- Email: [email protected]
Multimodality Therapy of Esophageal Cancer
Multimodality Therapy of Esophageal Cancer* Cameron D. Wright, MD
Multimodality therapy of esophageal cancer has been evaluated in several clinical trials, with positive results in terms of improved survival compared with single-modality therapy. A case report is presented describing the use of paclitaxel in a multimodality regimen for a patient with a bulky esophageal tumor. In addition, results are described of a clinical trial in which patients received a paclitaxel-based regimen as part of multimodality therapy for esophageal cancer. (CHEST 1999; 116:461S– 462S) therapy of esophageal carcinoma apM ultimodality pears to improve survival. The addition of chemotherapy (cisplatin and fluorouracil) to radiation therapy increased survival compared with radiation therapy alone in a randomized trial reported by Herskovic and colleagues.1 Walsh and colleagues2 recently reported that multimodality therapy (cisplatin, fluorouracil, and radiation therapy) followed by surgical resection improved survival compared with surgical resection alone. Urba and associates3 have recently reported that multimodality therapy (cisplatin, vinblastine, fluorouracil, and radiation therapy) followed by transhiatal esophagectomy improves survival compared with transhiatal esophagectomy alone, with an approximate doubling of survival. However, the optimal multimodality regimen remains unknown. Paclitaxel is a newer chemotherapy agent with a high response rate in metastatic esophageal cancer, which also acts as a radiation sensitizer.4 Our group has recently evaluated the introduction of paclitaxel in a multimodality regimen in an effort to improve survival in esophageal cancer.5
Case Report The patient is a 34-year-old previously healthy man who initially presented with dull, deep chest pain. A cardiac workup was negative. A barium swallow demonstrated an irregular esophagus. The patient had slight difficulty eating but denied significant dysphagia. There was no history of heartburn. He admitted to a 20-lb weight loss. Esophagoscopy demonstrated diffuse tumor within the thoracic esophagus, and biopsy specimens revealed a very poorly differentiated esophageal cancer. A chest CT scan showed a huge bulky esophageal tumor (maximum diameter, 7 cm) extending from the thoracic inlet to the gastroesophageal junction. No lymphadenopathy was seen. A bone and brain scan was negative for metastatic disease. A positron emission tomographic scan of the chest and upper abdo*From General Thoracic Surgery, Massachusetts General Hospital, Boston, MA. Correspondence to: Cameron D. Wright, MD, Massachusetts General Hospital, General Thoracic Surgery, Fruit Street, Boston, MA 02114; e-mail: [email protected]
men demonstrated significant uptake along the esophagus with no evidence of metastatic disease. The patient underwent intensive induction chemoradiotherapy, which he tolerated well without complication. Chemotherapy consisted of two cycles of cisplatin, fluorouracil, and paclitaxel, administered 4 weeks apart. Cisplatin (20 mg/m2) was infused for 1 h on days 1 to 5. Fluorouracil (800 mg/m2/d) was given as a continuous infusion on days 1 to 5. Paclitaxel was given for a period of 3 h as a single infusion (100 mg/m2). Radiation therapy was concurrently administered in which the initial volume (gross tumor and elective volume) was treated once a day and a boost volume (gross tumor) was given as a concurrent boost for 10 days on a twice daily schedule during chemotherapy administration. A total of 58.5 Gy was administered to the gross tumor, and the proximal esophagus and stomach received 45 Gy. After chemoradiotherapy, repeat CT scans of the chest and abdomen demonstrated marked reduction in the size of the tumor and showed no evidence of metastatic disease. A repeat positron emission tomographic scan demonstrated there was still activity over the esophagus, with no evidence of metastatic disease. Eighty days after the beginning of therapy, the patient underwent esophagectomy via an Ivor Lewis approach. His postoperative course was uncomplicated, and he was discharged on the eighth postoperative day. His pathology report demonstrated no evidence of residual cancer in the esophagectomy specimen. Multiple lymph nodes were replaced by hyaline material, suggesting that metastatic carcinoma was present before induction therapy. All resected lymph nodes were free of tumor. The patient returned to good health and has returned to work. He remains free of disease 24 months after the initiation of therapy.
