Nuclear Oncology, 1 Ed.

CHAPTER 32

ASSESSMENT OF RESPONSE TO ANTITUMOR TREATMENT

Masahiro Yanagawa • Noriyuki Tomiyama • Tadashi Watabe • Kayako Isohashi • Jun Hatazawa

INTRODUCTION

In recent years, cancer mortality rates have continued to increase so that it is expected that in the future, cancer will be the most common cause of death worldwide. Anticancer drugs, surgery, and radiation therapy are the major cancer treatment modalities. The goals for anticancer drug administration can be described as follows: Reduce or eliminate cancer tissue, prolong life, and relieve symptoms. Many patients undergo neoadjuvant therapy before resection, others receive adjuvant therapy after resection, and still others receive continued palliative chemotherapy.

Currently, various treatment options for cancer are available, including use of novel agents that target specific molecules (such as Avastin [bevacizumab], Tarceva [erlotinib], and Iressa [gefitinib]). Selection of an effective treatment and appropriate evaluation of treatment response are important to accomplish prolonged survival and to preserve quality of life.

Selection of appropriate methods to evaluate therapeutic efficiency is a crucial component of effective cancer treatment. Imaging assessments, such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography/CT (PET/CT), are mainstream methods universally used to evaluate treatment responses.

Many approaches have been developed to objectively assess treatment response, beginning with the original report by Moertel in 1976 and the subsequent development of the World Health Organization (WHO) criteria in 1979, followed by publication of the Response Evaluation Criteria in Solid Tumors (RECIST) in 2000, and RECIST 1.1 in 2009.14 RECIST is widely used as an anatomic tumor response metric but is known to have limitations when tumors have obscure margins or scar tissue is present after treatment. Moreover, some caution is required when using RECIST to predict outcomes of treatment with the novel molecularly targeted agents, because RECIST is based on the reduction of morphologic size.510 These agents, which tend to be more cytostatic than cytocidal, offer a substantial improvement in outcome even without major shrinkage of tumors that would be characterized by a partial or complete RECIST response.11,12

PET, with the glucose analog 18F-fluorodeoxyglucose (FDG), has been widely used as a technique to evaluate metabolic activity in tumors. This metric is more informative for the evaluation of treatment response after chemotherapy than simply reduction of tumor volume.13 Recently, Wahl et al.14 proposed the PET Response Criteria in Solid Tumors (PERCIST) as a new standardized method for quantitative assessment of metabolic tumor response. PERCIST data are expected to provide improved information for a therapeutic strategy for cancer patients.

ASSESSMENT OF THERAPEUTIC RESPONSE OF VARIOUS TUMORS

Brain Tumors

For brain tumor patients, treatment response is usually evaluated by gadolinium (Gd)-enhanced MRI. However, one of the major problems encountered is difficulty differentiating treatment-induced necrosis from recurrent or progressive tumor on MR images.15 In addition, after treatment with antiangiogenic agents, a decrease in contrast enhancement does not reflect tumor regression.1618 This type of response is because of a normalization of abnormally permeable microvessels, mostly noted with antiangiogenic treatment, leading to a rapid decrease of contrast enhancement of Gd-enhanced MR images, but not reflecting a real decrease in tumor activity or size.1921 Another major problem is underestimation of the tumor invasion area because of a limitation of Gd-enhanced MR images, on which enhanced lesions can simply represent collapse of the blood–brain barrier. On 11C-methionine (11C-MET) PET images, tracer uptake is sometimes observed in areas having no Gd-enhancement on MR images (Fig. 32.1). Thus, use of conventional MR techniques to monitor response is not appropriate, especially for antiangiogenic therapies. To overcome these limitations of conventional MRI, advanced PET imaging can potentially assess biologic changes in tumors. Depending on the radiotracer used, responses at the molecular level are visualized by PET which assess tumor metabolism and cell proliferation.

FIGURE 32.1. (A) Gd-enhanced MR image, (B) PET/MR fusion image, (C)11C-MET-PET image of a 56-year-old man with glioblastoma. 11C-MET uptake was observed outside the Gd-enhanced lesion, which indicated tumor invasion.

PET with 18F-FDG directly reflects the glucose metabolic activity of tumor cells. 18F-FDG uptake has been shown to correlate with tumor cell density22 and grading and malignant behavior of gliomas,2325 and is predictive of patient outcome.26,27 In one report, 25 adult patients with recurrent high-grade gliomas were evaluated by 18F-FDG PET within 6 weeks of starting chemotherapy with bevacizumab and irinotecan. 18F-FDG PET was shown to be the most powerful predictor of both progression-free survival and overall survival (OS).28 However, variability of glucose uptake in recurrent high-grade gliomas and low tumor-to-background ratios, because of the high metabolic activity of healthy brain tissue, limit the usefulness of 18F-FDG PET to assess brain tumors.29 Another limitation is a treatment-associated inflammatory response leading to increased 18F-FDG uptake into inflammatory cells. Increased 18F-FDG uptake in tumors was observed in a study using a rat model for intracerebral gliosarcoma because of the presence of glucose-consuming activated macrophages.30

Amino acid transport, as well as protein synthesis, were both demonstrated to be enhanced in most gliomas and can potentially be used as imaging targets.31 Radiolabeled amino acids are more specific tracers for tumor detection and tumor delineation than 18F-FDG because of their low uptake in normal brain tissue. Radiolabeled amino acid tracers are not taken up by glycolytic inflammatory cells and, therefore, have been suggested to be more appropriate to discriminate between recurrence or progression versus nonspecific therapy-related changes.32 Use of a variety of radiolabeled amino acids, like 11C-MET, and aromatic amino acid analogs, like 18F-fluoroethyltyrosine (18F-FET), 18F-fluorotyrosine (18F-TYR), 18F-fluoromethyltyrosine (18F-FMT), and 18F-fluorodopa (18F-DOPA), has been proposed. Increased uptake rates are related to increased transport mediated by type-L amino acid carriers. Uptake of 11C-MET correlates with cell proliferation in vitro, Ki-67 expression, nuclear antigen expression, and microvessel density in areas of cell proliferation, suggesting that 11C-MET may be a good marker of tumor proliferation and neovascularization.33

Assessment of Therapeutic Response of Glioma: Comparison of 18F-FET PET and MRI

11C-MET-PET can distinguish tumor progression from stable disease with high sensitivity (90%) and specificity (92.3%) based on a threshold of a 14.6% increase in 11C-MET uptake.34 Equivalent findings with 18F-FET PET were reported in patients with gliomas after radiotherapy, radiosurgery, and multimodal treatment such as radioimmunotherapy.35 In contrast to the 92.9% specificity and 100% sensitivity of 18F-FET PET, specificity of conventional MRI alone was only 50%. After radioimmunotherapy, a threshold tumor-to-background ratio of 2.4 for 18F-FET uptake provided the best differentiation between recurrence and reactive changes (sensitivity 82%, specificity 100%).36 In a prospective study of stereotactic sampling of 18F-FET-positive glioma recurrences in 17 patients with low-grade gliomas, 6 patients with anaplastic gliomas, and 8 patients with glioblastomas, the positive predictive value of 18F-FET PET was 84%.37 18F-FET uptake in 11 patients with progressive low-grade gliomas during temozolomide chemotherapy was quantified with PET as metabolically active tumor volume, and was compared with the tumor volume on MR.38 Response was defined as a 10% reduction of the initial tumor volume, and eight patients had metabolic responses. Three months after the start of chemotherapy, the active 18F-FET volumes decreased to a mean of 44% from baseline in two patients. The first MRI volume responses were noted at 6 months. Responders showed a volume reduction of 31% ± 23% (mean ± SD) from baseline by 18F-FET PET, and 73% ± 26% by MRI. The time to maximal volume reduction was 8 ± 4.4 months by 18F-FET PET and 15 ± 3 months by MRI. Therefore, metabolic volume reduction estimated by 18F-FET PET was evident much earlier than tumor volume reduction by MRI.

