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Pathologic complete response in advanced non-small-cell lung cancer following preoperative chemotherapy: Implications for the design of future non-small-cell lung cancer combined modality trials
144
Abstracts/
Lung Cancer II (1994) 123-150
Combination chemotherapy with ICE (ifosfamide/carboplatin/ etoposide) has developedfrom the significant single-agent activity of the component drugs and the marked efficacy of hvod~g combinations. The ICE regimen has been associated with 2-year survivals of 30 % with minimum follow-up of 24 months. Patients populations in these studies were not staged intensively and the survival is therefore of considerable interest. The severe myelosuppression seen in the majority of patients requires close monitoring, and supportive care, particularly with antibiotics, is otten required. The use of hematopoietic growth factors in the future should ameliorate this toxicity. It is also important to note, however, that the depression in blood count is transient and currently allows treatment to be given at 4- to !I- week intervals even without growth factor support. It is highly likely that outpatient treatment based on oral formulations of ifosfamide and etoposide with bolus injections of carboplatin soon will be possible. Oral platinum compounds are also in a late stage of development. Other techniques for outpatient-based whichmay beassociated ICE therapy includeambulatorypumpinfusions, with less hematologic toxicity. Further developments of ICE-based chemotherapy regimens should providean important avenue of progress in the future therapy of small cell lung cancer. Pathologic complete response in advanced non-small-cell lung cancer following preoperative chemotherapy: Implications for the design of future non-small-cell lung cancer combined modality trials PistersRMW,RtisMG,GrallaRJ, ZamanMB,HeelanRT,MartiniN. Memorial Hospital, 1275 YorkAve. New York, NY 10021. J Clin Chtcol 1993;11:1757-62 Purpose: This report determines the incidence of pathologic complete response in patients with lccally advanced non-small-cell lung cancer (NSCLC)treatedwithmitomycin,vincaalkaloid,andhighdosecisplatin (MVP) chemotherapy, and estimates the effect of MVP on survival. Patients and Methods: We have identified and reviewed the course of 21 patients with advanced NSCLC who achieved a pathologic complete response following a median of three preoperative MVP combination chemotherapy courses including vinblastine or vindesine, cisplatin (120 mglm2), and mitomycin (n = 19). Results: All patients had a major objective response following preoperative chemotherapy and nine (43 W) had a clinical complete response. Nine patients with pathologic complete responses were among 73 entered on a preoperative chemotherapy program, yielding an incidence estimate of 12 46 (95 % confidence interval, 6 I to 22%). The median survival duration for all 21 patients has not been reached. The median follow-up duration is now 68months(range, 17to 109). Survivalestimatesare909bat lyear,62% at 3 years, and 54% at 5 years. Nine patients have relapsed with initial sites of recurrence as follows: brain (n = S), other systemic sites (n = 3), and locoregional (n = 1). One patient died in the postoperative period. Eleven patients remain disease-free and all have excellent functional status. Conclusion: We have observed pathologic complete responses in approximately 12% of ,advanced NSCLC patients treated with preoperative MVP chemotherapy. Thesepathologically determined responses were seen only in patients with major objective responses clinically. Pathologic complete response predicts excellent survival and functional level and should be considered a major end point in the evaluation of preoperative chemotherapy programs. Is there a role for vindesine in the treatment of non-small cdl lung cancer? Sorensen JB, Hansen HH. Depattment of Oncology, Rigshospitalet, 9 Blegdamswj, DK-2100 Copenhagen. Invest New Drugs 1993; 11: 10333. Vindesine is a semisynthetic derivativeofvinblastinewhich has been
evaluated in clinical studies since the late 1970’s. The literature on vindesine in the treatment of non-small cell lung cancer has been reviewed and all aspects of vindesine treatment in this disease has been covered. It is concluded that vindesine as a single agent yields a response rata of 18 46 based on the treatment of 295 patients included in phase II trials (95% confidence limits 13%-22%). No difference was observed among the three major histologic types of non-small cell lung cancer. In phase III trials, the response rate and confidence limits are at a similar level. Combination chemotherapy including vindesine plus cisplatin ranks among the most active treatments in non-small cell lung cancer and is as active as etoposide plus cisplatin, both with respect to response rate and survival. It has not been documented that the addition of one or two other drugs to the combination of vindesine yields an increase in survival. When best supportive care was compared with a combination of vindesine plus cisplatin, the group with chemotherapy was attributed a survival advantage in all three studies published, and the difference was statistically significant in two of these threestudies. Thus, vindesine has a well documented activity in non-small cell lung cancer and ranks among the most active single agents in this disease. Vindesine is also part of several active combination chemotherapies among which the combination of vindesine plus cisplatin is particularly interesting, because it has been repeatedly shown to prolong survival as compared to supportive care. Especially this latter point leads to the conclusion that there is a role for vindesine in the treatment of non-small cell lung cancer. However, the concept of chemotherapy in this disease remains investigational even though the advances seen in recent years clearly merit further studies.