Phase I/II Clinical Trial Forty-six patients have been enrolled in our phase I/II paclitaxel induction protocol. The median age was 61 years, 85% were male, 96% were white, and 83% had adenocarcinoma. Pretreatment staging demonstrated that 14 patients were designated T2N0, 4 were T2N1, 15 were T3N0, 11 were T3N1, and 2 were T4N0. Three paclitaxel dose levels were investigated: 75, 125, and 100 mg/m2. A dose of 100 mg/m2 was chosen as the dose to continue the phase II trial because of dose-limiting grade 4 esophagitis at paclitaxel 125 mg/m2. Four patients had progressive disease during induction therapy (liver, 2; CNS, 2) and two patients died during induction therapy. Forty patients were taken to the operating room, and all 40 underwent resection. Two patients died postoperatively of ARDS. Thirty-five percent of the patients achieved a pathologic complete response rate, and 60% were downstaged compared with their pretreatment staging. Mean follow-up is currently 23 months, with a median survival of 30 months. The median disease-free survival is 27 months. One-, 2-, and 3-year survival is 75%, 65%, and 50%, respectively. Treatment mortality was 8.7%. Longer follow-up will be necessary to determine whether the enhanced survival justifies the toxicity of this program. CHEST / 116 / 6 / DECEMBER, 1999 SUPPLEMENT
461S
References 1 Herskovic A, Martz K, al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992; 326:1593–1598 2 Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996; 335:462– 467 3 Urba S, Orringer M, Turrisi A, et al. A randomized trial comparing surgery (S) to preoperative concomitant chemora-
462S
diation plus surgery in patients (pts) with resectable esophageal cancer (CA): updated analysis [abstract 983]. Proc Am Soc Clin Oncol 1997; 16:277a 4 Ajani JA, Ilson DH, Daugherty K, et al. Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst 1994; 86:1086 –1091 5 Wright CD, Wain JC, Lynch TJ, et al. Induction therapy for esophageal cancer with paclitaxel and hyperfractionated radiotherapy: a phase I and II study. J Thorac Cardiovasc Surg 1997; 114:811– 816
Multimodality Therapy of Chest Malignancies—Update ’98
Multimodality therapy of esophageal cancer has been evaluated in several clinical trials, with positive results in terms of improved survival compared with single-modality therapy. A case report is presented describing the use of paclitaxel in a multimodality regimen for a patient with a bulky esophageal tumor. In addition, results are described of a clinical trial in which patients received a paclitaxel-based regimen as part of multimodality therapy for esophageal cancer. (CHEST 1999; 116:461S– 462S) therapy of esophageal carcinoma apM ultimodality pears to improve survival. The addition of chemotherapy (cisplatin and fluorouracil) to radiation therapy increased survival compared with radiation therapy alone in a randomized trial reported by Herskovic and colleagues.1 Walsh and colleagues2 recently reported that multimodality therapy (cisplatin, fluorouracil, and radiation therapy) followed by surgical resection improved survival compared with surgical resection alone. Urba and associates3 have recently reported that multimodality therapy (cisplatin, vinblastine, fluorouracil, and radiation therapy) followed by transhiatal esophagectomy improves survival compared with transhiatal esophagectomy alone, with an approximate doubling of survival. However, the optimal multimodality regimen remains unknown. Paclitaxel is a newer chemotherapy agent with a high response rate in metastatic esophageal cancer, which also acts as a radiation sensitizer.4 Our group has recently evaluated the introduction of paclitaxel in a multimodality regimen in an effort to improve survival in esophageal cancer.5
Case Report The patient is a 34-year-old previously healthy man who initially presented with dull, deep chest pain. A cardiac workup was negative. A barium swallow demonstrated an irregular esophagus. The patient had slight difficulty eating but denied significant dysphagia. There was no history of heartburn. He admitted to a 20-lb weight loss. Esophagoscopy demonstrated diffuse tumor within the thoracic esophagus, and biopsy specimens revealed a very poorly differentiated esophageal cancer. A chest CT scan showed a huge bulky esophageal tumor (maximum diameter, 7 cm) extending from the thoracic inlet to the gastroesophageal junction. No lymphadenopathy was seen. A bone and brain scan was negative for metastatic disease. A positron emission tomographic scan of the chest and upper abdo*From General Thoracic Surgery, Massachusetts General Hospital, Boston, MA. Correspondence to: Cameron D. Wright, MD, Massachusetts General Hospital, General Thoracic Surgery, Fruit Street, Boston, MA 02114; e-mail: [email protected]