Early detection of treatment response has also been reported in glioma patients after radiochemotherapy.39 Surgery and subsequent radiochemotherapy was used to treat 22 patients with glioblastomas. The 18F-FET PET studies were performed before and 7 to 10 days after completion of therapy. Response was defined as a decrease of more than 10% in the maximal tumor-to-brain uptake ratio. There were 16 early responders by 18F-FET PET (72.7%) and six nonresponders (27.3%). Early responders, as revealed by PET, had a significantly longer median disease-free survival (DFS) (10.3 versus 5.8 months; p < 0.01) and OS (“not reached” versus 9.3 months; p < 0.001).

Monitoring Anticancer Immunotherapy by Means of 11C-MET PET

Recent advances in tumor immunology have led to identification of a number of tumor-associated antigens on cancer cell membranes. For example, the Wilms tumor gene (WT1) product is overexpressed in malignant gliomas, and WT1 immunotherapy for patients with recurrent glioblastoma is regarded as a safe therapy with a favorable clinical response. The median survival after initial vaccination is 36.7 weeks, which is remarkably longer than that of 14.6 months after standard treatments for glioblastoma. The effects, based on the RECIST guidelines, of WT1 immunotherapy were evaluated by contrast-enhanced MRI. However, the RECIST-based response rate (complete response and partial response [CR+PR]) was only 9.5%, whereas the disease control rate was 57.1% of 21 patients studied, which indicated that use of RECIST criteria and contrast-enhanced MRI is not a sensitive method for evaluation of response to anticancer immunotherapy. Response evaluations of patients with malignant gliomas following immunotherapy targeting the WT1 gene product were reported by PET-based criteria as well as size-based criteria.

The Osaka group prospectively compared RECIST-based, 18FDG PET–based and 11C-MET–based evaluation of the effects of WT1 peptide immunotherapy in patients with recurrent glioblastoma. Six patients with recurrent glioblastoma following initial surgical resection, external radiation, and chemotherapy were enrolled. Inclusion criteria were: (1) age ranging from 16 to 80 years; (2) expression of WT1 in the glioma cells, determined by immunohistochemistry; (3) HLA type A*2402 positivity; (4) estimated survival of more than 3 months; (5) performance status from 0 to 2 (Eastern Cooperative Oncology Group); (6) no severe organ function impairment; and (7) procurement of written informed consent from the patient. All patients had histologically proven glioblastoma (Grade 4) based on WHO criteria. Recurrence or progression of tumors was monitored by contrast-enhanced MRI during initial and maintenance therapy. No patient had chemotherapy or radiotherapy during the 4 weeks prior to WT1 immunotherapy. The patients were intradermally injected at 2-week intervals with an HLA-A*2402-restricted, modified 9-mer WT1 peptide emulsified with Montanide ISA51 adjuvant at 1 mg/kg body weight. The patients underwent 11C-MET PET and 18FDG PET before and after the WT1 vaccination. The 11C-MET and 18FDG uptakes were measured 20 to 30 minutes and 60 to 70 minutes after intravenous injection of 11C-MET and 18FDG, respectively. The maximum uptake in the recurrent glioblastoma (% uptake compared to contralateral cerebral cortex) and the volume having abnormally high accumulation (20% or more compared to contralateral cerebral cortex) were assessed in each PET study. Patients were classified 4 weeks after initiation of vaccination by RECIST with MRI as follows: Partial response (PR, n = 1, survival period = 248 days), stable disease (SD, n = 4, alive at 453, 661, 936, and 960 days, or progressive disease (PD, n = 1, alive at 812 days), resulting in a response rate (CR + PR) of 18%. In the 11C-MET PET evaluation, the maximum uptake of 11C-MET before therapy (220 ± 48%) was significantly decreased after therapy (161 ± 50%, p < 0.01). The volume of abnormally high accumulation (17.6 ± 10.9 mL) was significantly decreased after therapy (9.2 ± 7.3 mL, p < 0.01). The 18FDG PET revealed lower accumulation of 18FDG in the tumor than in the contralateral cortex in all patients. After vaccination, the maximum uptake of 18FDG was unchanged in four patients, 30% decreased in one patient, and 50% increased in one patient (Fig. 32.2). Residual tumor cell volume could be more accurately estimated by means of 11C-MET PET than 18FDG PET after WT1 immunotherapy. The scenario of tumor volume expansion seen on contrast-enhanced MRI and elevated 18FDG uptake may predominantly indicate an activated host-immune system following WT1 immunotherapy.

FIGURE 32.2. (A, B) Contrast-enhanced MR images, (C, D)18F-FDG PET, and (E, F)11C-MET-PET in a WT1 immunotherapy responder (63-year-old man, alive 826 days after treatment completion). (A, C, E) Before therapy; (B, D, F) after therapy. The contrast-enhanced tumor lesion expanded after treatment caused by peritumoral edema. The FDG PET demonstrated a remarkable increase in metabolically active volume corresponding to morphologic changes observed on MR imaging. The MET-PET showed round-shaped uptake, indicating a decreased volume of viable tumor cells.

To evaluate WT1 immunotherapy response in patients with recurrent malignant glioma, we further developed the parametric response map (PRM) by means of 11C-MET PET evaluations.40 11C-MET PET data before and after WT1 immunotherapy were registered onto pre- and post-WT1 contrast-enhanced T1-weighted MR images, respectively, using normalized mutual information with the VINCI image analyzing software from the Max Planck Institute for Neurological Research in Cologne, Germany. This data set delineated changes in maximal tumor length and tumor volume, and PRM parameter changes, such that a negative PRM value resulted from a decrease in 11C-MET uptake after WT1 immunotherapy, indicating treatment response. Study results indicated that changes seen on contrast-enhanced MRI in tumor length and volume did not correlate with the OS period. Contrast-enhanced MRI findings probably reflected immune reactions, such as increased capillary permeability, rather than tumor viability. On the other hand, the PRM parameter derived from 11C-MET PET did predict the OS period.

