Systemic Chemotherapy for Advanced Esophageal Cancer

Transcription

1 Systemic Chemotherapy for Advanced Esophageal Cancer Progress Report Agop Y. Bedikian, MD, FACP* *Oncologist, Department of Oncology, King Faisal Specialist Hospital and Research Centre AY Bedikian, Systemic Chemotherapy for Advanced Esophageal Cancer: Progress Report. 1982; 2(4): KEYWORDS: Esophageal neoplasms, Drug therapy, combination Introduction Cancer of the digestive system afflicts more patients around the world than cancer originating in any other organ system. It is the most common cause of death from neoplastic disease in the United States. Cancer of the esophagus is one of the most lethal malignancies. The first description of fleshy growths obstructing the esophagus was made by Galen in the second century, and carcinoma of the esophagus was noted to be a frequent cause of dysphagia by Avicenna in the tenth century. Since the first report on surgical resection of esophageal cancer by Torek in 1913, advances were made in the diagnosis, surgical, and radiological therapy of esophageal carcinoma. However, the overall survival rate did not change significantly. This is mainly because the disease is diagnosed at the advanced stage, which makes the patient ineligible for curative surgical resection. Radiotherapy and systemic chemotherapy remain the most frequently utilized modalities for palliation for these patients. Approximately 98 percent of esophageal cancers are squamous cell carcinomas, and more than one-half originate in the cervical and thoracic portions. In general, carcinoma of the distal one-third of the esophagus is treated primarily by surgical resection, whereas carcinomas arising in the proximal esophagus are usually unresectable and are treated with radiation therapy. At present, more than 85 percent of the patients treated with surgery and radiation therapy will have progession of disease as a result of the tendency of esophageal carcinoma to spread through submucosal lymphatics to the paraesophageal structures. Single-Agent Chemotherapy In the past, chemotherapy has been reserved for the patient with advanced metastatic disease. Early trials with bleomycin reported more than a 50 percent response rate; subsequent evaluation of this antitumor agent has given responses ranging from zero to 60 percent. 1-3 Partial response (PR) is defined as a reduction of more than 50 percent in the size of the tumor measured on esophagograms. The criteria for response have not been uniform in these clinical trials and histologic documentation of complete disappearance of the tumor has not been a requirement for designation of a response as complete (CR). In general, the responses have been short-lived. Kolaric, et al. reported responses in four of 15 patients with esophageal cancer treated with bleomycin alone. 4 Tancini and colleagues reported one complete and three partial responses in 29 patients treated by a variety of dosage schedules of bleomycin. 5 Recently published medical literature indicates that doxorubicin hydrochloride (Adriamycin ) has limited activity against esophageal cancer. Kolaric, et al. reported one complete and five partial responses in 18 patients. 6 The Eastern Cooperative Oncology Group compared the activity of Adriamycin with those of and 5-fiuorouracil (5-FU) in a randomized study. 7 Responses were seen in one of 18 (five percent), two of 27 (seven percent), and four of 26 (15 percent) patients treated with Adriamycin,, and 5-FU respectively. Although the number of patients entered in the clinical trials is small, the reported cumulative singleagent activity with conventional agents is as folio ws: bleomycin (21/96), Adriamycin (8/41), mitomycin C (5/33), (3/32), 5- FU (5/31), and CCNU (3/19). Data on efficacy of new antitumor agents against esophageal cancer are summarized in Table 1. The number of patients entered in these studies has been too small to allow any definite conclusion about their activities. Vindesine (desacetyl vinblastine amide sulfate, a derivative of vinblastine) was evaluated in 25 patients with squamous cell carcinoma of the esophagus at the Memorial Sloan-Kettering Cancer Center. 8 One complete and two partial responses were observed in 22 evaluable patients. Subsequent clinical trials confirmed the very modest activity of vindesine against esophageal cancer. 9,10 The Southwest Oncology Group evaluated the efficacy of cis-platinum against esophageal cancer. 11 Responses were seen in six of 15 evaluable patients. However, other investigators found cis-platinum to have no activity against esophageal cancer or at best a modest activity with a response rate of 33 percent. 12,13 Overall responses with cis-platinum were observed in 11 (24 percent) of 45 patients

