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A phase II trial of dacarbazine, fluorouracil and epirubicin in patients with neuroendocrine tumours. A study by the Italian Trials in Medical Oncology (I.T.M.O.) Group
Annals of Oncology 6: 77-79, 1995. © 1995 Kluwer Academic Publishers. Printed in the Netherlands.
Short report A phase II trial of dacarbazine, fluorouracil and epirubicin in patients with neuroendocrine tumours. A study by the Italian Trials in Medical Oncology (LT.M.O.) Group M. Di Bartolomeo, E. Bajetta, A. M. Bochicchio, C. Carnaghi, L. Somma, V. Mazzaferro, M. Visini, V. Gebbia, S. Tumolo & P. Ballatore Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy
endocrine tumours 1/6; and Merkel cell carcinoma 3/5. The median duration of response was 5 months (range 2-11). Background: Previous experiences in the treatment of neuro- Stable disease was observed in 13 cases (34%). Out of the 18 endocrine tumours have demonstrated some activity of single cases in progression, 17 had not responded to previous mediagents such as adriamycin, fluorouracil (FU), streptozotocin cal treatment. No symptom control was observed in 4 pts and dacarbazine (DTIC). Opinions concerning the usefulness with carcinoid syndrome. Treatment toxicity was moderate of polychemotherapy in carcinoid tumours are discordant, and included nausea and vomiting, alopecia, leukopenia and whereas better results have been achieved in other endocrine mucositis. pancreatic neoplasms. Based on this background, we used Conclusions: Our results document the moderate efficacy multidrug chemotherapy with DTIC, FU and epirubicin in of the regimen in all of the histologic types. The major difthe treatment of different neuroendocrine tumours. ference in comparison with previous studies was the lower Methods: The study involved 38 pts with progressive and response rate observed in patients with neuroendocrine tumeasurable disease. The treatment schedule was FU 250 mg/ mours. m2 i.v., epirubicin 25 mg/m2 i.v., and DTIC 200 mg/m2 i.v. on days 1, 2 and 3 every 3 weeks. Results: The responses achieved by histologic types were Key words: dacarbazine, epirubicin and fluorouracil combicarcinoids 2/20, medullary thyroid carcinoma 1/7, neuro- nation, neuroendocrine tumours, carcinoids Summary
Introduction
Patients and methods
Tumours of the neuroendocrine system represent a heterogeneous group of carcinomas which include carcinoids, endocrine carcinomas of the pancreas, medullary thyroid carcinomas (MTC) and Merkel cell carcinomas. These neoplasms have a common neuroendocrine differentiation and remarkably similar histopathologic features. Surgery is the chosen treatment for local disease as many of these tumours grow slowly and a reduction of tumour burden can have a positive impact on the quality of life and survival of patients [1]. The efficacy of chemotherapy with single agents such as fluorouracil (FU), doxorubicin, streptozotocin and dacarbazine (DTIC) has been occasionally reported, with a response rate of 10%-20% [2, 3]. Polychemotherapy seems to be more effective in the treatment of endocrine pancreatic tumours, although there is disagreement about its usefulness in carcinoids. Based on this background, we decided to test the combination of DTIC, FU and epirubicin (drugs which have proved to be the most active for these tumours when used alone) in the treatment of various neuroendocrine tumours with progressive disease.
