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© 2003 American Society for Clinical Oncology Preoperative Mitomycin, Ifosfamide, and Cisplatin Followed by Esophagectomy in Squamous Cell Carcinoma of the Esophagus: Pathologic Complete Response Induced by Chemotherapy Leads to Long-Term Survival
From the Birmingham Heartlands Hospital and Cancer Research UK, Trials Unit, Institute of Cancer Research, University of Birmingham, Birmingham, United Kingdom. Address reprint requests to S.J. Darnton, PhD, Department of Thoracic Surgery, Birmingham Heartlands Hospital, Birmingham B9 5SS, United Kingdom; e-mail: jane.darnton{at}heartsol.wmids.nhs.uk.
Purpose: Squamous cell carcinoma of the esophagus remains an aggressive disease with a poor prognosis, even after curative-intent surgery. This article analyzes the impact of preoperative chemotherapy with mitomycin, ifosfamide, and cisplatin (MIC) on a cohort of 68 patients. Patients and Methods: From 1988 to 1994, 68 patients with potentially operable squamous cell carcinoma of the esophagus were entered onto two phase II trials of neoadjuvant chemotherapy with mitomycin 6 mg/m2, ifosfamide 3 g/m2, and cisplatin 50 mg/m2 and received between two and four cycles of treatment at 3-weekly intervals. Two patients were removed from the analysis when they were found to have malignancy other than squamous cell carcinoma of the esophagus.
Results: Forty (61%) of 66 patients had a radiologic response to chemotherapy (18 complete responses and 22 partial responses), and 52 (79%) of 66 patients went on to have the primary tumor resected. There were nine pathologic complete responders, seven of whom remain fit and well after at least 60 months of follow-up. The overall median survival was 12.4 months (95% confidence interval, 9.6 to 18.8 months). The complete response and node-negative patients survived significantly longer than those in other categories (log-rank Conclusion: MIC is an easily administered, well-tolerated, and efficacious regimen as neoadjuvant therapy for patients with squamous cell carcinoma of the esophagus. These results warrant further investigation.
CARCINOMA OF the esophagus is an aggressive disease with an overall 5-year survival rate of 6.3% and a 5-year survival after curative-intent surgery of approximately 20%.1 Until 2002, the gold standard of care for operable esophageal cancer was surgical resection. Although surgery can lead to cure of early cases in which there is no regional involvement, the high probability of intra and extra-thoracic relapse has led to the development of approaches incorporating either preoperative chemotherapy or chemo-irradiation. Such strategies seek to downstage the primary tumor and to eliminate potential systemic micrometastases, thus improving patient survival. The Medical Research Council (MRC) OE02 randomized phase III trial of surgery with or without preoperative chemotherapy in resectable cancer of the esophagus has, however, demonstrated a survival advantage at 2 years for patients receiving chemotherapy before surgery (43% compared with 34% for surgery alone).2 Several studies have shown that improved disease-free and overall survival, resulting from neoadjuvant chemotherapy, are only achieved in patients who have an objective response to treatment. There is a particular advantage for those who achieve a pathologic complete response (pCR), ie, no tumor found on examination of the resected specimen.3,4 Undoubtedly, one of the difficulties with this approach is the low activity of the cytotoxic regimens used. The most widely used combination is cisplatin and an infusion of fluorouracil over 4 or 5 days.2,5 In the Intergroup Trial,5 the regimen produced a radiologic response rate of only 19% and a pCR rate of only 2.5%, with high toxicity and poor compliance. The authors of OE02 conducted a systematic search for randomized trials of preoperative chemotherapy, both published and unpublished. These small trials when summated (total of only 1,227 patients) did not allow clear conclusions about the benefit or harm of neoadjuvant chemotherapy for esophageal carcinoma to be drawn. The disappointing response rates observed in chemotherapy trials predating MRC OE02 have persuaded some investigators to add radiotherapy to the preoperative treatment. Geh6 has pooled the results of 46 nonrandomized trials (2,704 patients) of neoadjuvant chemoradiotherapy (CRT) and calculated an average pCR rate of 24%. This pCR rate has been at the expense, however, of worrisome levels of morbidity and mortality. Meta-analysis is necessarily compromised by the heterogeneity of histologies, regimens, and treatment schedules. In the European Organization for Research and Treatment of Cancer randomized trial of CRT and surgery versus surgery alone, there was such a high postoperative mortality rate in the CRT arm (12%, compared with 4% in the surgery-alone arm) that, though the pCR rate was 26%, any overall survival benefit possibly owing to the treatment was negated.7 Disease also usually recurs at distant sites after CRT plus surgery.1 This pattern of recurrence emphasizes that the low activity of the systemic chemotherapy used is the limiting factor in improving long-term survival. The majority of neoadjuvant chemotherapy