Muhammad Ali Chaudhry • Lujaien Al-Rubaiey Kadhim • Richard L. Wahl
A total of 40,250 new cases of head and neck cancers (HNCs) will be diagnosed in 2013, with a mortality rate of approximately 7,850 in the United States.1 Incidence rates are twice as high in men than they are in women, with the incidence in women declining 1% from 2004 to 2008.1 HNCs are categorized according to the area in which they begin—the oral cavity, pharyngeal, laryngeal, paranasal sinuses and nasal cavity, and salivary glands. It is a heterogeneous type of cancer with each site having its own set of symptoms and risk factors.2 A detailed description of staging of the different types of HNCs is available in the AJCC Cancer Staging Manual.3
Several risk factors contribute to the development of HNC, with tobacco and alcohol use implicated in 75% of cases2; the risk is 5- to 25-fold greater in smokers than in nonsmokers.4 Although the risk of developing HNC substantially decreases with smoking cessation, second-hand smoke has also been shown to be associated with HNC—particularly pharyngeal and laryngeal cancers.4 Alcohol, on the other hand, is related to a greater degree with cancers of the oropharynx, hypopharynx, and larynx.4
Infectious agents also play a role in HNC. Epstein–Barr virus (EBV) and Human papillomavirus (HPV) are the only two viruses that can reliably be implicated as risk factors for HNC.5 EBV seems to be associated with nasopharyngeal carcinomas whereas HPV accounts for approximately 50% of oropharyngeal carcinomas.5 Interestingly, the number of cases of HNC caused by HPV is on the rise in the United States, whereas the development of the disease caused by other causes is decreasing.2 Other possible risk factors for HNC include gastroesophageal reflux, ionizing radiation exposure,5 unhealthy diet, and low body mass index.6 In addition to the environmental risk factors described above, genetic predisposition might also affect the incidence of HNC. Although a history of alcohol and tobacco exposure are the dominant risk factors for HNC, genetic susceptibility may be equally important. Family studies have reported a three- to eight-fold increased risk of HNC in first-degree relatives of patients with HNC.7 In addition to familial predisposition, several genetic polymorphisms involved in carcinogen metabolism, alcohol cell cycle control, and alcohol metabolism have been identified and associated with an increased risk for HNC, namely GSTM1-null genotype, GSTT1, EPHX1 genes and ALDH2*1/*2, p53 codon 72 Pro/Pro and EPHX1 codon 113 Tyr/His, and His/His genotypes.8,9
Early symptoms may be nonspecific, such as a lump or sore throat that does not heal, difficulty in swallowing, and a voice change or hoarseness.10 Diagnosis, however, is often made at a late stage of the disease when patients clinically present with a neck mass, pain, dysphagia, odynophagia, partial airway obstruction, foreign body sensation, cranial neuropathies, or trismus.11 As is the case in signs and symptoms, treatment options are variable and depend on the site of cancer, making HNC one of the more complex cancers to treat.
Appropriate surgical procedures, radiation targets, and indications for chemotherapy are guided by the specific site of the disease, stage, and pathologic findings.12 Approximately 30% to 40% of patients who present with stage I or stage II disease will most likely receive single-modality treatment with surgery or radiotherapy, whereas combined-modality therapy is generally recommended for the remaining 60% of patients with locally or regionally advanced disease.12
Unresectable tumors are defined as tumors that cannot be removed or locally controlled after surgery, as well as tumors that cannot be removed without causing unacceptable morbidity, and primary tumors of patients with distant metastasis.12 Typically, these tumors involve the cervical vertebrae, brachial plexus, deep muscles of the neck, or carotid artery.12 Conversely, patients with resectable tumors may or may not undergo surgery. Definitive treatment with radiotherapy, with or without chemotherapy, may pose as a better option than surgery in some patients.10,12,13
Typically, a comprehensive or selective cervical nodal dissection will be performed along with primary tumor resection. Comprehensive neck dissection removes all lymph node groups and is often recommended for N3 disease.12Selective neck dissection takes into account the fact that there is a common pathway for the spread of HNC to regional nodes and is often recommended even for N0 disease.12 Lesions of the oropharynx, hypopharynx, nasopharynx, and larynx are usually managed by neoadjuvant therapy first in order to control the tumor and preserve organs.14 Salvage surgery and neck dissection may then be indicated as a second line of treatment for patients who did not have a complete clinical response to neoadjuvant therapy.10,12,13 Adding surgical resection of the residual mass following induction chemotherapy to the treatment plan has been reported to improve overall survival in patients with advanced stage disease who achieve less than 90% partial response to the neoadjuvant chemotherapy.15
Over the years, radiotherapy has become an increasingly important modality in the treatment of head and neck malignancies. Intensity-modulated radiation therapy (IMRT) has revolutionized the treatment of a variety of malignancies including HNCs. It has led to minimizing damage to adjacent normal/nondiseased organs.
Natural history, anatomy, and clinical findings continue to guide radiotherapy planning. The selection of radiation dose depends on the primary tumor and measurements of gross adenopathy.12 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and positron emission tomography/computed tomography (PET/CT) helps to delineate primary tumor volume (gross tumor volume [GTV]). This was traditionally based on anatomical imaging (e.g., CT, magnetic resonance imaging [MRI]); however, more and more centers are using PET/CT to determine GTV (Fig. 2.1). A reduction in the size of the GTV has been demonstrated in a landmark study by Daisne et al.16comparing the role of co-registered CT, MRI, and 18F-FDG PET in GTV delineation of laryngeal cancer in patients scheduled for laryngectomy. 18F-FDG PET was closest to depict the true tumor volume compared to the reference surgical specimen. All modalities overestimated the extension of the tumor, with an average of 29%, 65%, and 89% for 18F-FDG PET, CT, and MRI, respectively. However, all three imaging modalities, including 18F-FDG PET, failed to identify a small fraction of the macroscopic tumor (approximately 10%), mainly superficial mucosal extensions.17
Postoperative irradiation, on the other hand, is determined by stage, histology, and pathologic findings and is generally recommended for patients with advanced disease, multiple positive nodes, and perineural/lymphatic/vascular invasion.10,12,18
FIGURE 2.1. Planning CT (A), corresponding 18F-FDG PET scan (B), and fusion image (C) from a 46-year-old patient with locally advanced nasopharyngeal carcinoma. Notice differences in target volume delineation whereby CT gross tumor volume (GTV) delineation (red ) overestimates the PET-GTV (yellow ).
