the optic notch, just medially to the anterior clinoid process. The optic nerves join and decussate to form the optic chiasm, an X-shaped structure that sits just superiorly to the sella turcica with the center immediately anterior to the pituitary stalk.⁹⁴ The optic nerves and chiasm are thin (<5 mm diameter) and visualization is best performed using thin-cut (≤3 mm) T1- or T2-weighted magnetic resonance imaging. Contouring the optic nerves/chiasm is challenging, and it is important to ensure that these structures are drawn in continuity (i.e., there is not a gap in the contours). Appropriate contouring of these structures is facilitated by visualizing this region in multiple planes and using fused imaging modalities (e.g., utilizing the magnetic resonance images in the axial and coronal planes to track the optic nerves/chiasm and sagittal computed tomography [CT] views to see the sella turcica).

Dose/Volume/Toxicity Data. The data for the incidence of RION with conventional fractionation for selected studies^{95–96,97–102} are summarized in Figure 13.3. The risk of RION appears to rise steeply past 60 Gy. None of the patients in the study by Parsons et al.⁹⁵ with a maximum point dose (D_max) to the optic nerves/chiasm <59 Gy developed RION. In the study by Martel et al.,⁹⁶ the average maximum chiasm and nerve dose was 53.7 Gy (range 28 to 70 Gy) and 56.8 Gy (range 0 to 80.5 Gy) for patients without RION. The optic nerves had received a D_max of 64 Gy with 25% of the volume receiving >60 Gy for patients with moderate to severe complications. Jiang et al.⁹⁷reported no incidence of ipsilateral RION for a dose <56 Gy and a <5% incidence at 10 years for a dose <60 Gy at ~2.5 Gy/fraction.

The risk of RION appears to be related to the fraction size. Parsons et al.⁹⁵ reported 15-year actuarial rates of RION for total doses of 60 to <70 Gy of 50% versus 11% at ≥1.9 versus <1.9 Gy dose/fraction, respectively. No patients treated twice daily with 1.2 Gy/fraction developed RION. At total doses of 70 to 83 Gy, the incidence was 33% versus 11% for ≥1.9 versus <1.9 Gy/fraction and 12% for 1.2 Gy twice-daily fractions. Bhandare et al.¹⁰³ noted reductions in RION rates for twice- versus once-daily treatment.

Results from proton treatments appear consistent with those utilizing photons.^{102,104–106} Note that the proton doses are reported as cobalt gray equivalent (CGE), reflecting their greater biologic effect, and that photons were often used in combination with protons. Most proton series have reported a very low incidence of RION, and in the few cases of reported RION, a threshold dose in the range of 55 to 60 CGE has been observed, consistent with the photon experience. As with photons, many patients exceeding this threshold did not develop RION. Wenkel et al.,¹⁰⁶ Noel et al.,¹⁰⁴ Weber et al.,¹⁰² and Nishimura et al.¹⁰⁵ used a D_max constraint to the optic structures of 54, 55, 56, and 60 CGE, respectively.

Because of the small size of the optic nerves/chiasm and steep dose gradients in radiosurgery, most studies of RION involving SRS use the D_max to the optic nerves/chiasm as the critical dose metric.⁸⁸ As shown in Table 13.2, single-fraction SRS studies describe a range of threshold D_max for RION. In analyzing their early experience with radiosurgery, Tishler et al.¹⁰⁷ reported RION at D_max as low as 9.7 Gy and recommended 8 Gy as the dose limit for the optic nerves/chiasm in SRS. Stafford et al.¹⁰⁸ found RION in four of 215 patients receiving a median D_max of 10 Gy. The D_max in the patients ranged from 0.4 to 16 Gy, and three of the four had received previous external beam radiotherapy to this area. They estimated a 1.7%, 1.8%, 0%, and 6.9% incidence of RION for D_max of <8, 8 to 10, 10 to 12, and >12 Gy, respectively.

Conversely, Pollock et al.¹⁰⁹ observed no cases of RION in 62 patients with nonfunctioning pituitary adenomas receiving a median D_max of 9.5 +/- 1.7 Gy to the optic apparatus during single-fraction SRS, using a 12 Gy D_max as the dose constraint for the optic apparatus. From a study of 50 patients with benign base-of-skull tumors treated with single-fraction SRS and a median follow-up of 40 months, Leber et al.¹¹⁰ estimated a 0%, 27%, and 78% risk of RION for D_max of <10, 10 to <15, and ≥15 Gy, respectively. No data for dose–volume and RION were available for hypofractionated stereotactic radiotherapy (4 to 8 Gy/fraction).⁸⁸

FIGURE 13.3. Incidence of radiation-induced optic neuropathy (RION) in selected studies.^{95–96,97–102} Points offset from 0% to 1% were shifted to clearly show range bars. The single patients in the studies by Parsons et al.⁹⁵ and Martel et al.⁹⁶ with events in the 55–60 Gy range were treated to 59 Gy and 59.5 Gy, respectively. (From Mayo C, et al. Radiation dose-volume effects of optic nerves and chiasm. Int J Radiat Oncol Biol Phys 2010;76[3 Suppl]:S28–S35.)

Factors Affecting Risk. There appears to be an increased risk of RION with increasing age.⁹⁵ Parsons et al.⁹⁵ reported that none of the 38 patients in the 20- to 50-year-old range developed RION, even though the reported optic nerve doses were >60 Gy for 58% and >70 Gy for 26%. In contrast, for patients with doses >60 Gy, the incidence was 26% and 56% for the 50- to 70- versus >70-year-old age groups. RION in children is poorly characterized, but treatment of the developing optic apparatus should be approached cautiously. Reports on the effect of other factors such as adjuvant chemotherapy, diabetes mellitus, and hypertension have been inconsistent. Minimal data are available on reirradiation of the optic apparatus and the effect of the interval between courses on RION. Flickinger et al.¹¹¹ found that one of 10 patients undergoing reirradiation of the optic apparatus developed RION—the affected received an initial 40 Gy, and after a 7.5-year interval, an additional 46 Gy, both at 2 Gy/fraction.

Mathematic/Biologic Models. The original Lyman-Kutcher-Burman normal tissue complication probability volumetric modeling⁴ estimated TD₅₀ = 65 Gy, n = 0.25, and m = 0.14. The dose–response data from Jiang et al.⁹⁷ (1.5–2.2 Gy/fraction) suggests TD₅₀ 72 to 75 Gy. Martel et al.⁹⁶ and Brizel et al.¹¹² estimated TD₅₀ at 72 and 70 Gy, respectively. Extrapolation of the Parsons dose–response data⁹⁵ suggests that TD₅₀ exceeds 70 Gy.

Special Situations. There is a suggestion that RION may occur at lower doses in patients with pituitary tumors, as complications at doses as low as 46 Gy at 1.8 Gy/fraction have been reported.^100,113,114 Mackley et al.¹⁰⁰ and van den Bergh et al.¹¹³ constrained the optic structure D_max to 46 and 45 Gy, respectively. The RION latency also appeared shorter in patients with pituitary tumors. The average latency was 10.5 and 31 months (range 5 to 168 months) in patients with pituitary targets and nonpituitary targets, respectively.^100,114

Recommended Dose–Volume Limits. The estimate by Emami et al.¹ of a 5% risk of blindness within 5 years of treatment for a dose of 50 Gy appears inaccurate. The QUANTEC review⁸⁸ suggests that the incidence of RION was unusual (<2%) for D_max <55 Gy, particularly for fraction sizes <2 Gy. The risk increases (3% to 7%) in the region of 55 to 60 Gy and becomes more substantial (>7% to 20%) for doses >60 Gy when dose per fraction of 1.8 to 2.0 Gy is used. The patients with RION treated in the 55 to 60 Gy range were typically treated to doses in the very high end of that range (i.e., 59 Gy). For particles, most investigators found that the incidence of RION was low for a D_max <54 CGE. One exception to this range was for pituitary tumors, in which investigators used a constraint of D_max <46 to 48 Gy for 1.8 Gy/fraction.

The aforementioned studies suggest that the incidence of RION in single-fraction radiosurgery is rare for D_max <8 Gy, increases in the range of 8 to 12 Gy D_max, and becomes >10% when D_max exceeds 12 Gy. Though the QUANTEC paper presents isoeffect curves for RION over a range of 2 to 12 Gy/fraction using various radiobiologic models, the authors emphasize that there are no data in the hypofractionated range and caution that the curves should not be used to predict toxicity in this regime.

Future Studies. In addition to reporting detailed dose–volume data for patients with and without RION receiving radiation to the optic apparatus, investigators must consistently, completely, and accurately contour the optic apparatus.

Toxicity Scoring Criteria. Visual deficits should be scored using the CTCAE v. 4.0.³⁷

TABLE 13.4 SELECTED STUDIES OF RADIATION-INDUCED BRAINSTEM TOXICITY WITH CONVENTIONAL FRACTIONATION OR HYPERFRACTIONATION

Brainstem

Clinical Significance. As with the optic apparatus, irradiation of the brain, base of skull, and neck can deliver a significant dose to the brainstem, which is frequently the dose-limiting structure.

Endpoints. Radiation-induced damage to the brainstem may be manifest as specific cranial neuropathies; focal motor, sensory, or balance deficits; or mild to life-threatening global dysfunction. This is reflected in the CTCAE,⁹¹which scores brainstem-related toxicity on the basis of symptoms. The study of radiation-induced brainstem injury is challenging because (a) the reported incidence of injury is low, (b) survival time is short for many patients, (c) formal grading of brainstem effects is subjective and is often characterized categorically (i.e., “yes–no”) for cranial neuropathy, and (d) for patients with intracranial tumors, it is often difficult to distinguish between side effects and disease progression.¹¹⁵

Challenges Defining Volumes. Contouring the brainstem on axial MRI is usually straightforward, although it requires special attention to the superior extent and interfaces at the cerebral and cerebellar peduncles where the borders are indistinct. Coronal and sagittal views, in addition to axial images, are frequently helpful in visualizing the brainstem and its interfaces. The adult brainstem volume is on the order of 35 ± 8 mL.¹¹⁶

Dose/Volume/Toxicity Data. Studies of potential radiation-induced brainstem toxicity in conventionally fractionated partial-brain, base-of-skull, or neck irradiation variably report crude radiographic and functional toxicities over typically short follow-up periods.^{99,102,104–106,117–126} Reported toxicities attributable to radiation of the brainstem and dose constraints are presented in Table 13.4. Uy et al.¹²⁶ reported brainstem necrosis in one of 40 adult meningioma patients treated with intensity-modulated radiation therapy (IMRT). For this patient, the D_max was 55.6 Gy, and the absolute volume of brainstem that exceeded 54 Gy was 4.7 mL. Jian et al.¹²¹ noted a grade 1 neurologic deficit in three of 48 patients with nasopharyngeal cancer treated with 1.2 Gy twice-daily photons to 74.4 Gy and concomitant chemotherapy.

In the largest study, Debus et al.^117,118 reported on 367 patients with base-of-skull tumors with a combination of conformal photon and proton radiation therapy. Nineteen late brainstem-related toxicities were observed, including three deaths. On univariate analysis, significant predictors of toxicity were D_max >64 CGE, V₅₀ CGE >5.9 mL, V₅₅ CGE >2.7 mL, V₆₀ CGE >0.9 mL, two or more skull-based surgeries, diabetes, and high blood pressure. On multivariate analysis only V₆₀ >0.9 mL, two or more skull-based surgeries, and diabetes were predictive. In a study of 46 patients with recurrent base-of-skull meningiomas, treated to a median brainstem D_max of 58.0 CGE, Wenkel et al.¹⁰⁶ found that one patient developed brainstem injury at a dose that exceeded an unspecified constraint value by 10%. Two others with neurologic toxicities had brainstem doses that exceeded the constraints as shown in Table 13.4.

In pediatric patients with brainstem glioma (treated with opposed lateral fields that encompassed the majority of the brainstem), no toxicity was reported at doses of 54 to 60 Gy at 2 Gy/fraction, 75.6 Gy at 1.26 Gy twice daily,¹¹⁹or 78 Gy at 1 Gy twice daily.¹²³ The primary limitation of these studies was the short median survival, <12 months. Of 32 patients treated to 72 Gy twice daily in combination with recombinant β-interferon, there was at least one treatment-related death.¹²⁴

Most pediatric protocols for central nervous system tumors recommend doses >54 Gy, and separate brainstem dose constraints are often absent. Merchant et al. studied 68 patients with infratentorial ependymoma treated with surgery and conformal RT (54 to 59.4 Gy).¹²² In patients with full recovery, a considerable portion of the brainstem received over 60 Gy (V₆₀ = 7.8 ± 1.4 mL). There was no difference in brainstem recovery based on absolute or percent volume of the brainstem that received more than 54 Gy. Differences in these values for patients without full recovery were not statistically significant. One patient died with autopsy-confirmed residual tumor and focal areas of brainstem necrosis. The mean brainstem dose was 59 Gy, and he also exhibited severe perioperative morbidity after two surgeries.

A limited number of studies report brainstem toxicity in single-fraction SRS or hypofractionated stereotactic radiotherapy (HFSRT).^{127,128–131} A broad range of prescription isodose levels and dose metrics are reported, making it difficult to develop a predictive dose–volume model for brainstem toxicity.¹¹⁵ In the study with the largest number of patients, Foote et al.¹²⁷ analyzed the outcome in 149 vestibular schwannoma patients treated with SRS between 1988 and 1998; 41 were treated before 1994, when radiosurgery was primarily based on CT imaging, and 108 after 1994, when planning was MRI based. Large single-fraction doses (10 to 22.5 Gy) were used. Their analysis revealed a “learning curve,” with a 5% and 2% actuarial 2-year rate of facial and trigeminal neuropathies, respectively, for patients treated after 1994 compared with 29% for both neuropathies for the earlier patients. This study found a significant increase, with a 2-year actuarial rate of facial and trigeminal neuropathies of 29% and 7% for patients treated before and after 1994, respectively. The authors ascribe this difference to the use of MRI rather than CT-based imaging and lower prescription doses in the latter years. A univariate analysis showed an incidence of cranial nerve neuropathy of 2% for <12.5 Gy versus 24% for >12.5 Gy (p <.0003). On multivariate analysis, the prescription dose >12.5 Gy, prior surgery, and treatment prior to 1994 were significant variables.

Mathematic/Biologic Models. The Emami review estimates a 5-year, 5% rate of complications, defined in that study as “necrosis/infarct,” at 50, 53, and 60 Gy delivered to the whole, two-thirds of, and one-third of the brainstem, respectively.¹ The corresponding Lyman-Kutcher-Berman (LKB) parameters for calculation of the normal tissue complication probability (NTCP) were n = 0.16, m = 0.14, and a tolerance dose for 50% probability of these complications (TD₅₀) equal to 65 Gy.²⁶ These estimates and model parameters appear overly conservative. For example, the LKB model estimates a 12% risk of severe complications for 54 Gy to the whole brainstem or a 3% risk of complications when the proton dose constraints (Table 13.4) are utilized. The clinical data would suggest that a larger TD₅₀, smaller m, or larger m values might produce more reasonable estimates of toxicity. For example, an LKB model with a larger TD₅₀ (72 Gy) or smaller m (0.1) would reduce the predicted risks to <5% or <1%, respectively. However, there are insufficient existing dose/volume/complication data to generate a more accurate model estimate at this time.

