Annals of Surgical Oncology Cite Track
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10.1245/ASO.2006.01.001
Annals of Surgical Oncology 13:214-220 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Induction Cisplatin and Paclitaxel Followed by Combination Chemoradiotherapy with 5-Fluorouracil, Cisplatin, and Paclitaxel Before Resection in Localized Esophageal Cancer: A Phase II Report

Leonard R. Henry, MD1, Melvyn Goldberg, MD1, Walter Scott, MD1, Andre Konski, MD2, Neal J. Meropol, MD3, Gary Freedman, MD2, Louis M. Weiner, MD3, Perry Watts, MSIS4, Mary Beard, BA, CTR, CCRP5, Susan McLaughlin, RN, CCRP5 and Jonathan D. Cheng, MD3

1 Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111
2 Department of Radiation Oncology, Fox Chase Cancer Center 333 Cottman Avenue, Philadelphia, Pennsylvania 19111
3 Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111
4 Department of Biostatistics, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111
5 Office of Protocol Management, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111

Correspondence: Address correspondence and reprint requests to: Jonathan D. Cheng, MD; E-mail: j_cheng{at}fccc.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Multimodality therapy for esophageal cancer holds promise for improving outcome in this lethal disease. On the basis of encouraging data from a phase I trial, we conducted a phase II study of preoperative chemotherapy, followed by concurrent chemoradiotherapy and surgery.

Methods: Patients with clinically staged resectable esophageal cancer were treated with induction cisplatin and paclitaxel, followed by 45 Gy of external beam radiation with concurrent infusional 5-fluorouracil and weekly cisplatin and paclitaxel. Four to eight weeks after multimodality induction, esophagectomy was performed in suitable patients. Study end points were survival, pathologic complete response, and toxicity.

Results: Twenty-one patients were enrolled with a median age of 58 years, and all patients were clinically staged II or III. Sixteen (76.2%) patients completed the trial, of whom four (25%) had a pathologic complete response. One patient died from postoperative complications. Grade 3 or 4 toxicity was observed in 76% of patients, and dose-limiting toxicity was seen in 6 of the first 14 patients, thus necessitating a planned dose reduction of paclitaxel. At a median follow-up of 30 months, 13 patients remain alive. The 2-year disease-specific survival for the study population was 78%.

Conclusions: This regimen of multimodality therapy before resection resulted in an encouraging 2-year survival rate but a disappointing rate of pathologic complete response and was toxic, necessitating a predetermined paclitaxel dose reduction. The incorporation of taxanes into induction strategies for esophageal cancer seems promising, but the optimal schedule remains undefined.

Key Words: Esophageal cancer • Induction • Neoadjuvant • Management • Toxicity


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cancer of the esophagus, although less common in the United States, remains a lethal malignancy. With mortality rates roughly equivalent to incidence, significant improvements are needed in current treatment regimens. Surgical resection, chemoradiation, or trimodality therapy of surgery and chemoradiation are the accepted treatment options for localized esophageal cancer. Although treatment provides varying degrees of local tumor control and palliation of symptoms, long-term survival, unfortunately, remains poor.

Given that most patients with localized esophageal cancer succumb to their initially occult metastatic disease, one of the principal benefits of delivering optimal chemotherapy before definitive local treatment in esophageal cancer is the early treatment of occult distant micrometastasis at presentation. This may be advantageous because the probability of a tumor’s resistance to chemotherapy likely increases with increasing tumor size.1 In addition, giving systemic therapy up front may also benefit patients who might not be able to tolerate it after an esophagectomy.

Local failure rates after surgery alone are high. Esophageal cancer is characterized by extensive local growth, invasion, and a propensity for regional lymph node metastasis. Radiotherapy decreases the risk of local failure. The use of radiosensitizing doses of chemotherapy during radiotherapy (concurrent chemoradiotherapy) has been demonstrated to further increase both local control and survival.2–4

Walsh et al.5 demonstrated an improved survival with induction chemoradiotherapy for esophageal cancer in a randomized controlled trial. Bosset et al.6 similarly showed an improved disease-free survival in patients treated with induction therapy, although overall survival was not changed.