2 Table 1. Esophageal cancer: newly evaluated antitumor agents No. of Response Treatment patients Patients % References Vindesine , 9, 10 Cis-platinum , 13, 14 Methyl-GAG , 16, 17, I8 VM VP Methyl-GAG (polyamine synthesis inhibitor) also is active against esophageal cancer. This compound was investigated early in the past decade and was shown to have activity against leukemias and solid tumors including esophageal cancer. Falkson reported responses in 24 percent of 21 patients treated with daily doses of methyl- GAG. 15 The severe toxicity associated with this dosage schedule, however, resulted in loss of interest in the drug. In 1979, Knight and colleagues reported reduction of severity of toxicities of methyl-gag when administered by the weekly schedule. 16 One of two patients with esophageal cancer included in this phase 1 study achieved a partial response. Similarly, a minor response was observed by Mitchell and colleagues during early clinical trials with the drug. 17 Chapman and coworkers carried out a phase II evaluation of methyl-gag administered by the weekly schedule in patients with squamous cell cancers of several primary origins. 18 They reported two (11 percent) partial responses lasting three and five months each, and three (17 percent) minor responses among 18 evaluable patients with esophageal cancer. Overall, the response rate to methyl-gag at this time is 19 percent in 43 patients. Of the two recently introduced derivatives of podophyllotoxin, only VP showed activity against esophageal cancer. 19 Responses were seen in two of nine patients treated with etoposide (VP ) compared with none in 15 patients treated with VM-26. Multidrug Combination Chemotherapy Multidrug regimens have been designed to enhance the antitumor activity of conventional anticancer agents. Both vindesine and cis-platinum have already been incorporated into these regimens. Table 2. However, bleomycin/cis-platinum and bleomycin/adriamycin combinations gave 19 percent response rates each in 58 and 16 patients respectively and showed no advantage over the single-agent activity reported with these antitumor agents. 20,21 combination, on the other hand, resulted in one complete and three partial responses in five patients. 5 The three-drug combination bleomycin/vinde-sine has been evaluated at Memorial Sloan-Kettering Cancer Center and given encouraging results. Responses were observed in 21 (52 percent) of 40 patients. 20 Comparable response rates have been reported in small numbers of patients treated with bleomycin/vincristine,, bleomycin/mitomycin C, and bleomycin/cisplatinum/ three-drug regimens Table 2. Esophageal cancer: cumulative data on combination chemotherapy Response Treatment No. of patients Patients % References cis-platinum Adriamycin / bleomycin vindesine

3 vincristine/ mitomycin C Combined Modality Treatment A combined modality approach has been evaluated in patients with locally advanced esophageal cancer. Table 3. Kolaric and coworkers compared efficacy of bleomycin, Adriamycin, and bleomycin/adriamycin combination alone and each in combination with radiotherapy. 5,6,21 The multimodality regimens gave overall and complete response rates superior to those of chemotherapy-alone arms in these trials. The bleomycin/adriamycin two-drug regimen disappointingly gave no advantage over results obtained by bleomycin or Adriamycin in combination with radiotherapy. Franklin and his colleagues gave radiotherapy concurrently with four-day continuous intravenous infusion of 5-FU and intravenous bolus of mitomycin C on day one. 25 Twenty-eight patients with locally advanced esophageal cancer were treated and 21 were evaluable for response. The overall response rate was 80 percent. Histologic evaluation of the resected specimens in these patients indicated that the complete response rate was 28 percent. Overall, nine patients were able to have curative resection of the esophagus following multimodality treatment. The median survival duration of the 21 patients was over nine months (range 2 to 32+ months). In two other studies, patients with locally advanced esophageal cancer were treated with three-drug chemotherapy regimens for one or two cycles followed by either radiotherapy or surgical resection. 22,26 In both of these studies, although no complete responses were observed, 55 to 58 percent of the patients achieved partial response with chemotherapy alone. Radiotherapy following two cycles of chemotherapy with vincristine/bleomycin/ resulted in complete response in 60 percent of the patients with an overall response of 88 percent. 22 The one-year survival was 64 percent. In this study, however, complete response was based on radiologic findings, and microscopic residual disease could have been present in some of these complete responders. In the vindesine/bleomycin study, however, microscopic residual disease was detected in all patients who had surgical resection. Thirty-five percent of these were rendered disease-free with surgery, while in 38 percent of the patients the residual disease was only microscopic. Summary This review shows that chemotherapy for esophageal cancer is at an early stage of development. Although several multidrug regimens have produced significant tumor regressions in a small fraction of the patients, histologically confirmed complete remissions are rare. The multimodality approach has made it possible to achieve complete remissions in more than one-third of the patients, resulting in marked improvement in survival. Thus, clinical trials should continue in an attempt to find new, effective antitumor agents to design effective regimens capable of favorably influencing patient survival when administered with other treatment modalities. Standardization of tumor measurements and criteria for response will be of paramount importance for accurate comparison of efficacy of treatment regimens. Table 3. Multimodality treatment of esophageal cancer % Response No. of % 1-year Treatment CR PR Overall patients survival References Radiotherapy (XRT) Bleomycin XRT Adriamycin ? 6 Adriamycin /XRT ?