Recommended Dose–Volume Limits. The QUANTEC study concludes that the entire brainstem may be treated to 54 Gy using conventional fractionation with limited risk of severe or permanent neurologic effects.^115,122 While the precise dose–volume relationship is unclear, partial volumes of the brainstem (1 to 10 mL) may be irradiated to a maximum dose of 59 Gy for dose fractions ≤2 Gy. The risk appears to increase markedly at doses >64 Gy. In radiosurgery, it appears that a maximum brainstem dose of 12.5 to 13 Gy is associated with a low (<5%) risk of cranial neuropathy in patients with vestibular schwannomas treated with single-fraction SRS. The risk appears to increase rapidly when the marginal prescription dose is >15 Gy or when the target volume exceeds 4 mL.^115,127,132 However, doses of 15 to 20 Gy have been used to treat brainstem metastases with a low reported rate of complications, potentially because of the limited survival time for these patients.^129,133

Future Studies. Uniform, complete reporting of patient-specific dose/volume/outcome data for patients with and without complications are required.

Toxicity Scoring Criteria. Patients should undergo a complete history and physical examination at regular intervals with particular attention to the neurologic exam. Toxicity should be scored and reported using the CTCAE v. 4.0.⁹¹

Auditory Apparatus

Clinical Significance. Radiation therapy to brain tumors and head and neck cancers may damage the cochlea and/or acoustic nerve, leading to sensorineural hearing loss (SNHL) and compromised quality of life.¹³⁴

Endpoints. SNHL following conventionally fractionated radiotherapy is typically measured by a decrease in the bone conduction threshold at 0.5 to 4 kHz,¹³⁴ the primary range for human speech, using pure-tone audiometry (PTA). While the technique is well established and standardized, a broad range of specific audiometric parameters are used to characterize SNHL, including the frequency (range) used for testing, the threshold chosen for a clinically significant change in the bone conduction threshold (BCT, 10 to 20 dB), and the control/standard used for comparison. In stereotactic radiosurgery, SRS, or HFSRT, hearing status is more commonly evaluated using the Gardner-Robertson scale, which is based on both PTA and speech discrimination. Hearing loss after SRS/HFSRT may be characterized by changes in Gardner-Robertson hearing grade or retention of serviceable hearing (i.e., functional hearing with the aid of a hearing aid) or any measurable hearing. In addition, the length of follow-up will influence reported hearing loss, as deficits may develop more rapidly following single-fraction SRS than HFSRT, and hearing loss increases over time in both situations.

Challenges Defining Volumes. Contouring of the acoustic nerve and brainstem is best accomplished on high-resolution, contrast-enhanced T1-weighted and fast imaging with steady-state precession MRI. The cochlea and associated bony anatomy are better delineated on fine-cut (≤1 mm slice thickness) CT scans. Both the acoustic nerve and cochlea are small structures, and the dose gradient at the latter structure is often quite steep. Moreover, the acoustic nerve anatomy is distorted by the tumor, significantly increasing its apparent diameter. Thus, the dose to these structures is typically characterized by an average or maximum dose, rather than a dose–volume distribution. In many studies, the primary dose metric was the dose to the acoustic neuroma, rather than the normal tissue structures per se, which is not unreasonable as the dose to the tumor appears to be correlated with the dose received by the acoustic nerve.⁴⁵

Dose/Volume/Toxicity Data. SNHL at key frequencies following radiotherapy for head and neck cancer with conventionally fractionated radiotherapy^{134–135,136–139,140,141} is summarized in Figure 13.4. Pan et al.¹³⁵ prospectively studied the BCT in 31 patients after unilateral RT with standard fractionation using changes seen in the contralateral ear as standard (0.25 to 8 kHz). Changes in BCT >10 dB were rarely observed unless the corresponding difference in mean cochlear dose was >45 Gy. The dose to the contralateral cochlea ranged from 0.5 to 31.3 Gy (mean, 4.2 Gy). Honore et al.¹⁴⁰ retrospectively estimated mean cochlear doses in 20 patients treated with radiation therapy for head-and-neck cancer.^142–144 A dose–response relationship was observed at 4 kHz, but not at other frequencies.

FIGURE 13.4. Mean dose response for sensorineural hearing loss (SNHL) at (A) 4 kHz,^{135,136–137,139,140} (B) 0.5–2 kHz,^{135,136–137,139} and (C) all frequencies¹⁴¹ (0.25–12 kHz). (From Bhandare N, et al. Radiation therapy and hearing loss. Int J Radiat Oncol Biol Phys2010;76[3 Suppl]:S50–S57.)

TABLE 13.5 HEARING PRESERVATION IN STEREOTACTIC RADIOSURGERY AND RADIOTHERAPY

Chen et al.¹³⁶ retrospectively studied 22 patients treated with RT for nasopharyngeal cancer (with fraction sizes from 1.6 to 2.3 Gy and concurrent/adjuvant chemotherapy) and studied BCT 12 to 79 months post-RT. A significant increase in hearing loss (change in BCT of >20 dB at one frequency or >10 dB at two consecutive frequencies) was observed for all frequencies (0.5 to 4 kHz) when the mean dose received by the cochlea exceeded 48 Gy. Van der Putten et al.¹⁴¹ retrospectively evaluated changes in BCT after head and neck radiotherapy in 21 patients with unilateral parotid tumors (fraction sizes 1.8 to 3.0 Gy). Using the contralateral ear as a control, SNHL, defined as a >15 db difference in BCT at three or more frequencies between 0.25 and 12 kHz, was seen when mean doses received by the cochlea were >50 Gy. Oh¹³⁹ prospectively studied changes in BCT (0.25 to 4 kHz) post-RT in 25 patients with nasopharyngeal cancer (fraction size 2 Gy). In that study, inner ear doses were high (63 to 70 Gy), and hearing loss (a >15 db decrease in BCT from baseline) correlated with total dose received by the inner ear.

Table 13.5 summarizes the reported incidence of hearing loss for single-fraction SRS and fractionated stereotactic radiotherapy (FSRT) in the treatment of vestibular schwannomas.^{142,143,145–154} The range of hearing loss reported is broad, in part due to the variation in the definition of hearing preservation and the length of follow-up. Nonetheless, several studies suggest that there is a relationship between the volume/length of acoustic nerve irradiated and/or the dose to the nerve and cochlea with hearing loss. In a study of 82 patients treated to a marginal dose of 12 Gy in single-fraction SRS, Massager et al.¹⁵⁵ found that increased intracanalicular tumor volume (<100 vs. ≥100 mm³) and volume-averaged intracanalicular dose were significant predictors of increased hearing loss. Pollock et al. reported that hearing preservation was more likely when tumors <3 cm versus >3 cm in diameter were treated with single-fraction SRS.¹⁵⁶

Niranjan et al.¹⁵⁷ found that the dose extending beyond the intracanalicular tumor volume and the prescription dose were the most important factors adversely affecting hearing. In that study, serviceable hearing was preserved in 100% of patients treated with a marginal tumor dose of ≤14 Gy in single-fraction SRS versus 20% in those receiving >14 Gy. Similarly, Kondziolka et al. and Lunsford et al. reported significantly improved hearing preservation rates when the marginal dose was reduced from 16 to 20 Gy to 12 to 14 Gy.^150,151

Several studies suggest that the rate of hearing preservation is improved with FSRT versus single-fraction SRS.^142–144 However, there is an issue of selection bias in that patients are frequently selected for fractionated treatment because their hearing is good. Meijer et al.¹⁵² found no significant difference in hearing preservation in acoustic neuroma patients treated with four to five fractions of 5 Gy HFSRT vs. 10 to 12.5 Gy single-fraction SRS (61% vs. 75%), though trigeminal nerve preservation was significantly higher with HFSRT (98% vs. 92%).

Factors Affecting Risk. While the mean total dose to the cochlea during fractionated radiation therapy to the head and neck and to the acoustic nerve in SRS for vestibular schwannomas is a dominant factor in affecting hearing loss postradiotherapy (see earlier), the effects of fraction size and twice- versus once-daily treatment are not well characterized. Cisplatin, administered during or after radiotherapy, may exacerbate SNHL.^136,158,159

Mathematic/Biologic Models. The results of SNHL in conventionally fractionated radiotherapy of head and neck cancers have been fit using multivariate regression models, as discussed in the QUANTEC paper.¹³⁴

Special Situations. The QUANTEC analysis applies only to adult patients; hearing loss after radiotherapy may be more problematic in pediatric patients, particularly in combination with chemotherapy.¹⁶⁰ In patients with neurofibromatosis type 2, treatment of vestibular schwannomas by SRS appears to result in increased hearing loss, as well as poorer tumor control, compared to patients with sporadic tumors.^161–163

Recommended Dose–Volume Limits. For conventionally fractionated RT, the mean dose to the cochlea should be limited to ≤45 Gy (or more conservatively ≤35 Gy) to minimize the risk for SNHL.¹³⁴ Because a threshold for SNHL has not been established, the dose to the cochlea should be kept as low as possible to prevent hearing loss. To minimize hearing loss while maintaining adequate control of vestibular schwannomas, the QUANTEC authors recommend a marginal dose of 12 to 14 Gy for single-fraction SRS.^127,134,164 Though data for hypofractionated regimens are quite limited, the authors speculate that a total dose of 21 to 30 Gy, presumably delivered in three 7-Gy, five 5-Gy, or ten 3-Gy fractions, would provide an acceptable balance of hearing preservation and tumor control.¹³⁴

Future Studies. The effects of concurrent chemotherapy in radiotherapy for head and neck cancer, of acoustic nerve length irradiated and fractionation in vestibular schwannomas, and of the absolute dose to the cochlea in all settings would benefit from prospective, multi-institutional studies.

Toxicity Scoring Criteria. An audiometric evaluation should be performed for both ears immediately before radiotherapy and biannually thereafter. The QUANTEC authors recommend that a “clinically significant hearing loss” should be defined as an increase in the threshold of 10 dB in postradiotherapy BCT or a decline of 10% in a speech discrimination evaluation.¹³⁴

FIGURE 13.5. Incidence of transverse myelopathy from selected studies. A: Cervical cord: data for selected studies^{168,171–174} shown by  with probability of myelopathy corrected for estimated survival and solid line fit to these data by the method of Schultheiss. B: Thoracic cord: data for selected studies^175–186 shown by ◊ with probability of myelopathy corrected for estimated survival. Solid line is the best fit to the cervical cord data, as thoracic cord data were insufficient to permit an adequate fit. (Adapted from Schultheiss TE. The radiation dose-response of the human spinal cord. Int J Radiat Oncol Biol Phys 2008;71(5):1455–1459.)

Spinal Cord

Clinical Significance. Although the spinal cord proper is from the base of the skull through the top of the lumbar spine, individual nerves continue down the spinal canal to the level of the pelvis. Thus, portions of the spinal cord and canal are often included in radiotherapy fields during treatment of malignancies involving the neck, thorax, abdomen, and pelvis.¹⁶⁵ In addition, metastatic disease to the bony spine is encountered in ~40% of all cancer patients,¹⁶⁶ and this disease is often treated with radiotherapy. Though rare, radiation-induced spinal cord injury (i.e., myelopathy) can be severe, resulting in pain, paresthesias, sensory deficits, paralysis, Brown-Sequard syndrome, and bowel/bladder incontinence.¹⁶⁷

Endpoints. Myelopathy is defined as a grade 2 or higher myelitis, per CTCAE v. 4.0.⁹¹ Under this definition, asymptomatic changes in the cord detected radiographically and mild signs/symptoms, such as the Babinski sign or L’hermitte syndrome, would not be classified as myelopathy. Consequently, a diagnosis of myelopathy is based on the appearance of signs/symptoms of sensory or motor deficits, loss of function, or pain, now frequently confirmed by magnetic resonance imaging. Radiation myelopathy rarely occurs less than 6 months after completion of radiotherapy and, in most cases, appears within 3 years.¹⁶⁸

Challenges Defining Volumes. In conventional external-beam RT, the field generally encompasses the entire circumference of the cord, vertebral body, and spinal nerve roots and precise organ definition is not critical apart from correctly identifying the level of the involved cord. Delineation of the cord in radiosurgery is unsettled, with various studies contouring the critical organ in the axial plane as the spinal cord, the spinal cord expanded 2 to 3 mm, the thecal sac and its contents, or the entire spinal canal.¹⁶⁹ As the volume receiving a high dose often extends superiorly and inferiorly to the target, several studies expand the critical organ volume above and below the target volume. For example, RTOG protocol 0631, a study of image-guided radiosurgery of spine metastases, defines the cord as the unexpanded cord itself visualized in MRI and extends the volume of the partial spinal cord 5 to 6 mm above and below the target volume.

TABLE 13.6 TRANSVERSE MYELOPATHY IN STEREOTACTIC RADIOSURGERY (SRS) OF THE SPINE

 

Dose/Volume/Toxicity Data. Schultheiss^165,170 compiled and analyzed published reports of radiation myelopathy in 335 and 1,946 patients receiving radiotherapy to the full-circumference, previously unirradiated cervical^{168,171–174} and thoracic^175–186 spines, respectively (Fig. 13.5A,B). While a small number of these patients received relatively high doses per fraction, none was treated using stereotactic techniques to exclude a portion of the circumference of the cord. Note that the dose to the cord is the prescribed dose reported in those studies; typically, dosimetric data were not available to calculate the true cord dose. As discussed later, the rate of myelopathy appears very low below total doses of 50 Gy for conventional radiation delivered at 2 Gy per fraction.

Published reports of radiation myelopathy from radiosurgery to the spine are summarized in Table 13.6.^187–194 Of the exactly 1,400 cases of spinal radiosurgery presented in the published literature, there are only 12 reported instances of radiation-induced myelopathy, equaling a crude rate of 0.8%. Because the survival is generally short for most of these patients, this may be an underestimate of the true rate of injury. Given the small number of reported cases of myelopathy, as well as the variation in published dosimetric parameters, it is not feasible to construct a quantitative model for the risk of myelopathy as a function of cord dose in spinal radiosurgery. In fact, most of the cases of myelopathy involved cord doses well within the range of doses not associated with myelopathy, as discussed later.

Factors Affecting Risk. Animal studies suggest that the immature spine is somewhat more susceptible to radiation-induced complications and the time to manifestation of damage is shorter.^{196,197–199} Though the literature on radiation-induced myelopathy in children is sparse, care should be exercised in irradiating a child’s spine because of the increased sensitivity of the developing central nervous system and bone to ionizing radiation.²⁰⁰ There are a handful of reports of myelopathy at relatively low radiation doses to the spine postchemotherapy.^201–204 Many chemotherapeutic agents are directly neurotoxic²⁰⁵ and should be used with caution during irradiation of the central nervous system.²⁰⁶

Mathematic/Biologic Models. Schultheiss¹⁷⁰ calculated the risk of myelopathy as a function of dose using a probability distribution model, using the data for cervical and thoracic spinal cord myelopathy adjusted for estimated overall survival. A good fit to the combined cervical and thoracic cord data was not possible, and separate analyses were performed. For the cervical cord data, D₅₀ = 69.4 Gy and α/βratio = 0.87 Gy provided a reasonable fit of the data, as shown in Figure 13.5. The 95% confidence interval was 66.4 to 72.6 Gy for D₅₀ and 0.54 to 1.19 Gy for α/β ratio. At 2 Gy per fraction, the calculated probability of myelopathy is 0.03% at a total dose of 45 Gy and 0.2% at 50 Gy. Because of the dispersion of the thoracic data, it was not possible to obtain a good fit to those data. As shown in Figure 13.5b, the data points for the thoracic cord generally lie to the right of the dose–response curve generated from the cervical cord. This suggests that the thoracic cord may be less radiation sensitive than the cervical cord.