Assessment of Therapeutic Response: Comparison of 18F-Fluorothymidine (18F-FLT PET) with MRI

A thymidine analog, 3′-deoxy-3′-18F-fluorothymidine (18F-FLT), has been developed to image tumor cell proliferation.41 18F-FLT is transported into tumor cells via nucleoside transporters and is subsequently phosphorylated by thymidine kinase 1 to 18F-FLT 5-phosphate. In a previous report, 30 patients underwent 18F-FLT PET before and 2 and 6 weeks after the start of bevacizumab combination therapy.42 A metabolic response was defined as a decrease in standardized uptake values (SUVs) from baseline equal to or greater than 25%. Treatment response was assessed by MRI at 6 weeks, according to the Response Assessment in Neuro-oncology criteria. Early and late changes in tumor 18F-FLT uptake were more predictive of OS than MRI criteria (p < 0.001 and p = 0.01, respectively). 18F-FLT uptake changes were also predictive of progression-free survival (p < 0.001). On the basis of the 6-week 18F-FLT PET response, there were 16 responders (53%) and 14 nonresponders (47%), whereas MRI identified nine responders (seven partial response, two complete response, 31%) and 20 nonresponders (13 stable disease, seven progressive disease, 69%). In seven of the eight discrepant cases between MRI and PET, 18F-FLT PET demonstrated response earlier than MRI. Among various outcome predictors, multivariate analysis identified 18F-FLT PET changes at 6 weeks as the strongest independent survival predictor (p < 0.001; hazard ratio, 10.051). New treatment strategies with antivascular agents (e.g., the antivascular endothelial growth factor receptor-1 antibody, bevacizumab) are difficult to monitor reliably by conventional imaging techniques, because treatment-induced reduction of contrast enhancement predominantly represents reduced vascular permeability.43 18F-FLT PET proved to be superior compared to contrast-enhanced MRI in predicting treatment response of malignant gliomas to bevacizumab plus chemotherapy.44

Dynamic 18F-FLT PET was performed in 15 patients with recurrent high-grade brain tumors; imaging was performed at baseline, after one course of therapy (2 weeks), and at the end of therapy (6 weeks) and 18F-FLT kinetics were investigated.45 The standard 3-compartment model was corrected for the blood volume fraction in tissue (Vb) and for metabolites, and the partial volume was used to estimate kinetic parameters. The largest change in kinetic parameters occurred between baseline and 2 weeks of treatment. Significant changes were found for Vb, influx rate constant (Ki), volume of distribution, early SUV, and late SUV. After stratification to OS, the patients with the best prognosis had a change at 2 weeks of treatment that persisted at 6 weeks, whereas the patients with short survival times had returned to baseline values at 6 weeks. High correlations were found between SUV and Ki, indicating that, in clinical practice, simple uptake measurements are sufficient for therapy monitoring and predicting short- and long-term survival.

TABLE 32.1

SUMMARY OF PET TRACERS USED FOR THE EVALUATION OF BRAIN TUMORS TO ANTITUMOR TREATMENT

PET Imaging of αV β3-Integrin

Glycosylated arginine-glycine-aspartic acid peptide (18F-Galacto-RGD) was demonstrated to successfully identify the expression in glioblastoma of the integrin αVβ3, which is associated with tumor-induced angiogenesis via basic fibroblast growth factor, and which is also found in small blood vessels, where it is thought to promote extensive tumor progression.46

Fluciclatide binds with a high affinity to αVβ3-integrin and αVβ5-integrin, which are highly expressed on tumors and in tumor neovasculature. In a rat xenograft model, 18F-fluciclatide detected changes in tumor uptake after acute antiangiogenic therapy with sunitinib markedly earlier than any significant volumetric changes were observable.47 These results suggest that PET imaging of αVβ3-integrin may provide clinically important information for monitoring the response to antiangiogenic therapy.

In summary, PET can detect early metabolic responses to treatment in brain tumors as well as precisely evaluate tumor extent and activity, as compared to conventional MRI. PET is a suitable modality for evaluating therapy response to antiproliferative drugs, antiangiogenic treatment strategies, and tumor progression (Table 32.1). Further study is needed to determine the appropriate criteria and timing for response evaluations and selection of the most suitable tracer for each treatment type.

Esophageal Cancer

Esophageal cancer has a high mortality rate. In the early stage, esophagectomy is selected as a treatment having curative potential. Although surgery has remained the standard treatment for esophageal cancer, postoperative prognosis is unsatisfactory, with 5-year survival rates of 40% at most.48 Moreover, most patients at presentation already have locally advanced esophageal cancer or distant metastases. Therefore, multidisciplinary approaches, such as use of neoadjuvant chemotherapy (NAC) and/or radiotherapy followed by surgery, are now frequently adopted in patients with locally advanced esophageal cancer, resulting in improved prognosis for those who respond to induction therapy.49

On the other hand, some studies have suggested that patients with locally advanced esophageal cancer who respond to chemoradiotherapy might not receive any additional benefit from surgery.50 Thus, appropriate selection of methods to evaluate therapeutic efficiency is crucial for effective treatment.

New Methods to Evaluate Therapeutic Efficiency

RECIST is widely used as an anatomic tumor response metric, but it is known to have limitations for tumors that have obscure margins or when there is scar tissue after treatment.14 In patients with esophageal cancer, measurement of the longest diameter of lesions on CT and resultant evaluation of treatment response are difficult. The general use of 18FDG PET for response evaluation to chemotherapy in esophageal cancer patients has been reported previously.5153 The following two novel methods will be the focus of this section: Assessment by the PERCIST criteria and evaluation of intratumor heterogeneity by texture analysis of baseline PET scans.

Assessment by PERCIST

As mentioned in the introduction section of this chapter, PERCIST has been recently proposed as the new standardized method to assess chemotherapeutic response metabolically and quantitatively.14 Yanagawa et al.54 demonstrated that use of PERCIST was the best method for evaluation of treatment response for patients with esophageal cancer as it is closely related to prognosis.

The method to evaluate therapeutic efficiency according to PERCIST is as follows.14,54 First, the entire tumor was manually enclosed using a volume of interest (VOI) to identify the pixel with the maximum SUV in the tumor on PET. Second, the mean SUV of the tumor was measured using a maximal 1.2-cm diameter VOI, which was placed on the hottest area within each tumor that included the pixel with the maximum SUV. This mean SUV of the tumor by the volumetric method corresponded to SUVpeak of the tumor. The SUVpeak was normalized to lean body mass (SULpeak = SUVpeak [lean body mass]/[total body mass]). Finally, it was determined whether the SULpeak of the tumor was higher than 1.5 times the liver SUL mean + 2SDs (in a 3-cm-diameter spherical region of interest in the normal right lobe of the liver).14,54

Results of some studies5153 have demonstrated that the cutoff values of maximum SUV reduction rates were useful for discrimination of PET responders and nonresponders. However, these values varied, ranging from 35% to 70%. The main reason may be due in part to the wide variety of 18FDG PET evaluation criteria, timing after start of therapy, techniques, and end points used. Thus, a standardized method should be established to evaluate therapeutic response. Yanagawa et al.54 demonstrated that neither reduction rates of SULpeak by PET nor reduction rates of tumor diameter by CT were useful for prediction of survival and recurrence. However, patients with complete metabolic response (CMR) by PERCIST had better prognosis: CMR is a complete resolution of 18F-FDG uptake within the measurable target lesion, meaning that it is less than the mean liver activity (1.5 × [mean SUL of the liver] + 2SD) and indistinguishable from the surrounding background blood-pool levels with no new 18F-FDG–avid lesions in a pattern typical of cancer (Table 32.2). A PERCIST change was the most significant prognostic indicator for predicting DFS (hazard ratio [HR]: 4.060; 95% CI: 1.195 to 13.789; p = 0.025) and OS (HR: 8.953; 95% CI: 1.188 to 67.506; p = 0.034) in the multivariate Cox proportional hazards regression analysis.54

TABLE 32.2

A BRIEF ACCOUNT OF OBJECTIVE THERAPEUTIC RESPONSES ACCORDING TO THE RECIST AND PERCIST CRITERIA

For example, even if the reduction rate (RR) in SUL is high, residual tumors after treatment often exhibit intense 18F-FDG uptake. Moreover, even if the reduction of SUL is low, residual tumors show faint 18F-FDG uptake, which is less than the mean liver activity and indistinguishable from the surrounding background blood-pool levels. Therefore, reduction of SUL may not always correlate with prognosis. On the other hand, PERCIST might be more useful to predict prognosis, because both the reduction of SUL and the value of SUL after chemotherapy are evaluated (Fig. 32.3). Considering that imaging, as a noninvasive procedure (generally, accurate information about pathologic prognostic factors and resection level is obviously difficult to obtain before surgery), is commonly and widely used to evaluate treatment response, PERCIST is considered to be the best method for evaluation of treatment response in esophageal cancer.