Furthermore, using induction strategies allows assessment of the efficacy of treatment by examining the resected histological specimens. Studies suggest that a pathologic complete response (CR) to induction chemotherapy and radiotherapy accurately predicts improved disease-free survival and overall survival in patients undergoing esophageal resection.7,8

The optimal regimen of induction therapy would yield a high rate of pathologic CR while not exposing the patient to untoward toxicity. Traditionally, 5-fluorouracil (5-FU) and cisplatin have been the standard agents. Paclitaxel has demonstrated efficacy against esophageal cancer in patients with metastatic disease.9 The search for a more effective induction regimen with acceptable toxicity has recently resulted in the publication of several small trials incorporating new agents (such as paclitaxel) in the preoperative treatment of patients with esophageal cancer. These trials have demonstrated encouraging results with regard to therapeutic index, pathologic CR, and early overall survival.10–13

We have also explored the use of paclitaxel in an induction strategy for patients with esophageal cancer. Goldberg et al.14 recently reported the results of a phase I study that demonstrated an encouraging 4-year disease-free survival of 45% in patients treated with an intensive regimen of preoperative chemoradiation (60 Gy plus 5-FU, paclitaxel, and cisplatin) with consolidation chemotherapy (paclitaxel and cisplatin) after resection. Acute toxicity and postoperative complications were common and thought to be due to the aggressive three-drug chemotherapy regimen and high radiation dose of 60 Gy. Furthermore, only 3 of 22 patients tolerated postoperative adjuvant chemotherapy in this study, and this prompted the change of the chemotherapy administration to the preoperative setting, as well as dosage adjustments. This study was a phase II trial that used lower radiation doses and delivered all chemotherapy before surgery in an attempt to build on the encouraging survival results from our phase I trial with less toxicity. The end points were overall survival, disease-free survival, pathologic CR, and toxicity.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Criteria for eligibility included biopsy-proven, potentially resectable (T2/3, N0/1) adenocarcinoma, squamous cell carcinoma, adenosquamous or undifferentiated carcinoma involving the esophagus or gastroesophageal junction, and ability to give informed consent. The presence of a positive celiac node by computed tomographic (CT) scan was exclusionary unless the node was histologically confirmed to harbor no cancer. Additional exclusionary criteria included neutropenia (absolute neutrophil count <1800/µL), thrombocytopenia (<100,000/µL), renal insufficiency (creatinine >1.5 mg/100 mL or creatinine clearance <60 mL/min), and abnormal bilirubin (>1.5 times the upper limit of normal) or aspartate aminotransferase (>3 times the upper limit of normal). The Institutional Review Board at Fox Chase Cancer Center approved the protocol. Informed consent was obtained for all patients.

Treatment Schema
CT scanning of the chest, abdomen, and pelvis and endoscopic ultrasonography (EUS) were used to stage the primary tumor. However, EUS was not successfully performed in 7 of the first 10 patients. Liver function tests and barium swallow were also obtained in all patients. Additional studies were obtained at the discretion of the attending physicians. Treatment was initiated with cisplatin (75 mg/m2) and paclitaxel (175 mg/m2) given every 3 weeks for two cycles. Repeat CT scanning of the chest, abdomen, and pelvis was obtained. In patients without disease progression, concurrent chemoradiation began 3 weeks after completion of induction chemotherapy and consisted of 45 Gy (1.8-Gy fractions) given Monday through Friday for 5 weeks. 5-FU (200 mg/m2/day) was administered via continuous infusion throughout the duration of radiotherapy. Cisplatin (25 mg/m2) and paclitaxel (50 mg/m2/day) were administered weekly on days 1, 8, 15, 22, and 29 of radiotherapy. Patients with resectable disease (T0 to T3, any N, M0) then underwent resection 5 to 8 weeks after completion of combined chemoradiotherapy. Tissue was obtained and reviewed from biopsy samples at diagnosis, before chemoradiation, and from the operatively resected specimen.