At the high doses per fraction encountered in radiosurgery, the applicability of the linear-quadratic model is controversial and the biologically equivalent doses presented in Table 13.6 should be used solely for making rough comparisons of the different dose regimens. In particular, data obtained at a low dose per fraction should not be extrapolated to regimens employing doses of 10 Gy or more per fraction.^165,207 Applying the Schultheiss model¹⁷⁰ to spinal radiosurgery appears to overestimate the risk of myelopathy. For example, using the α/β ratio of 0.87 Gy, the model yields an estimated risk of myelopathy of 0.8%, 13.6%, 50%, and 73% for 12, 13, 13.7, and 14 Gy, respectively, delivered in a single fraction. In contrast, Ryu et al.¹⁹⁵ found only one case of myelopathy in 86 patients treated with single-fraction spine radiosurgery at a mean cord D_max of 12.2 Gy (± 2.5 Gy standard deviation) and no cases in the subset of 39 lesions prescribed 18 Gy and treated to a mean cord D_max of 13.8 Gy. Note that the Medin et al.²⁰⁸ study of single-fraction irradiation of the swine spinal cord shows a steep dose–response curve with a median effective D_max of 20 Gy.

Special Situations. The need to reirradiate previously treated cord is often encountered in the setting of recurrent spine metastases following spinal irradiation or new spine lesions within a previously treated lung, pancreas, or esophageal field. In evaluating reirradiation of the spinal cord, the dose regimen for each course, the volume and region (re)irradiated, and the time interval between the courses of radiation therapy must be considered.²⁰⁹ Animal studies support a time-dependent model of repair for radiation damage to the spinal cord.^{196,210–214} For example, Ang et al.¹⁹⁶ treated the thoracic and cervical spines of rhesus monkeys to 44 Gy and then reirradiated these animals with an additional 57 Gy at 1 to 2 years or 66 Gy at 2 to 3 years, yielding aggregate doses of 101 and 110 Gy, respectively. Of 45 animals evaluated, four developed myelopathy by the end of the observation period. The reirradiation tolerance model developed from these and similar data²¹⁰ estimates a recovery of 34 Gy (76%), 38 Gy (85%), and 45 Gy (101%) at 1, 2, and 3 years, respectively. Under conservative assumptions, an overall recovery of 26 Gy (61%) was calculated.

Table 13.7 summarizes published reports involving reirradiation of the spinal cord in humans using both conventional and full-circumference external-beam radiotherapy.^{209,215–227} For purposes of comparing different regimens, an α/β ratio of 3 Gy was used to calculate the biologically equivalent dose in Gy₃. In all of these studies, the median interval between courses was at least 6 months, and only a small number of cases were treated at intervals <6 months. Note that few cases of myelopathy are reported despite large cumulative doses, with essentially no cases of myelopathy observed for cumulative doses <60 Gy in 2 Gy equivalent doses. These observations are consistent with the predictions of postradiotherapy repair observed in the animal models.

As discussed earlier, radiosurgery at a high dose per fraction is increasingly employed in the treatment of spinal lesions. Though reports of toxicity are rare, the follow-up time is short and patient numbers small. Prudence should be observed when prescribing the dose and every reasonable effort made to limit the dose to the cord by immobilization, image guidance, and attention to patient comfort. Estimates of toxicity based on conventional fractionation should not be applied to such treatments without further careful study.

Recommended Dose–Volume Limits. With conventional fractionation of 2 Gy per day including the full cord cross-section, total doses of 50 Gy, 60 Gy, and ~69 Gy are associated with a 0.2%, 6%, and 50% rate of myelopathy. The level of acceptable risk will depend on the clinical scenario; that is, a 5% risk of myelopathy may be acceptable in treatment of a primary spinal cord tumor but not in irradiation of a lung lesion. For reirradiation of the full cord cross-section at 2 Gy per daily fraction after prior conventionally fractionated treatment, cord tolerance appears to increase at least 25% 6 months after the initial course of RT. In spine radiosurgery, a maximum cord dose of 13 Gy in a single fraction or 20 Gy in three fractions appears associated with a <1% risk of myelopathy. In comparison, Sahgal et al.²²⁸ recommend a de novo single-fraction maximum point dose to the thecal sac of 10 Gy to avoid myelopathy entirely, and RTOG protocol 0631 specifies a cord D₁₀ and D_0.35mL of 10 Gy and D_max of 14 Gy for the involved spine.

Future Studies. A model of dose/volume/outcome for spinal cord toxicity will require that more extensive and detailed data be collected over many years, including data on entire cohorts of patients treated with radiotherapy and radiosurgery, not just those with myelopathy. Dosimetric parameters to be collected should include D_max, D₁, D₁₀, D₅₀, D_0.1mL, D_0.35mL, and D_{1 mL}, and the volume of the involved segment of the spinal cord, as well as the prescribed total dose, dose per fraction, involved spinal level(s), portion of the vertebral body irradiated, irradiation technique, and patient characteristics/demographics. In addition, preclinical studies identifying the fundamental mechanisms of radiation-induced toxicity would be valuable.

Toxicity Scoring Criteria. Toxicity should be scored and reported using CTCAE v. 4.0.⁹¹

TABLE 13.7 TRANSVERSE MYELOPATHY IN REIRRADIATION OF THE SPINE

 NECK

Larynx and Pharynx

Clinical Significance. Radiation therapy is often utilized as the primary treatment of early-stage laryngeal cancers in an effort to preserve speech and swallowing. However, radiation-induced progressive edema and associated fibrosis can lead to long-term problems with phonation and swallowing.²²⁹ Irradiation of the pharynx and larynx, particularly in combination with concurrent chemotherapy, can produce severe dysphagia, compromising nutrition, protection of the airway, and quality of life.

Endpoints. The critical larynx-specific endpoints examined were laryngeal edema and vocal function.²³⁰ Dysphagia, resulting from laryngeal and/or pharyngeal dysfunction, may be assessed by instrument-based swallowing studies,²³¹ by observer-based criteria (e.g., CTCAE v. 4.0⁹¹), or by patient-reported quality-of-life questionnaires.

Challenges Defining Volumes. Phonation and swallowing are complex processes involving multiple anatomic structures in close proximity to one another. The relative importance of various normal tissue structures affecting vocal function and swallowing is controversial. In studying vocal dysfunction, doses to the epiglottis, base of tongue, lateral pharyngeal walls, pre-epiglottic space, aryepiglottic folds, false vocal cords, upper esophageal sphincter, and cricoid cartilage have been considered.^230,232,233 Radiation-induced dysphagia has been correlated with the dose to the pharyngeal constrictor muscles and specific points in the supraglottic and glottic larynx.^{232,234–237} Precise identification of these structures for treatment planning requires a high-resolution, contrast-enhanced CT scan.

Dose/Volume/Toxicity Data. On multivariate analysis, Sanguineti et al.²³³ found that the mean laryngeal dose or percentage of volume receiving >50 Gy and neck stage were the only independent predictors of grade 2 or greater laryngeal edema. Vocal function is usually well preserved after radiotherapy for stage T1 laryngeal cancer²³⁰ (typically 60 to 66 Gy). Less information is available regarding voice quality after treatment of more locally advanced laryngeal cancers. However, Dornfeld et al.²³² found a strong correlation between speech quality and the doses delivered to the aryepiglottic folds, pre-epiglottic space, false vocal cords, and lateral pharyngeal walls at the level of the false vocal cords. In particular, a steep decrease in vocal function was observed when the dose to these structures exceeded 66 Gy.

In a prospective study using intensity-modulated radiotherapy to reduce dysphagia in patients undergoing chemoradiation, Feng et al.²³⁵ observed a strong correlation between the mean doses and the dysphagia endpoints (Fig. 13.6). Aspiration was observed when the mean dose to the pharyngeal constrictors was >60 Gy and the dose–volume threshold for the pharyngeal constrictor volume receiving ≥40, ≥50, ≥60, and ≥65 Gy was 90%, 80%, 70%, and >50%, respectively. For aspiration to occur, the glottic/supraglottic larynx dose–volume threshold was >50% of volume receiving ≥50 Gy. In a retrospective study of conventional radiotherapy, Jensen et al.²³⁶ found that doses <60 Gy to the supraglottic area, larynx, and upper esophageal sphincter were associated with a low risk of aspiration. Dornfeld et al.²³² found that swallowing difficulties increased progressively with radiation doses >50 Gy to the aryepiglottic folds, false vocal cords, and lateral pharyngeal walls near the false cord. Levendag et al.²³⁷ reported that a median dose of 50 Gy to the superior and middle pharyngeal constrictor muscles predicted a 20% probability of dysphagia and that this increased significantly beyond a mean dose of 55 Gy.

Factors Affecting Risk. The addition of concurrent chemotherapy to high-dose RT at least doubles the risk of laryngeal edema and dysfunction.²³⁰ Severe laryngeal dysfunction secondary to tumor will often persist following radiotherapy, and a laryngectomy may be preferred to chemoradiation in this setting.

Mathematic/Biologic Models. Rancati et al.²³⁸ fit dose–volume data for grade 2 to 3 laryngeal edema using the Lyman-Kutcher-Burman model and the logit model with the dose–volume histogram reduced to the equivalent uniform dose (EUD). Both models fit the clinical data well. The best fit parameters for the Lyman-Kutcher-Burman model were n = 0.45 ± 0.28, m = 0.16 ± 0.05, and TD₅₀ = 46.3 ± 1.8 Gy. Based on these findings, the investigators suggested an EUD of <30 to 35 Gy to reduce the risk of grade 2 to 3 laryngeal edema. The Feng et al. study²³⁵ suggests that a 50% normal tissue complication probability is observed at mean doses of 50 to 60 Gy to the pharyngeal constrictors and the larynx (Fig. 13.6).

FIGURE 13.6. Probability of aspiration (proxy for dysphagia) versus larynx dose for selected studies.^235,236 Solid line fit of logit model to combined data; dotted lines represent 68% confidence area. (From Rancati T, et al. Radiation dose-volume effects in the larynx and pharynx. Int J Radiat Oncol Biol Phys 2010;76[3 Suppl]:S64–S69.)

Special Situations. Pretherapy vocal and swallowing function should be considered when assessing the functional response to radiation therapy of the larynx and pharynx.²³⁹

Recommended Dose–Volume Limits. To minimize the risk of laryngeal edema, the QUANTEC authors recommend limiting the mean noninvolved larynx dose to 40 to 45 Gy and the maximal dose to <63 to 66 Gy, if possible, according to the tumor extent.²³⁰ Minimizing the volume of the pharyngeal constrictors and larynx receiving >60 Gy and reducing, when possible, the volume receiving >50 Gy is associated with reduced dysphagia/aspiration.²³⁰ Of course, the impact of any such dose reduction on tumor control must be considered, given the uncertainties in target delineation.

Future Studies and Toxicity Scoring Criteria. Prospective studies that include pretherapy assessments of vocal and swallowing function should be conducted to correlate observer-rated scores such as the CTCAE v. 4.0 system,⁹¹patient-reported quality scores, and objective swallowing.²³⁰ Such studies should focus on patients receiving concurrent chemoradiation, as this population is at the greatest risk of laryngeal/pharyngeal toxicity. While CTCAE-based scoring is simple and widely utilized, objective measurement by a speech pathologist is often necessary to quantify swallowing dysfunction following radiotherapy.

Salivary Glands

Clinical Significance. In radiotherapy of head and neck tumors, the parotid, submandibular, and minor salivary glands often receive substantial doses of radiation. Reduced salivary production is a common toxicity and adversely affects the patient’s quality of life. Inadequate salivary function leads to multiple problems, including poor dental hygiene, a propensity to oral infections, sleep disturbances, pain, and difficulty chewing and swallowing.²⁴⁰ The majority of stimulated salivary production comes from the parotid glands, while resting (unstimulated) salivary production is due primarily to the submandibular, sublingual, and numerous small oral salivary glands.²⁴¹

Endpoints. Xerostomia (dry mouth secondary to inadequate saliva production) can be assessed based on the patient’s symptoms (altered taste or sensation of dryness) and/or quantitative saliva production.

Challenges Defining Volumes. Parotid and submandibular salivary glands can be adequately delineated on contrast-enhanced CT scans. However, during irradiation, parotid glands typically shrink during RT, potentially resulting in decreased gland sparing. For example, Robar et al.²⁴² found that while the medial position of the parotid gland was stable over a course of radiation therapy, the lateral borders shrank ~1 mm/week, yielding total displacements of 4 to 6 mm.

Dose/Volume/Toxicity Data. A variety of dose–volume parameters have been correlated with salivary endpoints, including subjective xerostomia and objective stimulated/unstimulated salivary flow. In particular, mean parotid gland dose^242–245 appears associated with whole-mouth or individual gland salivary production. Table 13.8 summarizes the reported dose–volume predictors for salivary flow, the incidence of complications, and salivary function recovery. Minimal reduction in flow is observed at mean doses <10 to 15 Gy, decreases gradually over the range of 20 to 40 Gy, and is markedly reduced above 40 Gy.^243,247 The risk of xerostomia is reduced when at least one parotid gland or submandibular gland is spared.²⁴⁸ In the study by Portaluri et al., ²⁴⁹ patients receiving <30 Gy to the contralateral parotid reported either no or mild subjective xerostomia.

Some recovery of salivary function occurs over time, with the dose required to obtain an equivalent reduction in salivary flow increasing at longer follow-up times (Fig. 13.7).^{245,248,250–253} The whole-mouth or ipsilateral salivary measurement-based tissue dose required for a 50% response (TD₅₀) tends to be lower than the scintigraphy-based TD₅₀, yielding a higher TD₅₀ compared with those derived from salivary flow data. The wide variation in the reported TD₅₀ values may be the result of several factors, including variations in dose distributions, salivary measurement methods, segmentation, and inherent tissue sensitivity.

Factors Affecting Risk. Patient factors (e.g., gender and age) and the use of chemotherapy have typically not correlated with xerostomia risk. However, pretreatment salivary function and medications affecting salivary function can influence the risk of xerostomia.²⁴⁰

Mathematic/Biologic Models. As noted earlier, there is a wide variation in the observed dose/volume/toxicity relationship, depending on the patient population, treatment technique, and endpoint selected. Thus, models predicting the risk of xerostomia as a function of dose–volume parameters have yielded a broad range of parameters.^{240,243,247,252,255,256} Because the glands seem to respond independently to irradiation, the function of the parotid glands should be modeled separately. Attempts to predict the effect of fraction size on toxicity using the linear-quadratic model have returned low to high α/β ratios, perhaps because the different endpoints examined represent acute versus late effects.²⁴⁰

Special Situations. Submandibular gland sparing appears to reduce the risk of both stimulated and unstimulated xerostomia.²⁴⁸ The mean dose to the oral cavity (which contains minor salivary glands) has been found to be an independent risk factor in some studies²⁵⁴ but not others,²⁵⁷ probably because of differences in technique. Although quantitative data are admittedly sparse, amifostine has been shown to increase the functional tolerance of the parotid and submandibular glands to therapeutic radiation.²⁵⁸

Recommended Dose–Volume Limits. Severe xerostomia (long-term salivary function <25% of baseline) can usually be avoided if at least one parotid gland receives a mean dose of less than about 20 Gy or if both glands receive a mean dose of less than approximately 25 Gy. In patients with head and neck cancer treated with IMRT, the mean dose to each parotid gland should be kept as low as possible, taking into account the desired target coverage. Similarly, keeping the dose to the submandibular glands to modest levels (<35 Gy) may reduce the severity of xerostomia.²⁴⁰

Future Studies. Key questions on radiation-induced salivary gland dysfunction and xerostomia include:

1. Does partially sparing the submandibular glands or salivary minor glands have a positive impact on quality of life (QOL)?

