Japanese Journal of Clinical Oncology Advance Access originally published online on June 16, 2005
Japanese Journal of Clinical Oncology 2005 35(6):316-323; doi:10.1093/jjco/hyi095
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© 2005 Foundation for Promotion of Cancer Research
Clinical Impact of Criteria for Complete Response (CR) of Primary Site to Treatment of Esophageal Cancer
1 Division of Digestive Endoscopy and Gastrointestinal Oncology, 2 Division of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba and 3 Department of Internal Medicine, Saku Central Hospital, Saku, Nagano, Japan
For reprints and all correspondence: Makoto Tahara, Division of Digestive Endoscopy and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. E-mail: matahara{at}east.ncc.go.jp
Received January 25, 2005; accepted May 4, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: With the development of chemoradiotherapy for esophageal cancer, the complete response (CR) rate would become an important surrogate end-point. However, the Response Evaluation Criteria in Solid Tumors (RECIST) do not provide criteria for a response at the primary site of esophageal cancer. The objective of this study was to assess the validity of the endoscopic CR criteria for the primary site of esophageal cancer treated with chemoradiotherapy.
Methods: We reviewed 139 patients with T1–T4, N0–1, M0–1a esophageal cancer treated with definitive chemoradiotherapy from August 1992 to April 1999. CR was tentatively defined upon endoscopic observation of the entire esophagus as: (i) disappearance of the tumor lesion; (ii) disappearance of ulceration (slough); and (iii) absence of cancer cells in biopsy specimens.
Results: CR at the primary site (primary-CR) was achieved in 80 patients (58%). Of these, 71 (89%) were evaluated as having primary-CR within 6 months from the start of therapy. With a median follow-up of 53 months, a remarkable difference in the 5-year survival rate was observed between patients evaluated as having primary-CR and having non-CR (46 and 6%, P < 0.0001). Local failure was observed in 15 patients and the local control rate in patients with primary-CR was 78% at 5 years.
Conclusions: These criteria appear to represent an appropriate surrogate end-point because they are convenient to apply, require only a short time before a primary-CR can be declared and their fulfillment can predict long-term survival. It is recommended that RECIST include precise endoscopic findings for primary lesions in esophageal cancer in the CR criteria.
Key Words: Response Evaluation Criteria in Solid Tumors (RECIST) • esophageal cancer • chemoradiotherapy • complete response (CR) • endoscopy
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Definitive chemoradiotherapy for patients with locally advanced esophageal cancer has resulted in high complete response (CR) rates and has greatly impacted on survival (1–4). Recent results obtained with chemoradiotherapy in clinical trials have supported a new standard of care in non-surgical treatment of potentially curable esophageal cancer. With the development of chemoradiotherapy, the CR rate would become an important surrogate end-point in the treatment of esophageal cancer. However, we are not aware of any published clinical studies on chemoradiotherapy for locally advanced esophageal cancer that have precisely outlined CR criteria for the primary site. Slabber et al. (5) used standard Eastern Cooperative Oncology Group (ECOG) response criteria, which considered gastrointestinal malignancies as ‘non-measurable, non-evaluable’ lesions and defined CR as: (i) complete disappearance of all clinically detectable malignant disease for at least 4 weeks; and (ii) pathological proof of a clinically CR after rebiopsying areas of known malignant disease. The Radiation Therapy Oncology Group (RTOG) phase III intergroup trial (RTOG 85-01) described evaluation after treatment as including esophagoscopy and barium esophagography, with biopsy if the patient was symptomatic (2). However, these methods of evaluation have not been fully validated.
New guidelines, ‘Response Evaluation Criteria in Solid Tumors (RECIST)’, were published in 1999 (6) and have become the most commonly used criteria worldwide. RECIST gives specific size requirements for measurable lesions at baseline to distinguish target from non-target lesions. It is difficult to measure accurately the primary site of esophageal cancer as distinct from the normal esophageal wall in one dimension, because a computed tomography (CT) scan detects a primary lesion of esophageal cancer according to wall thickness of the esophagus. Therefore, the primary site of esophageal cancer is often identified as a ‘non-target lesion’.
Although non-target lesions are taken into account in the evaluation of the best overall response, CR for non-target lesions is defined as the disappearance of all non-target lesions and normalization of tumor marker levels. However, it is impossible to confirm the disappearance of primary site lesions in esophageal cancer by CT scan. Furthermore, development of cicatrical stenosis of the esophagus after chemoradiotherapy often prevents accurate evaluation of tumor response by esophagography, which is usually performed to provide useful information on the degree of luminal narrowing and the location and length of the lesion in the diagnosis of esophageal cancer.