Evaluation of Intratumor Heterogeneity by Texture Analysis

In many previous reports, the PET image index used for assessment of metabolic response was often the mean SUV or the SUVmax. However, 18F-FDG tumor uptake is influenced by various conditions, such as increased metabolism, perfusion, cell proliferation, tumor viability, tumor aggressiveness, or hypoxia.5557

Tixier et al.58 hypothesized that these physiologic parameters might be responsible for tumor uptake heterogeneity, and, therefore, they evaluated intratumor heterogeneity using a textural analysis of baseline PET scans as a new parameter for the prediction of therapy response in esophageal cancer.

In image processing algorithms, simplifying assumptions are made about the uniformity of intensities in local image regions. However, images of real objects often do not exhibit regions of uniform intensities. Identifying the perceived qualities of texture in an image is an important first step toward building mathematical models for texture. Tixier et al.58 defined texture as a spatial arrangement of a predefined number of voxels allowing the extraction of complex image properties, and they defined a textural feature as a measurement computed using a texture matrix: The reader is referred to the original article for more information. The method used has two steps. First, matrices describing textures on images were extracted from tumors, and textural features were subsequently computed using these matrices. All parameters characterize in some way tumor heterogeneity at the local and regional levels, using texture matrices or global scales and image-voxel-intensity histograms. They assessed the predictive value of 18F-FDG uptake heterogeneity characterized by textural features extracted from pretherapy 18F-FDG PET images of patients with esophageal carcinoma, as compared with the use of SUVmax and SUVmean; the correlation between image parameters and overall patient survival was not assessed in this study. Analysis of results from 41 patients with newly diagnosed esophageal cancer treated with combined radiochemotherapy (external-beam radiotherapy and chemotherapy with alkylatinlike agents [5-fluorouracil-cisplatin or 5-fluorouracil-carboplatin]) demonstrated that relationships between pairs of voxels, characterizing local tumor metabolic nonuniformities, were able to significantly differentiate all three patient groups (nonresponders [progressive or stable disease], partial responders, and complete responders, p < 0.0006). Significant factors for prediction of response to therapy included the size of nonuniform metabolic regions and the corresponding intensity of nonuniformities within these regions (p < 0.0002). Receiver operating characteristic curve analysis showed that tumor textural analysis can provide nonresponder, partial responder, and complete responder patient identification with higher sensitivity (76% to 92%) than any SUV measurement. Tixier et al.58 concluded that textural analysis of the intratumor tracer uptake heterogeneity on baseline 18F-FDG PET scans can predict response to combined chemoradiation treatment of esophageal cancer patients, and that textural features from PET images provide useful information for personalizing patient management.

Lung Cancer

Lung cancer is the leading cause of cancer mortality worldwide. The most common form of lung cancer is non–small-cell lung cancer (NSCLC). To improve the survival of patients with NSCLC, there has been a focus on earlier diagnosis and, once cancer has been confirmed, on improved treatment selection and planning. At present, a multimodality approach that includes preoperative chemoradiotherapy has been used in the clinical setting. Although complete pathologic response to such NAC and radiotherapy is an important prognostic indicator for prolonged DFS, in fact, it is difficult to evaluate the pathologic factors before biopsy or surgery has been performed.

Presently, the imaging techniques are the ultimate methods for accurate assessment of the impact of preoperative chemotherapy and/or radiotherapy in the clinical setting. As with other tumors, in NSCLC, RECIST14 is widely used for evaluation of therapeutic efficiency. However, it is difficult to distinguish residual tumor from necrosis or fibrosis59 on CT and/or MRI using RECIST because this is based on an anatomic tumor response metric. PET imaging, because focused on functional information rather than anatomy, might overcome these drawbacks and provide better accuracy in monitoring response, given that functional changes are expected to precede morphologic changes.

In recent years, there has been remarkable progress in treatment of NSCLC. Epidermal growth factor receptor (EGFR) has emerged as an important molecular target for advanced or recurrent NSCLC. Reversible EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, were found to have antitumor activities in second- or third-line therapy.60 On the other hand, it has been shown that antiangiogenic therapy targeting the vascular endothelial growth factor (VEGF) signaling pathway (e.g., bevacizumab) provides a survival benefit in patients with solid malignancies, including NSCLC.61 However, response to molecularly targeted agents, including the antiangiogenic therapy, is not necessarily reflected by drug-induced changes in tumor size (Fig. 32.4).62 Therefore, appropriate selection of methods for evaluation of therapeutic efficiency is crucial for effective cancer treatment.

FIGURE 32.3. A 64-year-old man with cancer in middle/lower thoracic esophagus. A: CT (coronal image) before chemotherapy (5-fluorouracil, adriamycin, and cisplatin) shows that the long axis of tumor is 72 mm. B: CT (coronal image) after chemotherapy shows that the long axis of tumor is 59 mm. The reduction rate is 18%. Objective therapeutic response by Response Evaluation Criteria in Solid Tumors (RECIST) is stable disease. Tumor SULpeak before chemotherapy is 7.96 by (C)18F-FDG PET and (E)18F-FDG PET/CT. Tumor SULpeak after chemotherapy is 1.98 by (D)18F-FDG PET and (F)18F-FDG PET/CT. The reduction rate is 75%. Tumor SUL is almost indistinguishable from surrounding background blood-pool levels. Objective therapeutic response by PET Response Criteria in Solid Tumors (PERCIST) is complete metabolic response. There is a difference in response classification between RECIST and PERCIST.

Use of various quantitative PET parameters measuring functional changes induced by treatment for lung cancer has been challenged by using PET imaging with a variety of radiolabeled tracers other than 18F-FDG. Evaluation of therapeutic efficiency using PET/CT with 18F-FDG, 18F-FLT, and H215O are the focus of this section.

Evaluation of Therapeutic Efficiency Using PET/CT with 18F-FDG

PET with 18F-FDG has shown substantial promise during the past decade in aiding in the noninvasive preoperative staging of lung cancer.63 In particular, the widespread implementation of PET/CT with 18F-FDG has allowed not only evaluation of the primary lesion, but also more accurate detection of both nodal and distant forms of metastatic disease.64

When considering the effects of treatment for lung cancer, early prediction of tumor response is crucially important in patients with advanced NSCLC. The majority of patients with advanced NSCLC undergo palliative therapy with platinum-based chemotherapy regimens, which has been demonstrated to improve quality of life and to prolong median OS by approximately 2 months.65

Weber et al.66 examined whether changes in tumor glucose use measured by PET with 18F-FDG allow prediction of tumor response and patient outcome after the first cycle of platinum-based chemotherapy (carboplatin/paclitaxel, cisplatin/vinorelbine, cisplatin/docetaxel, and cisplatin/etoposide). This prospective study demonstrated that effective chemotherapy caused a rapid reduction of tumor glucose use in 57 patients with advanced NSCLC. After one cycle of platinum-based chemotherapy (21 days), a metabolic response seen by PET imaging was significantly correlated with best response to this chemotherapy regimen. In patients without a metabolic response, the response rate was only 4%, whereas it was 71% in patients with a metabolic response. For patients with a metabolic response, the 1-year survival rate was 44%, whereas it was only 10% in patients with no metabolic response. Weber et al.66indicated that PET imaging might be used to predict the clinical outcome of chemotherapy at an early stage of treatment.