Chemotherapy alone is rarely used to treat patients with HNC; still, it may be used in combination with radiation therapy to enhance its therapeutic effects.10,19 Some of the most commonly used chemotherapy agents include cisplatinum, carboplatinum, and taxane. Studies have shown that concomitant chemoradiation (e.g., cetuximab) increases survival time and reduces the risk of recurrence.10,19 This advantage, however, does not come without costs, as chemoradiation causes severe adverse effects, and as such, is not recommended for patients who are less fit or with metastatic disease.10,19
Progress in molecular biology and immunology has led to a biologic approach to the treatment of HNC. In this setting, molecules that play a role in the development and maintenance of cancerous cells are targeted for treatment directed at growth factors, receptors, inducing apoptosis, or regulating the antitumor immune response.20 For example, the antitumor immune response may be enhanced by harvesting and activating patients’ lymphocytes (specifically, T-cells) in vitro, then introducing them back into the patients as a vaccination.21 Alternatively, dendritic cell vaccines may also be used, as dendrites have the ability to initiate a primary immune response.21 Epidermal growth factor receptors (EGFR) are overexpressed in many patients with HNC, leading to cellular resistance to radiotherapy and poor prognosis.22 Thus, EGFR inhibitors have been used in combination with chemoradiotherapy for the treatment of HNC.22 Currently, the most commonly used antibody targeting EGFR is cetuximab which is FDA approved for patients with recurrent or metastatic HNC; other agents under study include hR3, matuzumab, panitumumab, gefitinib, and erlotinib.23 However, HNC is a highly heterogeneous disease with each subtype responding differently to treatment, including biologic therapy. In addition, the complexity of HNC renders it difficult to achieve disease control by targeting only one molecular pathway; as such, it may be worthwhile to use these biologic agents with conventional therapy in combinations tailored to the patient depending on the location and staging of HNC.
Carcinomas of Paranasal Sinus and Nasal Cavity
The standard mode of treatment for paranasal sinus and nasal cavity cancers is a combination of radiotherapy and surgery. Surgery usually consists of fenestration with removal of the tumor bulk, resection of the floor of the anterior cranial fossa in selected patients, and removal of the eye if the orbit is extensively invaded by cancer.24 High-dose radiation (up to 74 Gy) is typically indicated when there are sufficient grounds to expect permanent control, with treatment volume encompassing the maxillary antrum and involved hemiparanasal sinus and contiguous areas.25
The principal treatment of nasopharyngeal carcinoma for the primary lesion site and the neck is high-dose radiotherapy with chemotherapy.26 The location and size of the primary tumor and lymph nodes dictate the dose and field margins of radiotherapy; usually consisting exclusively of external beam radiotherapy.26 Surgery in patients with nasopharyngeal cancer is reserved for nodes that fail to regress after radiotherapy or for nodal recurrence after complete clinical response.26 It is important to note that approximately 30% to 40% of patients receiving external beam radiotherapy to the entire thyroid gland or the pituitary gland develop hypothyroidism, making it essential to incorporate thyroid-function testing in the pre- and posttherapeutic evaluation of these patients.27
Carcinomas of Lips and Oral Cavity
Cervical node dissection in patients with lip and oral cavity carcinoma is usually performed if regional nodes are positive with the possibility of achieving good functional results following ablation of large posterior oral cavity tumors.28 Large primary lesions, regional lymph nodes, and bulky nodal metastasis are managed by external beam radiotherapy, with or without interstitial implantation.28 For early stage cancers, the type of treatment is determined by the predicted functional or cosmetic results, typically consisting of surgery or radiotherapy with high cure rates.28 Consideration of the impact of therapy on the quality of life must also be evaluated and prosthodontics and rehabilitation are equally as important as treatment in patients with lip and oral cavity cancer.
Unlike other sites of HNC, the literature on the treatment of oropharyngeal cancer lacks comparisons between the different treatment options and, as a result, there is no single treatment that can reliably be identified as superior to other therapeutic regimens.2 The choice of treatment thus is determined by stage and the physical and emotional condition of the patient.2
Carcinoma of Salivary Gland
Superficial parotidectomy is performed for low-grade malignancies of the superficial portion of the parotid gland whereas total parotidectomy is indicated for all other types of lesions.25 Accumulating evidence suggests that surgical resection can be enhanced by postoperative radiotherapy for high-grade tumors when margins are involved, for large tumors, and for cases of lymph node metastasis.25
With the exception of early stage disease, treatment primarily involves surgery followed by postoperative radiation therapy. Some early stage disease can be successfully treated with radiotherapy alone whereas combined-modality treatment is considered for patients who present with stage III or stage IV disease.29 Some studies report that combined radiotherapy and chemotherapy offer better tumor control with tissue preservation than does radiotherapy alone.30 Furthermore, patients with resectable advanced-stage disease should undergo neoadjuvant therapy while preserving the larynx.31
Radiation therapy may be preferred for superficial cancers without laryngeal fixation or lymph node involvement in order to preserve the voice; surgery is typically preserved for salvaging failures.32 Some curative surgical procedures, however, are also capable of maintaining vocal function.32 The selection of appropriate surgery must take into account the anatomic problem and performance status. As is the case with hypopharyngeal cancer, advanced-stage laryngeal cancer is often treated with combined radiotherapy and surgery.25 However, the cure rate for advanced tumors is low and as such, it is recommended that the patient be placed into clinical trials of chemotherapy, hyperfractionated radiotherapy, radiation sensitizers, or particle beam radiotherapy.25
IMAGING IN HEAD AND NECK CARCINOMAS
PET/CT Imaging in Head and Neck Cancer
Clearly, the choice of treatment for HNC requires careful evaluation in order to select the optimal treatment for each individual patient. It is thus essential to utilize the tools available through advances in technology. Contrast-enhanced Computed Tomography (CE-CT) is, to date, the initial study in the assessment of HNC.33 CT scanning is generally preferred over MRI to assess lymphadenopathy because of higher accuracy at lesser cost and shorter study time.33 MRI, on the other hand, is used to evaluate tumor spread to areas closer to the skull base.33 These methodologies, however, have some limitations. For example, CT images have poor soft tissue contrast and MRI is susceptible to artifacts. In addition, the utility of both anatomic modalities for nodal staging in HNC is debatable and anatomic restaging becomes increasingly difficult following postoperative and postchemoradiotherapy changes to normal anatomic structures. As a result, fused imaging using PET/CT has become increasingly popular.34
PET/CT combines anatomical and functional data into a single image, allowing for accurate localization of metabolic abnormalities by way of an IV-injected radiotracer.34 The most commonly used radiotracer is a glucose analog, 18F-fluorodeoxyglucose (18F-FDG)34 – PET/CT in this review refers to the use of 18F-FDG unless otherwise specified. Quantification of tumor glucose uptake is typically measured as a standard uptake value (SUV) with tumors exhibiting significantly greater SUV than normal tissue.34 PET/CT scanning offers the advantage of a whole-body scan in one session. In addition to planning treatment, it may be used in various stages for the management of HNCs.
Detection of Unknown Primaries
In approximately 10% to 15% of patients with head and neck squamous cell carcinoma, the source of the disease may remain obscure despite clinical, radiographic, and endoscopic evaluation.35 PET/CT may guide surgeons to the potential source of the primary tumor and thus reduce morbidity associated with radiation of the entire pharyngeal mucosa, larynx, and bilateral neck should the primary site remain unknown.35 In general oncology, only 20% to 27% of metastatic cancer of unknown primary (CUP) origin is detected by conventional radiologic methods (e.g., ultrasonography, CT, MRI, and PET alone).36 Typically in HNC, patients will present with a pathologically confirmed enlarged cervical lymph node in which conventional imaging has failed to localize the primary tumor site.37 In a study by Nanni et al.,36 18F-FDG PET/CT scans were obtained for patients with proven metastatic disease and negative conventional diagnostic procedures; PET/CT detected occult primary tumors in 57% of cases, while failing to identify the primary malignancy in 39% of cases. Although it seems like a low value, the sensitivity of 57% for PET/CT is better than the sensitivity of 24% to 40% described in literature for conventional imaging in the detection of unknown primaries (Table 2.1).36
A meta-analysis of studies published between 2000 and 2009 evaluated the utility of PET/CT specifically to detect unknown primary tumors in patients with cervical lymph node metastasis and negative standard work up.40PET/CT detected the primary tumor in 28% of patients, with 30/180 false-positive lesions.40 The authors concluded that PET/CT may thus be recommended in the initial work up of CUP.40 Two recent studies corroborated the usefulness of PET/CT to detect unknown primaries in HNC. In a study by Roh et al.,43 patients with cervical metastasis of CUP were evaluated with head and neck CT and whole-body 18FDG PET/CT. PET/CT was significantly more sensitive to detect occult primary tumors in comparison to CT with a reported sensitivity of 87.5% versus 43.7%, respectively. The second study also evaluated patients with CUP and reported the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 18FDG PET to be 87%, 68%, 61%, and 90%, respectively, with only three false negatives and 13 false positives.38 Furthermore, PET scans resulted in a therapeutic change in 25% of patients due its ability to localize the primary tumor.38 Therefore, combined PET/CT is a useful primary screening method to detect occult primary tumors presenting with metastatic neck lesions and should be considered in routine clinical practice (Fig. 2.2).