4 Adriamycin Adriamycin /XRT FU/Mitomycin C/XRT ? 25 vincristine/ x 25 0(60) 55 (28) 55(88) (XRT) vindesine (Surg) 26 0(35) 58 (38) 58 (73)? 26 ( ) = Response rate after second modality treatment REFERENCES 1. Bonadonna G, De Lena M, Monfardini S, et al.: Clinical trials with bleomycin in lymphomas and in solid tumors. Eur J Cancer 8: Bedikian AY, Valdivieso M, Bodey GP: Systemic chemotherapy for advanced gastrointestinal cancer. South Med J 73(8): Bedikian AY : Treatment of common malignant neoplasms of digestive system: an overview. Proceedings of Twenty-sixth Annual Clinical Conference on Cancer 1981 /Cancer 2001: An International Colloquium (B). In press 4. Kolaric K, Maricic Z, Dujmovic I, et al.: Therapy of advanced esophageal cancer with bleomycin, irradiation and combination of bleomycin with irradiation. Tumori 62(3): Tancini G, Bajetta E, Bonadonna G: Terapia con bleomicina da sola o in associazione con nel carcinoma epidermoide dell esofago. Tumori 60: Kolaric K, Maricic Z, Roth A, et al. : Adriamycin alone and in combination with radiotherapy in the treatment of inoperable esophageal cancer. Tumori 63(5): Desai D, Gelber R, Ezdinli E, et al.: Chemotherapy of advanced esophageal carcinoma. Proceedings of American Association for Cancer Research and American Society of Clinical Oncology 20: Kelsen DP, Bains M, Cvitkovic E, et al. : Vindesine in the treatment of esophageal carcinoma: a phase II study. Cancer Treat Rep 63: Popkin J, Pennacchio J, Byrne R. et al.: Phase II study of vindesine (DVA) infusion in advanced cancer. Proceedings of American Association for Cancer Research and American Society of Clinical Oncology 22: Luedke S, Luedke D, Petruska P, et al.: Phase II trial of vindesine (V) in advanced cancer. Proceedings of American Association for Cancer Research and American Society of Clinical Oncology 22: Panettiere FJ, Leichman L, O Bryan R, et al.: Cis-diamminedichloride platinum (II), an effective agent in the treatment of epidermoid carcinoma of the esophagus. A preliminary report of an ongoing Southwest Oncology Group Study. Cancer Clin Trials 4(1): Davis S, Shanmugathasa M, Kessler W: Cis-dichlorodiammineplatinum (II) in the treatment of esophageal carcinoma. Cancer Treat Rep 64(4-5): Ravry MF, Moore M: A phase II pilot study of cis-platinum (II) (DDP) in advanced squamous cell esophageal cancer (SCE). Proceedings of American Association for Cancer Research and American Society of Clinical Oncology 21: Creagan ET, O'Fallon JR, Woods JE, et al.: Cis-platinum (P) by 24-hr infusion in advanced upper aerodigestive cancer (ADC). Proceedings of American Association for Cancer Research and American Society of Clinical Oncology 22: Falkson G: Methyl-GAG (NSC-32946) in the treatment of esophagus cancer. Cancer Chemother Rep 55: Knight WA II, Livingston RB, Fabian C, et al.: Methylglyoxal bis-guanylhydrozone (Methyl GAG, MGBG) in advanced human malignancy. Proceedings of American Association for Cancer Research and American Society of Clinical Oncology 20: Mitchell E, Killen J, Korsmeyer S, et al. : Phase II studies with methylglyoxal bis-guanylhydrazone (Methyl-G). Proceedings of American Association for Cancer Research and American Society of Clinical Oncology 22: Chapman R, Kelsen D, Gralla R, et al. : Phase II trials of methylglyoxal bis (guanylhydrazone) (MGBG) in 3 solid tumors. Proceedings of American Association for Cancer Research and American Society of Clinical Oncology 22: Radice PA. Bunn PA Jr, Ihde DC: Therapeutic trials with VP and VM-26: active agents in small cell lung cancer, non-hodgkin s lymphomas and other malignancies. Cancer Treat Rep 63(8): Kelsen DP, Bains M. Chapman R, et al. : Cisplatin, vindesine and bleomycin (DVB) combination chemotherapy for esophageal carcinoma. Cancer Treat Rep 65(9 10): Kolaric K, Maricic Z, Roth A, et al.: Combination of bleomycin and adriamycin with and without radiation in the treatment of inoperable esophageal cancer. A randomized study. Cancer 45 (9): Marcial VA, Velez-Garcia E, Cintron J, et al.: Radiotherapy preceded by multidrug chemotherapy in carcinoma of the esophagus. A pilot study of the radiation therapy oncology group. Cancer Clin Trials 3: Lad TE: Platinum, mitomycin-c, and bleomycin chemotherapy of esophageal carcinoma. Proceedings of American Association for Cancer Research and American Society of Clinical Oncology 21: Hentek V, Vogl SE, Kaplan BH, et al.: Combination chemotherapy of advanced esophageal cancer (ECa) with (M), bleomycin (B), and diamminedichloroplatinum (D). Proceedings of American Association for Cancer Research and

5 American Society of Clinical Oncology 20: Franklin R, Steiger Z, Vaishampayan G, et al. : Combined therapies in esophageal squamous cell cancer (ESCC). Proceedings of American Association for Cancer Research and American Society of Clinical Oncology 21: Kelsen DP, Chapman R, Bains M: Cisplatin, vindesine, and bleomycin combination chemotherapy of esophageal cancer. Proceedings of American Association for Cancer Research and American Society of Clinical Oncology 22: