Japanese Journal of Clinical Oncology Advance Access published online on August 2, 2007
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hym072
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© 2007 Foundation for Promotion of Cancer Research
Influence of Delayed Tumor Clearance on Reliability of Complete Response Rate in Chemoradiotherapy for Head and Neck Cancer
1 Radiation Oncology Division
2 Gastrointestinal Medical Oncology Division
3 Head and Neck Surgery Division
4 Diagnostic Radiology Division, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
For reprints and all correspondence: Mitsuhiko Kawashima, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. E-mail: mkawashi{at}east.ncc.go.jp
Received March 12, 2005; accepted March 23, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONMETHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Objective: The relationship was studied between the timing of assessment of complete response and ultimate cure rate in the chemoradiotherapy of advanced head and neck cancer.
Methods: A retrospective review was conducted regarding tumor responses at 4 weeks, 3 months, and 6 months after concomitant chemoradiotherapy using cisplatin and 5-FU for 70 patients with stage III/IV squamous cell carcinoma of the oropharynx, hypopharynx and supraglottic larynx. Predictive values of tumor responses at these three time points for survival and tumor control at 2 years were tested using the chi-square test.
Results: Twelve (17%) patients achieved complete response (CR) at 4 weeks. Because of late regression or early recurrence, the CR rate changed to 18/70 (26%) and 24/70 (34%) at 3 and 6 months, respectively. CR or not at 6 months was significantly correlated with all survival endpoints (P < 0.001), but not those at 4 weeks and 3 months (P > 0.100). Kaplan–Meier estimate of overall survival at 5 years was 63% (95% CI 43–84%) for 24 CR patients at 6 months.
Conclusion: CR rate at 6 months was a better surrogate endpoint than that at 4 weeks or 3 months in this series of patients.
Key Words: head and neck cancer • chemoradiotherapy • response rate • surrogate end point
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INTRODUCTION |
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TOPAbstractINTRODUCTIONMETHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Recent advances in chemoradiotherapy (CRT) for head and neck cancer have resulted in a modest but significant improvement in overall survival for patients with this disease (1,2). However, improvement is still needed in local–regional and systemic tumor control after CRT. The concomitant administration of chemotherapy involving platinum derivatives with accelerated fractionation radiotherapy (RT) with or without neoadjuvant chemotherapy is currently being investigated (3–12), and more recently, the effectiveness of taxanes (13,14) and/or molecular targeting agents (15) is gaining interest. These developments, as well as advances in the technology of RT delivery such as intensity-modulated RT, have led to an urgent need for improved methodology enabling rapid and appropriate estimation and comparison of safety and efficacy for a wide variety of therapeutic approaches. The most important and robust endpoint to evaluate the effectiveness of CRT is overall survival rate at specific time points, usually 2–5 years after treatment. The complete resolution of tumor mass at certain time points is generally thought to be a prerequisite for achieving disease-free survival. Therefore, number of phase II and III trials have reported complete response (CR) rates as a surrogate for ultimate outcomes. However, the timing for estimating CR rate varies considerably, or is not even cited in the reports. This retrospective study was conducted to analyze the incidence of slow regression or early recurrence in patients receiving our chemoradiotherapy regimen to provide data to analyze the adequacy of the timing to estimate CR rate as a reliable and more rapidly evaluable end-point for an expected cure rate in patients who received CRT for head and neck cancer.
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METHODS |
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Patients
A chemoradiotherapy protocol was started in June 1995 consisting of cisplatin and 5-FU concomitant with RT (FP-RT protocol) for previously untreated, biopsy-proven stage III/IV squamous cell carcinoma of the oropharynx, hypopharynx and larynx in our institution. From that time to November 2002, 76 medically fit patients out of 179 who underwent RT as a primary treatment for stage III/IV disease received FP-RT with informed consent. Our institutional review committee approved the study design, which involved retrospective review of the patients' medical records. Six patients who were lost to follow-up within 2 years without evidence of tumor recurrence were excluded from the analyses. Patient characteristics are listed in Table 1. Tumors were re-staged according to the TNM Classification 6th edn (UICC 2002). Median diameter of the primary tumor and largest nodal disease on pretreatment computed tomography (CT) or magnetic resonance imaging (MRI) were 5 cm (range, 2–11 cm) and 4 cm (0–12 cm), respectively. Sixty patients (86%) had at least one tumor of
5 cm in maximum diameter at the primary and/or nodal stations, and otherwise eight patients (11%) had primary and/or nodal disease of 4 cm.
