Japanese Journal of Clinical Oncology Advance Access originally published online on August 18, 2007
Japanese Journal of Clinical Oncology 2007 37(8):590-596; doi:10.1093/jjco/hym076
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© 2007 Foundation for Promotion of Cancer Research
Neoadjuvant, Surgery and Adjuvant Chemotherapy without Radiation for Esophageal Cancer
1 Department of Surgical Oncology
2 Department of UMMG/UM Surgery
3 Department of Hematology/Oncology
4 Department of General Surgery
5 Division of Biostatistics
6 Department of Pathology, University of Miami
7 Sylvester Comprehensive Cancer Center, Division of Hematology and Oncology, Miami, Florida, USA
For reprints and all correspondence: Bach Ardalan, Sylvester Comprehensive Cancer Center, Division of Hematology and Oncology, Suite 3550, 1475 NW 12th Ave, Miami, FL 33136, USA. E-mail: bardalan{at}med.miami.edu
Received January 31, 2007; accepted April 19, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTS: CLINICAL AND PATHOLOGIC...DISCUSSIONConflict of interest statementReferences |
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Background: A phase II trial to evaluate neoadjuvant (NAD), surgery and adjuvant (AD) combination chemotherapy without radiation therapy (RT) for patients with esophageal adenocarcinoma staged with endoscopic ultrasound and CT as T3N1 was carried out.
Methods: Thirty-three eligible patients were enrolled. NAD therapy was administered in two 49-day cycles and included cisplatin, floxuridine, paclitaxel and leucovorin. Esophageal resection was performed followed by AD therapy.
Results: Thirty-three patients initiated NAD therapy; 10 experienced grade 3 and 4 toxicities, which included leucopenia, fatigue, nausea, diarrhea and stomatitis. Additionally, 16 patients experienced grade 1 and 2 hematologic and non-hematologic toxicities. Fifteen patients were down-staged, of whom five were T2, seven were T1, and three had nodal disease with no evidence of residual cancer in the esophageal bed. Fifteen patients remained T3, and two showed progressive disease. Thirty-two patients proceeded to surgery and 30 were resected. Although all resected patients were eligible for AD therapy, 15 did not receive it either because of patient refusal or surgeon recommendation. Fifteen patients received AD therapy: nine who had remained T3 and six who had down-staged. Three patients experienced grade 3 and 4 toxicities similar to those in NAD therapy. Six patients had grade 1 and 2 toxicities. Kaplan–Meier estimates of overall survival at 1, 3 and 5 years were 73% (95% CI: 58–88%), 52% (95% CI: 34–69%) and 29% (95% CI: 13–45%), respectively. Median survival was 42 months.
Conclusion: Deletion of RT may safely allow for more aggressive chemotherapy and increase chances of survival. The results need to be confirmed in a randomized phase II or larger phase III trial.
Key Words: GI-esophagus-med • chemo-phase I-II-III • GI-esophagus-surg • chemotherapy • esophageal cancer
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTS: CLINICAL AND PATHOLOGIC...DISCUSSIONConflict of interest statementReferences |
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Cancer of the esophagus ranks among the 10 most frequent cancers in the world, with greater than 300 000 new cases per year (1). Most cases arise in developing nations, with marked geographic variation in incidence and predominantly squamous cell histology. In the USA, the incidence rate is approximately five cases per population of 100 000, with more than 14 520 new cases and an estimated 13 570 deaths in 2005 (2–5). During the past two decades, the incidence of adenocarcinoma of the esophagus and esophagogastric junction has dramatically increased in the USA and Western Europe, and the worldwide rates may be increasing as well (2–7).
Management of patients with esophageal cancer presents some of the greatest challenges currently faced by clinicians. Although highly curable in its earliest stages, it is usually fatal even when moderately advanced (8). Despite treatment, most individuals who clinically manifest esophageal cancer die within three years of diagnosis (8). The clinical outcome is predicted by the extent of the local disease and also by the presence of occult metastatic cells disseminated prior to treatment and are largely resistant to conventional systemic therapies. Metastatic cancer cells have been detected at high rates in the bone marrow of patients with stage T2–T3 disease (9–13). It is imperative, therefore, that any successful treatment plan addresses control of systemic disease as a primary and early goal.