Toxicity, Complications, and Dose Adjustments
Toxicity data were gathered prospectively on all patients. Operative complication data were collected prospectively on the 16 patients who underwent esophagectomy on study. Operative death was defined as death within 30 days of operation or within the initial postoperative hospitalization. The Common Toxicity Criteria Version 2.0 scored toxicity. Dose-limiting toxicity (DLT) was defined as toxicity necessitating a 2-week interruption of treatment, grade 3 toxicity persisting over 2 weeks, or any grade 4 nonhematological toxicity. Paclitaxel dose modification was planned after evaluation of the first 14 patients and was targeted to achieve DLT in 20% of patients. If no DLTs were observed in the first 14 patients, the dose of paclitaxel would be increased to 60 mg/m2. Conversely, if 5 or 6 DLTs were observed, the paclitaxel dose would be decreased from 50 to 40 mg/m2, and more than 6 DLTs would have resulted in termination of the trial after 14 patients.

Assessment of Response
A clinical CR was defined as complete resolution of all clinically detectable disease by radiographic imaging. A partial response indicated >50% reduction in the tumor mass in bidimensional measurement. Stable disease was assessed as primary tumor reduction of <50% or an increase <25% of the primary tumor, and progressive disease indicated a new disease site or growth of the primary site of >25%.

Gross residual tumor in the resected specimen was histologically sampled transversely every centimeter, with multiple sections at each level. When residual tumor was not grossly apparent after treatment, the entire area of the prior tumor location was sectioned longitudinally and histologically fixed. StaM pathologists then reviewed multiple sections from each specimen block for complete histological examination. A pathologic CR was defined as the absence of microscopic tumor in the resected specimens. Partial pathologic response specimens demonstrated a treatment effect with residual gross or microscopic tumor.

Statistical Analysis
The study goal for achieving a pathologic CR was 50%. Patient accrual was targeted at 30 patients to provide 95% power to detect a 25% difference in the pathologic CR rate with a significance of .2. Estimation of disease-specific overall and disease-free survival was calculated by the Kaplan-Meier method. Univariate analyses of the effects of covariates on survival were analyzed by the log-rank test. A P value of <.05 was considered significant. Statistical analyses were performed with SAS software (SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Between June 2000 and September 2003, 21 patients (19 men) were enrolled on this study. The median age was 58 years (range, 46–77 years). Tumor location, histology, and stage of the primary cancer are listed in Table 1Go. Five patients did not complete the trial (two secondary to complications, two because of disease progression, and one because of withdrawal). Three of the five had esophagectomy off study. Because of excessive toxicity observed after 21 patients, with a disappointing rate of pathologic CR, the trial was terminated before the accrual goal of 30 patients.


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  		TABLE 1. Patient summary (n = 21)
 
Toxicities from the induction chemotherapy and chemoradiotherapy were significant (Table 2Go): 76% experienced grade 3 or 4 toxicity. The most frequent and severe toxicities were hematopoietic and gastrointestinal in origin. DLT was seen in 6 of the first 14 patients. The paclitaxel dose was subsequently reduced to 40 mg/m2 in the next seven patients. After this reduction, only one additional patient experienced DLT, but six of seven still experienced transient grade 3 or 4 nonhematological toxicity.


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  		TABLE 2. Toxicity of induction chemotherapy and concurrent chemoradiotherapy
 
A clinical CR was observed to the induction regimen in all 16 patients who completed the trial. Two patients had progressive disease after the induction regimen. Three patients taken oM study for other reasons (listed previously) did not have their clinical response assessed. Therefore, on the basis of an intent-to-treat analysis, the clinical response rate of this induction program was 76%.

