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Combination cyclophosphamide, adriamycin, and vincristine rapidly alternating with combination cisplatin and VP-16 in treatment of small cell lung cancer
Combination Cyclophosphamide, Adriamycin, and Vincristine Rapidly Alternating with Combination Cisplatin and VP- 16 in Treatment of Small Cell Lung Cancer
RONALD 6. NATALE, M.D.* BRENDA SHANK, M.D., Ph.D. BASIL S. HILARIS, M.D. ROBERT E. WITTES, M.D.+ New
York.
New
York
From the Solid Tumor Service, Department of Medicine, and the Department of Radiation Therapy, Memorial Sloan-Kettering Cancer Center, New York, New York. This work was supported in part by National Institutes of Health Contract NOl-CM-57043 (Division of Cancer Treatment, National Cancer Institute) and by Public Health Service Grant CA-05826 from the National Cancer Institute, National Institutes of Health, Education and Welfare, Bethesda, Maryland. Manuscript accepted December 14. 1984. * Current address and address for reprint requests: University of Michigan, Department of Medicine, Division of Hematology/Oncology, 4701 Upjohn Center, Ann Arbor, Michigan 48109. t Current address: Cancer Therapy Evaluation Program, Division of Cancer Treatment, Landow Building, Room 4A-22, Bethesda, Maryland 20205.
Forty-four patients with small cell lung cancer were treated with an intensive chemotherapy induction program consisting of combination cyclophosphamide, Adriamycin, and vincristine rapidly alternating with combination cisplatin and VP-16 followed by prophylactic cranial radiotherapy. After chemotherapy induction and cranial radiotherapy, patients with limited disease received multiple-field radiotherapy consolidation to the primary tumor site and mediastinum using thoracic computed tomographic scanning for field planning, and patients with extensive disease received chemotherapy maintenance. Patients with limited disease in complete remission following radiotherapy consolidation received no further treatment unless disease recurred. It was found that cyclophosphamide, Adriamycin, and vincristine could be alternated with cisplatin plus VP-16 at two-week intervals in 80 percent of patients on an outpatient basis and that two thirds of patients achieved clinical complete remission after two courses of each regimen. Locoregional radiotherapy delivered via multiple fields was effective in increasing the complete remission rate in patients with limited disease and was well tolerated. The median survival time was 18.5 months in 24 patients with limited disease and 12.2 months in 20 patients with extensive disease. Four patients with limited disease who received chemotherapy induction and radiotherapy consolidation without maintenance chemotherapy and one patient with extensive disease remain alive and disease-free at more than five years. We previously reported that the combination of cisplatin and VP-16 was a highly active induction regimen in small cell lung cancer, producing a 95 percent rate of objective response rate and a 47 percent rate of complete remission [ 11. Tumor regression occurred rapidly and reached a maximum after two courses of cisplatin (60 mg/m*) on Day 1 and VP-16 (120 mg/m*) on Days 4, 6 and 8, given three weeks apart. Additional tumor regression did not occur following the cisplatin plus VP-16 induction in 38 patients with small cell lung cancer despite treatment with cyclophosphamide (1,000 mg/m*), Adriamycin (40 mg/m*), and vincristine (1.4 mg/m*) given together on Days 42, 63, 84, and 105. The median survival of 21 patients with limited and 17 patients with extensive disease was 22 and 11 months, respectively, with four patients with limited disease remaining clinically free of disease more than three years after the start of therapy. Analysis of
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initial sites of relapse confirmed our earlier experience, that is, patients with limited disease tended to have first disease recurrence at the site of the primary tumor complex, whereas patients with extensive disease tended to have initial recurrence at multiple intra- and extrathoracic sites. These results established the high activity of combination cisplatin and VP-16 in small cell lung cancer but raised questions regarding its relative non-crossresistance with cyclophosphamide, Adriamycin, and vincristine. Since the treatment interval between two non-cross-resistant drug regimens may be critical to the emergence of a doubly-resistant tumor cell population, we designed the following study in which cyclophosphamide, Adriamycin, and vincristine and cisplatin plus VP-16 were given in alternating sequence as rapidly as possible. Furthermore, in an attempt to eradicate residual tumor following chemotherapy induction, highdose radiation therapy to the primary disease complex and mediastinum was given to patients with limited disease. Computed transaxial tomographic scanning of the thorax was used for radiation treatment planning. Following chemotherapy induction and radiation consolidation, patients with limited disease in complete remission received no further therapy unless disease recurred; patients with limited disease not achieving complete remission and all patients with extensive disease continued to receive chemotherapy maintenance for one year. This report describes the details and results of the study. PATIENTS
AND METHODS
A total of 44 consecutive, previously untreated patients with histologically or cytologically confirmed small ceil lung cancer were treated. Eligibility criteria included no prior history of cancer, normal renal function (serum creatinine below 1.2 mg/dl or creatinine clearance of at least 60 ml per minute), and informed consent. At the start of therapy, all patients provided a complete history and underwent physical examination and laboratory evaluation including complete blood cell and platelet counts, 12-channel biochemical profile, serum electrolyte and creatinine determination, chest roentgenography, bone marrow aspiration and biopsy, and measurement of serum carcinoembryonic antigen and 5’nucleotidase. Radionuclide liver scanning was used in patients with hepatomegaly or abnormal results of biochemical liver function tests. Results of the initial evaluation permitted classification of patients into categories of limited disease (tumor confined to hemithorax and ipsilateral cervical nodes) or extensive disease (metastases to contralateral lung or nodes, liver, bone, and/or brain or presence of a pleural effusion). Treatment was given on an outpatient basis. All patients received an induction regimen consisting of four cycles of chemotherapy followed by prophylactic whole-brain irradiation. Chemotherapy cycles 1 and 3 consisted of cyclophosphamide (1,200 mg/m*), Adriamycin (50 mg/m*), and
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vincristine (1.4 mg/m*) given intravenously on Day 1 of each cycle. Cycles 2 and 4 consisted of cisplatin (60 mg/m2) intravenously on Day 1 and VP-16 (120 mg/m*) intravenously on Days 4,6, and 8 of the cycles. Each cycle was given as soon as the white blood cell count returned to more than 3,000/mm3 and the platelet count returned to more than 100,000/mm3 following the nadir induced by the preceding cycle. Cranial irradiation was delivered as 500 rads on three consecutive days, four days rest, then 300 rads on five consecutive days (4,000-rad equivalent by the NSD concept) [2]. Patients with limited disease received consolidation radiotherapy to the primary site and mediastinum on a 10 MV Mevatron 12 linear accelerator, 250 rads on four days a week for a total of 18 fractions (5,000-rad equivalent by the NSD concept). Multiple-field treatment plans were devised utilizing simulation films to determine field length and spinal cord location and thoracic computed tomographic scanning to determine precise tumor and mediastinum location and volume. Cyclophosphamide (500 mg/m*) and vincristine (1.4 mg/m*) were given intavenously on Days 1 and 15 of radiotherapy. Patients with limited disease not in complete remission following chest radiotherapy and all patients with extensive disease received maintenance chemotherapy for a total of 12 months of treatment or until disease progression. Maintenance consisted of lomustine (100 mg/m*) orally on Day 1, methotrexate (30 mg/m2) intravenously on Days 1, 8, 15 and 22, procarbazine (100 mg/m* per day) orally on Days 1 to 14 inclusive; cyclophosphamide (1,000 mg/m*), Adriamycin (30 mg/m*), and vincristine (1.4 mg/m*) intravenously together on Day 43; and cisplatin (50 mg/m2) intravenously on Day 71 and VP-16 (120 mg/m*) intravenously on Days 74, 76 and 78. The entire sequence was recycled on Day 99. This treatment regimen was reviewed and approved by the Clinical Research and Human Investigations committees of Memorial Sloan-Kettering Cancer Center in accord with assurances filed with and approved by the Department of Health and Human Services. Established clinical response criteria and categories of clinical response were used [3], and response status was determined by monthly physical examination, chest roentgenography, blood chemistry values, and repeated bone marrow aspiration and biopsy and radionuclide scanning. The Karnofsky scale was used to assess performance status. Response duration was measured from the start of therapy to the time of first evidence of disease relapse or progression. Survival was measured from the start of therapy to the time of death. Patient Characteristics. Twenty-four patients with limited disease and 20 patients with extensive disease who had previously untreated small cell lung cancer were entered into the study. The median age was 60 (range 41 to 76) the median Karnofsky score was 70 percent (range 50 to 100 percent), and there were 27 men and 17 women. Documented sites of tumor metastases in patients with extensive disease included liver (12 patients), bone (11 patients), contralateral lung or nodes (eight patients), and pleural effusion (four patients). Eleven patients had more than one extensive disease site. Pretreatment serum carcinoembryonic antigen values were obtained in 40 patients. Carcinoembryonic antigen was
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elevated (more than 5.0 rig/ml) in nine (39 percent) of 23 patients with limited disease and in 13 (76 percent) of 17 patients with extensive disease; carcinoembryonic antigen values above 20 rig/ml were observed in four (17 percent) patients with limited disease and in nine (53 percent) patients with extensive disease.
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Toxicity during induction in 44 Patients Numberof Patients withToxicity perCourse CAV-I PtvP-1 CAV-2 PtvP-2
White blood cell count >3.0 2.0-2.9 1.0-1.9
RESULTS Toxicity. Forty-three of 44 patients completed all four cycles of chemotherapy induction; one patient with poor performance status (Karnofsky score 50) and widely metastatic disease (bilateral lung, nodes, liver, and bone) died of aspiration pneumonia and sepsis 20 days after the start of therapy. Table I details the hematologic and renal toxicities observed during chemotherapy induction. Myelotoxicity, predominantly leukopenia, was dose-limiting but moderate during induction; a documented white blood cell nadir below 3,000/mm3 and platelet nadir below 100,000/mm3 occurred in 66 (38 percent) and 27 (15 percent), respectively, of 173 induction cycles (Table I). Recovery from or absence of myelosuppression (white blood cells above 3,000/mm3 and platelets above 100,000/mm3) was observed by Day 15 in 80 percent of induction cycles and by Day 18 in 90 percent. Therefore, treatment could be “recycled” rapidly, and in 40 of 44 patients, induction was completed within 48 days from the start of therapy. Moderate increases in serum creatinine and blood urea nitrogen levels occurred with seven of 173 induction cycles. Six episodes were related to cisplatin administration, but all were reversible and only one necessitated subsequent treatment modification. Severe toxicity requiring hospitalization occurred in 18 (10 percent) of 173 induction cycles (14 patients); 16 cases were for neutropenia and fever, and two were for moderate nephrotoxicity. It is notable, however, that 90 percent of the induction cycles produced either insignificant toxicity or toxicity that could be successfully managed on an outpatient basis. One additional patient with extensive disease in partial remission died of drug-induced leukopenia and sepsis during maintenance chemotherapy. Radiation-related toxicities consisted chiefly of pneumonitis that occurred acutely in two patients and responded to steroid administration and that was chronic in six. In two of the six chronic cases, pneumonitis involved the lungs diffusely, was refractory to supportive measures, and contributed to death. Both cases occurred in patients with limited disease who had had persistent residual disease (partial remission) following radiation therapy and therefore received maintenance chemotherapy. In addition, there were three patients with mild reversible radiation-induced esophagitis and one patient with transient encephalopathy possibly
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Plateletcount >100,000 50-99,000
23 12 6 3'
35 5 3 0
20 12 7 4
29 9 4 1
39
36 4 3
36 6 1
35 5 3
40
43 0 0
39 2 1
3 2
<50,000
Serumcreatinine level <2.0 2.0-3.9 >4.0
43 1 0
2
Onedeath from sepsis. CAV = cyclophospbamide,Adriamycin,and vincristine;P + VP = cisplatinplusVP-16. l
related to cranial irradiation. Therapeutic Responses. Following chemotherapy induction, complete remission was achieved in 16 (67 percent) of 24 patients with limited disease and 13 (65 percent) of 20 patients with extensive disease status. The remaining patients had partial response, except for one patient with extensive disease who had a minor response (25 to 50 percent disease regression) of 11 weeks’ duration and another patient with extensive disease who died of drug-related leukopenia and sepsis (just described), both of whom are considered to have nonresponse. Following involved-field radiation therapy in the group with limited disease, four of the eight partial responses became clinical complete remissions, resulting in an 83 percent complete remission rate (20 of 24 patients) in the group with limited disease. The median duration of response was 12.7 months (range 4.1 to more than 70 months) in the group with limited disease and 10.1 months (range 2.0 to more than 63 months) in the group with extensive disease. Analysis of survival with a 60-month minimal follow-up time indicates a median survival of 18.5 months for the 24 patients with limited disease and 12.2 months for 20 patients with extensive disease. Five patients (four with limited disease and one with extensive disease) remain alive and disease-free with a minimal follow-up of 60 months (Figure 1). Fifteen of 20 patients with limited disease who had showed complete remission following induction and involved-field irradiation are evaluable for site of first disease recurrence (one patient died of a stroke during complete remission five months after the start of therapy, and four remain disease-free as noted above). The first site of relapse was within the intrathoracic treatment volume in nine of the 15 patients: in six patients, it was the sole initial site of relapse, and in three pa-
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Twelve of 15 patients with limited disease who had relapses after complete remissions (and therefore had not received maintenance chemotherapy) were treated with at least one course of cyclophosphamide, Adriamycin, and vincristine and one course of cisplatin plus VP-16 at the time of relapse. Two patients had clinical complete remissions (3.4 and 7.0 months’ duration), three had partial responses (3, 3.7, and 4.0 months’ duration), one had a minor response (1.5 months’ duration), and six had no response. COMMENTS l-
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Figure 1. Kaplan-Meier survival curves for 24 patients with limited disease (open circles) and 20 patients with extensive disease (solid circles). Tic marks represent six censored pafienfs: one who died of an acute cerebrovascular accident while in complete remission at five months and five who are alive and disease-free with more than 60 months of followUP.
tients, it was concurrent with a non-irradiated site. The site of first relapse was outside the irradiated field in six of the 15 patients: non-irradiated lung accounted for two cases, and liver, liver plus cervical nodes, abdomen, and brain accounted for one case each. Thus, including the four patients remaining disease-free, chemotherapy plus involved-field radiation therapy consolidation successfully controlled the primary tumor site in 10 (42 percent) of 24 patients with limited disease. In 32 of the 44 patients entered into the study, serum carcinoembryonic antigen levels were obtained serially (at one- to two-month intervals) after the start of therapy. In this group, the pretreatment carcinoembryonic antigen value was more than 5.0 rig/ml in 16 cases, more than 10 rig/ml in 15, and more than 20 rig/ml in 10. Objective clinical response to therapy was accompanied by a fall in carcinoembryonic antigen to less than 5.0 rig/ml in all cases, regardless of whether response was judged to be complete or partial, except in one patient in whom the lowest carcinoembryonic antigen value achieved during partial remission was 6.5 rig/ml. After normalization, a rise in the serum carcinoembryonic antigen level above 5.0 rig/ml accompanied or heralded disease recurrence in six of 10 patients with relapse. Patients with pretreatment carcinoembryonic antigen values below 5.0 rig/ml did not have elevated levels during treatment or at the time of disease recurrence. In addition, they did not differ from patients with pretreatment carcinoembryonic antigen values above 5.0 rig/ml with respect to response rate, response duration, or survival. 306
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Since the number of effective agents in small cell lung cancer is greater than can be given simultaneously, the use of mutually non-cross-resistant combination drug regimens administered in alternating sequence has emerged as a potentially fruitful treatment strategy. In Hodgkin’s disease, the superior results obtained by alternating Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) with mechlorethamine, Oncovin, procarbazine, and prednisone (MOPP), compared with MOPP alone, has served to reinforce this concept [4]. There have been several attempts to improve the treatment of small cell lung cancer by the use of alternating or sequential combination drug regimens. Cohen et al [5] used two courses of vincristine, Adriamycin, and procarbazine (VAP) following one course of cyclophosphamide, methotrexate, and CCNU (CMC)-a strategy that appeared to increase the overall response rate and complete remission rate in patients with small cell lung cancer. However, the survival of patients with response to CMC-VAP was not better than had been obtained previously with CMC alone. Furthermore the addition of a third combination drug regimen, VP-16 and ifosfamide, to CMC-VAP did not increase the complete remission rate or prolong survival compared with CMC-VAP alone. In our experience BCNU, methotrexate, and procarbazine (BMP) following two successive three-week courses of cyclophosphamide, Adriamycin, and vincristine (CAV) provided no additional therapeutic benefit in terms of either additional tumor shrinkage or increased survival [6]. Similar results occurred in our most recent study in which two successive cycles of cisplatin plus VP-16 were followed by four successive cycles of CAV [ 11. Maximal objective response occurred with the two cycles of cisplatin plus VP-16 alone, and no discernible additional benefit occurred with the four cycles of CAV. Likewise, Aisner et al [7] reported that CCNU, Oncovin, methotrexate, and procarbazine (COMP) administered after a maximal clinical response had been achieved with one to seven courses of cyclophosphamide, Adriamycin, and VP-16 (CAVP-16) did not improve response rate, survival, or the proportion of patients with long-term disease-free status compared with CAVP-16 alone. In a randomized ECOG trial [8], patients receiving cyclophosphamide, CCNU, and 79