RECIST does not refer to CR criteria for primary lesions by endoscopy in detail, and endoscopic methods of evaluation have not yet been fully validated. Additionally, RECIST has recommended that utilization of endoscopy for an objective tumor response should be restricted to purposes related to validation in specialized centers.
In the treatment of esophageal cancer, we have utilized endoscopy to evaluate tumor response accurately, and propose new endoscopic CR criteria for the primary site of esophageal cancer. Therefore, the objective of this study is to assess the validity of endoscopic criteria for CR of the primary site of esophageal cancer treated with chemoradiotherapy.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENTS
A total of 217 esophageal cancer patients were treated with definitive chemoradiotherapy between April 1992 and April 1999 at the National Cancer Center Hospital East (NCCHE). For this study, we selected 139 patients from the database who fulfilled the following criteria: (i) esophageal cancer patients treated with definitive chemoradiotherapy at the NCCHE between April 1992 and April 1999; (ii) histologically proven squamous cell carcinoma; (iii) clinical stage T1–T4, N0/1, M0/M1a by the International Union Against Cancer tumor node metastasis (TNM) classification; (iv) age
75 years with an ECOG performance status of 2; (v) adequate bone marrow, renal and hepatic function; (vi) no prior chemotherapy; (vii) no severe medical complications; and (viii) no other active malignancies (except early cancer). Patients with non-cervical primary tumors with positive supraclavicular lymph nodes were defined as M1a. Details of the treatment including the schedule and radiation field were described previously (4,7). Briefly, chemoradiotherapy consisted of two cycles of protracted infusion of 5-fluorouracil (5-FU) 400 mg/m2/day on days 1–5 and 8–12, and cisplatin (CDDP) 40 mg/m2 on days 1 and 8, every 5 weeks with concurrent radiotherapy consisting of 60 Gy in 30 fractions over 8 weeks. For patients who showed an objective response to treatment, additional chemotherapy was administered and consisted of protracted infusion of 5-FU 800 mg/m2/day on days 1–5 combined with CDDP 80 mg/m2 on day 1.
PROPOSED ENDOSCOPIC CR CRITERIA
Response at the primary site was evaluated as CR (primary-CR) by endoscopic examination when all of the following criteria were satisfied under observation of the entire esophagus: (i) disappearance of the tumor lesion; (ii) disappearance of ulceration (slough); and (iii) absence of cancer cells in biopsy specimens. When these criteria were not satisfied, a non-CR was designated. Existence of an erosion, a granular protruded lesion, ulcer scar and lugol voiding lesion did not prevent a CR evaluation. The first evaluation was performed 
1 month after the completion of chemoradiotherapy to determine whether or not disease progression was observed. Although repeat assessments were not essential to confirm primary-CR after the criteria for response were first met, endoscopic examinations were performed every 2 or 3 months. All 139 patients were reviewed according to the above criteria. Responses of metastatic lymph nodes were assessed according to the World Health Organization (WHO) criteria for measurable disease.
STATISTICAL ANALYSIS
Overall survival time was determined from the date of the first administration of chemoradiotherapy to the date of death or the last confirmation of survival. Time to locoregional failure was calculated from the date of the first administration of chemoradiotherapy to the date of documented locoregional disease, which was designated as the first failure. Time to determination of a primary-CR was considered to be the period between the date of the first administration of chemoradiotherapy and the date of the first confirmation of primary-CR. Survival analysis was performed using the Kaplan–Meier method (8).
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENT CHARACTERISTICS
Out of 217 patients who received definitive or palliative chemoradiotherapy during the period studied, 78 patients were excluded from analysis. The reasons for exclusion have been described in a previous report of this study population (7). For the present study, 139 patients were selected as subjects. Patient characteristics are shown in Table 1. The median age was 62 years (range 38–75). Most of the patients had good performance status. All had histologically proven squamous cell carcinoma. Fifteen patients had T1, 11 had T2, 60 had T3, 53 had T4 and 38 had M1a disease. Clinically involved sites in the 53 cases of T4 disease were as follows: tracheobronchial tree (n = 21), thoracic aorta (n = 22), both sites (n = 8) and other (n = 2). One hundred and thirty-three patients (96%) completed at least the chemoradiotherapy segment that included a total radiation dose of 60 Gy. Sixty-six patients (47%) received two or more additional cycles of chemotherapy.