FIGURE 32.4. A 62-year-old woman with advanced lung cancer in right upper lobe. A: CT (axial image) before EGFR-TKI therapy (gefitinib: EGFR-TKI = the epidermal growth factor receptor-tyrosine kinase inhibitor) shows that the long axis of tumor is 37 mm. B: CT (axial image) after EGFR-TKI therapy shows that the long axis of tumor is 30 mm. Tumor SULmax before EGFR-TKI therapy is 4.1 by (C)18F-FDG PET and (E)18F-FDG PET/CT. Tumor SULmax after chemotherapy is 1.5 by (D)18F-FDG PET and (F)18F-FDG PET/CT. Reduction of SUVmax (63%) is greater than that of the long-axis size (18%).

In NSCLC, some suggestions regarding prediction of response to neoadjuvant treatment have been presented based on data from PET scans alone or on evaluation of PET and CT scans side by side.66,67 However, none of these investigations has included an analysis of responses of mediastinal lesions and the primary tumor, because of the difficulty in detecting small mediastinal lymph node metastases by PET alone stemming from factors like elevated background activity in the mediastinum or partial volume effects that reduce the value of SUVmax.68

However, Christoph et al.69 analyzed the value of PET/CT during induction chemotherapy (CTx) followed by chemoradiotherapy (CTx/RTx) for NSCLC for predicting the histopathologic response of the primary tumor and mediastinum and the prognosis of the patient. In this study, SUVmax was corrected for background and partial volume effects according to the following formula: SUVmax, corr = background SUVmean + (measured SUVmax − background SUVmean)/recovery coefficient.55 Christoph et al.69 concluded that SUVmax,corr values from two serial PET/CT scans, before and after three chemotherapy cycles or later, allow prediction of histopathologic response in the primary tumor and mediastinal lymph nodes and have prognostic value. The diagnostic information from serial PET/CT scans during the 3-month induction therapy phase is high enough to ascribe to this method a substantial benefit for clinical patient management.69 Therefore, unsuccessful resections, performed in patients having residual disease in multiple lymph node stations because of the off-chance of improving prognosis, may be avoided. Residual disease in the mediastinum might then be targeted by a high-dose conformal radiotherapy boost.

Evaluation of Therapeutic Efficiency Using PET/CT with 18F-FLT

Second-line chemotherapy regimens for treatment of NSCLC have been established70 and new, targeted therapies, such as TKI, have shown activity in patients who progressed after platinum-based chemotherapy.71

In one recent study assessing tumor response to gefitinib, Takahashi et al.72 demonstrated that early determination of SUVmax with 18F-FDG PET after 2 days of treatment could predict clinical outcome earlier than conventional CT evaluation in patients with lung adenocarcinoma. In this way, although determining the SUV and percentage changes of SUVs during treatment are the measures used most widely for advanced NSCLC patients, use of various quantitative PET parameters other than SUV has been recently proposed for measurement of treatment-induced functional changes. There have been some previous reports on tumor treatment response evaluation of total lesion glycolysis (TLG) using 18F-FDG PET, or the analogous evaluation of total lesion proliferation (TLP) using 3′-deoxy-3′-18F-fluorothymidine (18F-FLT-PET).73,74 Determining TLG by 18F-FDG PET and TLP by 18F-FLT PET may be a promising approach, as these parameters represent tumor functional activity and volumetric data. Kahraman et al.75 reported on TLG and TLP for response prediction and prognostic differentiation in patients with advanced NSCLC treated with erlotinib. They assessed metabolic response using different cutoff values for percentage changes in TLG by 18F-FDG PET and in TLP by 18F-FLT PET, which were performed in 30 patients having untreated stage IV NSCLC before the start of therapy, and 1 week (early) and 6 weeks (late) later. Patients with a metabolic response measured by early changes in TLP and late changes in TLG and TLP had significantly better progression-free survival than metabolically nonresponding patients. In cases where use of a 45% cutoff value revealed no significant results, use of a lower cutoff value, of 20% or 30%, for definition of metabolic response resulted in better differentiation between metabolically responding and nonresponding patients. In this study of patients with advanced NSCLC,75 lower absolute early and late residual TLG and TLP levels under erlotinib treatment were more important factors predicting prolonged progression-free survival than were absolute baseline TLG and TLP levels.

Evaluation of Therapeutic Efficiency Using PET/CT with H215O

VEGF, which is overexpressed in many human malignancies, is the most important factor for angiogenesis (formation of new blood vessels), a critical determinant of growth and metastatic spread of tumors.76 Therefore, antiangiogenic therapy targeting the VEGF signaling pathway provides a survival benefit in patients with solid malignancies, including NSCLC. Bevacizumab is a humanized monoclonal antibody that targets circulating VEGF and subsequently prevents binding of VEGF to its receptors.61

Response evaluation of antiangiogenic drugs, however, is often difficult using conventional CT because therapeutic efficiency is not necessarily reflected by drug-induced changes in tumor size.62 Therefore, new imaging tools are needed to accurately assess the efficacy of antiangiogenic drugs. Although Fraioli et al.77 demonstrated that perfusion CT imaging may allow evaluation of lung cancer angiogenesis following treatment, previous studies have shown that quantification of tumor perfusion using radioactive water (H215O) and PET is a promising method to monitor antiangiogenic treatment.78,79

Van der Veldt et al.80 validated the quantitative accuracy of parametric perfusion images in 11 patients who underwent dynamic PET/CT with H215O twice on the same day. Parametric perfusion images were computed using a basis function implementation of the standard single-tissue compartment model, compared between input functions derived from blood sampler data from the radial artery and those derived from the ascending aorta as seen in the images themselves (image-derived input function [IDIF]) (Table 32.3). Volumes of interest (VOIs) were delineated on low-dose CT and parametric perfusion images. As a result, there was good correlation between perfusion values derived from the blood sampler input function and IDIF (Pearson correlation coefficient, r = 0.964; p < 0.001). The variability of tumor perfusion between a test and a retest was 16% and 20% when delineated on low-dose CT and parametric perfusion images, respectively.80 Van der Veldt et al.80 concluded that it was feasible to assess tumor perfusion in patients with NSCLC by dynamic H215O PET performed on a clinical PET/CT scanner, and that the use of an ascending aorta time–activity curve as the input function was an accurate alternative to arterial blood sampling. Figure 32.5 shows data from a patient with advanced lung cancer who underwent dynamic PET/CT with H215O twice, before and after chemotherapy (carboplatin, paclitaxel, and bevacizumab).