2. Is the (arbitrary) 25% salivary threshold the best quantitative measure with respect to QOL?

3. Should parotid gland shrinkage during RT explicitly be accounted for in functional predictions?

4. How should submandibular sparing be incorporated into predictive salivary function models?

5. How does oral cavity sparing quantitatively affect xerostomia?

6. Does the radioprotector amifostine provide a clinically significant benefit for whole-mouth salivary function?

Toxicity Scoring Criteria. The QUANTEC authors recommend that an observer-based system (e.g., CTACAE v. 4.0) be supplemented by a validated quality-of life instrument (e.g., the xerostomia questionnaire²⁵⁴) and/or quantitative salivary measurements.

TABLE 13.8 DOSIMETRIC PREDICTORS OF XEROSTOMIA

 CHEST

Lung

Clinical Significance. The lung’s primary function is the exchange of oxygen for carbon dioxide. Radiation-associated lung injury is one of the most common side effects seen in clinical oncology, and its risk limits the dose of radiation that can be used for treatment of thoracic tumors.

Endpoints. Radiation damage to the lung can result in symptomatic pneumonitis and fibrosis. Symptomatic radiation pneumonitis is characterized by dyspnea, cough, and occasionally a low-grade fever, typically occurring several weeks to months after radiation. Long-term lung fibrosis can lead to respiratory insufficiency. It is often challenging to distinguish radiation-related pulmonary symptoms from comorbid illnesses (e.g., exacerbation of chronic obstructive pulmonary disease, infection, cardiac events).²⁵⁹ Objective reductions in the lungs’ ability to move and exchange gas can be measured by formal pulmonary function tests (PFTs). The various endpoints shown in Table 13.9 are arbitrarily segregated by their manifestation (clinical vs. subclinical) and whether they reflect regional or global lung function.

TABLE 13.9 ENDPOINTS FOR RADIATION-INDUCED LUNG INJURY

Challenges Defining Volumes. Because the lungs move and their volume changes with respiration, there are inherent inaccuracies when defining the lung volume. As the mass of the lung is relatively constant during respiration and its density must decline with increased lung volumes, one could consider using dose–mass histograms rather than DVHs. To our knowledge, this approach has not been widely applied. Due to this variation in volumes with respiration, it is very likely that the dose/volume/outcome data are dependent on the type (if any) of respiratory control. The vast majority of dose/volume/outcome data are derived from free-breathing scans/treatment. These may not apply to patients being treated under, for example, breath-hold techniques. Further, there are uncertainties in defining the lung borders in the vicinity of the central airways. Variable inclusion of the conducting airways in the “defined lung” can influence interpatient/institutional comparisons.

Dose/Volume/Toxicity Data. Several parameters have been shown to be associated with the risk of radiation pneumonitis, including V₅ to V₇₀, mean lung dose (MLD), and model-based parameters.^9,260 These dosimetric parameters are mutually correlated, accounting for the fact that in most studies examining a range of V_x’s, many appear statistically significant.^261–276 Figure 13.8 summarizes the studies discussed here.

A normal tissue complication probability (NTCP) analysis from the Netherlands, in collaboration with the University of Michigan, suggests that using the MLD (linear function) is more predictive than using V_x (step function).²⁷⁰However, V₁₃ tended to be more predictive in situations where the MLD exceeded 20 Gy or V₁₃ exceeded 50%. The TD₅₀ values in this study were an MLD of 30.8 Gy, V₁₃ >77%, and V₂₀ >65%, similar to the MLD of 31.8 Gy reported in an earlier multi-institutional study.²⁶⁷ From a study at the Memorial Sloan-Kettering Cancer Center (MSKCC),²⁷⁶ a mean lung dose of ~26 Gy, V₁₃ of >80% to the ipsilateral lung, or V₄₀ of >32% to the lower lung results in a 50% risk of developing late complications. A mean lung dose of ~12 Gy or a V₁₃ of >40% to the ipsilateral lung results in a 5% late complication risk. A V₁₃ of 36% to the lower lung, 42% to the total lung, or 62% to the ipsilateral lung results in a 20% risk of developing late grade 3 or higher complications.

Another study from MSKCC of patients treated with radiation alone reported a significantly increased risk of grade 3 or higher pulmonary toxicity, 38% for V₂₅ >30% versus 4% for V₂₅ <30% (p = .04).²⁶¹ In subsequent studies from this same group, significant variables for predicting grade 3 or higher pulmonary toxicity include mean lung dose, the range of V₅ to V₄₀ of total lung, V₅ to V₄₀ of ipsilateral lung, and V₅ to V₅₀ of lower lung.^275,276 The range of V₅ to V₂₀ ipsilateral lung was most predictive.

FIGURE 13.7. Mean percentage of reduction in stimulated salivary flow rate versus mean parotid gland dose for selected studies^{245,248,250–253,254} using different follow-up durations. Nominal follow-up intervals of 1, 6, and 12 months represent ranges of 1 to 1.5, 6 to 7, and 12 months, respectively. Lines represent least-squares fit of data for each nominal follow-up interval. (From Deasy JO, et al. Radiotherapy dose-volume effects on salivary gland function. Int J Radiat Oncol Biol Phys 2010;76[3 Suppl]:S58–S63.)

Washington University was another of the early investigators to show the risk of pneumonitis significantly correlates with the V₂₀; the 2-year incidence of grade 2 or higher radiation pneumonitis was 36%, 13%, 7%, and 0% with a V₂₀ of >40%, 32% to 40%, 22% to 31%, and <22% (p = .0013), respectively.²⁶⁰ In another study by Washington University, radiation pneumonitis was significantly correlated with V₅ to V₈₀, with peak significance in the V₅ to V₁₅and V₇₀ to V₇₅ ranges; radiation pneumonitis was also significantly correlated with the dose delivered to 5% to 100% of the lung (D₅ to D₁₀₀), with peak significance in the D₃₀ to D₄₀ and V₉₀ to V₉₅ ranges.²⁶⁵

A study from Duke, in which 18% of patients received concurrent chemoradiotherapy, found that a V₃₀ of >18% versus <18% was associated with a risk of grade 1 or higher radiation pneumonitis of 24 versus 6% (p = .0003).²⁶⁴MLDs of <10, 10 to 20, 21 to 30, and >30 Gy were associated with risks of 10%, 16%, 27%, and 44%, respectively. A Japanese study of patients treated with platinum-based chemoradiotherapy found a 6-month risk of grade 2 or higher radiation pneumonitis to be 85%, 51%, 18.3%, and 8.7% (p <.0001) with a V₂₀ of ≥31%, 26% to 30%, 21% to 25%, and ≤20%, respectively.²⁸² In a University of Michigan study, a 10% risk for grade 2 or higher pneumonitis and fibrosis was associated with a V₂₀ of >30% and an MLD of >20 Gy. These thresholds provided a positive predictive value of 50% to 71% and a negative predictive value of 85% to 89%.²⁷⁷ In a study from M.D. Anderson Cancer Center (MDACC), the mean lung dose and V₅ to V₆₅ were highly correlated with risk of pneumonitis, and V₅ was the most significant factor in a multivariate analysis.²⁷² For a V₅ ≤42% versus >42%, the risk of grade 3 or higher pneumonitis at 1 year was 3% versus 38% (p = .001). In a Mayo Clinic study, V₁₀to V₁₃ was most predictive of radiation pneumonitis; a V₁₀ = 32% to 43%, V₁₃ = 29% to 39%, V₁₅ = 27% to 34%, and V₂₀ = 21% to 31% resulted in a 10% to 20% risk of pneumonitis.

Several dose-escalation studies have used V₂₀, V_eff, and/or NTCP to stratify the risk of toxicity as a function of dose.^285–288 In the RTOG 93-11 dose-escalation study,²⁸⁵ patients with a V₂₀ of <25% experienced a 7% to 16% 18-month actuarial rate of grade 3 or higher late lung toxicity with prescribed doses of 70.9 to 90.3 Gy; the absolute risk of grade 2 or higher late lung toxicity was 30% to 45%, with one fatal lung complication at the 90.3 Gy dose level. Patients with a V₂₀ of 25% to 36% treated to doses of 70.9 to 77.4 Gy experienced 15% grade 3 or higher late toxicity at 18 months and an 40% to 60% risk of grade 2 or higher late lung toxicity. D₁₅ was the most predictive variable for radiation pneumonitis.²⁶²

Factors Affecting Risk. The effect of dose to regions of the lung was investigated in a Dutch study,²⁷⁸ dividing the lung into central and peripheral; ipsilateral and contralateral; caudal and cranial; and anterior and posterior subvolumes. The mean regional doses to the posterior, caudal, ipsilateral, central, and peripheral lung subvolumes were significantly correlated with the incidence of steroid-requiring radiation pneumonitis. In a similar study from MSKCC, the risk of radiation pneumonitis was better correlated with the radiation dose to the inferior, as opposed to the superior, aspect of the lung.²⁷⁶

Tumor location within the chest may also be a factor affecting risk of pneumonitis. In the study from Washington University,²⁶⁵ inferior tumor location was the most significant predictor of radiation pneumonitis. Tumor location was not a strong correlate with radiation pneumonitis in RTOG 93-11, perhaps attributable, in part, to differences in treatment (with RTOG 93-11 treating smaller volumes to higher doses) and differences in tumor size and location (the RTOG 93-11 tumors tended to be smaller and more superiorly located).²⁶² Using a combined dataset of patients from RTOG 93-11 and Washington University, tumor location and MLD were significant predictors of toxicity.

Mathematic/Biologic Models. Most of the aforementioned studies used NTCP models to fit the toxicity data. In the QUANTEC analysis,²⁸⁴ a fit of the data for radiation pneumonitis as a function of MLD to the logistic expression (see Fig. 13.7) yields a predicted TD₅₀ = 30.8 Gy (95% confidence interval [CI], 28.7 to 33.9 Gy) and γ₅₀ = 0.97 (0.83 to 1.12). The latter parameter represents the percent increase in radiation increase in response per 1% increase in dose at the 50% dose–response level. A fit using the probit response function (equivalent to a fit of the Lyman model with n = 1) yields TD₅₀ = 31.4 Gy (95% CI, 29.0 to 34.7 Gy) and m = 0.45 (0.39 to 0.51), with the result essentially identical to that of the logistic fit in the region occupied by the data.

Special Situations. IMRT provides unique dose distributions for some patients with advanced-stage non–small-cell lung cancer,²⁸⁹ potentially reducing the risk of normal tissue injury. Investigators at MDACC compared rates of lung toxicity in their patients treated with IMRT versus 3D planning and noted a reduction in toxicity with the use of IMRT.²⁹⁰ A V₅ >70% was associated with a 21% risk of grade 3 or higher pneumonitis versus a 2% risk with V₅≤70% (p = .017). Similarly, a study from MSKCC found a low rate of clinical lung injury in patients with non–small-cell cancer treated with IMRT.²⁹¹

In a study from Dana Farber,²⁹² in which patients received thoracic IMRT after pneumonectomy for mesothelioma, six of 13 patients developed fatal pneumonitis. The median V₂₀, V₅, and MLD for patients who developed pneumonitis was 17.6%, 98.6%, and 15.2 Gy, respectively, versus 10.9%, 90%, and 12.9 Gy for those who did not develop pneumonitis. While these differences were not significant, the severity of the toxicities suggests caution in treating patients to large volumes after a pneumonectomy. In a study from Duke,²⁹³ one of 13 patients treated with IMRT for mesothelioma died from pneumonitis, and two others developed symptomatic pneumonitis. The median V₂₀, V₅, and MLD for patients developing pneumonitis were 2.3%, 92%, and 7.9 Gy, respectively, versus 0.2%, 66%, and 7.5 Gy for those who did not develop pneumonitis and 6.9%, 92%, and 11.4 Gy for the patient who developed fatal pneumonitis. In a study of mesothelioma patients treated at MDACC,²⁹⁴ six of 63 died from pulmonary-related causes (including two patients with fatal pneumonitis). The V₂₀ was significant on univariate and multivariate analyses (p = .017), with V₂₀ >7% corresponding to a 42-fold increase in the risk of pulmonary death.

Stereotactic body radiotherapy (SBRT) generally involves a few large fractions (e.g., three 18-Gy or five 10-Gy fractions) given over 5 to 20 days.^{295–296,297} Typically, the high-dose volumes in SBRT are small and dose gradients steep, minimizing dose to surrounding critical structures. However, because multiple beams are used, large volumes of lung receive low to medium doses.²⁹⁷ Consequently, the dose–volume characteristics of lung SBRT are quite different from those of conventional RT and deserve special consideration. Radiation pneumonitis is relatively uncommon after SBRT, usually <10%^296,298,299 but as high as 25% in one study.³⁰⁰ Bronchial injury/stenosis, an unusual complication with conventional dose fractionation,³⁰¹ has been associated with SBRT to perihilar/central tumors.²⁹⁶

Recommended Dose–Volume Limits. Individual studies note a dose–response relationship for radiation pneumonitis based on a variety of metrics. However, the QUANTEC analysis²⁸⁴ of the pooled data shows that there is no specific threshold for pneumonitis, with risks increasing gradually as dose increases. Since many dose–volume parameters of the lung (i.e., V₅ through V₃₀, MLD) are correlated with each other, there likely is not an “optimal” parameter. For patients with non–small-cell lung cancer, it is prudent to limit the V₂₀ to <30% to 35%, and the mean lung dose to <20 to 23 Gy, in order to reduce the risk of pneumonitis to <20%. In patients irradiated after pneumonectomy for mesothelioma, it is prudent to limit the V₅ to below 60%, V₂₀ to <4% to 10%, and the mean lung dose to <8 Gy.

Future Studies. Radiation-induced pneumonitis appears more commonly in patients with lower versus upper lobe tumors and may be better correlated with radiation doses to the lower versus upper lung. The cause of this correlation is presently unknown and requires further investigation, though it may be related to heart irradiation. Additional work is needed to better understand the impact of clinical factors (e.g., preradiotherapy functional status, tobacco use) and systemic agents (e.g., chemotherapy) on the risk of lung injury. Studies aimed at determining and exploiting the ability of biomarkers such as TGF-β(measured before and/or during lung radiotherapy) on radiation pneumonitis would be valuable.

Toxicity Scoring Criteria. The LENT-SOMA system should be used for scoring toxicity as it explicitly captures symptomatic, functional, and radiographic endpoints. A global score can be generated, but the granular data should be recorded and maintained.