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RESPONSE AND SURVIVAL
Primary-CR was achieved in 80 of the 139 patients [58%; 95% confidence interval (CI), 45–70]. Primary-CR rates in patients with T1, T2, T3 and T4 were 93% (14 out of 15), 82% (nine out of 11), 62% (38 out of 61) and 37% (19 out of 52), respectively. Persistence of local disease was observed in 59 patients (42%; 95% CI 31–53). Among the 87 patients with T1–T3, persistence of local disease was observed in 24 patients (28%; 95% CI 16–39). Among the 80 patients with primary-CR, persistence of regional lymph nodes was observed in seven (5%) patients. With a median follow-up of 53 months, the overall survival rate at 3 and 5 years among all patients was 37% (95% CI 31–43) and 29% (95% CI 24–34), respectively. The overall survival at 3 and 5 years was 55% (95% CI 43–67) and 46% (95% CI 36–56), respectively, among the primary-CR group, while overall survival was 11% (95% CI 8–13) and 6% (95% CI 4–8), respectively, among the primary-non-CR group (P < 0.0001, Fig. 1).
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TIME TO DETERMINATION OF A PRIMARY-CR
Time until determination of a primary-CR is provided in Table 2. Of the 80 patients, 71 (89%) were evaluated as having a primary-CR within 6 months from the start of therapy. However, in nine patients (11%), primary-CR was only determined after 6 months from the start of therapy because before that time biopsy specimens from the primary site were not obtained in two patients, disappearance of ulceration (slough) was not observed in three patients due to radiation esophagitis, and cicatrical stenosis of the esophagus was observed in four patients.
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FIRST RELAPSE SITE
The first relapse sites in patients with primary-CR are shown in Table 3. Among the 80 patients with primary-CR, local failure occurred in 15 (19%) patients, including two with both local and distant failure. Local failure was detected within 1 year from the start of therapy in 10 of these 15 patients (67%). Regional failure alone was observed in one patient (1%). Distant failure alone as the first failure occurred in 13 (16%) patients. Twenty-nine patients (36%) experienced treatment failure. Local control in patients with primary-CR is shown in Fig. 2. The local control rate among patients with primary-CR was 78% at 5 years; this curve appeared to plateau after 2.2 years.
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DEATH FROM CAUSES OTHER THAN TREATMENT FAILURE
Acute and late toxicity from this treatment regimen have been described previously (7). Briefly, there were three treatment-related deaths (2%), one each due to renal failure, septic shock or pneumonia. Seven patients (5%) without cancer recurrence died due to late cardiopulmonary toxicity, which was manifested as acute myocardial infarction, radiation pneumonitis or chronic heart failure. Sudden death of unknown origin occurred in three patients without disease failure. Another eight patients died of intercurrent disease. In summary, 19 patients (14%) died from causes other than treatment failure.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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We have proposed new endoscopic CR criteria for the primary site in the treatment of esophageal cancer. The development of cicatrical stenosis of the esophagus with this treatment often prevents observation of the entire esophagus. Therefore, ‘observation of the entire esophagus’ is considered to be necessary for endoscopic evaluation of the response to treatment. In common with the RECIST criteria, ‘disappearance of tumor lesion’ and ‘absence of cancer cells in biopsy specimens’ are indispensable to confirm CR after chemoradiotherapy. When we first began to evaluate CR by endoscopy, it was problematic how to deal with granular protruded lesions, erosions, ulceration and lugol voiding lesions. Granular protruded lesions were often observed with this treatment (Fig. 3). In the course of careful observation and obtaining repeat biopsy specimens from these lesions, local relapse was not observed. Therefore, this granular protruded lesion was considered as a hypertrophic cicatrix and would not prevent determination of a CR. After chemoradiotherapy, local relapses were often detected by endoscopy as ulceration (slough) of the esophagus. Therefore, ‘disappearance of ulceration (slough)’ is indispensable to confirm not only CR but also no recurrence. Chromoendoscopy using iodine solution is the most effective method of detecting squamous cell mucosal cancer (T1a) in the esophagus, which is an appropriate candidate for endoscopic mucosal resection (9,10). Iodine staining is based on a chemical reaction between iodine and glycogen. Glycogen-rich granules are mainly included in the prickle-cell layer of the normal stratified squamous epithelium. Therefore, esophagitis, cicatrix due to an ulcer scar and cancerous lesions that are immature and lose glycogen-rich granules at the prickle-cell layer can be recognized as an uncolored layer which is said to be a ‘lugol voiding lesion’ (Fig. 4). Because biopsy of the lugol voiding lesion makes it possible to distinguish between cancer, erosion due to esophagitis and cicatrix due to ulcer scar, the existence of a ‘lugol voiding lesion’ would not prevent application of the primary-CR criteria.