STUDIES EVALUATING THE PERFORMANCE OF PET/CT FOR THE DETECTION OF UNKNOWN PRIMARIES IN HNC FOLLOWING NEGATIVE CONVENTIONAL WORK UP
Treatment selection for a given patient depends on the TNM staging, and as such, precise staging is a crucial aspect of therapy planning in HNC. Conventional staging typically involves physical examination, endoscopy, and contrast-enhanced CT scan of the head, neck, and chest. MRI is reserved for the assessment of oral cavity and paranasal sinus cancers. These conventional techniques rely solely on abnormal morphologic features of the tumor that may be missed because of the presence of microscopic tumors in a structurally normal organ.39 Alternatively, PET/CT assesses the physiologic properties of the tumor in addition to its structural properties and can reliably provide information regarding the primary tumor, nodal metastasis, distant metastasis, and potential second primary tumors.
Several studies have demonstrated that 18F-FDG PET is at least as sensitive as MRI for the detection of primary tumors, whereas the combination of PET/CT can provide more useful information with higher sensitivity.40 Dammann et al.41 evaluated the efficacy of 18FDG PET, CT, and MRI for preoperative evaluation of HNC. Patients with histologically proven squamous cell carcinoma of the oral cavity and oropharynx were recruited for the study.41 18FDG PET correctly detected 86% of tumors; 75% of the tumors missed were less than 10 mm in diameter.41 MRI performed slightly better overall in comparison to CT and PET, with a reported sensitivity, specificity, and accuracy of 92%, 63%, and 88%, respectively, in comparison to 61%, 100%, and 66%, respectively, for CT and 87%, 63%, and 84%, respectively, for PET.41 The low specificity of PET may reflect its disadvantages compared to structural imaging, which can be overcome by combined PET/CT scanning (Fig. 2.3A,B). In another prospective study, patients with suspected primary HNC cancer underwent diagnostic and imaging procedures including panendoscopy, biopsy, PET, CT, and color-coded duplex sonography (CCDS).42 PET had the highest overall sensitivity and specificity for primary tumor detection, 95% and 92%, respectively.42 However, false-negative PET results were found in cases of small metastatic lymph nodes located close to the primary tumor. Despite these false negatives, the usefulness of PET for primary tumor evaluation was found to be similar to the “gold standard” panendoscopy whose sensitivity and specificity were 100% and 85%, respectively; although the authors concluded that panendoscopy is still the first-choice procedure to detect primary tumors because of its ability to assess the upper aerodigestive tract whereas PET is better at detecting recurrence.42 CT and CCDS performed poorly in comparison to PET, with a reported sensitivity of 68% and 74%, respectively, whereas specificity was 69% and 75%, respectively.42
FIGURE 2.2. A 45-year-old male with newly found cervical lymphadenopathy and subsequent biopsy showing squamous cell carcinoma with an unknown primary. PET/CT required for diagnosis of primary site and staging. Coronal CT image (A), corresponding coronal PET/CT (B). The FDG PET/CT scan demonstrates intense focal FDG uptake within the right fossa of Rosenmuller (SUVmax, 13.6); the underlying soft tissue mass, approximately measuring 1.4 × 1.9 cm, is the site of primary malignancy (white arrow ).
More recent studies compared hybrid PET/CT to conventional imaging methods for primary tumor staging. Deantonio et al. studied patients with proven HNC, all of whom underwent PET/CT scanning and routine CT simulation. Typically, simulation CT uses low current/voltage parameters with much reduced diagnostic capabilities. Clinical staging was analyzed by comparing findings of PET/CT with CT alone.44 PET/CT correctly identified all primary tumors and resulted in a change in clinical stage in 22% of patients in comparison to CT alone.44 These results, however, were based on a very small sample size. Roh et al.45 tested PET/CT in a much larger population of patients with untreated HNC. All patients were evaluated by CT, MRI, PET, and/or PET/CT.45 PET and PET/CT correctly identified the primary tumor in 97% of patients, with equal sensitivities reported for both modalities, 98% versus 97%, respectively, and only four false negatives.45 In contrast, the pooled accuracy for detecting primary tumors using CT and MRI was 87%, with 20 unidentifiable tumors, 16 of which were successfully detected by PET/CT.45 The authors concluded, contrary to most literature, that PET/CT scanning does not offer significant advantage over PET alone for the staging of primary tumors in HNC. Another study, however, compared fused PET/CT to PET alone for primary tumor detection in patients with nasopharyngeal carcinoma.46 PET/CT was found to be superior to CT alone and PET alone, with a reported sensitivity and accuracy of 90% each for PET/CT, 75% each for PET alone, and 75% each for CT alone (Table 2.2).46
At initial presentation, approximately 45% of patients with HNC have regional nodal metastasis (Fig. 2.3C–D).37 Cervical lymph node metastasis (LNM) is an important prognostic indicator in patients with HNC and is typically evaluated using radiologic imaging. The detection values of cervical LNM are similar with CT and MRI (1.5T scanner), with reported sensitivities ranging between 14% to 80% for CT and 29% to 85% for MRI.37 Several studies evaluated PET/CT in light of nodal involvement detection in HNC.
Schwartz et al.47 evaluated patients with squamous cell carcinoma of oral cavity, oropharynx, larynx, and hypopharynx; all patients underwent preoperative FDG PET with contrast-enhanced CT scans. Histologic findings served as a tool to evaluate the effectiveness of PET/CT and CT alone for nodal staging. PET/CT was found to be superior to CT with reported sensitivity and specificity of 96% and 98.5% for PET/CT and 78% and 98% for CT, respectively.47 Furthermore, PET/CT was able to detect nodal disease thought to be negative on CT scans alone and agreement between scan results and pathologic findings were stronger for PET/CT than for CT.47 These findings are in line with those of Murakami et al.48 who also compared PET/CT and CT alone for detection of nodal involvement in various types of HNC and reported a sensitivity, specificity, and accuracy of 84% versus 68%, 99% versus 94%, and 96% versus 89%, respectively.