Sixteen patients underwent esophagectomy on study via separate abdominal and right thoracotomy exposures, with a median hospital stay of 12 days (range, 9–32 days). The stomach was used as the conduit in all cases, and all esophagogastric anastomoses were constructed with the use of an end-to-end anastomotic stapling device. One patient underwent reoperation for bowel obstruction and died on postoperative day 32 of progressive acute respiratory distress syndrome. Operative complications were common (Table 3Go). Transfusion was required in more than half of the patients. Leak from the esophagogastric anastomosis occurred in 13%. In all, 69% of patients experienced postoperative complications. If one considers postoperative transfusion as a complication, then the rate increases to 81% of patients. No discernible differences were seen in postoperative complications after the dose reduction of paclitaxel.


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  		TABLE 3. Surgical complications (n = 16)
 
At operation, only 4 of the 16 patients who completed the trial had a pathologic CR. It is interesting to note that all four had stage III disease at presentation. One additional pathologic CR was noted in a patient who underwent esophagectomy oM study. The remaining (12 of 16; 75%) pathologic specimens all had varying degrees of partial responses to treatment. Five of the 16 demonstrated a "near" pathologic CR, with "rare tumor cells," "mostly acellular mucin," or a "microscopic focus of cancer within dense treatment effect" remaining. No pathologic CRs were observed in the seven patients after paclitaxel dose reduction. A potentially curative (R0) resection was achieved in all patients who underwent esophagectomy.

Tissue biopsy specimens were obtained after induction chemotherapy (before chemoradiotherapy) in 13 patients, and 4 failed to reveal the presence of invasive cancer (1 high-grade dysplasia, 1 intramucosal adenocarcinoma, 1 Barrett’s esophagus, and 1 with atypical squamous cells). Of these four, only one (25%) patient’s esophagectomy specimen demonstrated a pathologic CR. Nine patients had biopsy-confirmed invasive cancer present after induction chemotherapy. Of these nine, eight eventually underwent esophagectomy, and a pathologic CR was observed in four of the eight. The negative predictive value of esophagogastroduodenoscopy with biopsy (failing to demonstrate invasive cancer) after induction chemotherapy in predicting a pathologic CR to chemoradiation at resection was therefore only 25%, and the positive predictive value (predicting the presence of invasive cancer in the resected specimen) was 50%.

At a median follow-up of 30 months, 8 patients have died: 6 from esophageal cancer, 1 secondary to operative complications, and 1 from suicide. Of these patients, five had completed the trial, two were withdrawn secondary to disease progression, and one withdrew for medical reasons. Thirteen patients are alive and free of disease. The estimated 2-year cancer-specific overall and disease-free survival by intention to treat for the entire group are 78% and 81%, respectively. Survival by protocol completion, pathologic response, and pretreatment stage are listed in Table 4Go. Of the seven patients with stage III disease at diagnosis, four had a pathologic CR and, thus, had an improved overall survival.


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  		TABLE 4. Overall survival (disease specific)
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Using an aggressive three-drug trimodality regimen including induction chemotherapy, concurrent chemoradiotherapy, and surgical resection, we report an encouraging cancer-specific 2-year overall and disease-free survival. Our optimism remains tempered, however, in view of the high percentage of stage II patients enrolled in this study (which may in part be due to failure to successfully complete EUS early in the study) and the relatively short follow-up. Longer follow-up will be required to determine the durability of these promising results.

This treatment regimen demonstrated a significant pathologic treatment effect in >50% of patients receiving operation. However, the pathologic CR seen in only 25% of patients completing the protocol is disappointing. This rate of pathologic CR is at the low end of the typical CR rate to induction chemo-radiation of 20% to 35%5,6,15,16 and the 19% to 38% rate reported in trials specifically incorporating taxanes.10–13

Multiple potential explanations may exist for the low CR rate, and the rate may be attributable to the manner in which the specimens were sectioned and reviewed by our pathologists. Five additional specimens manifested a "near CR," and perhaps a less stringent review might have resulted in their classification as a CR. Unfortunately, methods of pathologic specimen sampling and CR criteria are often not mentioned in trials, and this makes comparisons between studies difficult. Additionally, the timing of surgery after induction therapy is likely to play some role in the percentage of CRs, because early resection after chemoradiation may not allow sufficient time to manifest the full treatment effect.