Limited smalkell lung carcinoma: High complete response rate and survival with short intensive chemotherapy and extensive irradiation. Results of a pilot study Tourani J-M, Levy R, Coscas Y, Even P, And&u J-M. Onc&gy/ Hematology Unit, Laennec Hospital, 42 rue de Sevres. 75340 Paris Ceder 07. Int J Gncol 1993;3:347-53. Sixteen patients with limited small-cell lung carcinoma (SCLC) were treated with three monthly courses of intensive chemotherapy (cisplatin: 40 mg/mZklay (D), Dl , D2 and D3; cyclophosphamide: 750 mg/m?/D, D4 and D5; adriamycim 50 mglm’/D, DS; vindesine: 2 mg/d/D, Dt and D5; etoposide: lOOmg/m*/D, Dl, D2 and D3; methylprednisolone: 120 mg/mr/D, Dl to D5). Thoracic and prophylactic brain plus spinal area irradiations were performed after completion of the third chemotherapy cycle. Thecompleteresponserate was 100%. Of these 16 patients, 7 experienced a relapse from 5 to 31 months after completion of treatment. The three-year survival rate was 54%. The main toxicities were hematological (neutropenia and thrombocytopenia) and digestive. We conclude from this pilot study that intensive tivedrug chemotherapy is a highly effective regimen for limited SCLC. This intensive chemotherapy regimen and extensive irradiation is feasible without major toxicity. This type of intensive combined-modality program deserves further study to definitely establish its long-term efficacy in localixed SCLC. The MIC regimen in non-small cell lung cancer CullenMH.Birmingham Oncology Centre, Queen Elizabeth Hospital, Birmingham BJS 277f. Lung Cancer (Ireland) 1993;9 SuppI 2:S81-9. The three most active single agents against non-small cell lung cancer (NSCLC) are mitomycin, ifosfamide, and cisplatin, which have been associatedwith responseratesof20,26and20%, respectively. APhase II study was thereforecommenced to evaluate a combination of the three drugs (MIC) in patients with inoperable, histologically confirmed NSCLC. The 56 46overall and 11% complete response rates established in that trial suggest that MIC is among the most active chemotherapy regimens evaluated for NSCLC with some improvement in performance
Abstracts/
Lung Cancer II (1994) 123-150
Combination chemotherapy with ICE (ifosfamide/carboplatin/ etoposide) has developedfrom the significant single-agent activity of the component drugs and the marked efficacy of hvod~g combinations. The ICE regimen has been associated with 2-year survivals of 30 % with minimum follow-up of 24 months. Patients populations in these studies were not staged intensively and the survival is therefore of considerable interest. The severe myelosuppression seen in the majority of patients requires close monitoring, and supportive care, particularly with antibiotics, is otten required. The use of hematopoietic growth factors in the future should ameliorate this toxicity. It is also important to note, however, that the depression in blood count is transient and currently allows treatment to be given at 4- to !I- week intervals even without growth factor support. It is highly likely that outpatient treatment based on oral formulations of ifosfamide and etoposide with bolus injections of carboplatin soon will be possible. Oral platinum compounds are also in a late stage of development. Other techniques for outpatient-based whichmay beassociated ICE therapy includeambulatorypumpinfusions, with less hematologic toxicity. Further developments of ICE-based chemotherapy regimens should providean important avenue of progress in the future therapy of small cell lung cancer. Pathologic complete response in advanced non-small-cell lung cancer following preoperative chemotherapy: Implications for the design of future non-small-cell lung cancer combined modality trials PistersRMW,RtisMG,GrallaRJ, ZamanMB,HeelanRT,MartiniN. Memorial Hospital, 1275 YorkAve. New York, NY 10021. J Clin Chtcol 1993;11:1757-62 Purpose: This report determines the incidence of pathologic complete response in patients with lccally advanced non-small-cell lung cancer (NSCLC)treatedwithmitomycin,vincaalkaloid,andhighdosecisplatin (MVP) chemotherapy, and estimates the effect of MVP on survival. Patients and Methods: We have identified and reviewed the course of 21 patients with advanced NSCLC who achieved a pathologic complete response following a median of three preoperative MVP combination chemotherapy courses including vinblastine or vindesine, cisplatin (120 mglm2), and mitomycin (n = 19). Results: All patients had a major objective response following preoperative chemotherapy and nine (43 W) had a clinical complete response. Nine patients with pathologic complete responses were among 73 entered on a preoperative chemotherapy program, yielding an incidence estimate of 12 46 (95 % confidence interval, 6 I to 22%). The median survival duration for all 21 patients has not been reached. The median follow-up duration is now 68months(range, 17to 109). Survivalestimatesare909bat lyear,62% at 3 years, and 54% at 5 years. Nine