trials in carcinoma of the esophagus have used identical chemotherapy schedules to treat the two main histologic types, squamous and adenocarcinoma. Previously, results of two sequential phase II trials of two and four preoperative cycles of mitomycin, ifosfamide, and cisplatin (MIC) in potentially resectable squamous cell carcinoma of the esophagus have been published by our group.8,9 This three-drug combination was first established as an active treatment for non–small-cell lung cancer and remains one of the most active combinations known in that disease.10 This regimen is well tolerated by patients with esophageal cancer. The radiologic response rate after neoadjuvant treatment of squamous cell carcinoma with MIC is, at 61%, the best result reported for any regimen in this disease site and histologic type. In this article, we have analyzed the radiologic and pathologic responses to MIC chemotherapy and the long-term survival data for the cohort of 66 patients studied in the previous two trials.
Patient Population Between 1988 and 1994, 68 patients were recruited into two sequential phase II clinical trials based at three centers, Birmingham Heartlands Hospital, Birmingham; The Royal Victoria Hospital, Belfast; and Belvoir Park Hospital, Belfast. All participating patients gave informed consent. The total cohort could be pooled for review because the patients enrolled in the two historical studies had identical entry criteria and received the identical MIC regimen. The eligibility criteria were histologic diagnosis of squamous cell carcinoma of the esophagus, creatinine clearance greater than 60 mL/min, normal liver function tests, hemoglobin greater than 10 g/dL, WBCs greater than 3.0 x 109/L, platelets greater than 150 x 109/L, radiologically assessable disease by barium swallow, and no previous malignancy. Patients with inoperable disease detected on computed tomography (CT) scans were excluded from the analysis, but those found to be inoperable with curative intent at laparotomy were included in the analysis. Endoscopic ultrasound (EUS) was not available at the time of the study. In the first study, radiologic reassessment was by CT and barium swallow at 3 weeks after the completion of the second course of chemotherapy. In the second study, radiologic reassessment was by barium swallow at 3 weeks after the completion of the second course of chemotherapy. Responders (complete response [CR] and partial response [PR]) proceeded to further courses of MIC and were reassessed by barium swallow 3 weeks after completion of the final course (cycle 3 or 4). Historically, only barium swallow (following the criteria of Miller et al11) was routinely available for the repeat radiologic assessment needed across these cases.
Two patients were excluded from long-term analysis: one because of previous treatment for breast cancer and one because the histopathology of the resected specimen (although described as squamous carcinoma on biopsy) proved, on resected pathology, to be a carcinoma of neuroendocrine type. The characteristics of the 66 patients considered in the present analysis are given in Table 1
The combination of mitomycin 6 mg/m2 (intravenous bolus), ifosfamide 3 g/m2 (intravenous infusion over 3 hours), and cisplatin 50 mg/m2 (intravenous infusion over 1 hour, with hydration administered before and after cisplatin infusion) was given as an inpatient regimen that was repeated every 3 weeks. It was intended to use a total of two or four cycles in the two trials. The second and subsequent cycles of chemotherapy were given if the WBC count was greater than 3.0 x 109/L and platelets were greater than 100 x 109/L. Surgery was planned for 3 weeks after the completion of the final cycle of chemotherapy or when recovery from chemotherapy allowed. Total thoracic esophagectomy was performed, with a standard two-field lymphadenectomy to include extensive sampling of the mediastinal and left gastric artery territories. Upper gastrointestinal continuity was re-established by interposition of the stomach with a cervical anastomosis as described by Matthews et al.12 Resected specimens were opened longitudinally, pinned out on a cork board, and mapped before processing. Sufficient full-thickness blocks were taken to sample tumor or to include entirely a volume previously occupied by tumor (in pCR cases). The consultant histopathologists sought diligently to isolate the maximum number of nodes from the resected specimens. Blocks were fixed routinely in formol saline and processed to paraffin wax. Sections were reported by a consultant histopathologist and graded and staged according to the International Union Against Cancer system.13 Postoperative surveillance consisted of outpatient visits commencing 8 weeks after surgery, then every 3 months for 1 year, then annually, or as indicated by clinical need. Patients symptomatic of recurrence received urgent follow-up. Recurrence at the primary site or at distant sites was detected by appropriate means, such as chest x-ray, barium swallow, CT, ultrasound examination, or endoscopy and biopsy. Survival and recurrence data were obtained from hospital records and the West Midlands Cancer Intelligence Unit, University of Birmingham, Birmingham, United Kingdom.