How to proceed when a PET/CT reveals a negative scan for nodal disease is still a matter of debate. PET/CT is generally viewed as the method of choice to stage HNC cancer, with the exception of staging patients with N0 neck; that is, no identifiable metastatic disease on physical examination or other diagnostic procedures.49 PET/CT may reveal false-positive or false-negative results when metastatic disease is not suspected or identified by physical examination or other diagnostic procedures.49 Several studies evaluated the role of PET/CT in patients with oral cancer staged N0 by clinical examination. One such study reported 53/72 false negatives and 11/72 false positives, resulting in a sensitivity and specificity of 26% and 99%, respectively, for PET/CT identification of nodal disease.50 Because of the high rate of false negatives from PET/CT evaluation, it is not recommended that treatment decisions be based on a negative PET/CT scan. Conversely, a positive PET/CT test can reliably diagnose metastatic disease with a high PPV (Table 2.3).
The incidence of metastases in HNC is relatively low, approximately 2% to 18% of cases, with rates tending to increase as the disease advances, especially in patients with primary malignancy of the hypopharynx and nasopharynx.39Screening for metastasis is, therefore, reserved for patients with locally advanced disease. Conventional work up for M staging includes chest radiography, abdominal ultrasonography, and skeletal scintigraphy.51 The combined sensitivity of these conventional techniques in detecting metastasis is reported to be 32.8% only.51 In a recent meta-analysis, PET/CT was compared to PET alone and CT alone.51 As expected, PET/CT was found to be superior to either modality alone (CT or PET). Of additional interest is the finding that 3.0T whole-body MRI and PET/CT had comparable sensitivities and specificities; indicating that 3.0T MRI might aid staging of M disease in the future.51,52
FIGURE 2.3. A 41-year-old male with newly diagnosed laryngeal carcinoma. PET/CT was indicated for staging purposes after suspicion of nodal metastases on CT. Axial PET (A) and fused PET/CT (B)demonstrate intensely FDG-avid laryngeal mass (SUVmax, 19.5), consistent with the patient’s primary malignancy (black and white arrows). Intensely avid right cervical lymphadenopathy is also noted involving level II and level III on axial PET (C) and fused coronal PET/CT (D) (black and white arrows ).
18FDG PET has been shown to be useful in defining perineural spread as well as osseous extension of the primary tumor.35 Perhaps the role of 18F-FDG PET/CT is strongest when evaluating its potential to detect metastatic disease (Fig. 2.4A–F). Chua et al.53 compared conventional work up, CT, PET, and PET/CT in their ability to detect metastases in patients diagnosed with nasopharyngeal carcinoma. PET/CT was found to be superior to the other three modalities, especially in comparison to conventional methods; the sensitivity, specificity, and accuracy are summarized in Table 2.4.53 These findings are supported by several other studies,52,54–56 all reporting a significant discrepancy between the sensitivity of PET/CT and conventional techniques in M staging.
In addition to detecting distant metastasis, PET/CT is also recommended for the detection of second primary tumors that, unlike metastasis, are typically present in patients with early stage disease.37 Patients with HNC are at an increased risk to develop second synchronous tumors in the upper aerodigestive tract because a large majority of patients consume alcohol and nicotine heavily.57 Evaluating additional foci of FDG uptake with PET/CT allows early detection of second primaries and, consequently, affects the therapeutic plan.35 Furthermore, PET/CT offers a whole-body scan, making it an attractive choice to evaluate patients with suspected metastasis and/or second primary tumors. To date, standard methods to stage second primary tumors of HNC include panendoscopy and radiologic imaging, namely contrast-enhanced CT.58 A large study of 589 consecutive patients assessed the ability of PET/CT to detect synchronous primaries in the initial work up of patients with proven head and neck squamous cell carcinoma.57 PET/CT detected 84% of the second tumors confirmed pathologically; which led to a change in therapy in 80% of patients.57 There was a small number of tumors not detected by PET/CT, however, PET/CT will not replace endoscopy to evaluate small and superficially growing tumors in the aerodigestive tract; the majority of tumors can be detected by PET/CT to a greater degree than conventional imaging.57
STUDIES EVALUATING THE PERFORMANCE OF FDG PET/CT IN COMPARISON TO CONVENTIONAL METHODS FOR T STAGING OF PRIMARY TUMORS IN HNC
STUDIES EVALUATING THE PERFORMANCE OF FDG PET/CT IN COMPARISON TO CONVENTIONAL METHODS FOR N STAGING IN HNC
FIGURE 2.4. Axial CT (A) and axial-fused PET/CT (B) of a 56-year-old female with a history of T4 squamous cell carcinoma of the floor of the mouth. FDG PET/CT was obtained for the purposes of staging. Scan demonstrates intensely FDG avid mass in the anterior floor of the mouth (white arrow ). Intensely FDG-avid centrally necrotic bilateral cervical lymphadenopathy also noted involving levels I–IV (red arrows). Coronal PET (C) and axial-fused PET/CT (D) show moderate to intensely FDG-avid omental thickening with scattered foci noted in the lower abdomen and pelvis (black and white arrows). Axial PET (E) and axial-fused PET/CT scan (F) also demonstrate intensely FDG-avid left common iliac lymph node along with the left para-aortic lymph node (black and white arrows).
STUDIES EVALUATING THE PERFORMANCE OF FDG PET/CT IN COMPARISON TO CONVENTIONAL METHODS FOR INITIAL M STAGING IN HNC
STUDIES EVALUATING 18F-FDG PET/CT FOR THE DETECTION OF SECONDARY PRIMARY TUMORS IN HNC
In a similar comparison between PET/CT and panendoscopy, it was reported that PET/CT had a slightly higher sensitivity to detect second primaries; with a sensitivity of 100% and specificity of 93.8%, for PET/CT versus 74% and 99.7%, respectively, for panendoscopy.58 The higher specificity of PET/CT was partly because of detecting lesions outside the area of coverage of panendoscopy (Table 2.5). Early detection of these second primary tumors, as well as accurate staging of HNC is paramount for the selection of appropriate treatment. Examinations by PET/CT should thus be evaluated with care as their interpretation will dictate patient management.