patients have relapsed with initial sites of recurrence as follows: brain (n = S), other systemic sites (n = 3), and locoregional (n = 1). One patient died in the postoperative period. Eleven patients remain disease-free and all have excellent functional status. Conclusion: We have observed pathologic complete responses in approximately 12% of ,advanced NSCLC patients treated with preoperative MVP chemotherapy. Thesepathologically determined responses were seen only in patients with major objective responses clinically. Pathologic complete response predicts excellent survival and functional level and should be considered a major end point in the evaluation of preoperative chemotherapy programs. Is there a role for vindesine in the treatment of non-small cdl lung cancer? Sorensen JB, Hansen HH. Depattment of Oncology, Rigshospitalet, 9 Blegdamswj, DK-2100 Copenhagen. Invest New Drugs 1993; 11: 10333. Vindesine is a semisynthetic derivativeofvinblastinewhich has been
evaluated in clinical studies since the late 1970’s. The literature on vindesine in the treatment of non-small cell lung cancer has been reviewed and all aspects of vindesine treatment in this disease has been covered. It is concluded that vindesine as a single agent yields a response rata of 18 46 based on the treatment of 295 patients included in phase II trials (95% confidence limits 13%-22%). No difference was observed among the three major histologic types of non-small cell lung cancer. In phase III trials, the response rate and confidence limits are at a similar level. Combination chemotherapy including vindesine plus cisplatin ranks among the most active treatments in non-small cell lung cancer and is as active as etoposide plus cisplatin, both with respect to response rate and survival. It has not been documented that the addition of one or two other drugs to the combination of vindesine yields an increase in survival. When best supportive care was compared with a combination of vindesine plus cisplatin, the group with chemotherapy was attributed a survival advantage in all three studies published, and the difference was statistically significant in two of these threestudies. Thus, vindesine has a well documented activity in non-small cell lung cancer and ranks among the most active single agents in this disease. Vindesine is also part of several active combination chemotherapies among which the combination of vindesine plus cisplatin is particularly interesting, because it has been repeatedly shown to prolong survival as compared to supportive care. Especially this latter point leads to the conclusion that there is a role for vindesine in the treatment of non-small cell lung cancer. However, the concept of chemotherapy in this disease remains investigational even though the advances seen in recent years clearly merit further studies.
Limited smalkell lung carcinoma: High complete response rate and survival with short intensive chemotherapy and extensive irradiation. Results of a pilot study Tourani J-M, Levy R, Coscas Y, Even P, And&u J-M. Onc&gy/ Hematology Unit, Laennec Hospital, 42 rue de Sevres. 75340 Paris Ceder 07. Int J Gncol 1993;3:347-53. Sixteen patients with limited small-cell lung carcinoma (SCLC) were treated with three monthly courses of intensive chemotherapy (cisplatin: 40 mg/mZklay (D), Dl , D2 and D3; cyclophosphamide: 750 mg/m?/D, D4 and D5; adriamycim 50 mglm’/D, DS; vindesine: 2 mg/d/D, Dt and D5; etoposide: lOOmg/m*/D, Dl, D2 and D3; methylprednisolone: 120 mg/mr/D, Dl to D5). Thoracic and prophylactic brain plus spinal area irradiations were performed after completion of the third chemotherapy cycle. Thecompleteresponserate was 100%. Of these 16 patients, 7 experienced a relapse from 5 to 31 months after completion of treatment. The three-year survival rate was 54%. The main toxicities were hematological (neutropenia and thrombocytopenia) and digestive. We conclude from this pilot study that intensive tivedrug chemotherapy is a highly effective regimen for limited SCLC. This intensive chemotherapy regimen and extensive irradiation is feasible without major toxicity. This type of intensive combined-modality program deserves further study to definitely establish its long-term efficacy in localixed SCLC. The MIC regimen in non-small cell lung cancer CullenMH.Birmingham Oncology Centre, Queen Elizabeth Hospital, Birmingham BJS 277f. Lung Cancer (Ireland) 1993;9 SuppI 2:S81-9. The three most active single agents against non-small cell lung cancer (NSCLC) are mitomycin, ifosfamide, and cisplatin, which have been associatedwith responseratesof20,26and20%, respectively. APhase II study was thereforecommenced to evaluate a combination of the three drugs (MIC) in patients with inoperable, histologically confirmed NSCLC. The 56 46overall and 11% complete response rates established in that trial suggest that MIC is among the most active chemotherapy regimens evaluated for NSCLC with some improvement in performance