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The main goal of objective confirmation of the response in clinical trials is to avoid overestimating the observed response rate. However, RECIST described that repeat studies to confirm changes in tumor size may not always be feasible or may not be part of standard practice in protocols where progression-free survival and overall survival are the key end-points (6). In chemoradiotherapy for locally advanced esophageal cancer, a key end-point is survival. Therefore, repeat assessments were not essential in applying this criterion to confirm primary-CR after the criteria for response are first met.
For a surrogate end-point to be an effective substitute for the clinical end-point, the effects of the intervention on the surrogate must reliably predict clinical benefit or harm based on epidemiological, therapeutic, pathophysiological or other scientific evidence (11,12). Furthermore, these surrogate end-points have been used to reduce the cost and duration of clinical trials. Surrogate end-points are rarely, if ever, adequate substitutes for definitive clinical outcomes in phase III trials. Among several explanations for this failure is the possibility that the disease process could affect the clinical outcome through several causal pathways that are not mediated through the surrogate, with the intervention's effect on these pathways differing from its effect on the surrogate. Even more likely, the intervention might also affect clinical outcome by unintended, unanticipated and unrecognized mechanisms of action that operate independently of the disease process (11).
Tumor response frequently has been used as a surrogate end-point in therapeutic trials of advanced cancer. Unfortunately, tumor response is not a reliable replacement outcome for survival (13). Many of the trials that have established treatment effects on this surrogate end-point have not shown any change in mortality rates. Some of the factors contributing to the failure of a surrogate end-point are a low proportion of CRs rather than just partial responses, a low proportion of responses that are truly durable long-term effects and a high likelihood that unintended mechanisms of action from these aggressive and toxic cancer therapies adversely affect survival. When administering chemoradiotherapy for locally advanced esophageal cancer, any cause of death other than from treatment failure was recognized as an unintended mechanism of action that adversely affects survival (11). Therefore, it is reasonable to propose that an adequate surrogate end-point for CR criteria in esophageal tumors should include the following: (i) simple procedure; (ii) short duration to determine a CR; (iii) possibility to predict long-term survival; (iv) low incidence of disease failure; and (v) acceptable incidence of death from causes other than treatment failure.
RECIST has recommended that utilization of endoscopy for objective determination of tumor response should be restricted to purposes of validation in specialized centers (6). No special endoscopic technique is required for meeting the following criteria by endoscopic examination of the entire esophagus: (i) disappearance of the tumor lesion; (ii) disappearance of ulceration (slough); and (iii) absence of cancer cells in biopsy specimens. Therefore, these criteria should be recognized as involving only a simple procedure and should gain wide acceptance.
With this chemoradiotherapy as scheduled, 4 months are needed for completion, and the first evaluation of the primary site for complete response is performed approximately 5 months from the start of therapy. In this study, most of the patients (89%) were evaluated as having primary-CR within 6 months from the start of therapy. This finding suggests that these criteria can be met in a short period of time not only from the start of therapy (mostly within 2 months) but also after completion of therapy (mostly within 2 months) to declare primary-CR.
A remarkable difference in the 5-year survival rate between patients evaluated as having primary-CR and non-CR was observed in this study. Furthermore, persistence of disease was the greatest cause of treatment failure. Therefore, we could predict long-term survival for patients with locally advanced esophageal cancer treated with definitive chemoradiotherapy according to these criteria.
In trials of cisplatin-based concurrent chemoradiotherapy for esophageal cancer, data on clinical outcomes for comparison with the present study were available from only two trials, which were the RTOG 85-01 and INT 0123 trials. The incidence of locoregional failure, distant failure and death from causes other than treatment failure in this study were similar to those in the above trials (3,14), suggesting that the clinical outcomes in this study were acceptable.
The accuracy of endoscopic ultrasound (EUS) for initial staging of esophageal cancer is widely accepted. After chemoradiotherapy, however, EUS examination is not helpful in patient management because it cannot accurately identify patients with pathological CR (15–17). This is largely because EUS cannot distinguish between residual tumor and the post-inflammatory changes that characterize effective chemoradiotherapy. EUS is of limited utility in guiding clinical decision making after chemoradiotherapy.
Recently, a retrospective study showed that EUS and EUS-guided fine needle aspiration biopsy (FNA) have the potential of identifying residual lymphadenopathy after pre-operative chemoradiotherapy (18). However, this result was very controversial because EUS-guided FNA was performed in only eight patients.