External beam radiation therapy is the most widely used conventional treatment in HNC.59 However, because of the proximity of anatomical structures in the head and neck, conventional radiotherapy targets both malignant and normal tissue, leading to a high probability of healthy tissue loss.59 Nonimage-guided radiation therapy further exposes normal tissue to radiation beams as the location of tumors and landmarks are inferred.60 Image-guided radiotherapy (IGRT), on the other hand, reduces the size and frequency of geometric uncertainty (Fig. 2.1).60 Technical precision, however, is still an issue and as such, IMRT, which minimizes radiation to healthy tissue, was introduced for the treatment of HNC.59
Traditionally, clinical target volume selection (CTV) was almost exclusively based on anatomic imaging and physical examination of the primary tumor and affected nodes. Although standard anatomic radiotherapy planning still consists of the use of CT and MRI, it does have several shortcomings. Interobserver variability in GTV delineation is a source of major concern, possibly caused by the difficulty in determining the exact boundary of a tumor by using CT.61 This problem with CT scans results in images that poorly differentiate between soft tissue structures and tumor extensions. There has been a growing interest in obtaining biologic information to complement the CT/MRI-based delineation; namely, by using 18F-FDG PET.62 Research regarding the use of PET in radiotherapy planning for HNC is still in its early stages, however, there is already evidence that radiation portals and planning target volumes (PTV) may be more accurately delineated with fusion PET/CT, with PET reportedly altering decision in approximately one-third of cases.35 Because PET has the capability of distinguishing metabolically active disease from surrounding tissue, it also has the potential to reduce interobserver variability in GTV delineation and localize tumors or diseased lymph nodes missed by anatomical imaging.62
IMRT allows for precise targeting and delivery of high-radiation doses to the primary tumor while minimizing radiation-induced damage to neighboring tissue.61,63 The introduction of this high-precision technology created the need for more-precise GTV delineation; and there have been several studies in literature that addressed this need specifically for cancer of the head and neck, and as such, HNC was one of the first applications of IMRT.61
An important study by Daisne et al.16 examined the differences between GTV delineation using PET, CT, and MRI and validated their accuracies by comparing the results of the three imaging modalities to surgical specimens. The study recruited 29 patients with stage II–IV squamous cell carcinoma of the oropharynx, hypopharynx, or larynx.16 There were no significant differences between CT-based GTV and MRI-based GTV delineation, whereas GTVs delineated with 18FDG PET were smaller in average compared to the other two modalities.16 Interestingly, even though PET-GTVs were smaller, they did not completely encompass the areas delineated by CT and MRI.16 With respect to surgical specimen, the GTV was even smaller than all three modalities, GTV at 18FDG PET being 16.3 cm in comparison to 12.6 cm of the surgical GTV.16 Of interest as well, CT, MRI, and PET all overestimated tumor extension and all three modalities failed to detect macroscopic tumor extensions.16 It is important to note, however, that GTV-PET was the closest imaging-derived GTV to the reference volume assessed from the surgical specimen; highlighting PET’s potential role in radiotherapy planning of HNC.16 Limited spatial resolution of PET, however, might lead to reduced sensitivity in targeting small lesions not identified by PET. This limitation is overcome by acquiring a combined CT and PET imaging (PET/CT).
Deantonio et al.44 contoured GTVs on CT, PET, and PET/CT for 22 HNC patients who were candidates for radiotherapy; the resulting volumes were analyzed and compared.44 In concordance with Daisne et al., PET-delineated GTVs were smaller than their CT counterparts, however, PET/CT-GTV were significantly greater than CT-GTV.44 Scarfone et al.64 also reported greater PET/CT-GTVs in comparison to CT-GTV, presumably because of the PET inclusion of 18FDG active regions missed by anatomical CT scanning. As was the case in Daisne et al., PET-derived volumes and CT-derived volumes did not completely overlap; 82% of the primary tumor volume defined by PET was entirely contained in the CT-GTV, whereas only 76% of PET-derived nodal volume was entirely contained in the nodal CT-GTV.64 Literature, however, is inconclusive with several other studies reporting smaller PET/CT GTVs compared to CT-GTVs47 and others reporting larger PET/CT GTVs in comparison to CT-GTVs.65
It is important to interpret the above results with caution, however, since false positives with PET/CT can still pose as a problem due to 18FDG being a nontumor-specific tracer. Also, the reported smaller GTVs might lead to a failure to target macroscopic tumor extensions. Conversely, larger GTVs based on PET/CT reported in some studies might reduce the possibility of geographic misses, thereby reducing tumor size more effectively and decreasing the probability of local recurrence.
A major source of imprecision in GTV delineation is interobserver variability.66 Riegel et al. assessed interobserver and intermodality variation analysis in 16 HNC patients. Four physicians contoured volumes for CT and PET/CT each. As was the case of mixed results in the studies described above, two physicians delineated PET/CT GTVs greater than CT-GTVs, whereas the other two physicians had fusion volumes smaller than CT volumes.66 Of great importance to the results of this study is the finding that all four physicians used their own methodology in delineating GTVs, with some physicians using contradictory methodology in comparison to the others.66 It is possible that some physicians do not know how to proceed when CT delineation is significantly different from delineation derived from PET; there is no consensus as to which modality should be given more weight.66 These findings highlight the importance of developing standard methodology to reduce observer variability. In a follow-up study, the four physicians were given a tutorial of PET/CT coregistered imaging and were asked to re-contour the images of the same 16 patients recruited for the previous study.67 Interobserver variability was significantly reduced, albeit not eliminated; nonetheless, marked improvement between the four observers was reported.67 A similar study examined interobserver variability between eight physicians across the same three modalities—PET, CT, and fused PET/CT.68 The authors reported a large range of volume as well as substantial variation between observers on all three modalities.68 Furthermore, mean CT volumes were larger than PET/CT volumes68; once again demonstrating the inconsistencies in the literature. Interestingly, the lowest interobserver reliability was found with contouring using PET/CT; contrary to the perception that tumor delineation with PET/CT would be more accurate and more consistent across physicians.68 This finding might be because of the lack of familiarity of the physicians with PET/CT delineation, due to the relatively recent introduction of fused PET/CT in oncology.68 Evidently, it is of utmost importance to develop standardized methods in PET/CT delineation in order to obtain the maximum potential of PET/CT.
Another reason for the varied PET-derived GTVs is segmentation. Due to PET’s low spatial resolution, identifying tumor borders using PET in many cases creates an indistinct visual of the tumor.69 As such, various methods have been developed for PET-GTV delineation; the most common being visual interpretation.69 The study compared five segmentation tools for 18FDG PET-GTV relative to CT-based GTV delineation.69 77 patients with stage II–IV HNC were recruited for the study, all of whom underwent scans in both modalities.69 The five PET segmentation tools were visual interpretation, 40% and 50% of the maximum tumor signal intensity, fixed SUV of 2.5, and the signal-to-background ratio method).69 Three key findings were highlighted by the authors. First, GTV-SUV of 2.5 failed to provide successful delineation in 35/77 patients.69 This finding might have partly been due to the substantial amount of background activity in the head and neck, resulting in poor differentiation of the boundaries between tumor FDG uptake and muscle metabolic uptake.69 Second, each segmentation tool resulted in marked differences on the PET-GTV.69 Third, greater than 20% of the PET-GTV were outside the CT-GTV domain in the majority of cases, regardless of the segmentation tool utilized.69
A more recent study assessed the performance of nine PET image-segmentation techniques in patients with pharyngo-laryngeal squamous cell carcinoma; these included five thresholding methods, level-set technique (active contour), stochastic expectation-maximization approach, fuzzy clustering-based segmentation (FCM), and spatial wavelet-based algorithm (FCM-SW).70 The discussion of the technical aspects of these PET delineation tools is beyond the scope of this chapter, however, for recent reviews, see Zaidi and El Naqa71 and Thorwarth et al.72 The segmentation results were compared to the 3D biologic tumor volume defined by histology.70 Four of the thresholding methods and the expectation-maximization overestimated the average tumor volume whereas the contrast-oriented thresholding method, the level-set technique, and FCM-SW underestimated it.70 Despite underestimation, the FCM-SW method was reportedly the most accurate technique in delineating the tumor as determined by comparison to the surgical specimen standard.70
New tools are continuously being developed because GTV delineation will ultimately affect the outcome of radiation therapy. Although the results of the above studies have shed some light on the methodologies for PET-based delineation, experience with implementing these tools in the research field is necessary before definitive conclusions can be made.