Many studies have examined the use of combined modality therapy in the treatment of esophageal cancer. In the RTOG 85-01 study, there was randomization of chemoradiotherapy versus radiation alone (14). Combined therapy had a survival advantage; however, the most common cause of treatment failure was persistence of disease (15–24). This confirms the need for surgical extirpation of the esophagus. Walsh et al. showed that this remains a systemic disease (25). In their study of chemoradiation followed by surgery versus surgery alone, median survivals were 16 vs 11 months, respectively. Multimodality therapy gave a three year survival of 32% versus 6% in the surgery alone group.
Cisplatin and fluoropyrimidines have been the backbone of chemotherapy for esophageal cancer (18,28,29). The paclitaxel family of drugs has shown activity in upper intestinal malignancies in several clinical studies (30). We, hence, suggested that a combination of these drugs could improve outcomes in esophageal cancer.
The aim of this study was to evaluate feasibility, toxicity profiles, response rate and overall survival of our chemotherapy with cisplatin, paclitaxel and floxuridine plus leucovorin.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTS: CLINICAL AND PATHOLOGIC...DISCUSSIONConflict of interest statementReferences |
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A phase II trial of neoadjuvant (NAD) and adjuvant (AD) chemotherapy consisting of cisplatin, paclitaxel, floxuridine (FUdR) and leucovorin was performed at the University of Miami Sylvester Cancer Center. This protocol was reviewed and approved by the Institutional Review Board. The primary endpoint of this study was overall survival. Secondary end points included relief of dysphagia, complete pathologic response, treatment related toxicity and surgical morbidity and mortality. Common Terminology Criteria for Adverse Event (CTCAE) recommended by National Cancer Institute were used to grade toxicities during chemotherapy.
Eligibility Criteria
Patients were eligible for this study if they were 18 years of age or older, had biopsy-confirmed esophageal adenocarcinoma, were surgical candidates, had adequate bone marrow function (white blood cells, WBC > 3000/mm3, absolute polymorph count >1500/mm3, platelets >100 000/mm3), renal function (creatinine 
2.0 mg/dl), liver function (bilirubin 2 x normal), and were able to give informed consent. Cisplatin can be used if creatinine is 2.0 mg/dl. All patients were staged based upon the results of endoscopic ultrasound and CT scan as T3N1. Lymph nodes were not biopsied. PET scan was not available. Tumors that extended into the proximal stomach had to primarily involve the distal esophagus or GE junction. Patients with concurrent infection or other primary malignancies were not candidates for this protocol.
Pretreatment Evaluation
All patients were seen and evaluated by both medical and surgical oncologists. The pretreatment evaluation included a detailed history and physical examination, electrocardiography and laboratory testing. The extent of disease evaluation included chest radiographs, CT scans of the chest, abdomen and pelvis and endoscopic ultrasound. The clinical TNM status and tumor stage were defined according to the 1997 guidelines of the American Joint Committee on Cancer Staging (26).
Dysphagia was assessed based on a four-point scale. Zero was the ability to tolerate a normal meal, 1 corresponded with tolerance to some solids, 2 corresponded to semisolid food only, 3 was the ability to swallow liquids only and 4 corresponded to the complete inability to swallow.
Neoadjuvant Chemotherapy
The treatment plan is outlined in Fig. 1. Chemotherapy was given in two 49-day cycles. On day one, the patients were treated with cisplatin (100 mg/m2). On day two, they received FUdR (80 mg/kg) and leucovorin (500 mg/m2). On day seven, they started a week of rest. On days 14 and 21, they received FUdR (150 mg/kg) and leucovorin (500 mg/m2). On day 28, paclitaxel (125 mg/m2) was infused, followed by FUdR (80 mg/kg) and leucovorin (500 mg/m2) on day 29. Day 36 started a week of rest and then on days 42 and 49 they received FUdR (150 mg/kg) and leucovorin (500 mg/m2). This completed cycle one of two.