[18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET), an emerging imaging technology based on differences in glucose uptake between neoplastic and surrounding normal tissue, has improved the accuracy of clinical staging of untreated esophageal cancer by detecting otherwise occult metastases (19–23). Many studies have reported that [18F]FDG PET is a valuable tool for non-invasive assessment of histopathological tumor response after the completion of neoadjuvant therapy for locally advanced esophageal cancer (24–26). Furthermore, some studies indicated that changes in [18F]FDG uptake or changes in standard uptake value (SUV) were predictive of disease-free survival and overall survival (25–27).
Furthermore, PET/CT is a new imaging modality that provides simultaneous functional and anatomic information. PET/CT has been reported to increase diagnostic confidence compared with either PET or CT imaging alone (28–30). PET/CT also helps in target volume delineation during planning for radiotherapy treatment of esophageal cancer (31,32). Better characterization of the target may improve local control as well as spare normal tissues from radiotherapy sequelae. After therapy, subtle metabolic findings on [18F]FDG PET may result in detection of residual disease after correlation with simultaneously acquired morphologic data. Alternatively, equivocal CT findings, which could represent either recurrent tumor or post-therapy fibrosclerosis, now can be distinguished with the additional information provided by [18F]FDG PET data. In the post-therapy setting, PET/CT might improve the accuracy of PET imaging in distinguishing recurrent disease from benign post-therapy changes. Radiation-induced esophagitis, however, results in false-positive [18F]FDG uptake. Furthermore, because of the limited spatial resolution of PET, lesions <0.5 cm may be undetectable. For these reasons, [18F]FDG PET cannot differentiate partial response from complete response and is of limited utility in guiding clinical decision making after chemoradiotherapy. As PET/CT systems are not yet in widespread use, further studies including comparison with the proposed endoscopic CR criteria or differential evaluation are necessary to establish its role in the evaluation of the response to therapy.
In order to improve local control, many attempts including intensification of radiation dose and accelerated or hyperfractionation radiation methods were made, but all of these methods failed to improve local control or survival (14,33–35). The addition of new agents, other than 5-FU plus cisplatin, may be promising. The addition of paclitaxel to the standard chemoradiotherapy regimen increased the response rate of locally advanced esophageal cancer, with a pathological complete response rate of 38% and an actuarial 3-year survival of 41%, which warrant further investigation (36). The addition of cetuximab, a monoclonal antibody to epidermal growth factor receptor, to high-dose radiation in locoregionally advanced squamous cell head and neck carcinoma resulted in a statistically significant and clinically meaningful improvement in locoregional control and overall survival (37). The use of molecular targeting agents in combination with chemoradiotherapy will be a major focus in future studies, because their toxicity profiles are clearly different from those of cytotoxic agents.
The survival of patients who have residual or recurrent tumor after chemoradiotherapy is dismal, and salvage treatment for such patients is indicated to improve the overall survival. Although some small studies have shown the feasibility and efficacy of salvage surgery, the high mortality associated with salvage surgery after chemoradiotherapy is another important issue. Although the optimal timing and modes of salvage treatment should be investigated in the future, early detection of residual or recurrent tumor that was limited to within the submucosal layer enabled endoscopic mucosal resection (EMR) as a substitute for salvage surgery (38). Photodynamic therapy (PDT) is an experimental cancer treatment modality that selectively destroys cancer cells by the interaction between absorbed light and a retained photosensitizing agent (39). In our experience, PDT was a safe and effective salvage treatment with a CR rate of 62% (40). A phase II trial of PDT for residual or recurrent esophageal cancer after definitive chemoradiotherapy is ongoing at our hospital.
In conclusion, the proposed endoscopic CR criteria appear to represent an appropriate surrogate end-point because they are convenient, require a short period of time (mostly within 6 months) to declare primary-CR, predict favorable survival and are associated with an acceptable frequency of disease failure and death from causes other than treatment failure. The proposed criteria would be of major importance in the process of evaluation of new treatment strategies. Since persistence of disease was the greatest cause of treatment failure for locally advanced esophageal cancer after chemoradiotherapy, it is important to evaluate accurately the tumor response. In the treatment of locally advanced esophageal cancer, moreover, the fact that RECIST does not refer to CR criteria for primary lesions in detail prevents not only appropriate clinical evaluation of response but also the fulfillment of requirements of a clinical trial. We feel that the RECIST criteria do not provide information to evaluate the primary sites of esophageal cancer. It is recommended that the precise endoscopic findings of primary lesions in esophageal cancer be added to the CR criteria in RECIST.
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Notes |
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Presented at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO).
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References |
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