Of interest is the finding that most of the CRs in this study occurred in patients with clinical stage III disease (rather than stage II) at diagnosis, thus leading to this group’s improved survival. Because of the sample size, we would not conclude that more advanced tumors are more likely experience CRs to this chemoradiation treatment plan. However, it may be reasonable to suggest that a more advanced preoperative stage does not preclude the likelihood of obtaining a pathologic CR to induction therapy.

Other studies incorporating taxanes in the pre-operative management of esophageal cancer have reported a wide variability in toxicity, from its being well tolerated10,11,13 to highly toxic.12,17 The level of toxicity associated with this study regimen is unacceptably high at the weekly paclitaxel dose at 50 mg/m2 when given with radiotherapy. The high level of toxicity seen in this trial is likely multifactorial in origin. First, toxicity data (including operative complications) were collected prospectively at each clinic visit, and there was a high rate of physician compliance in completing our standardized toxicity assessment form. Second (and likely the major cause of undue toxicity), we administered all three chemotherapy agents throughout the entire chemoradiation period at an aggressive dosing regimen, particularly with paclitaxel. Ajani et al.11 have published the results of a trial that used an induction strategy similar to ours but without paclitaxel during radiotherapy. They reported similarly encouraging short-term survival outcomes with substantially less toxicity, thus further suggesting that the concurrent use of paclitaxel with radiotherapy may be a major contributor to our high toxicity rate.

Perhaps of greater importance are the safety measures designed in this study to address this unexpectedly high toxicity rate. Although drug dosing was established for this trial according to our phase I study,14 we prospectively planned to assess toxicity in the phase II setting after accrual of the first 14 patients. The early stopping rules for toxicity in this trial allowed the incorporation of a planned change to the paclitaxel dose, in this case placing fewer patients at risk for untoward toxicity. Although not used in this study, this planned toxicity assessment also allowed for the provision of escalating the paclitaxel dose if few patients experienced significant toxicity, thus potentially maximizing the treatment benefit from chemotherapy.

In this study, 13 biopsy samples were obtained by esophagogastroduodenoscopy after the period of induction chemotherapy. Although the numbers associated with this trial are small, there was no reliable value in the biopsy results for predicting a response to chemotherapy. Functional imaging with fluorodeoxyglucose–positron emission tomography holds promise as a predictor of tumor response and survival after induction therapy, but its precise role in induction treatment schemata remains to be defined.18

At present, there is disagreement in the literature about whether induction therapy increases the rate of complications after esophagectomy.6,15 Although our operative mortality in this study was reasonable (6%), our study demonstrated a high rate of postoperative morbidity, including a relatively high rate of postoperative leak (13%) at the esophagogastric anastomosis. Although patients undergoing aggressive induction therapy may be significantly deconditioned before surgery and may require more perioperative blood transfusions, previous data from our institution have thus far not supported the contention that induction therapy increases operative complications after esophagectomy.19

In conclusion, this trimodality trial of induction chemotherapy followed by combination chemoradiotherapy and surgery demonstrated encouraging short-term survival but disappointing rates of pathologic CR and untoward toxicity. Although the use of paclitaxel in induction strategies remains promising, we suggest that doses >40 mg/m2 of paclitaxel, when given weekly with radiotherapy in esophageal cancer, may engender excessive toxicities. Furthermore, we demonstrated the value and feasibility of planned interim toxicity assessments with predetermined dose modification schemata in this phase II trial and encourage their routine incorporation in other studies derived from phase I experiences.

Received for publication January 6, 2005. Accepted for publication August 16, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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  18. Downey RJ, Akhurst T, Ilson D, et al. Whole body 18FDG-PET and the response of esophageal cancer to induction therapy: results of a prospective trial. J Clin Oncol 2003; 21:428–32.[Abstract/Free Full Text]
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