TABLE 32.3

FUNCTIONAL IMAGING MODELa

In general, antiangiogenic drugs such as bevacizumab are assumed to contribute to improved delivery of subsequent chemotherapy by transiently normalizing abnormal tumor vasculature. There was a recent investigation of this concept using PET and 11C-labeled docetaxel in 10 patients with NSCLC by Van der Veldt et al.,81 who reported a rapid and significant reduction in perfusion and 11C-docetaxel uptake after treatment with bevacizumab, and suggested that the clinical relevance of these findings was notable, because the study did not provide evidence for a substantial improvement in drug delivery to tumors, but rather showed an effect opposite to assumption. The group concluded that these findings highlighted the importance of drug scheduling and advocated further studies to optimize scheduling of antiangiogenic drugs.

Lymphoma

Because malignant lymphomas are characterized by systemic involvement, they are said to require exploratory examination of the whole body. Diagnosing the extent of the lesions and staging are necessary for deciding on the approach to treatment and predicting prognosis. Diagnosis by measuring lesion size, done primarily by CT, a morphologic diagnostic imaging method, is standard practice. However, as a result of the development and widespread adoption of PET and combined PET/CT in recent years, it is now possible to obtain functional information as well as anatomical information, and opportunities to perform PET/PET-CT to evaluate the extent and activity of malignant lymphoma lesions have increased.

Most histologic types of malignant lymphomas accumulate the glucose metabolism tracer 18F-FDG, because cell density is relatively high.82 These are often depicted by 18F-FDG PET/PET-CT, which has a high lesion detection rate.83 In 2007, the International Working Group in the United States published the revised International Workshop Criteria (revised IWC), which include the use of 18F-FDG PET. New criteria for evaluation of response to treatment of malignant lymphomas by PET and guidelines related to PET examinations were proposed, and firm criteria are anticipated.84

Staging of Lymphomas

It is well established that 18F-FDG PET is superior to65 gallium-citrate scintigraphy.85 Use of 18F-FDG PET has high sensitivity and specificity for malignant lymphoma diagnosis, and PET has the advantage of depicting lesions that are difficult to spot by other diagnostic imaging methods, such as lesions invading liver or spleen, and lesions in unexpected sites.8688 Moreover, although pathologic diagnosis by biopsy is essential for making a definitive diagnosis, PET, which makes it possible to conduct a whole-body evaluation in a single examination, also facilitates detection of lesions suitable for biopsy.

FIGURE 32.5. A 64-year-old man with advanced lung cancer in right upper lobe. A: CT (axial image) before chemotherapy (carboplatin, paclitaxel, and bevacizumab [antiangiogenic therapy targeting the vascular endothelial growth factor signaling pathway]) shows that long axis of tumor is 38 mm, which is almost the same on (B) CT (axial image) after chemotherapy. However, by PET, H215O accumulation (white circle) (D) after chemotherapy is lower than that (C) before chemotherapy.

18F-FDG accumulation by malignant lymphomas varies considerably according to the histologic type (Fig. 32.6). Two histologic types, diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), have avid 18F-FDG uptake, and because complete cures can be expected, more accurate staging by PET is recommended.84 Performing PET for diagnosis before treatment of these histologic types enables more precise assessments of responses to treatment (Fig. 32.7). On the other hand, because relatively large amounts are also taken up by two other histologic types, follicular lymphoma (FL) and mantle cell lymphoma (MCL), high rates of lesion detection by PET have been reported.83 However, because 18F-FDG accumulation by these histologic types is not uniform and no improvement in the survival rate in response to treatment can be expected, performing PET to monitor progress is not strongly recommended at present.84 Because 18F-FDG accumulation is not uniform in any of the histologic types other than the two mentioned above, the usefulness of PET to monitor treatment is uncertain, and performing PET is not recommended. Nevertheless, because 18F-FDG PET is an excellent means of evaluating activity, PET diagnosis is said to be effective when assessing the response to treatment of only those cases in which it has been possible to confirm abnormal accumulation at lesion sites by PET before treatment.

FIGURE 32.6. 18F-FDG accumulation in malignant lymphomas is variegated. A: Maximum intensity projection (MIP) image of a diffuse large B-cell lymphoma case. The invasive lesions in the left axillary lymph nodes and the spleen have high 18F-FDG accumulation (SUVmax = 13.6). Diffuse light accumulation in bone marrow was seen, but the invasion by lymphoma cells was not confirmed by subsequent bone marrow biopsy. B: MIP image of a Grade 3 follicular lymphoma case. The invasive lesions in abdominal lymph nodes have moderately strong 18F-FDG accumulation (SUVmax = 6.2). C: MIP image of a mucosa-associated lymphoid tissue lymphoma case. The nodal lesions appearing in the diaphragm (top and bottom) have mild accumulation (SUVmax = 4.9).

FIGURE 32.7. A 72-year-old man with diffuse large B-cell lymphoma presented for 18F-FDG PET/CT scans before and after chemotherapy. This patient had bilateral widespread nodal lesions with strong accumulation by 18F-FDG PET/CT (A) before therapy; (B) scan after therapy revealed complete resolution of disease. This patient continues to be in a complete remission 2 years after therapy.

However, caution is required, because PET diagnosis also has limitations. PET is not very reliable for judging bone marrow infiltration, irrespective of the histologic type of malignant lymphoma, and evaluation by bone marrow biopsy is desirable.89 Lesions are poorly depicted by PET (false-negatives) in some tissue types, such as mucosa-associated lymphoid tissue (MALT) lymphoma and T-cell lymphoma (in which 18F-FDG PET has low sensitivity). There are limits to the use of PET to depict small lesions, under 1 cm in diameter, and limits according to the morphology of the involvement (influence of the partial volume effect of the PET scanner) must also be kept in mind. Therefore, assessments need to be made in combination with other examination modalities, as appropriate.90 In addition, normal physiologic accumulation occurs in organs such as the brain, liver, tonsils, and intestine, in the urinary tract in association with excretion, and in noncancerous brown adipose tissue and muscle, so care must be taken not to mistakenly diagnose these as abnormal accumulations.

Assessment of Treatment Response

The goal of treating malignant lymphomas is to induce a remission, but additional treatment is necessary in cases in which a remission is not achieved, and so it is necessary to assess the response to treatment accurately. In the past the response of malignant lymphomas to treatment was evaluated by using IWC on the basis of morphologic methods, principally CT examinations.91 However, malignant lymphomas are often treated by combining radiotherapy with chemotherapy as the principle treatment, and under those circumstances scar tissue tends to form after treatment. This residual mass, mainly composed of necrosis or fibrosis, is seen after therapy in one-third of patients with NHL and two-thirds of those with HL.91,92 Consequently, even when treatment has been effective clinically, because of the presence of residual masses and soft tissue densities on CT images, evaluations of complete remission unconfirmed (CRu) are often made, and the actual response to treatment remains unclear.