Statistical Analysis
Toxicity and survival data were collected from all 66 patients. Patient characteristics are given in Table 1  . The sex of the study sample was almost equally distributed (48% of the patients were male and 52% were female). Patients had a median age of 64 years. Toxicity was low, and there were no preoperative deaths. One patient, intended to receive two cycles of MIC, had only one cycle (an emergency resection was needed after esophageal dilatation and perforation). Forty-three patients completed two cycles. The decision to give second or further courses of MIC was based on the total WBC count. In patients receiving two cycles of chemotherapy, there was no delay to treatment or to surgery. Three patients, intended to receive four cycles, had only three cycles and proceeded to surgery. One of these patients had dysphagia resistant to dilatation, and two patients had prolonged neutropenia: one of these required RBC transfusion before surgery. Of the 19 patients completing four cycles, one had a delayed third course (because of chest infection), and two had a delayed fourth course (one because of low WBC count and one because of chest infection). No patient had a dose modification, and no patient had surgery delayed by hematologic toxicity. Nineteen patients completed four cycles.
The radiologic responses to MIC chemotherapy are given in Table 2
The histopathologic status of the 52 resected patients is shown in Table 2 . Overall, nine (14%) of 66 patients had a pCR. Lymph nodes sometimes prove impossible for the pathologist to detect macro- or microscopically after chemotherapy. This was the case in two patients. In the other seven pCR cases, the number of nodes examined was one, three, five, five, six, seven, and 11. Eight of the pCR cases were radiologic complete responders on barium assessment, and one was read as a partial responder. Thirty-two patients (48%) were found to be node-negative but had residual cancer in the resection specimen. Twenty-five patients (38%) were categorized as other pathologic category (N1 or not resected). In terms of extension beyond two courses of MIC, two of the patients who had achieved radiologic PR after two courses improved to radiologic CR after four courses and proved, after resection, to be pathologic complete responders. In this present review, numbers are small, but in the 52 patients who underwent resection, the pCR rate was five (15.6%) of 32 of those receiving two courses, one of three receiving three courses, and three (18.8%) of 16 of those receiving four courses of MIC.
There were seven postoperative deaths (six within 30 days of operation). Of these seven, only three had curative-intent surgery (one patient was explored and found to be unresectable, and in three patients, the surgeons deemed the resection to have been macroscopically incomplete). Fifty-two (79%) of the 66 patients had died by the time of analysis. At the time of censure (December 2000) all patients surviving had been followed up for at least 6 years. Median survival of all patients was 12.4 months (95% CI, 9.6 to 18.8 months). Two-year and 5-year survival were estimated at 33.3% and 25.8%, respectively. Survival for the group of patients who underwent resection was 42.3% at 2 years and 32.7% at 5 years. Survival estimates are given in Table 3
Patients with a radiologic response (CR or PR) survived 13 months longer on average than nonresponders (21.6 v 9.0 months;  2LR = 11.2; P < .001; Table 3 and Fig 1 ). Thus the cohort conformed to the expected pattern where responders have a better outcome.