The 38 patients who entered this I.TJVLO. group study came from five different centers, coordinated by the Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. All patients selected for the trial had histological confirmation of neuroendocrine tumours or carcinoids. Each patient was required to have measurable lesions and progressive disease before entering the study. Biochemical markers (as well as 24-hour urine 5-hydroxyindolacetic acid (5HIAA) in the case of functional carcinoids, serum hormone levels in endocrine pancreatic tumours, and calcitonine in patients with MTC) were followed as available, but these were not the only response criteria considered. The patients may have been previously treated by means of surgery, radiation therapy, any chemotherapy other than DTIC, FU and epirubicin and/or immunotherapy. The other eligible criteria were: age <75 years; a performance status of 0-2 (ECOG scale); and adequate renal (serum creatinine <2 mg/dl), hepatic (bilirubin <3 mg/ ml) and hematological function (WBC >4000/mm 3 and platelets > 100.000/mm3). The exclusion criteria included CNS metastasis, concomitant severe illness and a life expectancy of less than 3 months. The chemotherapy dose consisted of epirubicin 25 mg/m2, DTIC 200 mg/m2 and FU 250 mg/m2 i.v., given daily for three days; cycles repeated every three weeks. The drug dosages were modified as follows: in the WHO grade 1-4 myelotoxicity at the moment of delivery of a new cycle, a delay of one or two weeks was required; thereafter, in the persisting WHO grade 1-3 myelotoxicity, the dosage was reduced by 25%. In the stable disease, the treatment was
78 slopped after eight cycles. A complete evaluation of all disease sites was performed every three cycles. A maximum of twelve cycles was administered to responding patients. Each patient was required to have at least one measurable lesion. A decrease in hormone marker levels without an objective response in terms of tumour mass, was not accepted as an objective response. History, physical examination, hemogram, blood biochemistry and tumour measurements by means of ultrasound-computed tomography and radiography were performed every three cycles. Tumour response was defined according to the International Union Against Cancer criteria. Biochemical response was defined as a return of elevated tumour markers to within the normal range or sharing a decrease of 50% or more in comparison with the previous month.
Results
Table 1. Characteristics of patients with an objective response to treatment. Age
Sex
Histological type
Site of metastases
Primary site
ObjecResponse tive duration response (months)
20
M
Liver
Stomach
PR
5
48
M
Neuroendocrine Carcinoid
Pancreas
PR
10
72 29
F
Skin Thyroid
PR PR
3 11
65
M
Skin
PR
3
58
F
Unknown
PR
6
66
F
Skin
PR
2
M
Liver Lymph-nodes Merkel cell Lymph-nodes Medullary Lymph-nodes carcinoma Bone Merkel cell Lymph-nodes Skin Carcinoid Liver Lymph-nodes Merkel cell Lymph-nodes Skin
All of the 38 patients included in the study were evaluated for tumour response and toxicity. sion was observed in four patients with abnormal The predominant histologica] type was carcinoid 5-HIAA urinary excretion, all of these cases remained (diagnosed in 20 patients). Medullary thyroid carcino- in stable disease throughout treatment. mas were present in seven cases, Merkel cell carcinoNo deaths were caused as a result of the chemothermas in five and other neuroendocrine tumours in five. apy and the level of toxicity was acceptable. LeukoOne patient had a well-differentiated neuroendocrine penia was observed in two patients (WHO grade 3) and tumour of the lung. The primary sites of ten foregut car- nine patients (WHO grade 1-2). Vomiting and nausea cinoids were the pancreas (n — 6), stomach (n — 2), lung were observed infivepatients (WHO grade 3). Mucosi(n = 1) and branches (n -= 1); six patients had hindgut tis was reported in ten patients (grade 3 in three cases carcinoids and four had carcinoids with an unknown and grade 1-2 in seven cases). All patients had aloprimary site. Nineteen patients had multiple disease pecia. There was no cumulative toxicity. sites, the most common metastatic site being the liver. Thirty-three patients had an ECOG performance status of 0-1, and five patients a performance status of 2. Discussion Their median age was 53 years (range 20-72). Abnormal 5-HIAA urinary excretion was present in seven The low incidence of neuroendocrine tumours, which patients (median 30 mg/24 h; range 15-400), and car- include neoplasms with different biological and clinical cinoid syndrome in four patients. Thirteen patients had characteristics, reduces the possibility of establishing a had previous surgery. Cytotoxic drugs (including strep- standard treatment [4, 5]. tozotocin) were administered in four cases, endocrine Data previously published in literature have demontherapy with octreotide in 22, and immunotherapy in strated that the drug associates which have proven to be five. Six patients had not received any previous therapy of substantial value in the chemotherapy of endocrine whereas twelve had received more than one treatment. pancreatic tumours are doxorubicin and streptozotocin After a median treatment duration of six cycles, a [2], but