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The same rule of stopping and dose reducing was used in NAD and AD therapy. If a patient developed grade 3 or higher toxicity, chemotherapy was suspended until resolution of the given toxicity. Drug doses were reduced by one level. Level one dose reduction: cisplatin 80 mg/m2; paclitaxel 115 mg/m2; days 2, 29 FUdR at 60 mg/kg; days 14, 21, 42 and 49, FUdR at 130 mg/kg. Level two dose reduction: cisplatin 60 mg/m2; paclitaxel 100 mg/m2; days 2, 29, FUdR at 60 mg/kg; days 14, 21, 42 and 49 FUdR at 110 mg/kg.
Evaluation During the Study
Patient evaluation during NAD chemotherapy included interim history and physical exams, performance status, weight measurements, changes in dysphagia and laboratory testing. After completion of NAD therapy, endoscopic ultrasound and CT scans of the chest, abdomen and pelvis were performed to restage the disease and ensure resectability. Patients with advancing disease on NAD therapy were removed from the study protocol. Further therapy was at the discretion of the clinician.
Surgical Resection
Esophageal resection was performed 4–6 weeks after completion of NAD chemotherapy. Acceptable approaches to resection included transhiatal esophagectomy with gastric pull-up or an Ivor–Lewis esophagogastrectomy. Frozen sections were obtained to ensure microscopically negative proximal and distal margins. Radical lymphadenectomy was not performed. Either a stapled or hand sewn anastomosis was performed at the discretion of the operating surgeon.
Post-operative Follow-up
AD therapy was offered to all patients after surgical resection except those with complete pathological response. Patients were followed routinely by both medical and surgical oncologists. Each patient was seen every 3 months for one year, then once every 6 months in the next year and then yearly. At each of those visits, they were evaluated with CT scan of the chest, abdomen, pelvis, laboratory tests and a detailed history with physical examination.
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RESULTS: CLINICAL AND PATHOLOGIC CHARACTERISTICS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTS: CLINICAL AND PATHOLOGIC...DISCUSSIONConflict of interest statementReferences |
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Thirty-three eligible patients were enrolled in the study between 1998 and 2002. Eighteen cases (55%) were primary esophageal and 15 (45%) were located at the GE junction. Twenty-six patients (78%) had difficulty swallowing solids and 13 (39%) required a semi-solid or liquid diet only. Thirty (91%) patients had a Karnofsky performance score greater than 80 and the median score was 90 (range 60–100). Twenty-nine of the patients (88%) were male. The median age was 68 years (range 48–80; Table 1).
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NAD therapy was administered to all patients. Twenty-eight patients (85%) completed both cycles of NAD therapy and five (15%) received only one cycle (Table 2). During NAD therapy, 10 patients (33%) experienced grade 3 and 4 toxicities. There were seven incidences of leucopenia and 10 of fatigue, nausea, diarrhea and stomatitis. In response, patients were treated with growth factors and chemotherapy was delayed for a maximum of one week per event. In case of diarrhea, patients were given diphenoxylate and fluid replacement. Chemotherapy was resumed once toxicities were reversed and baseline status was regained. Dose reductions were then made accordingly in two levels. Ten patients were dose-reduced one level, and three patients were dose-reduced two levels. Once dose reductions took place, the patient remained on that dosage for the remainder of treatment. Sixteen patients (48%) experienced grade 1 and 2 toxicities which included low platelets and albumin, leucopenia, anemia, nausea, fatigue, vomiting, diarrhea, constipation, stomatitis and alopecia. These toxicities were well tolerated. Three patients (9%) had no toxicity (Table 3).