PET diagnosis based on cell metabolism, on the other hand, makes it possible to confirm abnormal 18F-FDG accumulation at sites where residual tumor is present, and it is useful for distinguishing this from posttreatment changes (Fig. 32.8). The ability to do so is also linked to being able to mitigate the risk of performing excessive additional treatment. It has been reported that, in patients with aggressive lymphomas, a comparison of IWC assessments (largely based on the size of the masses) with PET assessments (based on 18F-FDG accumulation) revealed that even when masses and soft tissue densities remained, the recurrence rate was low if 18F-FDG accumulation was no longer seen.92

In 2007, the revised IWC were published, and 18F-FDG PET was included as a method to assess response to treatment. Per the revised IWC, evaluations are made on the basis of a combination of lesion size and 18F-FDG accumulation after the completion of treatment, but an assessment of complete remission (CR) is made when abnormal FDG accumulation has completely disappeared, even if lesions remain visible on CT scans. On the other hand, when new abnormal accumulation has developed, an assessment of progression of disease (PD) is made. The revised IWC take into account the impact on 18F-FDG accumulation of associated inflammation or necrosis after chemotherapy or radiotherapy, and there is a rule regarding the optimal time for scanning: At least 3 weeks after the completion of treatment, but, if possible, after an interval of 8 to 12 weeks. There is also a report claiming that semiquantitative evaluation by measuring the SUV, which indicates the degree of 18F-FDG accumulation, is useful; however, at present, visual evaluation is sufficient, and abnormal accumulation is said to be present if accumulation is greater than that in the mediastinal blood pool, which is used as the standard.84 In the revised IWC it is recommended that response to treatment be assessed by PET for patients with DLBCL and HL (the two histologic types in which there is avid 18F-FDG accumulation and CR is considered the endpoint of treatment), and that the status of the tumors after treatment be determined accurately. For other histologic types, it is recommended that PET be used to assess the response to treatment only in cases in which it was possible to confirm 18F-FDG accumulation at lesion sites by PET before treatment was started.

FIGURE 32.8. A staging 18F-FDG PET/CT prior to chemoradiotherapy for a 51-year-old man with Hodgkin lymphoma—(A) and (B) CT images; (C and D) PET images; (E and F)18F-FDG PET/CT images. A, C, E: Images before treatment show strong accumulation in enlarged right axillary lymph nodes. B: The soft tissue mass persisted after treatment but was smaller. D, F: Because there was no 18F-FDG accumulation at follow-up, the situation was defined as a complete response. This patient continues to be in a complete remission 18 months after therapy.

The number of cases in which a CR is achieved, according to the revised IWC, which incorporates the use of 18F-FDG PET, is expected to increase, but caution is also necessary in regard to the problem of false positives in cases in which inflammation persists after treatment and in cases in which colony-stimulating factors, such as granulocyte colony-stimulating factor (G-CSF), have been administered. Assessments must be made after taking into account the patient’s hematologic examination findings and medication history, among other factors.

In recent years, it has been reported that early assessments of response to treatment by PET during the treatment period were found to be associated with subsequent outcome.93,94 Because PET is capable of detecting changes in tumor metabolism that occur before morphologic changes develop, it has the advantage of allowing assessment of response to treatment at an earlier stage, and is highly useful clinically. Nevertheless, there are the problems of the timing of performance of the examination, standardization of the evaluation criteria, and false positives as a result of inflammation associated with treatment; at the present time the usefulness of PET examinations during the course of treatment is uncertain. Reports of future results are eagerly awaited.

Follow-Up Evaluation After Completion of Therapy

Malignant lymphomas are characterized by repeated remissions and relapses, and regular follow-up examinations are necessary. Ordinarily, history taking, the physical findings, and hematologic examination findings, including soluble interleukin-2 receptor (sIL-2R) and lactate dehydrogenase (LDH) measurements, are said to be useful. There seem to be many institutions where CT is performed as an imaging examination, but no consensus has been achieved as to the usefulness of performing regular follow-up imaging examinations. Although there are some reports that 18F-FDG PET/PET-CT provides helpful information for recurrent search and prognostic value in HL, aggressive NHL and FL, the role of the surveillance 18F-FDG PET/PET-CT is not established.90,92,9597 The report of the large-scale prospective cohort study is anticipated.

In summary, 18F-FDG PET/PET-CT is a useful noninvasive imaging modality for staging, restaging, and assessment of response to treatment in patients with malignant lymphoma. Interim and surveillance 18F-FDG PET/PET-CT scanning may improve malignant lymphoma patient outcomes.

Breast Cancer

NAC has been used as a primary therapeutic strategy in patients with locally advanced breast cancer. Evaluation of the response to NAC is predominantly based on the changes in tumor size using the RECIST criteria, in which tumor size is measured in one dimension with the longest diameter in the plane of measurement. In some circumstances, it may be difficult to distinguish viable tumor tissue from necrotic or fibrotic scar tissue when using ultrasound and mammography.98,99 In the newest version of the RECIST criteria (version 1.1),4 PET may be considered to support CT for confirmation of complete response (CR). Specifically, similar to the use of biopsy, 18F-FDG PET may be used to upgrade a response to a CR in cases in which residual radiographic abnormality is thought to represent fibrosis or scarring. However, many recent studies have shown that 18F-FDG PET also allows assessment of tumor biologic response at an early stage after the beginning of treatment and that 18F-FDG PET allows noninvasive visualization and quantitative assessment of many biologic processes that are modulated during therapy and that generally precede morphologic changes.100104 Avril et al.105 reported a positive correlation between pretreatment 18F-FDG uptake and breast cancer cell proliferation. Recently, several studies have demonstrated a correlation between early changes in the SUVmax and the final pathologic response after completion of NAC.101,106109 Early prediction of the final pathologic response to NAC might afford an opportunity to change to a more effective therapy and thereby avoid the toxicity and cost of ineffective therapy. Absence of residual cancer cells in the primary tumor following NAC is strongly associated with improved DFS and OS. However, the ability to implement early 18F-FDG PET as a surrogate marker for treatment efficacy in clinical practice remains unclear because of substantial heterogeneity of results across studies. This may be, in part, because of the difference in study design, including the timing of early 18F-FDG PET evaluation, the histologic criteria, the phenotypic diversity of breast cancer, the definition of pathologic response, the method used for SUV determination, the type of SUV, and the cutoff determination of SUV.

In current clinical practice, immunohistochemistry is used to define subgroups with different therapeutic responses and outcome. We will discuss three broad groups: Estrogen receptor (ER)-positive, human epidermal growth factor receptor type 2 (HER2)-positive, and triple-negative tumors (i.e., when ER, progesterone receptor (PgR), and HER2 are all negative). Neoadjuvant endocrine therapy has gained wide acceptance for ER-positive breast cancer because of its recognized efficacy in the adjuvant setting and the fact that conventional cytotoxic chemotherapy may be less effective in ER-positive breast cancer. Most hormone-positive tumors have low FDG uptake. Schwarz-Dose et al. reported that low early 18F-FDG uptake in ER-positive tumors was predictive of a poor response to NAC. Serial 18F-FDG PET studies have shown that an early increase in 18F-FDG uptake in response to an estrogen agonist predicted the response to endocrine therapy and subsequent patient outcomes,110,111 suggesting that this metabolic flare could be a marker for the activation of estrogen signaling in the tumor. The chemosensitivity of ER-positive tumors can vary but is mostly limited and pathologic CR (pCR) is rarely obtained in this group. Approximately 40% of patients with ER-positive breast cancer do not show an objective clinical response to neoadjuvant endocrine therapy. In the GeparTrio trial, pCR was obtained in 10% of the patients with positive hormonal status when compared with 43.2% in the group of negative hormonal receptor tumors. Because of low histologic CR of ER-positive patients, it is critical to identify factors that can predict chemosensitivity. The development of ER imaging agents for PET, of which the most successful has been 18F-16a-17b-fluoroestradiol (FES), appears to be worthwhile. Indeed, the tumor uptake of FES appears to predict the clinical response to endocrine therapy.