PET/CT radiotherapy planning images must first be co-registered with the treatment-planning CT. In order to reliably register the PET/CT to the CT image, it is preferable to perform the PET/CT scan in the treatment position; however, doing so is problematic and might cause a financial burden on the patient if they have to acquire another PET/CT for diagnostic/staging purposes as well. Ireland et al.73 recruited five patients with HNC, all patients underwent PET/CT in addition to conventional x-ray CT for radiotherapy treatment planning. The authors reported that nonrigid registration in the diagnostic position PET/CT resulted in a more accurate match to the planning CT, compared to rigid registration in the treatment position PET/CT.73 Furthermore, the nonrigid algorithm reduced the registration error significantly compared to rigid registration PET/CT of the treatment position.73 Despite the relatively small sample size, the study demonstrates quantitative evidence that nonrigid, diagnostic-position PET/CT registration is more accurate than a rigid transformation for radiotherapy planning. It is thus possible for some patients to undergo a single PET/CT session for both staging and radiotherapy planning purposes.73
A similar study evaluated the accuracy of both diagnostic-position PET/CT and stand-alone PET for radiotherapy treatment planning.74 The study included image data for 12 patients with HNC treated with external beam radiotherapy who underwent both diagnostic PET/CT scans and treatment CT scans.74 Registration accuracy was reported to be better for PET/CT than PET alone; with manual registration yielding better results than rigid registration.74 However, registration errors with PET/CT can be greater than 5 mm, going up to 17 mm, when acquiring the scan in the nontreatment position, a finding which renders the utility of PET/CT GTV delineation questionable in the head and neck region.74 Because of the changes in patient placement from diagnostic to treatment position affecting the accuracy of registration, the authors concluded that PET/CT acquired in the treatment-planning position is the optimal method to minimize registration errors.74
Adaptive Radiotherapy Planning
Metabolic activity might be indicative of tumor cell density; therefore, monitoring changes in 18FDG uptake during treatment might aid in decision making, namely in escalating treatment dose if required. Only two studies to date addressed the possibility of adapting treatment dose as per changes in PET/CT results taken at baseline and again during therapy.75 Ten patients with pharyngolaryngeal cancer treated with chemoradiation underwent CT, T2-MRI, and 18FDG PET scans.75 As expected, the mean primary tumor GTVs decreased significantly during the course of treatment, with reductions ranging from 54% to 74% compared to pretreatment GTVs.75 Furthermore, PET-based adaptive planning reduced the irradiated volumes by 15% to 40% compared to pretreatment planning CT.75 These results were not replicated by a second study which reported an increase in median values of GTV-PET over the course of treatment (Table 2.6).76 More research is warranted to replicate these results and subsequent studies should evaluate the efficacy of adaptive radiotherapy on several end points such as overall survival and progression-free survival. Some studies have reported that maximum SUV of the primary tumor was not predictive of risk of disease recurrence and as such, metabolically active areas on 18FDG PET might not provide just cause for escalating or reducing radiation dose during therapy.77,78 Adjusting radiation dose and GTV delineation through repetitive PET/CT imaging is a promising approach that would ultimately result in less damage to normal tissue and possibly improved prognosis. It is important to note, however, that 18FDG might not be the most suitable tracer for adaptive radiotherapy as it is not tumor specific. This is especially an issue, during and after radiotherapy, where inflammatory processes might hinder accurate differentiation between normal and malignant tissue 18FDG uptake. Future studies should thus also focus on evaluating the efficacy of tumor-specific tracers.
RESULTS SUMMARY OF TWO STUDIES UTILIZING SERIAL 18F-FDG PET/CT FOR ADAPTIVE RADIOTHERAPY PLANNING
Assessment of Treatment Response
Evaluating the head and neck that has been exposed to chemoradiation is challenging becasue of the loss of normal fat planes and distortion of normal structures.35 This problem renders anatomic imaging difficult to interpret and as such, 18FDG PET has been proposed as a solution for imaging the posttherapy neck.
18FDG PET/CT Postneoadjuvant Therapy
Martin et al.79 evaluated the accuracy of PET in assessing 78 HNC patients treated with primary chemoradiotherapy. Each patient underwent a pretreatment scan, a posttreatment scan after 12 weeks of completing treatment, and was followed up for a minimum of six months.79 In comparison to clinical examination and CT scans, PET demonstrated higher accuracy in predicting complete response (92%), with a reported NPV of 95%.79 There were only three false positives from PET, two of which were caused by inflammatory processes.79 However, PET’s inability to distinguish between inflammation and residual tumor led to a relatively low PPV of 82%.79
Similar results were reported by Moeller et al.80 Patients with locally advanced cancer of the oropharynx, larynx, or hypopharynx underwent PET/CT and contrast-enhanced CT imaging 6 to 8 weeks after completion of neoadjuvant treatment; imaging responses were correlated with clinical and pathologic response. Baseline SUV measures did not reveal any significant differences between responders and nonresponders; however, postradiation SUV values were higher in nonresponders compared to responders for both primary tumor and nodes.80 As in Martin et al., the PPV of PET/CT was relatively low, whereas the NPV was very high. Although PET/CT did outperform contrast-enhanced CT, the differences were not significant.80 The findings from this and other similar studies are summarized in Tables 2.7and 2.8.
Timing of the PET/CT might also play a role in the effectiveness of 18FDG uptake to predict treatment response. Obtaining a PET/CT scan soon after completion of therapy (i.e., 4 to 8 weeks) results in higher false-positive rates compared to obtaining the scan at 8 weeks post chemoradiotherapy.81 Increase in 18FDG uptake from inflammatory processes following treatment might also result in false negatives because of the elevated background activity masking the metabolic activity of a residual mass; therefore, it is recommended to wait at least 8 to 12 weeks before obtaining a posttreatment PET/CT scan (Fig. 2.5A,B).
18FDG PET/CT Postsurgery
Postoperative tissue changes cause difficulties in interpreting clinical and anatomic test results; consequently, malignant activity in HNC patients treated with surgical resection must be evaluated on a metabolic basis. Shintani et al.82evaluated the utility of 18FDG PET/CT in HNC patients early after surgery and before beginning adjuvant radiotherapy; PET/CT results were compared to biopsy findings. Only 45.8% of biopsies positive for cancer were correctly identified by PET/CT; with PET/CT changing postoperative adjuvant treatment plan in 15.4% of patients.82 Despite this low PPV, PET/CT scans have the potential of changing patient management and sparing them overly aggressive treatment as well as reducing toxicity; as such, the value of PET/CT for adjuvant treatment planning needs to be studied further.
18FDG PET/CT During Treatment
Brun and colleagues examined whether the metabolic rate (MR – calculated from multiplying blood glucose with tissue concentration of 18FDG in a region at the time, and dividing the product over the lumped constant set to 1 and assumed constant over time and plasma 18FDG concentration as a function of time and the 18FDG SUV could predict therapy outcome after only one cycle of chemotherapy.83 Low MR values of the primary tumor were found to be significantly correlated with complete remission, locoregional control, and survival; with estimated overall survival measuring at 72% for low MR and 35% for high MR of the primary tumor.83 Analysis of MR of the primary tumor accurately predicted complete remission in 23/24 patients, whereas only 13 of 21 patients with a high MR achieved complete remission.83 Interestingly, SUV reportedly had a poorer association with survival, indicating that, contrary to popular belief, MR might be of greater prognostic value than SUV.83
The scientific community is still unclear about the optimal timing to perform an interim PET/CT scan; and despite these promising findings, the results must be interpreted with caution because of the small sample size.83 However, there is a general consensus that predicting response to treatment as early as possible is more beneficial than waiting to obtain a scan after completion of therapy as the ultimate goal of therapy monitoring is modification of ineffective treatments. Much more data is needed before conclusions can be made regarding the utility of interim PET/CT in HNC.
Restaging, Recurrence, and Surveillance
Despite aggressive therapy with curative intent, recurrence rate remains relatively high in HNC, especially within the first 2 years after treatment (Fig. 2.6A,B).84 Second tumors are highly prevalent in HNC and improved lesion localization can be achieved by the combination of PET and CT.35 Detecting residual disease and/or recurrence by conventional methods, however, is challenging because of the structural tissue distortion induced by therapy.35
DIAGNOSTIC ACCURACY OF FDG PET/CT FOR DETECTING PRIMARY RESIDUAL TUMOR IN HNC AFTER DEFINITIVE CRT
DIAGNOSTIC ACCURACY OF FDG PET FOR DETECTING LYMPH NODE METASTASIS IN HNC AFTER DEFINITIVE CRT
As is the case in monitoring treatment response, PET/CT has the ability to distinguish between malignant tissue and postoperative tissue changes. One of the first prospective studies to evaluate the diagnostic accuracy of 18FDG PET in comparison to conventional imaging for the detection of recurrence in HNC was conducted by Anzai et al.85 18FDG PET yielded a sensitivity and specificity of 88% and 100%, respectively in comparison to 25% and 75%, respectively, for MRI or CT.85 More recently, Krabbe et al.84 evaluated the role of 18FDG PET to detect recurrence in patients with advanced squamous cell carcinoma of the oral cavity. Sensitivity and NPVs were high; however, because of a substantial number of false positives, specificity and PPV were found to be low (Table 2.9). When comparing PET/CT to PET alone, fusion imaging was reported to have higher specificity and positive and NPVs, with equivalent sensitivity measures.86 Overall, PET/CT was more accurate than PET alone for the detection of recurrence and led to avoidance of unnecessary invasive procedures in 57% of patients in comparison to 35% for PET.8618FDG PET was also found to be superior to CT and technetium-99m tetrofosmin single photon emission computed tomography (SPECT),87 CT/MRI,88 and MRI89 for the detection of recurrent HNC.
FIGURE 2.5. A 45-year-old male with a history of nasopharyngeal carcinoma, now status postchemoradiation therapy. FDG PET/CT scan (A, TOP) demonstrates interval resolution of intense FDG uptake noted within the right fossa of Rosenmuller/nasopharyngeal area, as noted previously in the staging PET/CT scan (A, BOTTOM). Staging PET/CT shows intensely FDG-avid lymphadenopathy involving the left retropharyngeal, left intraparotid, right level II and III cervical regions (B, BOTTOM, white arrow ). Posttherapy scan demonstrates interval resolution of FDG uptake noted within the right level II/III cervical lymph node with residual non-FDG–avid lymph node within the right level II (B, TOP). Overall, the pattern is consistent with complete metabolic response to interval therapy.
FIGURE 2.6. Axial CT (A) and axial-fused PET/CT (B) of an 89-year-old female with a history of squamous cell carcinoma involving the tongue. The patient completed chemoradiotherapy and the FDG PET/CT was obtained for the purpose of assessing clinical suspicion of recurrence. Scan demonstrates intense FDG uptake within the base of the mouth (white arrow), highly suggestive of recurrence.
STUDIES EVALUATING THE PERFORMANCE OF FDG PET/CT IN DETECTING RECURRENCE IN HNC
With respect to follow-up, the National Comprehensive Cancer Network has recommended that a posttreatment 18FDG PET/CT be performed a minimum of 12 weeks after completion of chemoradiation/radiation therapy. Follow-up PET/CT has also been shown to be useful in detecting recurrence during posttreatment surveillance when clinical follow-up examinations are negative.90 In fact, Abgral et al. reported that 33% of the recurrences identified by PET/CT were missed on conventional follow-up.90 The prognostic value of posttreatment PET/CT has also been evaluated. Patients with a negative PET/CT scan have significantly better overall survival and disease-free survival in comparison to patients with positive scans; 57% versus 73% and 70% versus 42%, respectively.91 It is important to note, however, that although a negative posttreatment PET/CT scan is highly predictive of complete response, false-positive PET/CT findings are highly frequent and subsequently render the PPV of questionable worth.
The use of more quantitative parameters, namely, metabolic tumor volume (MTV), has been shown to be a better predictor of outcome compared to SUV measures. Murphy et al.92 found that response to treatment, as measured by posttreatment MTV, was more predictive of overall survival and disease-free survival than initial tumor burden, as measured by pretreatment MTV. Similar results were reported in other studies and, interestingly, SUV measures did not show any correlation with disease outcomes.93–95 However, tumor burden measured as a metabolic index (combination of SUV and MTV) was reported to be a better predictor of long-term survival than MTV and SUV alone.96
Although PET/CT in clinical oncology is the most advanced and well-established multimodality system available to date, there has been increasing interest in developing PET/MRI scanners.97 MRI offers superior soft tissue contrast in comparison to CT, especially in the head and neck area, and its combination with functional PET imaging might offer promising advances in the management of HNC. Generally speaking, there are currently two methods to combine PET and MR images; sequential and simultaneous.97 Sequential image fusion consists of retrospectively combining PET and MR images that were obtained from two different devices at different times.97 Using a process termed “image registration”, certain software are capable of aligning the data sets from PET and MR so that both images correspond to the same anatomic location; this can either be done manually by visual assessment using landmarks or fully automatically.97 Retrospective image registration, however, is time-consuming and may lead to inaccurate fusion caused by motion artifacts.97 The latter limitation might not pose as big a problem in the head and neck region as the head can be secured to prevent movement; as such, fused images can be aligned with greater accuracy than dual images obtained from different sites of the body (e.g., gastrointestinal tract).97
Simultaneous image fusion involves the use of hardware-based hybrid PET/MRI systems.97 This application is technically difficult as MRI may interfere with the image quality of PET and vice versa. Interference can be avoided by hybrid scanners that separate PET and MRI in the same room and rotating the patient from one scanner to the other using the same bed.97 Although accurate positioning is possible, this system, however, utilizes sequential scanning and as a result, is time consuming.97 This prototype being evaluated in Geneva and New York as of April 2010.97 Another prototype, available in Germany, obtains PET and MR images simultaneously by using a removable brain PET-detector that can be placed in the MR gantry of a modified 3.0 T MRI scanner.98,99 Excellent image quality, detailed resolution, and image contrast were reported by the authors, with no artifacts or interference by either MR or PET.98,99 However, the PET insert offers a very small field of view, limiting registration to brain structures and the nasopharynx while omitting the possibility of imaging laryngeal, hypopharyngeal, and oropharyngeal carcinomas.98,99 Whole-body imaging is still possible and the first simultaneous whole-body hybrid PET/MRI scanner was recently installed at the Technische Universitat Munchen in Germany, allowing scientists to begin studying whether PET/MRI will indeed offer a clear advantage over PET/CT in oncology.97
Because of the proximity of anatomic structures in the head and neck region, hybrid PET/MRI might be favored over PET/CT for T staging since the tumor border can be much more clearly defined in MR images.100 PET/MRI for N staging, on the other hand, does not seem to offer a clear advantage over PET/CT, with studies reporting similar accuracy in detecting lymph node involvement.100 Furthermore, as is the case with PET/CT, a large number of patients will be understaged with PET/MRI and as such, the new hybrid system will not likely replace staging by neck dissection.100 There is not yet sufficient literature to quantify PET/MRI’s utility in M staging, however, PET/MRI will most likely be preferred over PET/CT in areas of the body where MR offers superior soft tissue contrast in comparison to CT.
A recent study reported that PET/MRI fusion might offer a limited advantage over PET/CT for staging new cases of HNC since abnormalities can easily be detected by anatomic imaging because of the clear asymmetry of abnormal structures.101 The advantages of PET/MRI, however, are apparent in posttreatment and/or postoperative patients in whom normal anatomical structures lost their symmetry caused by treatment.101 In such cases, asymmetry alone is no longer indicative of malignancy. PET/MRI can clearly delineate tumor borders and differentiate between residual mass and scar tissue.101 Manual registration, however, was used for this study. Another group of scientists, on the other hand, successfully established an MR protocol for the neck using a whole-body MR Dixon sequence, which can be used for attenuation correction on the hybrid PET/MRI scanner.102
In summary, MR offers clear advantages over CT imaging such as superior soft tissue contrast, tumor delineation, and reduced metallic artifacts. Studies of the technical feasibility of hybrid PET/MRI scanners are still ongoing, and the clinical application of these systems has only been recently introduced in the field of oncology. Once technical limitations are overcome, research can begin to focus on the different combinations of MRI parameters and PET radiotracers, with the possibility of creating specific parameter/radiotracer combinations relevant to each type of cancer.
Newer Non-18FDG Radiotracers
As mentioned previously, 18F-FDG is not a tumor-specific tracer and it can accumulate in normal tissue because of other processes such as inflammation. Tumor cells, in addition to increased glucose metabolism, display abnormal characteristics that may be quantified by non-FDG PET tracers. New radiotracers are continuously being synthesized and tested to target hypoxia and proliferation.
1-11C acetate has been utilized to measure anabolic metabolism of malignant tissue as hypoxia has been associated with a more aggressive cancer phenotype and its quantification may aid in appropriate treatment selection.103 Sun et al.104 demonstrated, in vivo, the change from oxidative metabolism to aerobic glycolysis in tumor cells during radiotherapy. This switch was much more significantly pronounced in patients with partial response in comparison to those with complete response; the former group also had reportedly poorer outcomes.104 The authors concluded that poor oxygenation leads to radioresistance and local failure, which may be reversed if detected early during the course of treatment.104 In addition to measuring hypoxia, 11C-acetate may aid in the detection of well-differentiated tumors as well as delineation for radiotherapy planning. Few studies have examined this role of 11C-acetate in HNC with one study reporting promising results. Ten newly diagnosed patients with pathologically confirmed HNC were recruited for the study, with each subject receiving both 18FDG PET and 11C-acetate PET (ACE-PET).105 ACE-PET detected 100% of primary tumors, whereas 18FDG PET detected only 90%.105 Furthermore, 95% of LNF was detected by ACE-PET with only one false negative, in comparison to 62% detection rate of 18FDG PET with eight false negatives.105 Despite the small number of patients, the results imply that ACE-PET may be more sensitive than FDG PET for the detection of primary tumors and LNF.105 These results, however, must be interpreted with caution as choline uptake may be altered by hypoxia. In addition to differences between ACE and 18FDG in staging, GTV delineation by ACE-PET was 51% larger than the volumes delineated by 18FDG PET; however, it is not yet clear whether the results indicate poor GTV delineation by 18FDG, and if the extra 51% delineated by ACE-PET should receive a different dose regimen.105 More studies are needed to evaluate the role of ACE-PET relative to 18FDG PET in HNC.
Another more commonly used tracer to image hypoxia is 18F-fluoromisonidazole (FMISO). FMISO has been studied to a greater extent than 11C-acetate and results also imply good potential for imaging in HNC. 18FMISO-PET was reported to be a stronger predictor of survival in comparison to 18FDG PET; with possible implications in pretherapy imaging to determine appropriate treatment and dose painting to the hypoxic regions of the tumor.106 Regions of increased 18F-FMISO uptake can be successfully targeted for an IMRT boost without exceeding the normal tissue tolerance107; thus, significantly increasing tumor control probability without increasing the rate of predicted complications.108 18FMISO-PET, however, has low tumor-to-background contrast making its clinical use limited. An alternative hypoxia imaging radiotracer, 62Cu-diacetyl-bis(N4-methylthiosemicarbazone) (62Cu-ATSM), may be used for pretreatment evaluation and guide IMRT109,110; the clinical outcome has yet to be evaluated and compared with 11C-acetate, 18FMISO, and 18FDG.
Rapidly proliferating tissue may be indicative of malignancy, as such, several PET tracers have been developed to measure the proliferative index of tumor cells. 11C-choline may be used for this purpose and its value is more pronounced in patients who have already undergone therapy that renders 18FDG PET studies equivocal because of inflammatory processes. However, studies have reported no advantage of 11C-choline (CHOL)-PET over 18FDG PET for the detection of recurrences in HNC but CHOL-PET may be preferred because of the shorter uptake time.111–113
Tumor cell proliferation can also be imaged using 3-deoxy-3-18F-flurothymidine (18F-FLT). Dose escalation is thus also possible by 18FLT-PET scans during the course of treatment with studies reporting a decrease in 18FLT-SUV after 2 weeks of concurrent chemoradiotherapy.114,115 As is the case with 11C-choline, however, no significant advantage has been shown over FDG PET, with reportedly inferior ability of CHOL-PET to differentiate between reactive and metastatic lymph nodes in pretreatment patients.116
Finally, some tracers still under study include O-(2[18F]fluoroethyl)-L-tyrosine (18FET) for differentiation between residual mass and inflammatory or infectious lesions and 11C-methionine for GTV delineation. 18FET-PET has been reported to have greater specificity, but lower sensitivity, for differential diagnosis than 18FDG PET in patients with suspected malignancies in the head and neck region.117,118 Dual scans utilizing both 18FDG and 18FET may thus be appropriate for differential diagnosis in patients with equivocal conventional imaging as well as patients who demonstrate increased 18FDG uptake because of posttherapeutic inflammation. GTV delineation by 11C-methionine (MET)-PET was shown to be similar to results obtained from CT, and different from the contours defined by 18FDG PET GTV delineation119; there is insufficient evidence, however, to determine whether 18FDG-defined GTV results reliably in improved overall survival over MET-PET–defined GTV.
It is clear that the PET tracers other than 18FDG have the potential to overcome some of the limitations of 18FDG PET scanning, with the most promised evidence in adaptive radiotherapy planning and dose painting. For additional discussion of non-18FDG tracers, the reader is referred to Heuveling et al. (2011).120
Because of the introduction of PET/CT in clinical oncology over two decades ago, evidence has been accumulating regarding the advantages of PET/CT over conventional imaging in the head and neck region. These benefits have been reported to a great degree in the settings of radiation therapy planning and recurrence detection, as well as in staging and treatment response evaluation. With ongoing research on multimodality imaging (such as PET/MRI) and non-18FDG tracers, the use of PET in HNC will likely gain more popularity as technical improvements are made which allow for patient-tailored imaging and disease management.
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