FIGURE 13.8. The rate of radiation pneumonitis after fractionated partial lung radiotherapy as a function of (A) mean lung dose (MLD) and (B) lung volume receiving x Gy (V_x). (A) MLD: Confidence intervals (bars) represent ± 1 standard deviation. Results from Memorial Sloan-Kettering Cancer Center (MSKCC),²⁷⁵ Radiation Therapy Oncology Group (RTOG) grade 3 or higher pulmonary toxicity at 6 months; Duke,²⁶⁴ Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or higher at 6 months; Michigan,²⁷⁷ Southwest Oncology Group (SWOG) grade 2 or higher at 6 months; M.D. Anderson Cancer Center,²⁷² CTCAE grade 3 or higher, 1 year actuarial—includes concurrent chemotherapy patients; Netherlands Cancer Institute (NKI),²⁷⁸ SWOG grade 2 or higher at 6 months; Washington University (WU),²⁶⁵ SWOG grade 2 or higher; Michigan,²⁷⁹ SWOG grade 1 or higher; Heidelberg,²⁸⁰ RTOG acute grade 1 or higher; Milan,²⁸¹ SWOG grade 2 or higher, no time limit, patients without chronic obstructive pulmonary disease, includes induction chemotherapy patients; Gyeonggi,²⁶⁶ RTOG grade 3 or higher at 6 months, includes concurrent chemotherapy patients. Dashed line is best fit of these data fit to the logistic expression of the form [f/(1 + f)], where f = exp(b0 + b1 * MLD). Best-fit values (95% confidence intervals) are b0 = −3.87 (−3.33, −4.49) and b1 = 0.126 (0.100, 0.153), corresponding to TD₅₀ = 30.75 (28.7, 33.9) Gy and γ₅₀ = 0.969 (0.833, 1.122), where γ₅₀ represents the increase in response (measured as percentage) per 1% increase in dose around the 50% dose–response level. (B) V_x. Data from Yorke,²⁷⁵ Willner,²⁷³ Hernando,³⁶⁴ Tsujino,²⁸² Kong,²⁷⁷ Armstrong,²⁸³ Kim,²⁶⁶ Graham,²⁶⁰ Seppenwoolde,²⁷⁰ Wang,²⁷² and Schallenkamp.²⁶⁹ Some of the above data were modified or derived from the original publications, as described in Marks et al.²⁸⁴ (From Marks LB, et al. Radiation dose-volume effects in the lung. Int J Radiat Oncol Biol Phys 2010;76[3 Suppl]:S70–S76.)

FIGURE 13.9. Dose–response curves for long-term cardiac mortality in patients with Hodgkin disease (HD) and breast cancer treated with thoracic radiotherapy. NTCP = normal tissue complication probability, defined in that study as the excessive risk of ischemic heart disease. Curves were obtained by fitting data from breast cancer trials, a cohort of patients with Hodgkin disease, and the combined dataset. Plotted curves correspond to uniform irradiation of one-third of the heart volume. (From Eriksson F, et al. Long-term cardiac mortality following radiation therapy for Hodgkin’s disease: analysis with the relative seriality model. Radiother Oncol 2000;55[2]:153–162.)

Heart

Clinical Significance. The heart is a muscular organ typically located in the left hemithorax, which, via continuous rhythmic contraction, pumps blood throughout the blood vessels. The functional and structural complexity of the heart places it at risk for a spectrum of radiation and chemotherapy injuries that can manifest months to years following therapy.³⁰²

Endpoints. All components of the heart and pericardium are susceptible to radiation damage. Radiation-induced cardiac injury includes pericarditis, congestive heart failure, restrictive cardiomyopathy, valvular insufficiency and stenosis, coronary artery disease, ischemia, and infarction.

Challenges Defining Volumes. The substructures of the heart, as well as the intersection/border of the heart, great vessels, liver, diaphragm, and stomach, can be challenging to delineate on CT imaging. The heart moves during the respiratory and cardiac cycles, with different regions moving to different degrees. The uncertainties that accompany these anatomic/physiologic realities must be considered when contouring targets and normal tissue structures and when interpreting DVHs.

Dose/Volume/Toxicity Data. Multiple studies show an increased risk of cardiac morbidity following left- versus right-sided thoracic radiation in patients undergoing treatment for breast cancer. It is generally recognized that reducing the dose prescribed to the mediastinum and reducing the volume of heart in the radiation field reduce the risk of late toxicity.^{303–304,305} Recent studies from Duke demonstrated that an increased percentage of the left ventricle irradiated correlates with a greater risk of cardiac perfusion defects.^{306–307,308} Even over the range of low dose exposure (~8 to 20 Gy) to small volumes of the cardiac apex, an increased risk of heart disease has been reported.³⁰⁹

A study from Stockholm used normal tissue complication probability modeling to predict the risk of late heart toxicity in women treated for breast cancer.³¹⁰ The models predicted a TD₅₀ of 52 Gy for dose to the myocardium. A 5% risk of excess cardiac mortality at 15 years was associated with a myocardial dose of ~30 Gy, V₃₃ >60%, V₃₈ >33%, or V₄₂ >20%. Calculations using the whole-heart volume (as opposed to myocardium) yielded equivalent results.

The same group from Stockholm used a similar analysis to assess cardiac risk in Hodgkin disease patients.³¹¹ Patients were stratified based on a V₃₈ >35% versus <35%. The excess mortality risk at 15 years was 7.9% and 4.7%, respectively. The TD₅₀ was calculated to be 70 Gy. Heart doses of 42 and 53 Gy resulted in a 5% and 10% risk of cardiac complications, respectively. The corresponding values in the breast cancer patients were 37 Gy and 44 Gy, respectively (lower threshold doses and steeper gradient). The differences in complication probabilities and TD₅₀ between the breast cancer and Hodgkin disease cohorts (Fig. 13.9) suggest that radiation exposure to different portions of heart results in differences in cardiac risk, though there may be other confounding variables (i.e., patient age at treatment, overlapping breast cancer and cardiac disease risk factors, etc.).

A study from MDACC described the risk of pericardial effusions in patients treated for esophageal cancer.³¹² A mean dose >26 Gy and relative volumes of the pericardium treated at doses greater than 3 to 50 Gy (V₃ to V₅₀) showed the greatest risk, with the association strongest at V₃₀. For V₃₀ <46% versus >46%, the rate of pericardial effusion was 73% versus 13% (p = .001) 18 months postradiation. For a mean pericardium dose <26 Gy versus >26 Gy, the rate of pericardial effusion was 73% versus 13% (p = .001). A study from the University of Michigan³¹³ also demonstrated that a mean dose >27 Gy and a maximum dose of 47 Gy correlated with risk of pericardial effusion. However, only patients treated with 3.5-Gy fractions developed pericardial effusions.

The incidence of valvular disease has been related to mediastinal radiation doses >30 Gy and younger age at irradiation.³¹⁴ Subclinical valvular disease has been detected at 2 to 20+ years postradiation, but it appears to take much longer for clinical symptoms to become apparent (median interval 22 years from radiation to symptoms). For patients treated for Hodgkin lymphoma more than 10 years prior with radiation, aortic disease, usually consisting of mixed stenosis and regurgitation, is more common than mitral and right-sided valvular disease.^314,315

Factors Affecting Risk and Special Situations. Anthracycline chemotherapy can exacerbate radiation-elated cardiac toxicity. In Hodgkin disease patients, radiation exposure, in conjunction with anthracyclines, may impair ejection fraction and increase risk of myocardial infarction, congestive heart failure, and valvular disorders. A Dutch study³¹⁶ of 1,474 Hodgkin lymphoma survivors showed that risks of myocardial infarction and congestive heart failure were significantly increased, with standard incidence ratios of 3.6 and 4.9, respectively, for these survivors versus the general population. Mediastinal radiation alone increases the risks of myocardial infarction, angina pectoris, congestive heart failure, and valvular disorders (two- to sevenfold). The addition of anthracyclines further elevated the risks of congestive heart failure and valvular disorders, with hazard ratios of 2.81 and 2.10, respectively. The 25-year cumulative incidence of congestive heart failure following combined radiation and anthracycline chemotherapy was 7.9%.

Other risk factors for cardiac disease, particularly coronary artery disease, also must be considered. For example, a University of Rochester study³¹⁷ assessed the risk of coronary artery disease in survivors of Hodgkin lymphoma and also the prevalence of cardiac risk factors. The relative risk of cardiac death was 3.1 for males versus 1.8 for females. Other risk factors were more common than in the general population; among patients with Hodgkin lymphoma experiencing morbid cardiac events, 72% smoked, 72% were male, 78% had hypercholesterolemia, 61% were obese, 28% had a positive family history, 33% had hypertension, and 6% had diabetes.

Mathematic/Biologic Models. There are no well-accepted models for cardiac toxicities. Nevertheless, several authors have computed model parameters for various cardiac endpoints, as summarized in the QUANTEC review.³⁰²

Recommended Dose–Volume Limits. A heart V₃₀ to V₄₀ of ~30% to 35% is associated with a ~5% excess risk of cardiac death at ~15 years. A heart V₃₀ of >45% and a mean cardiac dose of >26 Gy are associated with a higher risk of pericarditis. In patients with breast and lung cancer, it is recommended that the irradiated heart volume be minimized as much as possible without compromising target coverage. In patients with lymphoma, the whole heart should be limited to 30 Gy if treated with radiation alone and to 15 Gy for patients also receiving anthracycline chemotherapy. Although there is no direct evidence that eliminating traditional cardiac risk factors alters the natural history of radiation-associated cardiac disease, it seems prudent to minimize such factors.^302,318,319

Future Studies. Issues that would benefit from further systematic study are the effects of radiation on specific subvolumes of the heart, the impact of modern radiotherapy techniques on cardiac toxicity, the relationship between heart irradiation and baseline cardiovascular risk factors on the development of cardiac disease, the effect of hypofractionation encountered in thoracic stereotactic body radiotherapy, and the global physiologic effects of thoracic radiotherapy (e.g., interactions between simultaneous heart and lung irradiation.)³⁰²

Toxicity Scoring Criteria. The QUANTEC authors recommend that the LENT-SOMA system^93,320 be considered to describe cardiac toxicity, as it explicitly includes clinical, radiologic, and functional assessments of cardiac dysfunction.

Esophagus

Clinical Significance. Acute esophagitis is very common and often severe in patients receiving radiation for intrathoracic malignancies (e.g., primary lung cancer and esophageal cancer). Patients with severe esophagitis may require a feeding tube and/or treatment interruptions.

Endpoints. Because most patients with thoracic cancers have a poor prognosis, acute toxicity may be considered more clinically relevant than late injury. Late esophageal complications include dysphagia, stricture, dysmotility, odynophagia, and rarely necrosis or fistula.

Challenges Defining Volumes. The esophagus can be challenging to visualize on axial imaging, and the use of dilute oral contrast can assist in its identification. Also, the esophagus often has folds such that its external contour as seen on an axial image may not accurately represent its true circumference. Indeed, in CT imaging the circumference of the esophagus appears highly variable on different axial levels, when in fact the esophagus has a relatively uniform circumference. One study has suggested that the dosimetric parameters that apply this prior anatomic knowledge are better predictors of acute and late esophageal injury than are traditional dosimetric parameters.³²¹

Dose/Volume/Toxicity Data. A variety of dose–volume parameters have been associated with the incidence of esophagitis.^{312,322–329} While a continuous dose–response curve for acute esophagitis is observed based on a range of dosimetric parameters, as shown in Figure 13.10, there is no consensus as to the optimal dosimetric predictors of acute or late esophageal injury.

In a series from Washington University, grade 3 to 5 esophageal toxicity (acute and late) was associated with a maximal dose (D_max) of >58 Gy, a mean dose of >34 Gy, and the administration of concurrent chemotherapy.³²⁸ The V₅₅ was not significant. A study from China reported that maximal dose >60 Gy, as well as the use of concurrent chemotherapy, was a significant factor for esophageal toxicity (acute and late).³²⁷ In a study from Duke, V₅₀, the surface dose receiving ≥50 Gy (S₅₀), the length of esophagus receiving >50 to 60 Gy, and a circumferential D_max >80 Gy were significant predictors of late esophageal toxicity.³²⁶ A V₅₀ >32% or an S₅₀ >32% resulted in crude rates of ~30% late esophageal toxicity versus 7% below these thresholds. With >3.2 cm of the esophagus receiving >50 Gy, late toxicity occurred in ~30%, versus 4% in those with <3.2 cm receiving >50 Gy (p = .008).

In another study from Duke, grade 1 or higher late toxicity was correlated with several dose parameters: the entire circumference receiving ≥50 Gy and ≥55 Gy; 75% of the circumference receiving ≥70 Gy; and maximal percentage of circumference receiving ≥60 to 80 Gy.³²² The rate of grade 1 or higher late toxicity was ~5% in patients with a V₅₀ to V₇₀ of 0% to 30% versus ~25% in those with a V₇₀ of 31% to 64% and ~10% in those with a V₅₀>60% (nonsignificant). Acute esophageal toxicity was the greatest predictor of late toxicity. In two studies, most of the patients who developed late grade 3 or higher toxicity had developed acute grade 3 or higher toxicity, though roughly 25% to 40% of patients who developed grade 3 or higher late toxicity had only grade 0 to 2 acute esophageal toxicity.^327,328

FIGURE 13.10. Incidence of acute esophagitis according to V_x (volume receiving more than x Gy) for selected studies. x-Axis values estimated from range of doses reported. Datasets annotated as follows: V_dose (investigator, number of patients, percentage with concurrent chemotherapy [CCT]). (From Werner-Wasik M, et al. Predictors of severe esophagitis include use of concurrent chemotherapy, but not the length of irradiated esophagus: a multivariate analysis of patients with lung cancer treated with nonoperative therapy. Int J Radiat Oncol Biol Phys 2000;48[3]:689–696.)

Factors Affecting Risk. Greater rates of acute esophagitis have been observed with more aggressive radiotherapy regimens (e.g., hyperfractionation, concurrent boost), the addition of concurrent chemotherapy, increasing age, and several other clinical factors (e.g., pre-existing dysphagia and increasing nodal stage). The incidence of grade 3 or higher acute esophagitis is ~1% for patients treated with once-daily radiotherapy alone versus as high as 49% with concurrent gemcitabine. Several studies have assessed the putative radioprotector amifostine. Three single-institution phase III studies suggested a benefit for amifostine in reducing the rate of grade 2 or higher esophagitis, but this result was not confirmed in a large cooperative group phase III randomized trial (RTOG trial 9801).^330–333

Mathematic/Biologic Models. Using data on grade 2 or higher acute esophagitis, two studies obtained relatively consistent estimates of Lyman-Kutcher-Burman model parameters, including TD₅₀ of 47 to 51 Gy.^7,323 Note that these parameters differ significantly from those derived from the Emami data,⁴ which examined a more clinically severe endpoint (stricture and perforation).

TABLE 13.10 RADIATION-INDUCED LIVER DISEASE IN PARTIAL LIVER IRRADIATION

FIGURE 13.11. Mean liver dose, corrected with linear-quadratic modeling for 2-Gy fractions versus Lyman normal tissue complication probability (NTCP) of classic radiation-induced liver disease (RILD) for primary and metastatic liver cancer. (From Pan CC, et al. Radiation-associated liver injury. Int J Radiat Oncol Biol Phys 2010;76[3 Suppl]:S94–S100.)