the reported response rate varies widely from PR was detected in seven patients (2 with carcinoids, 1 one study to another. One possible reason in the interwith MTC, 1 with neuroendocrine tumours and 3 with pretation of response to chemotherapy, which includes Merkel cell carcinoma); stable disease was documented objective tumour regression, the amelioration of horin 13 and PD in 18 cases, respectively. The main char- mone-related symptoms and the measurement of the decrease in circulating hormone levels. In the present acteristics of the responders are given in Table 1. One pancreatic carcinoid patient with liver and ab- study only tumour regression was considered an objecdominal lymph-node deposits was in PR after seven tive response, which resulted in a lower response rate. cycles of therapy. The patient underwent laparotomy The patients with a 'biochemical response' were conwith a total excision of extrahepatic abdominal disease sidered as being in stable disease if tumour regression and no microscopic residual disease was histologically did not show. documented. Liver transplantation was performed after Although few data have been published on the effi4 further consolidation cycles and liver histological cacy of DTIC as a single agent in neuroendocrine tuexamination revealed only microscopic residual dis- mours, the need for a new therapeutic combination has ease. The patient was still living without any evidence led to reconsideration of this drug. Moertel has recentof disease 16 months after transplantation and 26 ly documented the efficacy of the alternation of DTIC months after starting chemotherapy. No significant dif- and doxorubicin with FU and streptozotocin after ference was found between responders and non re- hepatic arterial occlusion [6], the integrated treatment sponders in terms of pretreatment. Biochemical regres- improves the rate and duration of regression in com-
79 parison with chemotherapy alone. Unfortunately, the results obtained with chemotherapy are negatively affected by differences in the pretreatment characteristics of the patients, such as the grade of differentiation, and the duration and extension of the disease. We recommend that patients with carcinoids and neuroendocrine tumours who are treated in research and use designed protocols should have similarities in order to improve the results of systemic therapy. The low-toxicity observed in our study might suggest a possible relationship between the dose-intensity and the responsiveness. A few reports on MTC therapy have shown a welldocumented response to systemic treatment, and the combination of doxorubicin, cisplatin and vindesina has produced some partial responses [7]. Based on the small number of patients with MTC, no clear conclusions can be drawn; nevertheless, further investigations are warranted. Merkel cell carcinoma is an unusual neuroendocrine tumour, which appears to be chemosensitive to regimes which are very similar to those used in lung cancer, unfortunately, responses are usually incomplete and short-lived [8]. The objective responses obtained in our Merkel cell carcinoma patients (3/5) confirm reports already published that it is a cancer which is responsive to chemotherapy.
Acknowledgement
Data management by Italian Trials in Medical Oncology (I.T.M.O.) Scientific Service.
References 1. Averbuch SD. Endocrine tumours. In Pinedo HM, Longo DL, Chabner BA (eds): Cancer Chemotherapy and Biological Response Modifiers Annual 13. Amsterdam: Elsevier Science Publishers 1992; 493-507. 2. Moertel CG, Lefkopoulo M, Lipsitz S et al. Streptozocon-doxorubicin, streptozotocin-fluorouracil, or chlorozotocin in the treatment of advanced islet-cell carcinoma. New Engl J Med 1992; 326: 519-23. 3. Zilembo N, Buzzoni R, Bajetta E et al. Salvage treatment after r-Inferferon alpha 2A in advanced neuroendocrine tumours. Acta Oncologica 1993; 32: 245-50. 4. Bajetta E, Zilembo N, Di Bartolomeo M et al. Treatment of metastatic carcinoids and other neuroendocrine tumours with recombinant interferon alpha 2A. Cancer 1993; 72: 3099-100. 5. Di Bartolomeo M, Bajetta E, Zilembo N et al. Treatment of carcinoid syndrome with recombinant interferon alpha 2A. Acta Oncologica 1993; 32: 235-8. 6. Moertel CG, Johnson CM, McKusick M et al. The management of patients with advanced carcinoid tumours and islet cell carcinomas. Ann Intern Med 1994; 120: 302-30. 7. Scherube H, Rave F, Ziegler R. Combination chemotherapy of advanced medullary and differentiated thyroid cancer. J Cancer Res Clin Oncol 1990; 116: 321. 8. Sharma D, Gurdip F, Grunberg SM. Chemotherapy of metastatic Merkel cell carcinoma; Case report and review of the literature. Am J Clin Oncol 1991; 14: 166-9. Received 25 April 1994; accepted 21 September 1994. Correspondence to: Dr. Emilio Bajetta Division of Medical Oncology B Istituto Nazionale per lo Studio e la Cura dei Tumori Via Venezian 1 20133 Milan Italy
Short report A phase II trial of dacarbazine, fluorouracil and epirubicin in patients with neuroendocrine tumours. A study by the Italian Trials in Medical Oncology (LT.M.O.) Group M. Di Bartolomeo, E. Bajetta, A. M. Bochicchio, C. Carnaghi, L. Somma, V. Mazzaferro, M. Visini, V. Gebbia, S. Tumolo & P. Ballatore Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy
endocrine tumours 1/6; and Merkel cell carcinoma 3/5. The median duration of response was 5 months (range 2-11). Background: Previous experiences in the treatment of neuro- Stable disease was observed in 13 cases (34%). Out of the 18 endocrine tumours have demonstrated some activity of single cases in progression, 17 had not responded to previous mediagents such as adriamycin, fluorouracil (FU), streptozotocin cal treatment. No symptom control was observed in 4 pts and dacarbazine (DTIC). Opinions concerning the usefulness with carcinoid syndrome. Treatment toxicity was moderate of polychemotherapy in carcinoid tumours are discordant, and included nausea and vomiting, alopecia, leukopenia and whereas better results have been achieved in other endocrine mucositis. pancreatic neoplasms. Based on this background, we used Conclusions: Our results document the moderate efficacy multidrug chemotherapy with DTIC, FU and epirubicin in of the regimen in all of the histologic types. The major difthe treatment of different neuroendocrine tumours. ference in comparison with previous studies was the lower Methods: The study involved 38 pts with progressive and response rate observed in patients with neuroendocrine tumeasurable disease. The treatment schedule was FU 250 mg/ mours. m2 i.v., epirubicin 25 mg/m2 i.v., and DTIC 200 mg/m2 i.v. on days 1, 2 and 3 every 3 weeks. Results: The responses achieved by histologic types were Key words: dacarbazine, epirubicin and fluorouracil combicarcinoids 2/20, medullary thyroid carcinoma 1/7, neuro- nation, neuroendocrine tumours, carcinoids Summary
Introduction
Patients and methods
Tumours of the neuroendocrine system represent a heterogeneous group of carcinomas which include carcinoids, endocrine carcinomas of the pancreas, medullary thyroid carcinomas (MTC) and Merkel cell carcinomas. These neoplasms have a common neuroendocrine differentiation and remarkably similar histopathologic features. Surgery is the chosen treatment for local disease as many of these tumours grow slowly and a reduction of tumour burden can have a positive impact on the quality of life and survival of patients [1]. The efficacy of chemotherapy with single agents such as fluorouracil (FU), doxorubicin, streptozotocin and dacarbazine (DTIC) has been occasionally reported, with a response rate of 10%-20% [2, 3]. Polychemotherapy seems to be more effective in the treatment of endocrine pancreatic tumours, although there is disagreement about its usefulness in carcinoids. Based on this background, we decided to test the combination of DTIC, FU and epirubicin (drugs which have proved to be the most active for these tumours when used alone) in the treatment of various neuroendocrine tumours with progressive disease.
The 38 patients who entered this I.TJVLO. group study came from five different centers, coordinated by the Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. All patients selected for the trial had histological confirmation of neuroendocrine tumours or carcinoids. Each patient was required to have measurable lesions and progressive disease before entering the study. Biochemical markers (as well as 24-hour urine 5-hydroxyindolacetic acid (5HIAA) in the case of functional carcinoids, serum hormone levels in endocrine pancreatic tumours, and calcitonine in patients with MTC) were followed as available, but these were not the only response criteria considered. The patients may have been previously treated by means of surgery, radiation therapy, any chemotherapy other than DTIC, FU and epirubicin and/or immunotherapy. The other eligible criteria were: age <75 years; a performance status of 0-2 (ECOG scale); and adequate renal (serum creatinine <2 mg/dl), hepatic (bilirubin <3 mg/ ml) and hematological function (WBC >4000/mm 3 and platelets > 100.000/mm3). The exclusion criteria included CNS metastasis, concomitant severe illness and a life expectancy of less than 3 months. The chemotherapy dose consisted of epirubicin 25 mg/m2, DTIC 200 mg/m2 and FU 250 mg/m2 i.v., given daily for three days; cycles repeated every three weeks. The drug dosages were modified as follows: in the WHO grade 1-4 myelotoxicity at the moment of delivery of a new cycle, a delay of one or two weeks was required; thereafter, in the persisting WHO grade 1-3 myelotoxicity, the dosage was reduced by 25%. In the stable disease, the treatment was
78 slopped after eight cycles. A complete evaluation of all disease sites was performed every three cycles. A maximum of twelve cycles was administered to responding patients. Each patient was required to have at least one measurable lesion. A decrease in hormone marker levels without an objective response in terms of tumour mass, was not accepted as an objective response. History, physical examination, hemogram, blood biochemistry and tumour measurements by means of ultrasound-computed tomography and radiography were performed every three cycles. Tumour response was defined according to the International Union Against Cancer criteria. Biochemical response was defined as a return of elevated tumour markers to within the normal range or sharing a decrease of 50% or more in comparison with the previous month.