Survival curves for patients with a pathologic category CR or N0 versus any other category are shown in Fig 2 . The CR and N0 patients survived significantly longer than patients in other categories (2LR = 18.8; P < .001). The combined CR and N0 patients survived on average 13 months longer than patients in the N1 or nonresected category (22.0 v 9.4 months; Table 3 and Fig 2). Of the 14 patients (21%) still alive, seven had achieved a pCR and seven were categorized as N0. Of the nine pCR patients, seven are still alive and disease free: one patient who had achieved pCR died at 22.0 months of pneumonia with hepatic recurrence, and one patient died at 60.6 months of a noncancer cause with cancer (of unstated source) known to be present.
A summary of the clinical progress of the patients is given in Table 4 . After surgery, 17 patients survived beyond the operative period and died subsequently from esophageal cancer: eight of distant relapse and eight of local-regional disease by direct invasion of the airways or anastomotic region, with one patient lost to follow-up. The distant sites were multiple in five patients and single in three patients. The sites involved were five recurrences to lung, three to distant lymph nodes, two to liver, two to bone, one to peritoneum, and one to skin.
This article is a combined analysis of two previous cohorts of patients with operable squamous cell cancer of the esophagus treated with neoadjuvant chemotherapy. We emphasize response as judged primarily by the pathologic response rate, the assessment of which is unequivocal. The two studies were carried out at a time when barium swallow was routinely used for assessment of response to chemotherapy. CT was not used for all cases, and EUS was not available. We can therefore describe radiologic response only on the barium swallow assessment. We report a pCR rate of 14%, which is appreciably higher than that of the pCR rate of 4% found for the fluorouracil/cisplatin treatment used in the MRC OE02 study.2 The latter did, however, exhibit a significantly improved overall patient survival versus control because it enrolled more than 800 patients, giving it more power than any other clinical trial of induction therapy in this disease. The OE02 chemotherapy followed by surgery cohort comprised mixed histologies (31% squamous carcinoma and 66% adenocarcinoma), and the specific survival by histology of the pCR cases was not given. Although the overall pCR rate was low, there was better microscopic clearance and less involvement of lymph nodes in the chemotherapy and surgery arm (58% v 68% in the surgery-alone arm; P = .009); thus downstaging by chemotherapy could have contributed to the survival advantage. The inclusion of mixed histologies renders any exact comparison of our review of two phase II studies with the results of OE02 impossible. Comparing chemotherapy plus surgery with surgery alone in the latter, there was an overall extension in survival time from 13.3 months to 16.8 months. Our pCR cases had a durable survival (seven of nine patients were alive at 60 months). This review includes patients treated in the period of 1988 to 1994. The participating centers treat patients on a tertiary and regional basis, and early-stage tumors rarely present. The median age at presentation was 64 years (range, 23 to 77 years). MIC toxicity was low, and there were no treatment-related deaths. The overall postoperative death rate of 11%, though high by present standards, is not dissimilar from that of 10% seen in both arms of the MRC OE02 trial2 or from the published historical (1992 to 1996) rate of 10% for patients (n = 1,125) resected with or without neoadjuvant treatment in the West Midlands region of the United Kingdom.15 During recent years, neoadjuvant CRT has been the subject of numerous phase II studies (reviewed by Geh et al1). It is important to stress that CRT should only be accepted into mainstream oncologic practice after the publication of large, randomized, controlled trials. Although pilot trials of preoperative CRT in carcinoma of the esophagus have led to some optimism because of pCR rates of up to 38% in resected specimens and an improved median survival relative to historical controls, the improvements in survival promised by this approach have not materialized in randomized trials. Thus the phase II pilot data of one group indicated a median survival of 29 months in 43 patients,4 but in the subsequent phase III randomized trial, the CRT group had a median survival of only 16.9 months, causing the trial to be abandoned early, with no survival advantage of CRT over surgery alone. This was despite a pCR rate of five (38%) of 13 in the cases with squamous histology.16 Furthermore, three other randomized trials exploring the CRT approach, incorporating a total of 456 patients, are entirely negative.7,17,18 The sole randomized trial reporting a survival advantage19 included only 113 patients and reported a median survival in the surgery arm of 11 months, far below the 15 to 18 months usually reported. Furthermore, although local recurrence is decreased by the addition of radiotherapy to chemotherapy, the pattern of relapse is distant in half the cases studied. This is because carcinoma of the esophagus is a metastatic disease in the vast majority of patients at presentation.20 Even patients who present with apparently local disease usually have distant metastases, as evidenced by results of postmortem studies21,22 and by the pattern of relapse of patients treated with surgery alone. Another worrisome element is that although modern CRT can secure excellent local control, it is at the expense of considerable toxicity. Hospital admission for parenteral feeding has been reported, as have treatment-related deaths.4 A retrospective Japanese