Special Situations. Esophageal toxicity data for hypofractionated treatments in stereotactic body radiotherapy to central thoracic lesions are quite limited,³³⁴ and long-term data in this and other altered fractionation settings (e.g., accelerated fraction and concomitant boosts) have not been comprehensively reported.³³⁵

Recommended Dose–Volume Limits. Given the available data, there are no strict dose–volume limits for the esophagus. Several parameters are associated with the risk of adverse events, and clinicians can apply these data as seems reasonable for the clinical situation. Unfortunately, the anatomic reality for many patients with locally advanced non–small-cell lung cancer is that the PTV (and certainly the GTV) is often immediately adjacent to the esophagus, and thus, it is not possible to limit the doses as desired without compromising target coverage. The ongoing phase III intergroup trial, RTOG 0617, has recommended (but has not mandated) that the mean dose to the esophagus be kept to <34 Gy.

Future Studies. IMRT may provide increased flexibility in sparing the esophagus during lung irradiation, and outcome as function of dose–volume should be systematically studied for this treatment technique. As in other organ systems, detailed outcome and dosimetric data should be reported, based on clearly defined methods of contouring the target and organs at risk.

Toxicity Scoring Criteria. Esophageal toxicities should be scored using the CTCAE v. 4.0.³⁷

 ABDOMEN/PELVIS

Liver

Clinical Significance. The liver is a vital organ, involved in the metabolism of ingested nutrients, detoxification, protein synthesis, bile production, glycogen storage, and red blood cell decomposition. The liver may be incidentally irradiated during radiation therapy of abdominal or thoracic tumors and will be irradiated in patients undergoing partial hepatic radiation for liver metastases or hepatocellular carcinoma. There is no effective treatment to reverse the process of radiation-induced liver disease (RILD); therefore, prophylaxis and prevention are best. Anticoagulants, paracentesis, and diuretics can be used to mitigate symptoms, while liver transplantation is required for frank radiation hepatopathy.

Endpoints. RILD generally presents as vague to intense right upper abdominal pain followed by abdominal swelling due to hepatomegaly and ascites, resulting in weight gain. Anicteric ascites often develops 2 to 4 months after irradiation; chemoradiation-induced liver disease may occur more rapidly (e.g., 1 to 4 weeks post radiation therapy in a bone marrow transplantation setting). Other sequelae of RILD include elevation of liver enzymes, jaundice, asterixis (tremor), encephalopathy, or coma.

The basic pathophysiologic sequelae of classic RILD is central vein thrombosis at the lobular level, which results in retrograde congestion leading to hemorrhage and secondary alterations in surrounding hepatocytes. This often occurs between 2 weeks and 3 months after therapy. Severe acute hepatic changes often progress to fibrosis or cirrhosis and liver failure.

Nonclassic RILD implies dramatic elevations of liver transaminases (greater than five times the upper limit) or decline in liver function in the absence of classic RILD. The underlying pathology of nonclassic RILD is unclear.³³⁶

Challenges Defining Volumes. The liver is readily identified on CT and MRI. For radiation planning, it must be recognized that the liver moves with the respiratory cycle.³³⁶

Dose/Volume/Toxicity Data. The liver parenchyma is composed of innumerable, redundant, parallel functional subunits, which allows the liver to potentially tolerate focal injury without clinical sequelae if adequate normal liver parenchyma can be spared.

In a study of 79 patients treated with liver radiotherapy at the University of Michigan, nine of 33 patients who received whole-liver radiotherapy developed late radiation toxicity versus none of 46 who underwent partial liver radiation.³³⁷ Several studies have explored partial liver radiation in more detail, many of which used mean liver dose as a dose–volume metric (Table 13.10). In a series from Taipei, patients with irradiated hepatocellular carcinoma who developed late liver toxicity had received a mean hepatic dose of 25 Gy (vs. 20 Gy in patients without toxicity, p = .02).³⁴⁶ In a Korean study of 105 patients with hepatocellular carcinoma, the mean dose and V₂₀ to V₄₀parameters to total liver and normal liver (total liver minus GTV) were investigated.³⁴⁵ The total liver V₃₀ was the only significant parameter (p <.001). Grade 2 or higher liver toxicity was observed in only 2.4% of patients with a total liver V₃₀ of ~60% and 55% of patients with a total liver V₃₀ of >60% (p <.001).

Factors Affecting Risk and Mathematic/Biologic Models. A wide variety of agents have been reported to elevate liver enzymes: nitrosoureas (BCNU), methotrexate, and some combinations of chemotherapy agents such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and proMace-MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, and MOPP). In bone marrow transplantation, preparatory regimens can be toxic.

As described earlier, the dose to partial liver volumes can impact the risk of RILD. Several studies have used NTCP modeling to help predict risks. In a study from University of Michigan, no late liver toxicity was observed with a mean liver dose <31 Gy, with normal tissue complication probability models being optimized with a TD₅₀ of 43 Gy and TD₅ of 31 Gy for whole-liver radiation; the risk of complications was strongly dependent on volume of liver irradiated.³³⁸ Other risk factors for late toxicity included primary hepatobiliary carcinoma (as opposed to metastatic disease), use of bromodeoxyuridine chemotherapy (as opposed to fluorodeoxyuridine), and male gender. The normal tissue complication probability models predict a TD₅ in excess of 80 Gy if less than one-third of the liver is irradiated. With irradiation of two-thirds of the liver, the TD₅ is on the order of 50 Gy and TD₅₀ on the order of 60 Gy.

In the series of hepatocellular carcinoma patients from Taipei (discussed earlier),³⁴⁶ the TD₅₀ for whole-liver, two-thirds liver, and one-third liver radiation was modeled to be approximately 43 Gy, 50 Gy, and 67 Gy, respectively. The TD₅ for whole-liver, two-thirds liver, and one-third liver radiation was modeled to be approximately 25 Gy, 28 Gy, and 38 Gy, respectively. The volume effect of liver radiation was less in this series. In another study from the same group, the mean liver dose and hepatitis B virus positivity were significant predictors of radiation toxicity; with NTCP modeling, the TD₅₀ was ~50 Gy.³⁴⁰

The data from Asia differs from that in the West, perhaps reflecting differences in the treated malignancy (mostly metastases in the West vs. primary liver cancer in Asia, which often occurs in the setting of liver cirrhosis), as shown in Figure 13.11. In addition, radiation fractionation, concurrent therapies delivered with radiation, and the fact that the majority of patients with hepatocellular carcinoma from Asia have hepatitis B viral infections may impact liver tolerance.³³⁶ Poor pre-existing liver function is also predictive of poorer tolerance to radiation.³³⁶

Special Situations. The hypofractionated delivery of radiation, using novel techniques such as SBRT and/or image-guided radiation therapy (IGRT), for primary and metastatic liver lesions presents a unique situation in which small volumes of normal liver receive very high doses of radiation per fraction. In a collaborative phase I study, the University of Colorado and Indiana University enrolled 18 patients with one to three liver metastases treated with three fractions of SBRT.³⁴⁷ No patients developed grade 2 or higher toxicity. Late radiographic changes of well-circumscribed hypodense lesions were commonly seen, corresponding to the 30-Gy dose distribution. In a follow-up analysis, including an additional 18 patients treated in a phase II study of three fractions of 20 Gy, one patient developed subcutaneous tissue breakdown; no radiation-related liver toxicity occurred.³⁴⁸ In a subsequent study, in which ≥700 mL of normal liver was required to receive <15 Gy in three fractions, no patient experienced RILD.³⁴⁹

Princess Margaret Hospital treated 41 patients with primary hepatocellular or intrahepatic biliary cancer in a phase I study of 24 to 60 Gy in six fractions.³⁵⁰ Using normal tissue complication modeling, patients were stratified into three different dose-escalation groups, based on the effective liver volume to be irradiated. Acute (<3 months) elevation of liver enzymes occurred in 24%, acute grade 3 nausea occurred in 7%, and acute transient biliary obstruction occurred in 5% of patients. In contrast, among 68 patients with liver metastases treated similarly with SBRT, two patients (3%) developed grade 3 liver enzyme changes, but no RILD or other grade 3 or higher liver toxicity was reported.³⁵¹

Recommended Dose–Volume Limits. For patients with liver metastases undergoing partial-volume liver radiation, the risk of radiation-induced liver toxicity appears to be more dependent upon the volume of liver irradiated. Partial volumes of liver can tolerate relatively high doses. Liver tolerances, however, are lower for patients with primary liver cancer (who are more apt to have underlying liver disease). For whole-liver radiation, doses ≤28 to 30 Gy in 2-Gy fractions (28 Gy for liver metastases and 30 Gy for primary liver cancer) and ≤21 Gy in 3-Gy fractions are recommended. For partial-liver radiation, treated with standard fractionation, the mean dose to normal liver (liver minus GTV) is suggested to be <30 Gy for liver metastases and <28 Gy for primary liver cancer.

Future Studies. Studies that better correlate dose–volume parameters with long-term clinical/objective outcomes are needed. The impact of treatment-related (including fractional dose and systemic therapies) and host-related variables should be better defined.

Toxicity Scoring Criteria. The CTCAE v. 3.0 grades hepatobiliary toxicity according to clinical criteria of jaundice, asterixis, and encephalopathy or coma for grades 2, 3, and 4, respectively. The much more commonly occurring alteration in liver enzymes, in the absence of symptomatic manifestations, is classified under the CTCAE metabolic/laboratory category of elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The use of CTCAE criteria for elevations of AST and ALT and other metabolic effects is advisable to promote consistency of reporting.

FIGURE 13.12. Graphic representation of the Baglan–Robertson^356,357 threshold model for acute small bowel toxicity. “Low risk” implies <10% and “high risk” >40% grade 3 toxicity. Absolute volume is based on contouring individual bowel loops, not the entire peritoneal space. (From Kavanagh BD, et al. Radiation dose-volume effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys 2010;76[3 Suppl]:S101—S107.)

Small Bowel/Stomach

Clinical Significance. The stomach and small bowel aid in the digestion and absorption of food and nutrients. Symptoms from radiation-related late toxicities include dyspepsia, gastric ulceration, diarrhea, bowel obstruction, and ulceration, fistula, or perforation.³⁵²

Endpoints. Nausea and vomiting can occur immediately or within hours after RT to the stomach or small bowel. The radiosensitivity of the gastric mucosa is reflected in the early depression of hydrochloric acid and pepsin secretion after modest radiation doses of 15 to 20 Gy. Although some recovery of cellular structure occurs, suppression can continue for 6 months to many years after irradiation. Usually, at total doses at or above 50 Gy, cellular and functional recovery is never complete. Ulcers are the most common complication of gastric irradiation and present clinically with dyspepsia, significant pain, and sometimes hemorrhage. An ulcer in this anatomic setting can lead to hemorrhage and perforation, which, although rare, can be fatal. Ulcerations have been described as typically antral, perhaps because of placement of radiation therapy fields, and develop as early as 2 to 12 months after treatment. Pyloric obstruction may be a late development due to fibrosis after ulcer healing.

The early onset of malabsorption of fat and hypermotility after modest doses of radiation illustrates the radiosensitivity of the small intestine. Usually, recovery at dose levels below 40 to 45 Gy occurs, although some persistence of small bowel dysfunction and mesenteric cramping may be noted. Surgical intervention and adhesions can precipitate a more serious course of events. Higher doses result in diarrhea, malabsorption of fat, and leakage of albumin into the bowel. If an obliterative arteritis develops, the risk of infarction and perforation remains despite recovery. The underlying lesion is one of ulceration and segmental enteritis that can lead to stenosis of the bowel lumen, with varying degrees of obstruction during the chronic period.

Challenges Defining Volumes. The stomach and small bowel are well visualized, particularly with the use of intravenous contrast and/or oral contrast. The stomach and small bowel position can be variable, and it is therefore recommended that patients avoid large meals or carbonated beverages prior to simulation and treatment.

Dose/Volume/Toxicity Data. Because stomach and small bowel are mobile and distensible, determining accurate dose–volume (or dose–surface) constraints is challenging. Late radiation-induced stomach injury has been reported to occur with increasing frequency with increasing doses. In a study from Walter Reed, the rates of gastric ulceration were 4% and 16% after treatment of <50 versus >50 Gy, respectively. Similarly, the rates of perforation were 2% and 14% in the same dose cohorts, respectively. Overall, the dose of approximately 50 Gy to the stomach is associated with about a 2% to 6% incidence of severe late injury. The volume effect for late stomach injury is not well defined. For late small bowel toxicity, doses of approximately 50 Gy are associated with obstruction/perforation rates that are approximately 2% to 9%.

There is a paucity of good quantitative data on dose–volume metrics that predict for gastric or bowel late toxicity. Nevertheless, there are data that demonstrate a volume effect. The risk of bowel obstruction among patients with rectal cancer whose fields extended to L1 or L2 was 30% versus 9% in those treated with pelvis-only fields.³⁵³ The University of Michigan investigated gastric and duodenal bleeding after radiation of patients with liver tumors.³⁵⁴Normal tissue complication modeling was consistent with a dose threshold (~60 Gy) for bleeding without a large volume effect.

Factors Affecting Risk. Factors affecting risk of late toxicity include total dose (with doses in excess of 40 to 50 Gy increasing the risk of late complications), fractional dose, prior abdominal surgery (which increases the risk of bowel obstruction), and concurrent chemotherapy use. In the European Organisation for Research and Treatment of Cancer (EORTC)Hodgkin lymphoma study, the rate of complications was 3% without prior abdominal surgery versus 12% with prior abdominal surgery.³⁵⁵

Mathematic/Biologic Models. The University of Michigan analyzed gastric bleeding among patients treated with radiation for liver tumors.³⁵⁴ Variables significantly impacting bleeding risk included NTCP, mean dose to stomach, and presence of cirrhosis. Data from William Beaumont Hospital has suggested that the volume of bowel exposed to radiation doses of >5 to 40 Gy correlates with risk of acute grade 3 toxicity; their studies^356,357 and others have shown small bowel V₁₅ to be highly significant (p < .0001).³⁵⁸ The model results are graphically depicted in Figure 13.12. Using NTCP modeling for patients undergoing preoperative radiation for rectal cancer, IMRT has been shown to reduce the anticipated rate of grade 2 or higher diarrhea from 40% to 27% (with further reductions if IGRT is also used).³⁵²

Special Situations. High-grade small bowel mucositis, ulceration, and perforation, as well as acute gastroparesis, have been reported in patients undergoing hypofractionated SBRT for pancreatic malignancies,³⁵⁹ though the reported rate of such grade 3 to 4 toxicities (albeit in a patient population with poor survival) has been relatively low in U.S. studies.^360–362 Among patients undergoing three- to five-fraction SBRT for liver metastases, bowel toxicity has been reported to occur with maximal doses to the bowel of >30 Gy.³³⁶

Recommended Dose–Volume Limits. Using the entire potential small bowel space, it is suggested that the small bowel exposed to V₄₅ to V₅₀ should be <195 mL to reduce acute toxicity (not discussed earlier)^352,363; while using the visualized loops of bowel, it is recommended that the V₁₅ should be <120 mL.^352,356 While these dose constraints were derived from acute toxicity data, they do provide guidelines that should help minimize risk of late toxicity as well. For the stomach, it is recommended to maintain the dose to the whole stomach to <45 Gy; a maximum point dose might be an important predictor of toxicity, but more data are needed to confirm this hypothesis.

Future Studies. More detailed dose–volume effects for late bowel toxicity are needed, particularly for altered fractionation (i.e., SBRT). As many gastrointestinal cancers are treated with chemotherapy, data on the impact of chemotherapy on acute and late stomach and bowel toxicity are needed.