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The patients on NAD therapy were followed closely. If there was clinical evidence of deterioration of disease, chemotherapy was stopped, endoscopic ultrasound and CT were performed and patient was referred to a surgeon. After the first cycle of NAD therapy, 25 patients (76%) either gained or maintained their weight compared with baseline and 19 (58%) showed an improvement in degree of dysphagia. Twenty-nine patients (88%) remained stable in their Karnofsky Performance Status and four (12%) declined. Among the 28 patients who received a second cycle of NAD therapy, 19 (68%) showed improvement in the degree of dysphagia and 18 (67%) either gained or maintained their weight compared with baseline. Twenty-four patients (86%) maintained stability in their Karnofsky Performance Status, while four (14%) declined. Fifteen patients were down-staged, of whom five were T2, seven were T1, and three had nodal disease with no evidence of residual cancer in the esophageal bed. Fifteen patients remained T3 and two showed progressive disease.
Of the 33 patients who received NAD therapy, 32 proceeded to surgery. One patient died from a vascular event prior to surgery. Two patients were found to have locally advanced disease to the peritoneum in the area of the esophageal hiatus. Thirty patients underwent R0 esophagectomy: 24 transhiatal and six Ivor Lewis esophagectomies. The average length of stay was 12 days with an average of 2.3 days in the ICU. The mean ASA score was 2.58 with mean operative time of 4.6 h and mean EBL of 565 ml. There was an average of 11.8 nodes removed per patient and nine patients (30%) were node negative. There were five anastomotic leaks, 12 pulmonary complications and one peri-operative death. Operative morbidity and mortality rates were 37 and 3%, respectively.
AD therapy was available for 29 resected patients (30 resected patients, excluding one peri-operative death), and 15 of these patients elected to continue treatment (Table 2). A number of patients refused AD therapy since they had experienced tiredness and fatigue in the NAD part of treatment. In some cases the surgeon would not have recommended AD therapy since the tumor had been removed with clear margins. Ten patients received both cycles of AD therapy and five received only one cycle (Table 2). Compared with the 14 patients who did not receive AD, the group given AD was younger (median age 63 vs 68.5) and included slightly fewer downstaged patients, six (43%) versus eight (57%).
Ten of the 33 patients enrolled on study are alive after a median follow-up of 73 months (range 45–89). Kaplan–Meier estimates of overall survival in our study cohort at 1, 3 and 5 years were 73% (95% CI: 58–88%), 52% (95% CI: 34–69%) and 29% (95% CI: 13–45%), respectively. Median survival was 42 months (95% CI: 14–52 months) (Fig. 2).
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In an exploratory analysis based on the 29 patients eligible for AD therapy, we investigated the effects of age, sex, race, ethnicity, disease site, severe NAD toxicity (grade 3–4), downstaging and AD therapy (per patient decision) on survival. Only AD therapy was associated with survival, reducing the risk of death by 63% after adjustment for downstaging (adjusted hazard ratio 0.37, P = 0.040). Kaplan–Meier plots of survival by AD therapy (15 resected patients who received one or two cycles AD versus 14 patients treated with NAD and surgery only) are given in Fig. 3.
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This phase II single arm study has examined the role of intensive chemotherapy prior to surgery followed by further AD chemotherapy. No radiation was administered to our patients. The chemotherapeutic protocol differed from those of MRC and Intergroup as we used paclitaxel, cisplatin and 24 h weekly infusion of FUdR. The NAD chemotherapy was delivered over 4 months in two cycles. At the time of the surgery, if the pathological specimen demonstrated no evidence of tumor, no further chemotherapy was offered. If microscopic disease was seen, the NAD chemotherapy was administered in an AD setting. If significant disease remained in the pathological specimen, it was up to the investigator to offer alternate chemotherapeutic agents.
Presently, with a median follow-up of over 50 months, only one patient's disease in this study has recurred locally. The majority that have recurred have done so systemically in such sites as brain, bone, spleen, adrenal gland, liver and lung. Median survival of our cohort of 33 patients was 42 months (95% CI: 14–52 months) and the proportion surviving 1, 3 and 5 years was 73% (95% CI: 58–88%), 52% (95% CI: 34–69%) and 29% (95% CI: 13–45%) respectively.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTS: CLINICAL AND PATHOLOGIC...DISCUSSIONConflict of interest statementReferences |
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Management of patients with locally advanced esophageal carcinoma is a great challenge faced by clinicians. Although more curable in its earlier stages, esophageal cancer remains a deadly systemic disease (8). The outcome of regional therapy (surgery or radiation alone) has been disappointing. This led to the innovative use of NAD chemotherapy with or without radiation prior to surgery, and/or AD chemotherapy. A problem with the clinical trials has been the shift in pathology of this disease, i.e. three decades ago squamous cell cancer predominated and today adenocarcinoma is the most frequent in the Western world (2–7). Most of the trials reported in the 1970s, 1980s and early 1990s examined predominately squamous cell carcinoma against various modalities of treatment. Those treatment regimens may not be adequate for this change in pathology.
Two large randomized phase III studies compared surgery alone with chemotherapy before surgery followed by adjuvant chemotherapy in operable esophago-gastric cancer patients: the Intergroup study included 440 patients (29) and the MAGIC trial 503 patients (28). The Medical Research Council (MRC) of UK randomized 802 patients to compare surgery alone versus NAD chemotherapy (18). The Intergroup and the MRC studies used cisplatin and 5-FU chemotherapy while in the MAGIC trial epirubicin was added to the combination. Out of these studies only the MRC demonstrated statistically significant improvement in median survival—16.9 months with chemotherapy versus 13.3 months with surgery alone and 9% improvement in 2 year survival in the chemotherapy group (18).
Although the Intergroup and the MAGIC trials showed that the preoperative cisplatin and 5-FU based regimens are tolerable; the improved survival has not been conclusively demonstrated (28,29).
The therapeutic bias in many centers for esophageal cancer is chemoradiation followed by surgery and adjuvant chemotherapy. Multiple studies have been done and the 3 year survival ranges from 40 to 42%. The local and distant failure rates are high and median survival is low. Median survival in a study from the Mayo clinic was 19 months and 3 year survival was 41%. Burmeister and colleagues reported 17 months median survival, and their patients had significant grade 3 toxicities. In a study done by Vita and colleagues 13 of 29 patients presented with distant metastasis while two of 29 had local recurrence. Minsky and colleagues from MD Anderson Institute reported a 24% distant failure and 39% locoregional failure in their study in 1999.
Our regimen offers many advantages. All of the patients were T3N1 pre-operatively, and 15 (47%) of 32 were downstaged pathologically. This is a significant finding since no radiation was given to any of our patients. Grade 3 and 4 toxicities were minimal as compared with the literature. In an exploratory analysis based on 29 patients eligible for AD chemotherapy, median survival was 54 months for those who elected AD therapy compared with 23 months for those who did not (Fig. 3). The 5- year survival rates were 73% (95% CI: 51–96%) and 19% (95% CI: 0–41%), respectively (see Fig. 3). Not all of the patients received AD therapy. Our study is in accordance with other centers where compliance with AD therapy is poor. In our study as seen in Table 3, the patients tolerated AD therapy with only one grade 3 and one grade 4 hematologic toxicity. One patient had a grade 3 non-hematologic toxicity. Although only 15 of 29 eligible patients received the AD therapy, we note that eight (53%) of these patients experienced grade 3–4 toxicity during NAD. By eliminating radiation therapy from the NAD protocol, we were able to administer broader and more prolonged courses of chemotherapy and reduce the surgical morbidity and mortality. We have shown that patients with locally advanced disease can be managed without radiation and still have improved survival. The results of our study need to be confirmed in a randomized phase II or larger phase III trial.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTS: CLINICAL AND PATHOLOGIC...DISCUSSIONConflict of interest statementReferences |
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None declared.
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Acknowledgments |
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Marilia Dinamarco is thanked for editorial review.
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Footnotes |
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This study has only been presented in part to American Society of Clinical Oncology. The content of this manuscript is original and does not directly or indirectly benefit financial interests of any of the authors.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTS: CLINICAL AND PATHOLOGIC...DISCUSSIONConflict of interest statementReferences |
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