Results
Table 1. Characteristics of patients with an objective response to treatment. Age
Sex
Histological type
Site of metastases
Primary site
ObjecResponse tive duration response (months)
20
M
Liver
Stomach
PR
5
48
M
Neuroendocrine Carcinoid
Pancreas
PR
10
72 29
F
Skin Thyroid
PR PR
3 11
65
M
Skin
PR
3
58
F
Unknown
PR
6
66
F
Skin
PR
2
M
Liver Lymph-nodes Merkel cell Lymph-nodes Medullary Lymph-nodes carcinoma Bone Merkel cell Lymph-nodes Skin Carcinoid Liver Lymph-nodes Merkel cell Lymph-nodes Skin
All of the 38 patients included in the study were evaluated for tumour response and toxicity. sion was observed in four patients with abnormal The predominant histologica] type was carcinoid 5-HIAA urinary excretion, all of these cases remained (diagnosed in 20 patients). Medullary thyroid carcino- in stable disease throughout treatment. mas were present in seven cases, Merkel cell carcinoNo deaths were caused as a result of the chemothermas in five and other neuroendocrine tumours in five. apy and the level of toxicity was acceptable. LeukoOne patient had a well-differentiated neuroendocrine penia was observed in two patients (WHO grade 3) and tumour of the lung. The primary sites of ten foregut car- nine patients (WHO grade 1-2). Vomiting and nausea cinoids were the pancreas (n — 6), stomach (n — 2), lung were observed infivepatients (WHO grade 3). Mucosi(n = 1) and branches (n -= 1); six patients had hindgut tis was reported in ten patients (grade 3 in three cases carcinoids and four had carcinoids with an unknown and grade 1-2 in seven cases). All patients had aloprimary site. Nineteen patients had multiple disease pecia. There was no cumulative toxicity. sites, the most common metastatic site being the liver. Thirty-three patients had an ECOG performance status of 0-1, and five patients a performance status of 2. Discussion Their median age was 53 years (range 20-72). Abnormal 5-HIAA urinary excretion was present in seven The low incidence of neuroendocrine tumours, which patients (median 30 mg/24 h; range 15-400), and car- include neoplasms with different biological and clinical cinoid syndrome in four patients. Thirteen patients had characteristics, reduces the possibility of establishing a had previous surgery. Cytotoxic drugs (including strep- standard treatment [4, 5]. tozotocin) were administered in four cases, endocrine Data previously published in literature have demontherapy with octreotide in 22, and immunotherapy in strated that the drug associates which have proven to be five. Six patients had not received any previous therapy of substantial value in the chemotherapy of endocrine whereas twelve had received more than one treatment. pancreatic tumours are doxorubicin and streptozotocin After a median treatment duration of six cycles, a [2], but the reported response rate varies widely from PR was detected in seven patients (2 with carcinoids, 1 one study to another. One possible reason in the interwith MTC, 1 with neuroendocrine tumours and 3 with pretation of response to chemotherapy, which includes Merkel cell carcinoma); stable disease was documented objective tumour regression, the amelioration of horin 13 and PD in 18 cases, respectively. The main char- mone-related symptoms and the measurement of the decrease in circulating hormone levels. In the present acteristics of the responders are given in Table 1. One pancreatic carcinoid patient with liver and ab- study only tumour regression was considered an objecdominal lymph-node deposits was in PR after seven tive response, which resulted in a lower response rate. cycles of therapy. The patient underwent laparotomy The patients with a 'biochemical response' were conwith a total excision of extrahepatic abdominal disease sidered as being in stable disease if tumour regression and no microscopic residual disease was histologically did