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Treatment
FP-RT consisted of RT with 2 Gy once daily fractionation concomitant with bolus infusion of cisplatin (40 mg/m2) on days 1 and 8 along with continuous infusion of 5-FU (200 mg/m2/day) from days 1 to 5 and 8–12 of RT. The dose was prescribed at the center of the gross tumor volume (GTV) of the primary tumor. Two weeks of planned split was set after administering 30 Gy/3 weeks, and the same treatment was repeated once thereafter. Primary tumor and involved lymph nodes were irradiated to a total dose of 60–72 Gy with 40–46 Gy of elective nodal irradiation covering the entire neck and retropharyngeal lymph node area using 6 MV X-ray. A 9–11 MeV electron beam was also used for selected lymph node regions as indicated. Twenty patients (17%) who were treated in the early period were prescribed a total RT dose of 60 Gy. They were also included in this study.
Evaluation of Response
A follow-up visit was requested at least once every 2 months within 2 years after completion of RT, and once every 3–6 months thereafter. Tumor responses at 4 weeks (4W), 3 months (3M) and 6 months (6M) post treatment were defined based on clinical examinations at these time points and CT/MRI studies were done at the nearest date of these time points with the assistance of a board-certified, experienced head and neck diagnostic radiologist. CT and/or MRI were planned at 4W, 3M and 6M, and once every 6 months thereafter. However, the actual CT/MRI studies were done at the time shown in Table 2 because of the congested examination schedules. Slice thickness of 5 mm was adopted for reconstruction of CT images, and 7 mm in axial and coronal images for MRI. Patients whose tumors could be directly evaluated by clinical examination, such as those located at the lateral wall of the oropharynx without nodal metastasis, were assessed for their response by physical examination alone, and complementary radiographic examinations were performed as indicated. This situation occurred mainly in patients who were defined as non-CR at any of the time points. There were patients who were defined as CR at the earlier time points and remained disease-free at the last follow-up. Because of the retrospective nature of this study, they were defined as CR at later time points even though they did not receive radiological examinations. Chest X-ray was done at intervals of 6 months, and other examinations including CT of the thorax and abdomen, gastrointestinal endoscopy and bone scan were performed as indicated.
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Definition of tumor response was classified as follows: complete response (CR), no clinically and radiologically detectable residual tumor; partial response (PR), clinically and/or radiologically detectable residual tumor with at least 30% decrease in the sum of the longest diameter of the tumor; and progressive disease (PD), at least a 20% increase in the sum of the longest diameter of the tumor. Otherwise tumors were defined as no change (NC). All patients were defined as PD when newly developed lesions at the head and neck or distant stations were observed. Complete disappearance of the disease after salvage surgery including neck dissection for residual disease was also defined as CR after these interventions in this series. The term ‘delayed response’ was defined as CR at 6 M although the tumor did not show CR at 4 W or 3 M.
Outcome Measures and Statistical Considerations
The relationship between overall survival (OS), local–regional recurrence-free survival (LRS), recurrence-free survival (RFS) at 2 years and tumor responses at 4 W, 3 M and 6 M were evaluated with the chi-square test. OS, LRS and RFS were calculated using the Kaplan–Meier method. Patient death of any cause was defined as an event in calculating OS. Tumor recurrence above the clavicle or patient death of any cause was defined as an event in estimating LRS. Tumor recurrences at any site or patient death of any cause were defined as events in calculating RFS. Statistical difference of survival curves was evaluated with the log-rank test.
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RESULTS |
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Outcomes of Treatment
Actual total radiotherapy dose administered to the tumor and involved nodes ranged from 28 to 72 Gy (median, 66 Gy). Twenty-one patients (30%) failed to receive
66 Gy because of early death or disease progression in two, aggravation of general condition because of far advanced disease or advanced age in nine, and physicians' discretion as described above in 10. All patients were followed up for more than 2 years or until death. A median follow-up period for surviving patients was 67 months (range, 25–103 months). Estimated OS rate at 2 and 5 years for all patients was 36% (95% confidence interval, 24–47%) and 21% (11–31%), respectively. LRS and RFS at 2 years were 25% (15–35%) and 21% (11–30%). At the time of this analysis in December 2005, 16 patients were still alive and disease-free. Two patients died of causes other than the index cancer, i.e. one died at 58 months due to malignant lymphoma of the stomach, and the other at 30 months due to gastric cancer. Otherwise all patients died of cause-specific deaths. Two patients underwent salvage surgery for recurrence of the primary tumor at 5 and 8 months after completion of RT, and survived without recurrence for 17 and 48 months thereafter. Otherwise eight patients received neck dissection for residual or recurrent nodal disease at 2–9 months and three patients were successfully salvaged for more than 5 years.
Methods for Evaluating Tumor Response
All but one patient who achieved CR, including those who showed delayed response, underwent confirmatory CT/MRI around the first time points when they were defined as CR as listed in Table 2. One patient with T4N0 disease at the lateral wall of the oropharynx, which was directly visible and palpable by physical examination, was evaluated as CR at 4 W without radiological examination. This patient survived and was radiologically disease-free for 6 years. One patient underwent salvage surgery at 5 months for residual primary tumor that revealed pathological CR, and two patients received neck dissection for residual nodal disease at 2 and 4 months. All of the three patients who underwent salvage surgery were classified as CR at 6 M.
Tumor Response
Tumor responses at 4 W, 3 M and 6 M are shown in Table 2. CR was achieved in 12 patients (17%) at 4 W, and overall response rate (CR + PR) at 4 W was 66/70 (94%). Of 66 patients who achieved CR or PR at 4 W, 32 (48%) experienced recurrence or early death within 6 months of completion of the treatments. Details of the time course of tumor response or recurrence are illustrated in Fig. 1. CR rate at 6 M increased to 24/70 (34%), whereas the response rate declined to 34/70 (48%).
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Of 24 patients who achieved CR at 6 M, 14 (58%) showed delayed response and three (13%) resulted in CR after salvage surgery. An example case showing delayed response is demonstrated in Fig. 2. As a whole, six (25%) and 13 (54%) patients experienced delayed responses at the primary and nodal stations without surgical interventions, respectively. There was no statistically significant relationship between maximum diameter of the primary tumor and occurrence of delayed response. On the other hand, 12 of 13 patients (92%) with nodal disease of
4 cm that resulted in CR at 6 M showed delayed response, while nine of 10 patients (90%) with nodal disease of <4 cm that achieved CR at 6M did not show delayed response (P < 0.001, Mann–Whitney U-test).
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Relationship between Tumor Response and Outcomes
OS, LRS and RFS at 2 years according to tumor response at 4 W, 3 M and 6 M are shown in Tables 3–5. Chi-square test showed whether or not CR only at 6M had a statistically significant correlation with OS, LRS and RFS at 2 years. Of note, no patients survived without disease for 2 years or longer who failed to achieve CR at 6 M. Kaplan–Meier estimations of OS according to the tumor response at 4 W, 3 M and 6 M are shown in Fig. 3. OS rate at 5 years for patients who achieved CR at 6 M was 63% (95 CI, 43–84%), while no patients survived for more than 4 years who failed to achieve CR at 6 M (CR versus non-CR at 6 M, P < 0.001). Ten patients were assessed as PR at 6 M; however, all of them died of cause-specific death subsequently because of local–regional failure in 7 and distant failure in 3. For patients achieving CR at 6 M, there was no statistically significant difference of OS, LRS and RFS between those who showed early and delayed responses (P > 0.200). There were three patients who were classified as achieving delayed response after surgical salvage, one revealed pathological CR at the primary and nodal stations, and two had residual cancer cells at nodal stations in the surgical specimens. All three patients survived without recurrence for more than 2 years after surgery. The statistical significance shown in Tables 3–5 or Fig. 3 were not changed when these three patients were excluded from the analyses.
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DISCUSSION |
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TOPAbstractINTRODUCTIONMETHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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The frequency of slow regression of the tumor after RT for head and neck cancer and its biological and clinical implications have been reported and discussed in the literature for many decades (16–20). Table 6 shows the results of CRT in a number of prospective trials with definition of the timing for response evaluation. Needless to say, primary endpoints for these studies were overall survival or local–regional tumor control, and tumor responses were regarded as reference materials for effectiveness of the CRT regimens. However, delayed response that were observed in this study, as well as in the previous reports (16,19), may confound the meaning of response rate for estimating anti-tumor effect in certain CRT regimens when description of the exact time point for evaluation is varied. Our retrospective study showed that large nodal disease demonstrated delayed responses more frequently. These findings are consistent with the results of an extensive review by Bataini et al. (19) regarding tumor clearance rate after RT alone that was measured mainly with physical examination for non-nasopharyngeal head and neck cancer. They showed that time–response curves of individual nodal radioresponsiveness in 708 patients with controlled primay with RT might reach a plateau 6 months after irradiation. They stated that a response evaluation at earlier time points, or even before completion of RT, was appropriate to estimate cure rate, especially in consideration of the safety of possible salvage surgery for resectable disease. Nevertheless, more than 30% of patients who were categorized as ‘poor risk’ in their classification achieved ultimate tumor control without surgical salvage (18,20,22). The most important and, to our knowledge, previously unrecognized finding in this study was that no patients were cured who failed to achieve CR that was confirmed by modern radiographic examination with uniform response criteria at 6 M.
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The CRT regimen in this study is currently considered inadequate in terms of the relatively low doses of cisplatin and 5-FU compared with that used in recently conducted trials, as well as the existence of a planned split in RT. Less than 66 Gy of total RT dose was given in some patients according to the discretion of the treating physicians. Most of the patients had far advanced, large and unresectable disease at the time of initial presentation, and these factors may also have impacted poor survival, local–regional control rate and time course of tumor regression in this study. We abandoned this protocol, and the possibility of more rapid tumor regression using more aggressive chemotherapy regimen and RT fractionation remain to be studied. However, it is unlikely that more intensive treatment may reduce the incidence of delayed responses, when we assume that this phenomenon reflects slow clearance of non-cancerous cells, i.e. necrotic debris and interstitial cells, rather than that of surviving cancer cells themselves (16,19). The time points that defined 4 W, 3 M and 6 M were not the times when radiological examinations were conducted, but when clinical evaluations were performed. Radiological study is considered to be the most important tool in evaluating tumor response, especially for nodal disease (23). Nonetheless, all of the lesions evaluated were directly visible or palpable in clinical examinations, and the evaluations were not performed by a single physician, but discussed between a team of experienced head and neck surgeons, radiation oncologists and medical oncologists at the same time. Therefore we believe that our method for response evaluation was sufficient to support our hypothesis that the most appropriate timing for determining CR rate was 6 M, instead of the earlier time points. There were three patients who achieved ‘delayed response’ after surgical salvage and survived without recurrence for more than 2 years. This implied that cancer-free status at 6 M was a prerequisite for long-term survival in this group of patients, while principal results in this study were not changed when these three patients were excluded from the analyses. Chi-square tests (Tables 3–5) were done because of the retrospective nature of this study, owing to which we could have clinical information for all patients at minimum follow up period of 2 years. The difference in survival that was shown in Fig. 3 seemed more important and, therefore, the reliability of the CR rate at 6 M that was observed in this retrospective observation needs to be evaluated further in prospective studies. Another possible issue may be that positron-emission tomography with [18F] fluorodeoxyglucose (FDG PET) was not utilized during this study period. Preliminary results have suggested that FDG PET was useful in providing prognostic information and early detection of recurrence in patients receiving CRT for head and neck cancer (24,25). Yao et al. reported 100% negative and 43% positive predictive value for expecting nodal failure using FDG PET 12 weeks after completion of definitive RT for patients with head and neck cancer (24). Early detection of recurrence is more important in patients suffering from this disease, as observed in three patients who underwent early salvage interventions and enjoyed long-term survival. Therefore whether the integration of PET in evaluating CR rate at earlier time points provides more reliable prognostic information and appropriate detection of patients who require surgical salvage are very important issues to be considered in future prospective studies.
In conclusion, a certain percentage of patients with advanced head and neck cancer showed delayed responses or early recurrences within 6 months in this series of patients. A statistically significant predictive value of CR rate was observed only when it was estimated at 6 months post CRT. It required a long period of time, i.e. 6 months, to estimate tumor cure using CR rate in clinical examination with CT/MRI images. Therefore the role of biological imaging to facilitate the estimation of viability of tumor mass at an earlier time point was emphasized. Standardization of reporting the CR rate may facilitate early and accurate execution of phase I/II trials and interim analysis of phase III trials as well. It seemed reasonable to consider CR rate at 6 M as one of the most reliable surrogate end points for expecting tumor cure, especially in studies involving patients with large nodal disease.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONMETHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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Footnotes |
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This study was presented at the 47th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Denver, CO, 16–20 October 2005. 
* Present address: Jichi Medical University, Tochigi, Japan.
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References |
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TOPAbstractINTRODUCTIONMETHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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