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methotrexate (CCM) alternating with two successive cycles of Adriamycin, vincristine, and procarbazine (AVP) had longer remission durations than patients receiving CCM alone, although objective response rates and overall survival were unaffected and toxicity was greater. The potential benefit of this treatment strategy has been partially supported by the results of only two studies. A randomized trial by NCOG [9] was reported to show an improved complete response rate and median duration of response and survival of patients with extensive disease treated with a sevendrug regimen consisting of VP-16, Adriamycin, and methotrexate (VAM) alternating with procarbazine, Oncovin, cyclophosphamide, and CCNU (POCC) compared with patients treated with POCC alone. However, the VAMPOCC regimen was not significantly superior to the POCC regimen in patients with limited disease, and survival beyond two years was not improved in either patient group. A prolonged remission duration with alternating therapy has also been reported by Osterlind et al [ lo] in an analysis of their randomized sequential versus alternating drug combination trial utilizing cyclophosphamide, CCNU, methotrexate, and vincristine (CCMV) followed by Adriamycin plus VP-16, although median and long-term survival rates were not improved. The reasons for the largely disappointing results obtained with alternating combination drug regimens in small cell lung cancer are unclear. One possible explanation may relate to the character of the combinations employed in these studies. Even when the individual combinations were themselves known to be active in previously untreated patients with small cell lung cancer, lack of cross-resistance with the alternate combination was far more often assumed than proved by the type of randomized cross-over design that is optimal for establishing the absence of cross-resistance. Unlike some of the studies in breast cancer [ 1 l- 131, Hodgkin’s disease [ 41, and non-Hodgkin’s lymphomas [ 141 that have addressed similar questions, it is uncertain that cross-resistance between the alternated combinations, whether measured by tumor regression or survival, was really absent. A second possibility has to do with the relative efficacy or degree of activity of the combinations themselves. Non-cross-resistance of two combinations used sequentially may be a necessary condition for increased efficacy, but it is certainly not a sufficient one. The drug regimens employed may need to possess, independent of each other, high activity as well as non-cross-resistance. The successful experience with Hodgkin’s disease [4], in fact, suggests that the regimens to be alternated must each be capable of inducing complete remission in a substantial fraction of the treated population. September
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The time interval between alternating cycles of two non-cross-resistant drug regimens may also be important. Notably, in all of the aforementioned studies, drug regimens were alternated at intervals of six weeks or more (often necessitated by the use of nitrosoureas) or several successive cycles of one regimen were administered before the switch to another was made. Assuming that small cell lung cancer is composed of tumor cell subpopulations that are intrinsically resistant to either drug regimen A or drug regimen 6 (but not both), the mathematical model of Goldie et al [15] predicts that prolonged intervals between administration of regimens A and B, or administration of two or more courses of one regimen before administration of another regimen greatly favors the spontaneous emergence of tumor cells resistant to both regimens (doubly-resistant tumor cells). We designed the present study to test the feasibility of alternating two highly and independently active combination drug regimens as rapidly as possible. Combination CAV is an established standard treatment regimen with high activity in small cell lung cancer and acute toxicity that is sufficiently short-lived to allow treatment with another regimen within at least three weeks of administration. Combination cisplatin and VP-16 has been shown to possess high activity both in previously untreated small cell lung cancer [l] and in small cell lung cancer refractory to combination CAV [ 16,171. In our study, CAV was alternated with cisplatin plus VP-16 every two weeks in 80 percent of the patients entered. The 67 percent complete remission rate obtained after four courses of therapy (CAV for courses 1 and 3; cisplatin plus VP-16 for courses 2 and 4) appears to be higher than the 47 percent complete remission rate obtained in our previous study when two successive courses of cisplatin plus VP-16 were followed by four successive courses of CAV [ 11. This suggested therapeutic advantage of rapidly alternating CAV and cisplatin plus VP-16 requires testing in an appropriately designed prospective randomized trial. The respectable medial survival (18.5 months) and incidence of long-term survival (17 percent alive and disease-free more than 5 years after diagnosis) among patients with limited disease that was achieved in this study with chemotherapy induction and involved-field radiotherapy alone suggests that maintenance chemotherapy may not be necessary in small cell lung cancer after induction regimens that yield a high complete remission rate. These results confirm the original experience of Johnson et al [ 181 and are in agreement with the recent preliminary studies of Feld et al [ 191 and Holoye et al [20] that show that long-term disease-free survival in patients with limited disease is achievable without prolonged cyclic maintenance chemotherapy. However, since six of 12 patients with limited disease and relapse from complete remission status in our study 1995
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obtained temporary objective disease regression following re-induction with CAV and cisplatin plus VP-16, more than four courses of chemotherapy are probably required to eradicate drug-sensitive tumor populations. Whether this should be in the form of prolonged induction therapy or several intermittent courses of intensive maintenance or “re-induction” chemotherapy requires further study. The precise value of radiotherapy to the primary disease complex in small cell lung cancer remains unclear. Our study demonstrates that locoregional high-dose radiotherapy with careful treatment planning is well tolerated and effective in increasing the complete remission rate. The fact that fewer relapses occurred at the primary disease site in this study compared with our previous trial that did not include radiotherapy [l] suggests that improved locoregional control can be achieved in some patients. That two of the four longterm disease-free survivors had only partial responses with induction chemotherapy and subsequently had complete remissions with radiotherapy adds to this impression.
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The serum carcinoembryonic antigen value was a useful adjunctive parameter in monitoring disease response in many patients. However, it was not useful in assessment of the quality (complete remission versus partial response) or duration of response. A rising carcinoembryonic antigen value during apparent clinical remission was predictive of subsequent disease recurrence but occurred infrequently and was not clinically useful. In summary, this study suggests that the use of rapidly alternating courses of combination drug regimens remains a hopeful treatment strategy in small cell lung cancer and deserves further investigation. Combination CAV and cisplatin plus VP-16 are two highly active drug regimens that are suitable for intensive administration in rapidly alternating sequence and on an outpatient basis. Locoregional radiotherapy delivered via multiple fields is effective in increasing the complete remission rate in patients with limited disease and is probably less toxic than conventional delivery schemes. Maintenance chemotherapy is not required for prolonged survival in all patients and requires critical re-evaluation.
REFERENCES
4.
5. 8. 7.
8.
9.
10.
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Sierocki JS. Hilaris BS, Hopfan S, et al: Cisdiamminedichloroplatinum (II) and VP-18: an active induction regimen for small-cell carcinoma of the lung. Cancer Treat Rep 1979; 83: 1593-1597. Orton CG, Ellis F: A simplification in the use of the NSD concept in practical radiotherapy. Br J Radio1 1973; 48: 529-537. Wittes RE, Hopfan S, Hilaris B, Golbey RB, Melamed M, Martini N: Oat cell carcinoma of the lung-combination treatment with radiotherapy and cyclophosphamide, adriamycin, vincristine and methotrexate. Cancer 1977; 40: 853859. Bonadonna G: Chemotherapy strategies to improve the control of Hodgkin’s disease: the Richard and Hinda Rosenthal Foundation Award Lecture. Cancer 1982; 42: 43094320. Cohen MH, lhde DC, Bunn PA, et al: Cyclic alternating combination chemotherapy for small cell bronchogenic carcinoma. Cancer Treat Rep 1979; 83: 183- 170. Sierocki JS, Hilaris BS. Hopfan S, et al: Small cell carcinoma of the lung: experience with a sixdrug regimen. Cancer 1980; 45: 417-422. Aisner J, Whitacre M, Van Echo DA, Wiernik PH: Combination chemotherapy for small cell carcinoma of the lung: continuous versus alternating non-cross-resistant combinations. Cancer Treat Rep 1982; 88: 221-230. Mehta C, Vogl SE for ECOG: Cycling non-cross resistant combination chemotherapy for small cell lung cancer in remission-50% prolongation of remission duration without prolongation of survival and with enhanced toxicity (abstr). Proc Am Sot Clin Oncol 1982; 1: 152. Sikic BI, Daniels JR, Chak L, et al: PDCC versus PDCC/VAM therapy for small-cell anaplastic (oat cell) lung cancer. In: Prestayko AW, Crooke ST, Baker LH, Carter SK, Schein PS, eds. Nitrosoureas: current status and new developments. New York: Academic Press, 1981; 221-231. Osterlind K, Sorensen S, Hansen HH, et al: Continuous versus alternating combination chemotherapy for advanced small
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Journal
of Medlclne
cell carcinoma of the lung. Cancer Res 1983; 43: 80858089. Brambilla C, Valagressa P, Bonnadonna G: Sequential combination chemotherapy in advanced breast cancer (abstr). Proc Am Assoc Cancer Res 1977; 18: 308. Tormey DC, Gelman R, Band P, et al: Comparison of single to alternating combination therapy in metastatic breast cancer (abstr). Proc Am Assoc Cancer Res Am Sot Clin Oncol 1980; 28: 888. Vogel C, Lefante J, East D, et al: Cyclophosphamide, adriamycin and 5-fluorouracil alternating with a cycle active regimen in metastatic breast cancer: a randomized cancer study group trial (abstr). Proc Am Assoc Cancer Res Sot Clin Oncol 1981; 22: 439. Bonadonna G, Monfardine S, Villa E: Non-cross resistant combinations in stage IV non-Hodgkin’s lymphomas. CancerTreat Rep 1977; 81: 1117-1123. Goldie JH, Coldman AJ, Gudauskas GA: Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat Rep 1982; 88: 439-449. Essers U, Knechten H, Seelis R, Ammon J: Etoposide after AC0 treatment for small-cell bronchogenic carcinoma. Cancer Treat Rev 1982; 9 (suppl A): 11 l-l 13. Evans WK. Feld R, Osoba D. et al: VP-18 alone and in combination with cisplatin in previously treated patients with small cell lung cancer. Cancer 1984; 53: 1481-1488. Johnson RE, Brereton HD, Kent CH: “Total” therapy for small cell carcinoma of the lung. Ann Thorac Surg 1978; 25: 5150-5154. Feld R, Evans WK, Yeoh JL. et al: Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung (abstr). Proc Am Assoc Cancer Res Am Sot Clin Oncol 1981; 22: 494. Holoye PY, Libnock JA, Byhardt RW, et al: Chemotherapy of small cell bronchogenic carcinoma with cytoxan, Adriamycin, methotrexate, high-dose vincristine and consolidation radiotherapy (abstr). Proc Am Assoc Cancer Res Am Sot Clin Oncol 1981; 22: 500.
11.
12.
13.
14.
15.
18.
17.
18.
19.
20.
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RONALD 6. NATALE, M.D.* BRENDA SHANK, M.D., Ph.D. BASIL S. HILARIS, M.D. ROBERT E. WITTES, M.D.+ New
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From the Solid Tumor Service, Department of Medicine, and the Department of Radiation Therapy, Memorial Sloan-Kettering Cancer Center, New York, New York. This work was supported in part by National Institutes of Health Contract NOl-CM-57043 (Division of Cancer Treatment, National Cancer Institute) and by Public Health Service Grant CA-05826 from the National Cancer Institute, National Institutes of Health, Education and Welfare, Bethesda, Maryland. Manuscript accepted December 14. 1984. * Current address and address for reprint requests: University of Michigan, Department of Medicine, Division of Hematology/Oncology, 4701 Upjohn Center, Ann Arbor, Michigan 48109. t Current address: Cancer Therapy Evaluation Program, Division of Cancer Treatment, Landow Building, Room 4A-22, Bethesda, Maryland 20205.
Forty-four patients with small cell lung cancer were treated with an intensive chemotherapy induction program consisting of combination cyclophosphamide, Adriamycin, and vincristine rapidly alternating with combination cisplatin and VP-16 followed by prophylactic cranial radiotherapy. After chemotherapy induction and cranial radiotherapy, patients with limited disease received multiple-field radiotherapy consolidation to the primary tumor site and mediastinum using thoracic computed tomographic scanning for field planning, and patients with extensive disease received chemotherapy maintenance. Patients with limited disease in complete remission following radiotherapy consolidation received no further treatment unless disease recurred. It was found that cyclophosphamide, Adriamycin, and vincristine could be alternated with cisplatin plus VP-16 at two-week intervals in 80 percent of patients on an outpatient basis and that two thirds of patients achieved clinical complete remission after two courses of each regimen. Locoregional radiotherapy delivered via multiple fields was effective in increasing the complete remission rate in patients with limited disease and was well tolerated. The median survival time was 18.5 months in 24 patients with limited disease and 12.2 months in 20 patients with extensive disease. Four patients with limited disease who received chemotherapy induction and radiotherapy consolidation without maintenance chemotherapy and one patient with extensive disease remain alive and disease-free at more than five years. We previously reported that the combination of cisplatin and VP-16 was a highly active induction regimen in small cell lung cancer, producing a 95 percent rate of objective response rate and a 47 percent rate of complete remission [ 11. Tumor regression occurred rapidly and reached a maximum after two courses of cisplatin (60 mg/m*) on Day 1 and VP-16 (120 mg/m*) on Days 4, 6 and 8, given three weeks apart. Additional tumor regression did not occur following the cisplatin plus VP-16 induction in 38 patients with small cell lung cancer despite treatment with cyclophosphamide (1,000 mg/m*), Adriamycin (40 mg/m*), and vincristine (1.4 mg/m*) given together on Days 42, 63, 84, and 105. The median survival of 21 patients with limited and 17 patients with extensive disease was 22 and 11 months, respectively, with four patients with limited disease remaining clinically free of disease more than three years after the start of therapy. Analysis of
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initial sites of relapse confirmed our earlier experience, that is, patients with limited disease tended to have first disease recurrence at the site of the primary tumor complex, whereas patients with extensive disease tended to have initial recurrence at multiple intra- and extrathoracic sites. These results established the high activity of combination cisplatin and VP-16 in small cell lung cancer but raised questions regarding its relative non-crossresistance with cyclophosphamide, Adriamycin, and vincristine. Since the treatment interval between two non-cross-resistant drug regimens may be critical to the emergence of a doubly-resistant tumor cell population, we designed the following study in which cyclophosphamide, Adriamycin, and vincristine and cisplatin plus VP-16 were given in alternating sequence as rapidly as possible. Furthermore, in an attempt to eradicate residual tumor following chemotherapy induction, highdose radiation therapy to the primary disease complex and mediastinum was given to patients with limited disease. Computed transaxial tomographic scanning of the thorax was used for radiation treatment planning. Following chemotherapy induction and radiation consolidation, patients with limited disease in complete remission received no further therapy unless disease recurred; patients with limited disease not achieving complete remission and all patients with extensive disease continued to receive chemotherapy maintenance for one year. This report describes the details and results of the study. PATIENTS
AND METHODS
A total of 44 consecutive, previously untreated patients with histologically or cytologically confirmed small ceil lung cancer were treated. Eligibility criteria included no prior history of cancer, normal renal function (serum creatinine below 1.2 mg/dl or creatinine clearance of at least 60 ml per minute), and informed consent. At the start of therapy, all patients provided a complete history and underwent physical examination and laboratory evaluation including complete blood cell and platelet counts, 12-channel biochemical profile, serum electrolyte and creatinine determination, chest roentgenography, bone marrow aspiration and biopsy, and measurement of serum carcinoembryonic antigen and 5’nucleotidase. Radionuclide liver scanning was used in patients with hepatomegaly or abnormal results of biochemical liver function tests. Results of the initial evaluation permitted classification of patients into categories of limited disease (tumor confined to hemithorax and ipsilateral cervical nodes) or extensive disease (metastases to contralateral lung or nodes, liver, bone, and/or brain or presence of a pleural effusion). Treatment was given on an outpatient basis. All patients received an induction regimen consisting of four cycles of chemotherapy followed by prophylactic whole-brain irradiation. Chemotherapy cycles 1 and 3 consisted of cyclophosphamide (1,200 mg/m*), Adriamycin (50 mg/m*), and
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vincristine (1.4 mg/m*) given intravenously on Day 1 of each cycle. Cycles 2 and 4 consisted of cisplatin (60 mg/m2) intravenously on Day 1 and VP-16 (120 mg/m*) intravenously on Days 4,6, and 8 of the cycles. Each cycle was given as soon as the white blood cell count returned to more than 3,000/mm3 and the platelet count returned to more than 100,000/mm3 following the nadir induced by the preceding cycle. Cranial irradiation was delivered as 500 rads on three consecutive days, four days rest, then 300 rads on five consecutive days (4,000-rad equivalent by the NSD concept) [2]. Patients with limited disease received consolidation radiotherapy to the primary site and mediastinum on a 10 MV Mevatron 12 linear accelerator, 250 rads on four days a week for a total of 18 fractions (5,000-rad equivalent by the NSD concept). Multiple-field treatment plans were devised utilizing simulation films to determine field length and spinal cord location and thoracic computed tomographic scanning to determine precise tumor and mediastinum location and volume. Cyclophosphamide (500 mg/m*) and vincristine (1.4 mg/m*) were given intavenously on Days 1 and 15 of radiotherapy. Patients with limited disease not in complete remission following chest radiotherapy and all patients with extensive disease received maintenance chemotherapy for a total of 12 months of treatment or until disease progression. Maintenance consisted of lomustine (100 mg/m*) orally on Day 1, methotrexate (30 mg/m2) intravenously on Days 1, 8, 15 and 22, procarbazine (100 mg/m* per day) orally on Days 1 to 14 inclusive; cyclophosphamide (1,000 mg/m*), Adriamycin (30 mg/m*), and vincristine (1.4 mg/m*) intravenously together on Day 43; and cisplatin (50 mg/m2) intravenously on Day 71 and VP-16 (120 mg/m*) intravenously on Days 74, 76 and 78. The entire sequence was recycled on Day 99. This treatment regimen was reviewed and approved by the Clinical Research and Human Investigations committees of Memorial Sloan-Kettering Cancer Center in accord with assurances filed with and approved by the Department of Health and Human Services. Established clinical response criteria and categories of clinical response were used [3], and response status was determined by monthly physical examination, chest roentgenography, blood chemistry values, and repeated bone marrow aspiration and biopsy and radionuclide scanning. The Karnofsky scale was used to assess performance status. Response duration was measured from the start of therapy to the time of first evidence of disease relapse or progression. Survival was measured from the start of therapy to the time of death. Patient Characteristics. Twenty-four patients with limited disease and 20 patients with extensive disease who had previously untreated small cell lung cancer were entered into the study. The median age was 60 (range 41 to 76) the median Karnofsky score was 70 percent (range 50 to 100 percent), and there were 27 men and 17 women. Documented sites of tumor metastases in patients with extensive disease included liver (12 patients), bone (11 patients), contralateral lung or nodes (eight patients), and pleural effusion (four patients). Eleven patients had more than one extensive disease site. Pretreatment serum carcinoembryonic antigen values were obtained in 40 patients. Carcinoembryonic antigen was
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elevated (more than 5.0 rig/ml) in nine (39 percent) of 23 patients with limited disease and in 13 (76 percent) of 17 patients with extensive disease; carcinoembryonic antigen values above 20 rig/ml were observed in four (17 percent) patients with limited disease and in nine (53 percent) patients with extensive disease.
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Toxicity during induction in 44 Patients Numberof Patients withToxicity perCourse CAV-I PtvP-1 CAV-2 PtvP-2
White blood cell count >3.0 2.0-2.9 1.0-1.9
RESULTS Toxicity. Forty-three of 44 patients completed all four cycles of chemotherapy induction; one patient with poor performance status (Karnofsky score 50) and widely metastatic disease (bilateral lung, nodes, liver, and bone) died of aspiration pneumonia and sepsis 20 days after the start of therapy. Table I details the hematologic and renal toxicities observed during chemotherapy induction. Myelotoxicity, predominantly leukopenia, was dose-limiting but moderate during induction; a documented white blood cell nadir below 3,000/mm3 and platelet nadir below 100,000/mm3 occurred in 66 (38 percent) and 27 (15 percent), respectively, of 173 induction cycles (Table I). Recovery from or absence of myelosuppression (white blood cells above 3,000/mm3 and platelets above 100,000/mm3) was observed by Day 15 in 80 percent of induction cycles and by Day 18 in 90 percent. Therefore, treatment could be “recycled” rapidly, and in 40 of 44 patients, induction was completed within 48 days from the start of therapy. Moderate increases in serum creatinine and blood urea nitrogen levels occurred with seven of 173 induction cycles. Six episodes were related to cisplatin administration, but all were reversible and only one necessitated subsequent treatment modification. Severe toxicity requiring hospitalization occurred in 18 (10 percent) of 173 induction cycles (14 patients); 16 cases were for neutropenia and fever, and two were for moderate nephrotoxicity. It is notable, however, that 90 percent of the induction cycles produced either insignificant toxicity or toxicity that could be successfully managed on an outpatient basis. One additional patient with extensive disease in partial remission died of drug-induced leukopenia and sepsis during maintenance chemotherapy. Radiation-related toxicities consisted chiefly of pneumonitis that occurred acutely in two patients and responded to steroid administration and that was chronic in six. In two of the six chronic cases, pneumonitis involved the lungs diffusely, was refractory to supportive measures, and contributed to death. Both cases occurred in patients with limited disease who had had persistent residual disease (partial remission) following radiation therapy and therefore received maintenance chemotherapy. In addition, there were three patients with mild reversible radiation-induced esophagitis and one patient with transient encephalopathy possibly
IN SMALL
Plateletcount >100,000 50-99,000
23 12 6 3'
35 5 3 0
20 12 7 4
29 9 4 1
39
36 4 3
36 6 1
35 5 3
40
43 0 0
39 2 1
3 2
<50,000
Serumcreatinine level <2.0 2.0-3.9 >4.0
43 1 0
2
Onedeath from sepsis. CAV = cyclophospbamide,Adriamycin,and vincristine;P + VP = cisplatinplusVP-16. l
related to cranial irradiation. Therapeutic Responses. Following chemotherapy induction, complete remission was achieved in 16 (67 percent) of 24 patients with limited disease and 13 (65 percent) of 20 patients with extensive disease status. The remaining patients had partial response, except for one patient with extensive disease who had a minor response (25 to 50 percent disease regression) of 11 weeks’ duration and another patient with extensive disease who died of drug-related leukopenia and sepsis (just described), both of whom are considered to have nonresponse. Following involved-field radiation therapy in the group with limited disease, four of the eight partial responses became clinical complete remissions, resulting in an 83 percent complete remission rate (20 of 24 patients) in the group with limited disease. The median duration of response was 12.7 months (range 4.1 to more than 70 months) in the group with limited disease and 10.1 months (range 2.0 to more than 63 months) in the group with extensive disease. Analysis of survival with a 60-month minimal follow-up time indicates a median survival of 18.5 months for the 24 patients with limited disease and 12.2 months for 20 patients with extensive disease. Five patients (four with limited disease and one with extensive disease) remain alive and disease-free with a minimal follow-up of 60 months (Figure 1). Fifteen of 20 patients with limited disease who had showed complete remission following induction and involved-field irradiation are evaluable for site of first disease recurrence (one patient died of a stroke during complete remission five months after the start of therapy, and four remain disease-free as noted above). The first site of relapse was within the intrathoracic treatment volume in nine of the 15 patients: in six patients, it was the sole initial site of relapse, and in three pa-
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Twelve of 15 patients with limited disease who had relapses after complete remissions (and therefore had not received maintenance chemotherapy) were treated with at least one course of cyclophosphamide, Adriamycin, and vincristine and one course of cisplatin plus VP-16 at the time of relapse. Two patients had clinical complete remissions (3.4 and 7.0 months’ duration), three had partial responses (3, 3.7, and 4.0 months’ duration), one had a minor response (1.5 months’ duration), and six had no response. COMMENTS l-
J
Figure 1. Kaplan-Meier survival curves for 24 patients with limited disease (open circles) and 20 patients with extensive disease (solid circles). Tic marks represent six censored pafienfs: one who died of an acute cerebrovascular accident while in complete remission at five months and five who are alive and disease-free with more than 60 months of followUP.