study23 of definitive CRT on a cohort of 139 patients (81% were stages T3 and T4) produced an overall radiologic CR rate of 56% and a 5-year survival rate of 29%, comparable with surgery. However, they experienced high levels of both acute and late toxicities. There were three treatment-related deaths. Only 63 of the cohort were alive at 24 months and 24 patients had late toxicity, notably pericardial effusion (median time of onset, 15 months) and pleural effusion (median time of onset, 19 months). Eight patients of the 24 with late complications died without cancer recurrence, with cause of death perhaps related to cardiopulmonary toxicity. A further consideration is that interventional treatment for late toxicities affects the quality of life of surviving patients. The optimal CRT regimen has not been defined and until that time, CRT should not be considered standard of care,6 certainly not as a replacement for surgery. Further refinement of the CRT approach using more effective chemotherapy regimens and conformally planned radiotherapy may in the future reduce toxicity and improve results in patients undergoing esophageal resections with curative intent. After meta-analysis of current regimens, however, CRT has been recommended for the palliative treatment of patients with small localized esophageal carcinoma, in whom resection is not possible.24 However, as chemotherapy alone increases survival of patients with esophagogastric cancer, it would be of interest to conduct a trial of CRT versus chemotherapy to see if the radiotherapy is necessary at all. The pressing need in the treatment of potentially resectable carcinoma of the esophagus is to develop better systemic therapy that will simultaneously address local and systemic control25 balanced against acceptable levels of morbidity and mortality.16 Assessment of the activity of chemotherapy agents in carcinoma of the esophagus has been hampered by both the limitations of radiologic staging and by the frequent inclusion of both squamous and adenocarcinomas in trials. It has been previously postulated that the natural history of the two histologies may be inherently different.26 The poor results of treatment with MIC chemotherapy in patients with esophageal adenocarcinoma27,28 reinforce this view and as a result, we consider that MIC should be restricted to tumors of squamous histology. In the MRC OE02 trial,2 there was no evidence that the effect of fluorouracil-based chemotherapy on survival varied by histology, and the relatively low pCR rate of 4% was not stratified by histologic type. The most active drugs against esophageal squamous carcinoma include fluorouracil,29 cisplatin,30 bleomycin,31 methotrexate,32 paclitaxel,33 irinotecan,34,35 and ifosfamide. Because of the limitations of single agents, combinations have been developed. Combined cisplatin and fluorouracil is the most widely used regimen. In the American randomized trial,5 only 467 patients, with adenocarcinoma and squamous cell cancer, were randomly assigned. Radiologic response to chemotherapy was not assessed, and a pCR rate of only 2.5% and a 2-year survival rate of 35% were reported. These results were broadly in line with those of the MRC OE02 trial, but because the chemotherapy used is of relatively low activity, the protocol decision to give only two preoperative courses of chemotherapy (v three in the American trial, plus two additional cycles postoperatively) was probably an inspired decision. The MRC protocol delivered less disadvantage to the nonresponding majority and produced the positive result. There were 66 patients in the analysis we report here. In the first study, reassessment was by CT and barium and in the second, by barium only. These historical methods of radiologic assessment are known to be imprecise. Even now, there is no completely accurate method of radiologic assessment of response to chemotherapy. More modern methods, such as EUS, magnetic resonance imaging, and positron emission tomography, are not 100% accurate against the gold standard of the histopathologic assessment of the resected specimens. Forty (61%) of 66 of our patients were assessed as having responded radiologically, but a macroscopic complete resection (R0) was achieved in only 32 (50%) of 64 who were surgically explored. This is a subjective judgment made by the surgeon at operation, a judgment sometimes made difficult by the presence of periesophageal fibrosis (with no included neoplastic cells found on subsequent histopathologic examination) occurring as a result of the response to chemotherapy. It would be desirable to be able to explore our data with respect to microscopic clearance of tumor burden. Historically, the status of the proximal and distal, but not the radial, resection margins were recorded in the final histopathology reports. Thus it is not possible to give an accurate figure for the percentage of R0 resections. We feel that this analysis rightly places emphasis on survival related to the definitive pCR and N0 status, which are available with accuracy, rather than to the less precise method of gross assessment of R0. With the level of efficacy of current chemotherapy regimens, including MIC, surgery is still an essential component of multimodality therapy for two major reasons. First, a pCR cannot be reliably detected on CT/endosonography. A true pCR can only be established after detailed histology of the resected specimen. Our experience with MIC is that approximately half of radiologic CRs (as judged by barium swallow) will be found subsequently to have cancer in the resected specimen on careful histopathologic examination. Second, approximately one third of the patients who had residual tumor in the resected esophagus, with lymph nodes clear of disease, were alive at 5 years.