not show. documented. Liver transplantation was performed after Although few data have been published on the effi4 further consolidation cycles and liver histological cacy of DTIC as a single agent in neuroendocrine tuexamination revealed only microscopic residual dis- mours, the need for a new therapeutic combination has ease. The patient was still living without any evidence led to reconsideration of this drug. Moertel has recentof disease 16 months after transplantation and 26 ly documented the efficacy of the alternation of DTIC months after starting chemotherapy. No significant dif- and doxorubicin with FU and streptozotocin after ference was found between responders and non re- hepatic arterial occlusion [6], the integrated treatment sponders in terms of pretreatment. Biochemical regres- improves the rate and duration of regression in com-
79 parison with chemotherapy alone. Unfortunately, the results obtained with chemotherapy are negatively affected by differences in the pretreatment characteristics of the patients, such as the grade of differentiation, and the duration and extension of the disease. We recommend that patients with carcinoids and neuroendocrine tumours who are treated in research and use designed protocols should have similarities in order to improve the results of systemic therapy. The low-toxicity observed in our study might suggest a possible relationship between the dose-intensity and the responsiveness. A few reports on MTC therapy have shown a welldocumented response to systemic treatment, and the combination of doxorubicin, cisplatin and vindesina has produced some partial responses [7]. Based on the small number of patients with MTC, no clear conclusions can be drawn; nevertheless, further investigations are warranted. Merkel cell carcinoma is an unusual neuroendocrine tumour, which appears to be chemosensitive to regimes which are very similar to those used in lung cancer, unfortunately, responses are usually incomplete and short-lived [8]. The objective responses obtained in our Merkel cell carcinoma patients (3/5) confirm reports already published that it is a cancer which is responsive to chemotherapy.
Acknowledgement
Data management by Italian Trials in Medical Oncology (I.T.M.O.) Scientific Service.
References 1. Averbuch SD. Endocrine tumours. In Pinedo HM, Longo DL, Chabner BA (eds): Cancer Chemotherapy and Biological Response Modifiers Annual 13. Amsterdam: Elsevier Science Publishers 1992; 493-507. 2. Moertel CG, Lefkopoulo M, Lipsitz S et al. Streptozocon-doxorubicin, streptozotocin-fluorouracil, or chlorozotocin in the treatment of advanced islet-cell carcinoma. New Engl J Med 1992; 326: 519-23. 3. Zilembo N, Buzzoni R, Bajetta E et al. Salvage treatment after r-Inferferon alpha 2A in advanced neuroendocrine tumours. Acta Oncologica 1993; 32: 245-50. 4. Bajetta E, Zilembo N, Di Bartolomeo M et al. Treatment of metastatic carcinoids and other neuroendocrine tumours with recombinant interferon alpha 2A. Cancer 1993; 72: 3099-100. 5. Di Bartolomeo M, Bajetta E, Zilembo N et al. Treatment of carcinoid syndrome with recombinant interferon alpha 2A. Acta Oncologica 1993; 32: 235-8. 6. Moertel CG, Johnson CM, McKusick M et al. The management of patients with advanced carcinoid tumours and islet cell carcinomas. Ann Intern Med 1994; 120: 302-30. 7. Scherube H, Rave F, Ziegler R. Combination chemotherapy of advanced medullary and differentiated thyroid cancer. J Cancer Res Clin Oncol 1990; 116: 321. 8. Sharma D, Gurdip F, Grunberg SM. Chemotherapy of metastatic Merkel cell carcinoma; Case report and review of the literature. Am J Clin Oncol 1991; 14: 166-9. Received 25 April 1994; accepted 21 September 1994. Correspondence to: Dr. Emilio Bajetta Division of Medical Oncology B Istituto Nazionale per lo Studio e la Cura dei Tumori Via Venezian 1 20133 Milan Italy