Approximately 20% of breast cancers overexpress HER2, a finding that is associated with a positive response to the anti-HER2 antibody, Herceptin(trastuzumab) (Fig. 32.9). In the setting of neoadjuvant therapy, the addition of trastuzumab to conventional cytotoxic chemotherapy improves the rate of CR and event-free survival. In a study by Buzdar et al.,112 the pCR rate was 65% in the patients receiving trastuzumab plus anthracyclines and taxanes and was 26% for patients who did not receive trastuzumab. A recent preclinical study showed a significant decrease in 18F-FDG uptake at 2 weeks after beginning trastuzumab therapy in tumors overexpressing HER2.113 However, clinical information is lacking, because most of the clinical studies evaluating the role of 18F-FDG PET monitoring of neoadjuvant therapy did not study trastuzumab or did not independently analyze patients receiving trastuzumab in association with chemotherapy when compared to patients receiving only conventional chemotherapy.104

FIGURE 32.9. A 71-year-old woman with right breast cancer. A: CT (axial image) before chemotherapy (5-fluorouracil, paclitaxel, and trastuzumab [molecularly targeted agent that inhibits HER2 protein]) shows that the long axis of tumor is 60 mm. B: CT (axial image) after chemotherapy shows that the long axis of tumor is 30 mm. Tumor SULmax before chemotherapy is 7.8 by (C)18F-FDG PET and (E) 18F-FDG PET/CT. Tumor SULmax after chemotherapy is 1.7 by (D)18F-FDG PET and (F)18F-FDG PET/CT. Reduction of SUVmax (78%) is greater than that of the long-axis size (50%).

Nearly 15% of breast cancers have a triple-negative phenotype. In contrast to the two preceding groups, no targeted therapy is currently available for this tumor phenotype; thus, conventional cytotoxic chemotherapy is used for triple-negative tumors. Patients with triple-negative breast cancer have a higher pathologic response rate to anthracycline-based treatment when compared to patients with non–triple-negative breast cancer.114,115 The rate of disease recurrence is high in this group despite high chemosensitivity. The poorer prognosis of triple-negative breast cancers might be related to a higher likelihood of relapse in those patients in whom pCR is not achieved.115 For patients with hormone-positive breast cancer, obtaining pCR is less critical in terms of survival.

Timing of 18F-FDG PET

Chemotherapy may cause an initial increase in 18F-FDG uptake because of the activation of energy-dependent cellular repair mechanisms. McDermott et al.106 performed 18F-FDG PET at baseline, after one cycle, at the midpoint and at the endpoint of chemotherapy. They suggested that the most appropriate time to evaluate the response to chemotherapy with 18F-FDG PET was between the end of the first cycle and the midpoint of chemotherapy. Three teams suggested that the optimal time to perform the early evaluation was immediately before the third cycle.100,103,109 In a study by Schwarz-Dose et al.,101 the authors reported that relative changes in SUV after the first and the second cycle of chemotherapy are a strong predictor of response irrespective of whether 18F-FDG PET was performed after the first or second cycle. When comparing different studies, we can observe that the decrement in the SUV value occurs rapidly during the first part of treatment, and, even if the decrease in SUVmax continues up until the end of chemotherapy, the curve tends to flatten out toward the end of it gradually. Therefore, performing 18F-FDG PET after the second cycle might be a good compromise that still allows a switch to an alternative therapy at an early stage in the event that the tumor is not responding to the regimen. Thus, assessment of tumor response should not be performed until several weeks after initiation of chemotherapy.116

Several meta-analyses have evaluated the accuracy of 18F-FDG PET for the prediction of response to NAC in patients with breast cancer. Cheng et al.117 assessed the comparative utility of 18F-FDG PET/CT and 18F-FDG PET and reported that the pooled sensitivity to predict histopathologic response in primary breast lesions was 0.847 and 0.826, respectively, whereas the specificity was 0.661 and 0.789, respectively. They concluded that 18F-FDG PET/CT and 18F-FDG PET have reasonable sensitivity in evaluating the response to NAC in breast cancer; however, the specificity was relatively low. Wang et al.118 also reported similar results with their meta-analysis; to predict the histopathologic response in primary breast lesions by 18F-FDG PET, the pooled sensitivity and specificity was 84% and 66%, respectively, and subgroup analysis showed that performing a post-therapy 18F-FDG PET early (after the first or second cycle of chemotherapy) was significantly better than that conducted at later time points (accuracy 76% versus 65%, p = 0.001). Furthermore, the best correlation with pathology was yielded by employing a RR cutoff value of SUV between 55% and 65%.

MRI also provides functional imaging techniques, such as dynamic contrast-enhanced MRI and diffusion-weighted imaging, which all show promising results as surrogate markers of the response to neoadjuvant therapy in patients with breast cancer. Tateishi et al.119 reported that 18F-FDG PET/CT and dynamic contrast-enhanced MRI performed after two cycles of NAC allowed prediction of the pathologic response in patients with breast cancer. The sensitivities of %SUVmax (66.7%) at 18F-FDG PET/CT and dynamic contrast-enhanced MRI after two cycles of NAC were not acceptable, but the specificities (96.4%) were high for stratification of pCR cases among patients with breast cancer.

For the accurate evaluation for the prediction of response to NAC in patients with breast cancer, serial PET examinations should be performed in the same center with the same instrumentation, and standardization of procedures is needed (e.g., imaging protocol, method of attenuation correction, and algorithm of reconstruction, etc.). New PET tracers might also play a role in the prediction or early evaluation of the response to therapy. For example, 18F-FLT, an analog of thymidine, is the most extensively studied, and 18F-FLT uptake is dependent on the cellular activity of thymidine kinase.120,121 The combination of PET and other functional imaging techniques available in the field of breast cancer (such as ultrasound and MRI) is another promising approach to facilitate the monitoring of the response of breast cancer to neoadjuvant therapy.

CONCLUSIONS

In conclusion, the treatment response after chemotherapy, radiotherapy, and their combination has been evaluated as tumor size change by CT and MRI and more recently as metabolic alterations by 18F-FDG PET or PET-CT. New tracers more specific to viable residual cancer cells are now being developed, including a marker of protein metabolism and nucleic acid metabolism. Moreover, PERCIST has been proposed as a new standardized method for quantitative assessment of metabolic tumor response. It is very important not only to select an effective treatment but also to evaluate treatment response appropriately, to better manage cancer patients for prolonged survival and for preserving quality of life.

FUTURE CONSIDERATIONS

As mentioned above, the current state of response to treatment evaluation in patients with cancers of the brain, lung, esophagus, and breast, as well as malignant lymphoma is summarized by the type of PET tracers used. The current treatment for these tumors is diversified and it is necessary to select a tracer that can properly evaluate the characteristics of the drug used, especially for molecular-targeted drugs. In particular, hematopoietic system malignancies, such as malignant lymphoma, tend to be more highly susceptible to chemotherapy than other solid cancers, so it is predicted that the tumor metabolism changes rapidly with treatment. This feature means that the choice of this therapy is spreading, and a technique to precisely evaluate early treatment response is needed. The clinical significance of obtaining metabolic information by PET/CT in addition to anatomical information will become more and more important in the future. Moreover, the definition of a responder, such as reduced SUV, has varied among the many studies performed previously. In the future, it is essential to optimize the timing for post-treatment PET evaluation and the criteria used to define therapeutic effect.

ACKNOWLEDGMENTS

The authors thank Seiki Hamada, MD, PhD, and Mamoru Furuyashiki, RT, of the Jinsenkai MI clinic for providing some images for use in this chapter.

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