men demonstrated significant uptake along the esophagus with no evidence of metastatic disease. The patient underwent intensive induction chemoradiotherapy, which he tolerated well without complication. Chemotherapy consisted of two cycles of cisplatin, fluorouracil, and paclitaxel, administered 4 weeks apart. Cisplatin (20 mg/m2) was infused for 1 h on days 1 to 5. Fluorouracil (800 mg/m2/d) was given as a continuous infusion on days 1 to 5. Paclitaxel was given for a period of 3 h as a single infusion (100 mg/m2). Radiation therapy was concurrently administered in which the initial volume (gross tumor and elective volume) was treated once a day and a boost volume (gross tumor) was given as a concurrent boost for 10 days on a twice daily schedule during chemotherapy administration. A total of 58.5 Gy was administered to the gross tumor, and the proximal esophagus and stomach received 45 Gy. After chemoradiotherapy, repeat CT scans of the chest and abdomen demonstrated marked reduction in the size of the tumor and showed no evidence of metastatic disease. A repeat positron emission tomographic scan demonstrated there was still activity over the esophagus, with no evidence of metastatic disease. Eighty days after the beginning of therapy, the patient underwent esophagectomy via an Ivor Lewis approach. His postoperative course was uncomplicated, and he was discharged on the eighth postoperative day. His pathology report demonstrated no evidence of residual cancer in the esophagectomy specimen. Multiple lymph nodes were replaced by hyaline material, suggesting that metastatic carcinoma was present before induction therapy. All resected lymph nodes were free of tumor. The patient returned to good health and has returned to work. He remains free of disease 24 months after the initiation of therapy.
Phase I/II Clinical Trial Forty-six patients have been enrolled in our phase I/II paclitaxel induction protocol. The median age was 61 years, 85% were male, 96% were white, and 83% had adenocarcinoma. Pretreatment staging demonstrated that 14 patients were designated T2N0, 4 were T2N1, 15 were T3N0, 11 were T3N1, and 2 were T4N0. Three paclitaxel dose levels were investigated: 75, 125, and 100 mg/m2. A dose of 100 mg/m2 was chosen as the dose to continue the phase II trial because of dose-limiting grade 4 esophagitis at paclitaxel 125 mg/m2. Four patients had progressive disease during induction therapy (liver, 2; CNS, 2) and two patients died during induction therapy. Forty patients were taken to the operating room, and all 40 underwent resection. Two patients died postoperatively of ARDS. Thirty-five percent of the patients achieved a pathologic complete response rate, and 60% were downstaged compared with their pretreatment staging. Mean follow-up is currently 23 months, with a median survival of 30 months. The median disease-free survival is 27 months. One-, 2-, and 3-year survival is 75%, 65%, and 50%, respectively. Treatment mortality was 8.7%. Longer follow-up will be necessary to determine whether the enhanced survival justifies the toxicity of this program. CHEST / 116 / 6 / DECEMBER, 1999 SUPPLEMENT
461S
References 1 Herskovic A, Martz K, al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992; 326:1593–1598 2 Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996; 335:462– 467 3 Urba S, Orringer M, Turrisi A, et al. A randomized trial comparing surgery (S) to preoperative concomitant chemora-
462S
diation plus surgery in patients (pts) with resectable esophageal cancer (CA): updated analysis [abstract 983]. Proc Am Soc Clin Oncol 1997; 16:277a 4 Ajani JA, Ilson DH, Daugherty K, et al. Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst 1994; 86:1086 –1091 5 Wright CD, Wain JC, Lynch TJ, et al. Induction therapy for esophageal cancer with paclitaxel and hyperfractionated radiotherapy: a phase I and II study. J Thorac Cardiovasc Surg 1997; 114:811– 816
Multimodality Therapy of Chest Malignancies—Update ’98