Toxicity Scoring Criteria. The CTCAE v. 4.0 is used to grade gastric and small bowel toxicity.⁹¹

FIGURE 13.13. Schematic diagram of bilateral kidney dose–volume histogram from selected studies, represented as regions associated with minimal (<5%), low (~5%), moderate to high (~5% to 30%), high (>30%), or undefined estimated risk of toxicity. Clinical situation that yielded risk estimates for each region is also indicated. Actual risks are patient and plan specific and are associated with substantial uncertainty. (Adapted from Dawson LA, et al. Radiation-associated kidney injury. Int J Radiat Oncol Biol Phys 2010;76[3 Suppl]:S108–S115.)

Kidneys

Clinical Significance. The kidney functions to remove wastes; regulate electrolytes; produce erythropoietin, which stimulates red blood cell production; and modulate blood pressure through the renin-angiotensin pathway as well as through fluid/electrolyte balance. Radiation nephropathy is an uncommonly reported toxicity, not because kidneys are radioresistant, but because clinicians carefully respect renal tolerance doses.

Endpoints. Five distinct clinical syndromes may overlap in symptoms, signs, and time sequence: acute radiation nephropathy, chronic radiation nephropathy, benign hypertension, malignant hypertension, and hyperreninemic hypertension secondary to a scarred encapsulated kidney (Goldblatt kidney). The signs (i.e., decreased glomerular filtration rate) and symptoms of radiation nephropathy are not distinguishable from other causes of renal damage, and these should be excluded. Acute (within 6 months) radiation-induced kidney injury is generally subclinical. Urinary findings consist of microscopic hematuria, proteinuria, and urinary casts. Blood alterations in β₂-microglobulin correlate linearly with both inulin and creatinine clearance and with later elevations of blood urea nitrogen (BUN). There is a 6- to 12-month latency period before the clinical expression of acute radiation nephropathy. In this subacute phase, the signs and symptoms include dyspnea, headaches, ankle edema, lassitude, anemia, hypertension, albuminuria, papilledema, elevated blood urea, and urinary abnormalities (granular and hyalin casts, red blood cells). Death may occur from chronic uremia or left ventricular failure, pulmonary edema, pleural effusion, and hepatic congestion. Chronic radiation nephropathy and hypertension do not develop until after 12 to 18 months. When chronic nephropathy is severe, death may result.

FIGURE 13.14. Dose–volume histogram thresholds for grade 2 or higher rectal toxicity from selected studies.^{378,379,380,381,382–386} Thicker lines indicate higher rates of overall toxicity (percentages are indicated on the figure along with the physical prescription dose). Threshold doses are expressed as the total equivalent dose delivered in 2-Gy fractions, adjusted using the linear-quadratic model with α/β = 3 Gy. The associated equivalent prescription doses are coded by color spectrum from lowest (blue) to highest (red). Volumes shown in the graph are based on the full length of the anatomic rectum. Note that these curves converge in the high dose range, implying that doses in this range are more consistently associated with rectal toxicity. (From Michalski JM, et al. Radiation dose-volume effects in radiation-induced rectal injury. Int J Radiat Oncol Biol Phys 2010;76[3 Suppl]:S123–S129.)

Challenges Defining Volumes. The kidneys are readily defined on contrast and noncontrast CT imaging. Ideally, the “functional” kidney parenchyma as opposed to the collecting system should be contoured.

Dose/Volume/Toxicity Data. Several studies have investigated whole-kidney dose tolerance, either after whole-abdominal radiation or total-body irradiation (generally delivered with lower fractional doses). Renal toxicity can occur after bilateral kidney doses ≥10 Gy, and the risk is quite high (50% to 80%) after 20 Gy. Thus, the kidneys have a relatively low threshold for damage. The dose–volume effect on the kidneys has been long recognized, even prior to the planning CT era, because kidneys are well visualized on plain simulation films. From these studies, when greater than half of the kidney receives doses >20 to 30 Gy, or greater than one-third receives >30 to 40 Gy, patients are at increased risk of developing renal atrophy, decreased kidney function, and hypertension.^{1,364–365,366}

There is little published on dose–volume parameters to predict late renal toxicity, in part because clinicians make an effort to minimize the volume of kidney exceeding the accepted tolerance dose. Low doses, 10 to 15 Gy, to large volumes of kidney increase the risk of nephrotoxicity,^77,367,368 while smaller volumes of kidney with doses exceeding ~20 to 25 Gy can result in late renal toxicity.^{77,367,369,370} In a series from Heidelberg, normal tissue complication modeling was used to estimate the risk of late complications.³⁶⁹ A median dose of ~17.5 to 21.5 Gy and 22 to 26 Gy corresponded to a 5% and 50% late complication risk (anemia, azotemia, hypertension, and edema), respectively. In another German study, reduced kidney function, as measured by scintigraphy changes, was analyzed as a function of dose and volume.³⁶⁷ After irradiation of 10% to 30%, 30% to 60%, and 60% to 100% of the kidney volume to 20 Gy, the incidence of reduced activity was <10%, ~40%, and >70%, respectively. After irradiation of 10% to 30%, 30% to 60%, and 60% to 100% of the kidney volume to 30 Gy, the incidence of reduced activity was ~35%, >90%, and >98%, respectively. In a Dutch study of patients with gastric cancer (treated with concurrent radiation and cisplatin or capecitabine), the left kidney V₂₀ of ≥64% and mean left kidney dose of ≥30 Gy were associated with a significant decrease in left kidney function as compared to the right.³⁷⁰

Recognizing the limitations described earlier, the QUANTEC study summarized the toxicity data for bilateral kidney irradiation in Figure 13.13.

Factors Affecting Risk. A variety of agents have been implicated as toxic or as radiosensitizers (i.e., retinoic acid, cisplatin, BCNU, actinomycin D), administered either singly or in combination chemotherapy. Of note, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers have been shown to delay the progression of radiation injury in the experimental setting.³⁷¹ Total-body irradiation (TBI) dose rates (≤6 cGy/minute versus ≥10 cGy/minute) have been shown to significantly impact risk of renal toxicity.³⁷² Patient-related factors may include underlying renal insufficiency, diabetes, hypertension, liver disease, heart disease, and smoking.³⁷³

Special Situations. Several reports have described the use of SBRT in the treatment of medically unresectable kidney cancer and/or in patients with only one functioning kidney. With limited follow-up, SBRT with high dose (≥10 Gy) has been reportedly well tolerated.³⁷³

Recommended Dose–Volume Limits.³⁷³ For whole (bilateral) kidney radiation, doses <10 Gy delivered over five to six fractions (at a <6 cGy/minute dose rate) and <15 to 18 Gy for radiation delivered over ≥5 weeks are recommended. For partial-kidney radiation, the volume of kidneys receiving >20 Gy predicts risk of renal toxicity. The recommendation for partial-kidney radiation is to maximally spare the kidneys and maintain a mean dose of <18 Gy to both kidneys, or maintain a V₆ <30% if one kidney cannot be adequately spared.

Future Studies. Studies are needed to better define partial kidney tolerance to radiation, investigating the impact of underlying kidney function, dose–volume exposure (accounting for regional variation), fractionated dose delivery, and radiation protectors.

Toxicity Scoring Criteria. The CTCAE v. 4.0 can be used to grade renal toxicity.⁹¹ Severity of injury can also be graded according to the glomerular filtration rate, serial urine protein, serum blood urea nitrogen, creatinine clearance, blood pressure, and symptoms of renal failure.

Rectum

Clinical Significance. The rectum is the terminal portion of the large intestines that functions as a temporary storage for feces, as well as providing the urge to defecate. A portion of the rectum is irradiated in patients undergoing radiation for prostate cancer, gynecologic cancers, and other pelvic tumors (such as sarcomas).

Endpoints. Acute rectal toxicity includes diarrhea or loose stools, tenesmus, proctitis, and rectal urgency and/or frequency. The most common late radiation-related rectal complication is bleeding. Rectal ulceration and fistula are much less common. Other late injuries include stricture and decreased rectal compliance, which can result in frequent small stool and/or tenesmus. The anus is also at risk of late complications including stricture and laxity, leading to fecal incontinence.

Challenges Defining Volumes. The rectum extends from the rectosigmoid junction to the anus, with the inferior extent variably defined as the level of the anal verge the ischial tuberosities or 2 cm below the ischial tuberosities, or above the anus (the most inferior 3 cm of the intestines). The rectum should be segmented from above the anal verge to the turn into the sigmoid colon, though the superior and inferior borders of the rectum are not always easy to define on CT imaging, and definition of the cranial and caudal extents is variable.³⁷⁴ The rectum is mobile and distensible, and therefore its position and volume can vary between and during radiation fractions.

The percentage of rectum or rectal wall receiving a given dose can be somewhat subjective (i.e., based on how much of the rectum is segmented); using the absolute volume of rectum³⁷⁵ or rectal wall is less subjective, though defining the rectal wall is not standardized. William Beaumont Hospital demonstrated that the rectal volume as well as rectal wall V₅₀ to V₇₀ values predict late toxicity, with the rectal wall being more predictive of grade 2 to 3 late effects; acute toxicity is also predictive of late toxicity.³⁷⁶ MDACC has also shown the rectal wall to be better predictive of late rectal bleeding.³⁷⁷

Review of Dose/Volume/Toxicity Data. Abundant dosimetric data have shown a correlation of risk with rectal volume and surface/rectal wall doses among patients undergoing radiation for prostate cancer. Figure 13.14 summarizes many of the studies discussed here.

MSKCC has shown a significant difference in the DVHs between patients who developed rectal bleeding versus those who did not after conformal radiation for prostate cancer.³⁷⁸ The percent rectum exposed to 62% and 102% of the prescription dose (70.2 or 75.6 Gy) was significant; the rectal wall being encompassed by the 50% isodose line, higher maximal dose to the rectum, and smaller rectal volume were also significantly adverse risk factors.^378,387 In a recent study of 1,571 patients treated at MSKCC, the use of IMRT and the lack of acute rectal toxicity predicted for lower risk of late rectal toxicity.³⁸⁸

In a randomized trial of 70 Gy versus 78 Gy from MDACC in the treatment of early- to intermediate-risk early-stage prostate cancer, the risk of grade 2 or higher late rectal complications was significantly greater with a rectal V₇₀≥25% versus V₇₀ <25% (46 vs. 16%, p = .001).³⁸⁹ A retrospective analysis from MDACC showed that the risk is a continuous function of dose and volume, with suggested cut-off points for lowering the complication risk: V₆₀≤41%, V₇₀ ≤26%, V₇₆ ≤16% or 3.8 mL, and V₇₈ ≤5% or 1.4 mL.³⁷⁹ At 6 years, the risk of grade 2 or higher late rectal complications was 54% for patients with a rectal V₇₀ ≥26% versus 13% for a V₇₀ <26%.

Among patients treated in the Dutch randomized trial of 68 versus 78 Gy for prostate cancer,³⁹⁰ the mean anal dose (as well as V₅ to V₆₀) significantly predicted the rate of grade 2 or higher gastrointestinal toxicity (at 4 years, 16% vs. 31% for a mean dose of <19 Gy versus >52 Gy).³⁹¹ The mean dose (as well as V₅ to V₇₀) also predicted the risk for use of incontinence pads (at 5 years, <5% vs. >20% for a mean dose <28 Gy vs. >46 Gy). The anorectal V₆₅ (as well as V₅₅ to V₆₀) was significantly predictive of rectal bleeding (4-year risk <1% and >10% for a V₆₅ <23% vs. >29%).³⁹¹ Several other studies have shown that the volume of rectum receiving >50 to 70 Gy has been shown to significantly correlate with late rectal toxicity.^{380,381,392,393} From a 1998 Dutch study, recommendations for the volume of rectal wall (vs. rectal volume) exceeding 65 Gy, 70 Gy, and 75 Gy are <40%, <30%, and <5%, respectively.³⁹⁴ Data from the Cleveland Clinic³⁷⁵ and William Beaumont Hospital³⁷⁶ showed a significantly increased risk of grade 2 or higher rectal toxicity with rectal or rectal wall V₇₀ to V₇₈ of ≥15 mL versus <15 mL (~20% to >30% vs. ~5% to 10%).³⁷⁶

Women undergoing radiation for gynecologic malignancies are also susceptible to rectal toxicity. From historical data, the incidence of severe proctitis in patients with cancer of the cervix is dependent on the prescribed point A dose, with a <4% incidence with doses of <80 Gy, a 7% to 8% incidence after 80 to 95 Gy, and a 13% incidence for doses of ≥95 Gy.^395,396 With modern radiation delivery, particularly with IMRT planning, the rate of severe gastrointestinal toxicity is low. In a University of Chicago series of 183 patients treated with conventional radiation and brachytherapy, 9% developed grade 1 to 2 rectal toxicity and 7% developed grade 3 toxicity; a history of diabetes, point A dose, and the pelvic external-beam radiotherapy dose were most significantly correlated with rectal toxicity. Among patients experiencing diarrhea or loose stools after pelvic radiotherapy, rectal toxicity becomes difficult to differentiate from small bowel toxicity. In another report from the University of Chicago, of 50 women treated with pelvic IMRT for gynecologic malignancies, acute gastrointestinal toxicity was correlated with small bowel dose (see above), but not rectum receiving 25% to 110% of the prescription.²⁴⁴ However, the rectum was constrained to receive <40 Gy to >40% with a maximum dose of 49 Gy.

Factors Affecting Risk. Several patient-related variables, such as history of diabetes and/or vascular disease, inflammatory disease, and age, may impact the risk of late toxicity.^390,397,398 Prior abdominal surgery is also relevant.³⁹⁹ From 1,010 prostate cancer patients enrolled in the RTOG 94-06, cardiovascular disease was significantly (p = .015) associated with a higher rate of late rectal toxicity, while diabetes, hypertension, rectal volume, rectal length, neoadjuvant hormone therapy, and prescribed dose per fraction (1.8 vs. 2 Gy) were not significant factors.

Mathematic/Biologic Models. Rectal toxicity has been modeled using the Lyman-Kutcher-Burman NTCP model, mostly from patients treated with 3D conformal radiation. Most data are suggestive of a small volume effect, meaning that small volumes receiving high dose are most predictive for late effects.³⁷⁴ The TD₅₀ of grade 2 or higher late rectal toxicity is estimated to be around 77 to 79 Gy (with 95% CIs of ~74 to 82 Gy).³⁷⁴ From the largest study to date of 1,010 patients enrolled in the RTOG 94-06, the TD₅₀ was 79 Gy; the fit based on dose-wall histogram data was not significantly different. Equivalent uniform dose has also been modeled as a predictor of late rectal toxicity.⁴⁰⁰

Special Situations. Stereotactic body radiotherapy for prostate cancer is under investigation. In one study 67 patients were treated with 7.25 Gy × 5, in which rectal DVH goals were V_18.1% <50%, V_29%<20%, V_32.6% <10%, and V_36.3% <5%.⁴⁰¹ Grade 3, 2, and 1 rectal toxicities were seen in 0%, 2%, and 12.5% of patients, respectively. Persistent rectal bleeding was not observed. In another study, after SBRT (9.5 Gy × 4), acute grade 1 to 2 and 3 rectal toxicity occurred in 33% and 0% of patients, respectively, and late grade 1 to 2 and 3 acute genitourinary toxicity occurred in 8% and 0%, respectively.⁴⁰² For patients treated with permanent interstitial brachytherapy^403,404 or afterloaded high-dose-rate brachytherapy⁴⁰⁵ for prostate cancer (either as monotherapy or as a boost), the dose–volume exposure of rectum has been correlated with late rectal toxicity. Combined external-beam radiation and brachytherapy may lower the threshold for rectal toxicity after prostate brachytherapy.⁴⁰⁶

Recommended Dose–Volume Limits. For patients undergoing radiation therapy in which the rectum is irradiated, it is recommended to limit the rectal V₅₀, V₆₀, V₆₅, V₇₀, and V₇₅ to less than 50%, 35%, 25%, 20%, and 15%, respectively. While the data supporting these dose constraints primarily are from prostate cancer patients treated with conventional radiotherapy, studies of patients undergoing IMRT for prostate cancer suggest similar dose constraints.⁴⁰⁷

Future Studies. Future studies should be directed at achieving accurate dose–volume distributions for the rectum, which is a mobile, distensible structure, and correlating these dosimetric characteristics with toxicity. More robust data are needed for hypofractionated radiation delivery to the rectum, as with SBRT or HDR brachytherapy, as well as with low-dose brachytherapy and combined modality approaches.

Toxicity Scoring Criteria. The CTCAE v. 4.0⁹¹ or RTOG scoring criteria can be used to grade rectal toxicity.

Urinary Bladder

Clinical Significance. The bladder is a highly distensible organ that collects urine. Symptoms from late radiation-related toxicities include increased urinary frequency, hematuria, and dysuria. Necrosis, contracted bladder, and hemorrhage are less common, severe effects. Perhaps late bladder toxicity is underreported due to its long latency as well as toxicity being attributed to more common causes.

Endpoints. Bladder injury can be broadly classified as focal damage (e.g., bleeding) or more global injury (e.g., reduced bladder capacity with secondary urinary frequency). Acute side effects from incidental bladder irradiation are common and include urinary frequency, urgency, and dysuria (symptoms that may also reflect acute urethral toxicity). Late effects attributable to global injury include dysuria, frequency, urgency, contracture, spasm, reduced flow, and incontinence. In contrast, late effects arising from focal injury include hematuria, fistula, obstruction, ulceration, and necrosis.

Challenges Defining Volumes. The bladder is a mobile and distensible structure, depending upon the volume of urine within the bladder. Postvoid residuals may vary due to variable emptying and constant filling. In contouring the bladder, either the volume of the bladder and contents or the bladder wall alone can be segmented (with the latter more representative of a surface).

Dose/Volume/Toxicity Data. Because the bladder is mobile and distensible, determining accurate dose–volume (or dose–surface) constraints is challenging. Detailed dose–volume (or dose–surface) constraints have not been published, in part due to the complexities of assigning dose–volume or dose–surface metrics to a mobile, distensible structure. Whole-bladder tolerances have been mostly studied in patients with urinary bladder cancer, while partial bladder tolerances have been mostly studied in patients with genitourinary (mostly prostate) and gynecologic cancers.⁴⁰⁸

For whole-bladder irradiation, doses in excess of 60 Gy, particularly with fraction sizes >2 Gy and/or accelerated radiation regimens, result in a significant risk of grade 3 or higher late toxicity. Risks are lower when the whole bladder receives 45 to 55 Gy followed by a boost to >60 Gy to a portion of the bladder, though toxicity risk has not been correlated to dose–volume metrics. With prostate cancer treated to high doses (≥72 Gy), the inferior portion of the bladder (e.g., trigone area) also receives ≥70 Gy. This tends to be well tolerated with respect to bladder toxicity. Arguably, the urinary toxicity that does develop after radiation is due in part to the prostatic urethra receiving suprathreshold doses.

Factors Affecting Risk. Prior pelvic surgery can result in increased risk of bladder toxicity as a direct result of bladder or urethral trauma and/or denervation of the bladder, which can cause urinary hesitancy or retention, resulting in overflow incontinence.⁴⁰⁸ Patients receiving anticoagulants may be at greater risk of hematuria. Cytoxan, independently or with radiation, can cause chronic hemorrhagic cystitis, incontinence, contractions, and vesicoureteral reflux. Radiation-sensitizing chemotherapy may increase risk of acute and late bladder toxicity, though data supporting this are lacking.

Mathematic/Biologic Models. Quantitative mathematic modeling of bladder toxicity is lacking.

Special Situations. Stereotactic body radiotherapy for prostate cancer is an emerging investigative approach. In one study, after SBRT (7.25 Gy × 5), grade 1 to 2 genitourinary toxicity occurred in 28% and grade 3 toxicity was reported in 3% of patients (two patients required cystoscopies and dilatation procedures for dysuria⁴⁰¹). Urinary incontinence, complete obstruction, or persistent hematuria was not observed. In another study, after SBRT (9.5 Gy × 4), acute grade 1 to 2 and 3 acute genitourinary toxicity occurred in 71% and 0% of patients, respectively, and grade 1 to 2 and 3 late acute genitourinary toxicity occurred in 11% and 5%, respectively; grade 3 toxicity included temporary urinary catheterization and intermittent self-catheterization.⁴⁰²

Recommended Dose–Volume Limits. For whole-bladder radiation, the reported risks of grade 3 or higher toxicity in doses of 50 to 60 Gy range from ≤5% to 40%. This variation is likely attributable to the challenges of correlating toxicity with dose delivered to a mobile structure, which is even more problematic when correlating partial volume exposures to toxicity. With the caveat of these issues, bladder constraints of ~15%, 25%, 35%, and 50% receiving ≥80 Gy, ≥75 Gy, ≥70 Gy, and ≥65 Gy, respectively, as recommended in the RTOG 0415 study of prostate cancer, are suggested. The protocol advises an empty bladder at the time of simulation and treatment; the bladder is segmented from the base to the dome.

Future Studies. Studies that incorporate the changing size and shape of the bladder may provide a better understanding of the dose–volume tolerance of the bladder. Incorporating day-to-day variation with adaptive planning DVHs and/or use of deformable modeling would be informative. More detailed studies are needed to assess regional variation in radiation susceptibility (i.e., trigone vs. dome).

Toxicity Scoring Criteria. The CTCAE v. 4.0 or RTOG scoring criteria can be used to grade genitourinary toxicity.

Penile Bulb

Clinical Significance. Radiation dose to the penile bulb can affect erectile function, as a direct result either of damage to this structure or of damage to surrounding structures, whose radiation-induced damage is correlated with the dose exposure of the penile bulb. The most common scenario in which the penile bulb is irradiated is in the treatment of prostate cancer. IMRT is often used to minimize the dose to the penile bulb.^409,410

Endpoints. Erectile dysfunction reported by the patient can be the result of treatment or other confounding factors including age, medications (particularly hormonal therapy), or comorbid conditions (e.g., diabetes, peripheral vascular disease, hypertension). Objective diagnostic tests can be performed to help establish the etiology of erectile dysfunction; these include nocturnal penile tumescence, somatosensory evoked potentials, bulbocavernous reflex latency, penile electromyography, color duplex Doppler ultrasound, dynamic infusion cavernosometry, and pharmacologic testing.

Challenges Defining Volumes. The anatomy of the pelvic floor is challenging to visualize on CT or MRI and hence definition of the penile bulb is somewhat subjective. The QUANTEC authors recommend defining the penile bulb as the most proximal portion of the penis sitting immediately caudal to the prostate.⁴¹¹

Dose/Volume/Toxicity Data. Several studies have investigated dose–volume parameters to predict risk of erectile dysfunction. In several studies, no correlation was discerned for penile bulb dose and erectile function.^409,412,413 In one study attempts were made to reduce the dose to the penile bulb (mean dose of 25 Gy), and thus, few patients received high dose to the penile bulb.⁴⁰⁹ In another study of 70 patients, no correlation was found for mean dose or maximal dose to the penile bulb, penile crura, or superiormost 1 cm of the penile crura; DVHs were also compared and found to be similar.⁴¹³

In a small (21 patients), early study from University of California, San Francisco, patients receiving a D₇₀ of <40%, 40% to 70%, and >70% to the penile bulb had a 0%, 80%, and 100% risk, respectively, of experiencing radiation-induced impotence.⁴¹⁴ In a study (29 patients) from Thomas Jefferson University, several dose–volume metrics were analyzed; a D₃₀ >67 Gy, D₄₅ >63 Gy, D₆₀ >42 Gy, and D₇₅ >20 Gy to the proximal penis were correlated with increased erectile dysfunction as well as decreased ejaculatory function.⁴¹⁵ In a study from Royal Marsden Hospital, a D₉₀ >50 Gy to the penile bulb was associated with significantly worse erectile function, while D₁₅, D₃₀, and D₅₀showed a similar (albeit not significant) trend toward increased doses in impotent versus intermediately potent versus potent patients.⁴¹⁶ The largest study (158 patients) to date to investigate penile bulb dose is an analysis of the RTOG 9406 dose-escalation study.⁴¹⁷ A median dose of ≥52.5 Gy was associated with a greater risk of impotence (50% vs. 25% at 5 years).

Factors Affecting Risk. The etiology of erectile dysfunction following radiation is likely multifactorial. In additional to radiation effects, pretreatment erectile function, diabetes, smoking history, and a history of hypertension have been implicated as important factors affecting risk, though the data to date have been somewhat conflicting.⁴¹⁶

Special Situations. Hormonal therapy, which is commonly used in patients with early-stage intermediate- to high-risk prostate cancer or advanced-stage prostate cancer, in and of itself can result in erectile dysfunction. However, the interaction (if any) of hormonal therapy and dose–volume delivery to the penile bulb is not well established.⁴¹¹ Proton therapy is a well-established treatment approach for prostate cancer and is becoming more widely utilized as more proton centers are developed. While proton therapy can reportedly lower penile bulb dose, the impact on erectile dysfunction is unknown.⁴¹⁸ Proton therapy may reduce postradiation testosterone suppression.⁴¹⁹ Interstitial brachytherapy (either with high–dose-rate sources using afterloaded catheters or with permanent low–dose-rate seeds) is a standard radiation modality as well. Data correlating erectile function with penile bulb dose from brachytherapy are sparse. In one study, there was no correlation between the penile bulb dose and postbrachytherapy erectile dysfunction.⁴²⁰ Stereotactic body radiotherapy for prostate cancer is an emerging investigative approach. The impact of hypofractionated SBRT on erectile dysfunction or the dose–volume parameters predictive of risk after prostate SBRT are not well studied. In one small study of 32 patients, penile bulb dose did not correlate with erectile dysfunction.⁴²¹

Recommended Dose–Volume Limits. Based on published data for photon external-beam radiation, the QUANTEC authors recommend keeping the mean dose to 95% of the penile bulb below 50 Gy, and limiting D₇₀ and D₉₀ to 70 Gy and 50 Gy, respectively.⁴¹¹

Future Studies. Studies should be directed at better anatomic definition of the putative anatomic sites impacted by erectile dysfunction and rigorous prospective correlation of dose–volume parameters with erectile dysfunction.

Toxicity Scoring Criteria. Pre- and posttreatment assessment of erectile dysfunction should be performed using the International Index of Erectile Function Scale.⁴¹¹

FIGURE 13.15. Composite diagram of normal tissue complication rates versus mean radiation dose.

 COMPOSITE SUMMARY OF DOSE/VOLUME/OUTCOME DATA

Table 13.11 summarizes the dose/volume/outcome findings in the QUANTEC reviews. Note that clinicians must understand the clinical situations from which the QUANTEC recommendations were derived, and there is no substitute for reading the original QUANTEC papers. At the same time, clinical judgment as applied to a specific patient is essential. In addition to the QUANTEC papers, the Emami paper continues to play an important role in estimating normal tissue toxicity during radiotherapy. Finally, as more comprehensive dose/volume/outcome data are developed—particularly in combination with emerging and evolving chemotherapy regimens—the radiation oncologist will need to continually and critically keep abreast of the clinical literature on normal tissue toxicity.

 CLINICAL APPLICATION, LIMITATIONS, AND IMPLICATIONS OF QUANTEC

Implications for Understanding the Underlying Mechanisms of Radiation-Induced Normal Tissue Injury

The consistent structure of the Emami dose–volume limits, and the application of that information to predictive models, may be taken to imply a uniform mechanism of radiation-induced injury. The diversity of the structure of the information obtained in the QUANTEC review suggests a more diverse mechanism of radiation-induced injury. An interorgan comparison of dose–response functions from the QUANTEC review is interesting (Fig. 13.15) and may have implications for our understanding of radiation-induced normal tissue injury.

1. There are marked variations in the dose–response curves for different organs, suggesting that there are different mechanisms for radiation-induced injury in different organs and/or that the endpoints selected for the different organs reflect a varied type of injury.

2. Organs that are classically considered structured in series (e.g., spinal cord, optic nerve, and small bowel, analogous to electrical circuits in series) have steep dose–response curves at doses beyond an apparent critical threshold. This is expected based on our understanding of the structure/anatomy of the series of organs: damage to a functional subunit can render the entire structure dysfunctional.

3. Several neural structures exhibit a similar threshold dose for injury: 55 to 60 Gy (corresponding to a BED of 100 for an α/β ratio of 3 Gy) for brain, brainstem, optic nerve, and spinal cord. This suggests that there may be a common mechanism of injury in these structures. Because all of these organs are dependent on the vasculature, it is tempting to implicate vascular injury as the common target for these organs.

4. Organs that are classically considered structured in parallel (e.g., lung, liver, parotid, and kidney, analogous to electrical circuits) experience injury at far lower doses and have more gradual dose–response curves compared to series organs. The presence of injury at lower doses suggests that a different mechanism of injury is occurring in these organs as compared to series organs. It appears that these organs each have critical components that are more sensitive to the radiation than are the critical components within the neuronal tissues. It is thus tempting to conclude that subunits such as hepatocytes, nephrons, and alveoli are relatively radiation sensitive.

5. During heterogeneous organ irradiation, the predictive value of mean organ dose in some parallel-structured organs is interesting but counterintuitive. Consider the lung. Relatively uniform fractionated whole-lung doses as high as 15 to 23 Gy have a very low risk of symptomatic pneumonitis. Thus, the lung’s “functional subunit” must generally be able to tolerate these doses. However, heterogeneous lung irradiation to a mean lung dose of 15 to 23 Gy is associated with a 10% to 25% risk of symptomatic pneumonitis. Thus, during heterogeneous lung irradiation, it is likely that the mean dose is merely a surrogate for the percent of lung exposed to various other doses of radiation. The same may be true in other parallel organs as well.

TABLE 13.11 QUANTEC SUMMARY: CLINICAL DOSE/VOLUME/OUTCOME DATA

    

 CONCLUSIONS

The QUANTEC effort is one further step in our field’s decades-long effort to better quantify the relationship between dose–volume parameters and clinical outcomes. As the scope of the QUANTEC review was largely limited to organ systems with meaningful dose/volume/outcome data, the review, by itself, is an incomplete tool to guide clinical care. Consistent and clear reporting of dose/volume/outcome data⁴²³ will enable further refinements in clinical guidelines and will hopefully improve patient care.

 ACKNOWLEDGMENTS

Supported in part by grants from the National Institutes of Health CA69579 (L.B.M.) and the Lance Armstrong Foundation (L.B.M.). Parts of this chapter were adapted from Rubin et al., ALERT: Adverse Late Effects of Radiation Therapy.

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