Ajani et al36 have expressed the opinion "To achieve the goal of curative resection of locoregional carcinoma in most (if not all) instances and to eliminate or delay metastasis, a chemotherapy regimen resulting in frequent major responses including 10% to 20% pathologic complete responses would be desirable. Moreover, such a regimen would have to limit toxic reactions to an acceptable level with prolonged use." Theoretically then, if a new chemotherapy regimen has low toxicity and induces a pCR rate What makes the MIC regimen so active in squamous cell carcinoma is not entirely clear. The dose of cisplatin is only 50 mg/m2/cycle. This is modest compared with other platinum-based regimens used in this disease site (80 mg/m2/cycle and 100 mg/m2/cycle, respectively).2,5 Mitomycin is an active drug, but it seems likely that the major difference is the use of ifosfamide. The MIC triplet combination is very well tolerated in comparison with regimens that add other drugs, such as irinotecan and mitomycin, to the widely used and studied dual combination of cisplatin and fluorouracil.33–35 In patients with squamous carcinoma, neoadjuvant MIC is active, relatively easy to administer, and of low cost and toxicity. It has also been shown that the majority of responders to preoperative MIC actually gain weight and come to surgery in an improved clinical condition.37 These characteristics would seem to suggest that the MIC regimen is a reasonable choice for use in further extended randomized trials of preoperative chemotherapy before curative-intent surgery for squamous carcinoma of the esophagus. Future studies using MIC should advance from the historical studies to recruit patients with potentially resectable squamous cell carcinoma of the esophagus (after appropriate preoperative endoscopic/CT/EUS/bronchoscopic staging) on a multicenter basis. The trial might test up to four neoadjuvant courses of the MIC regimen against the current United Kingdom gold standard of two neoadjuvant courses of cisplatin and fluorouracil, as used in the MRC OE02 study.2 The primary end points should comprise validated quality-of-life analysis, protocol-detailed histopathologic study of the resected specimen to determine pCR, and long-term survival of the patients.
The authors indicated no potential conflicts of interest.
We thank S.M. Allen, M.H. Cullen, J.P. Duffy, J.A. McAleer, K.G. McManus, H.R. Matthews, R.S. Steyn, and S.J. Walker for their contributions.
S.J.D. was supported by the Oesophageal Cancer Fund, Birmingham Heartlands Hospital, Birmingham, United Kingdom.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10%, it should be regarded as being sufficiently active to be worth testing against conventional therapy in a randomized trial. The pCR rate we report for MIC chemotherapy is nine of 66 patients or 14%, with a low toxicity and no chemotherapy-induced mortality. MIC is thus more active in squamous cell carcinoma than is any previously described preoperative chemotherapy regimen. In terms of survival, that of the entire cohort of 66 MIC-chemotherapy treated patients was 33% at 2 years, a figure not significantly different from most survival figures quoted after definitive CRT for squamous cell carcinoma.