tients, it was concurrent with a non-irradiated site. The site of first relapse was outside the irradiated field in six of the 15 patients: non-irradiated lung accounted for two cases, and liver, liver plus cervical nodes, abdomen, and brain accounted for one case each. Thus, including the four patients remaining disease-free, chemotherapy plus involved-field radiation therapy consolidation successfully controlled the primary tumor site in 10 (42 percent) of 24 patients with limited disease. In 32 of the 44 patients entered into the study, serum carcinoembryonic antigen levels were obtained serially (at one- to two-month intervals) after the start of therapy. In this group, the pretreatment carcinoembryonic antigen value was more than 5.0 rig/ml in 16 cases, more than 10 rig/ml in 15, and more than 20 rig/ml in 10. Objective clinical response to therapy was accompanied by a fall in carcinoembryonic antigen to less than 5.0 rig/ml in all cases, regardless of whether response was judged to be complete or partial, except in one patient in whom the lowest carcinoembryonic antigen value achieved during partial remission was 6.5 rig/ml. After normalization, a rise in the serum carcinoembryonic antigen level above 5.0 rig/ml accompanied or heralded disease recurrence in six of 10 patients with relapse. Patients with pretreatment carcinoembryonic antigen values below 5.0 rig/ml did not have elevated levels during treatment or at the time of disease recurrence. In addition, they did not differ from patients with pretreatment carcinoembryonic antigen values above 5.0 rig/ml with respect to response rate, response duration, or survival. 306
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Since the number of effective agents in small cell lung cancer is greater than can be given simultaneously, the use of mutually non-cross-resistant combination drug regimens administered in alternating sequence has emerged as a potentially fruitful treatment strategy. In Hodgkin’s disease, the superior results obtained by alternating Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) with mechlorethamine, Oncovin, procarbazine, and prednisone (MOPP), compared with MOPP alone, has served to reinforce this concept [4]. There have been several attempts to improve the treatment of small cell lung cancer by the use of alternating or sequential combination drug regimens. Cohen et al [5] used two courses of vincristine, Adriamycin, and procarbazine (VAP) following one course of cyclophosphamide, methotrexate, and CCNU (CMC)-a strategy that appeared to increase the overall response rate and complete remission rate in patients with small cell lung cancer. However, the survival of patients with response to CMC-VAP was not better than had been obtained previously with CMC alone. Furthermore the addition of a third combination drug regimen, VP-16 and ifosfamide, to CMC-VAP did not increase the complete remission rate or prolong survival compared with CMC-VAP alone. In our experience BCNU, methotrexate, and procarbazine (BMP) following two successive three-week courses of cyclophosphamide, Adriamycin, and vincristine (CAV) provided no additional therapeutic benefit in terms of either additional tumor shrinkage or increased survival [6]. Similar results occurred in our most recent study in which two successive cycles of cisplatin plus VP-16 were followed by four successive cycles of CAV [ 11. Maximal objective response occurred with the two cycles of cisplatin plus VP-16 alone, and no discernible additional benefit occurred with the four cycles of CAV. Likewise, Aisner et al [7] reported that CCNU, Oncovin, methotrexate, and procarbazine (COMP) administered after a maximal clinical response had been achieved with one to seven courses of cyclophosphamide, Adriamycin, and VP-16 (CAVP-16) did not improve response rate, survival, or the proportion of patients with long-term disease-free status compared with CAVP-16 alone. In a randomized ECOG trial [8], patients receiving cyclophosphamide, CCNU, and 79
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methotrexate (CCM) alternating with two successive cycles of Adriamycin, vincristine, and procarbazine (AVP) had longer remission durations than patients receiving CCM alone, although objective response rates and overall survival were unaffected and toxicity was greater. The potential benefit of this treatment strategy has been partially supported by the results of only two studies. A randomized trial by NCOG [9] was reported to show an improved complete response rate and median duration of response and survival of patients with extensive disease treated with a sevendrug regimen consisting of VP-16, Adriamycin, and methotrexate (VAM) alternating with procarbazine, Oncovin, cyclophosphamide, and CCNU (POCC) compared with patients treated with POCC alone. However, the VAMPOCC regimen was not significantly superior to the POCC regimen in patients with limited disease, and survival beyond two years was not improved in either patient group. A prolonged remission duration with alternating therapy has also been reported by Osterlind et al [ lo] in an analysis of their randomized sequential versus alternating drug combination trial utilizing cyclophosphamide, CCNU, methotrexate, and vincristine (CCMV) followed by Adriamycin plus VP-16, although median and long-term survival rates were not improved. The reasons for the largely disappointing results obtained with alternating combination drug regimens in small cell lung cancer are unclear. One possible explanation may relate to the character of the combinations employed in these studies. Even when the individual combinations were themselves known to be active in previously untreated patients with small cell lung cancer, lack of cross-resistance with the alternate combination was far more often assumed than proved by the type of randomized cross-over design that is optimal for establishing the absence of cross-resistance. Unlike some of the studies in breast cancer [ 1 l- 131, Hodgkin’s disease [ 41, and non-Hodgkin’s lymphomas [ 141 that have addressed similar questions, it is uncertain that cross-resistance between the alternated combinations, whether measured by tumor regression or survival, was really absent. A second possibility has to do with the relative efficacy or degree of activity of the combinations themselves. Non-cross-resistance of two combinations used sequentially may be a necessary condition for increased efficacy, but it is certainly not a sufficient one. The drug regimens employed may need to possess, independent of each other, high activity as well as non-cross-resistance. The successful experience with Hodgkin’s disease [4], in fact, suggests that the regimens to be alternated must each be capable of inducing complete remission in a substantial fraction of the treated population. September
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The time interval between alternating cycles of two non-cross-resistant drug regimens may also be important. Notably, in all of the aforementioned studies, drug regimens were alternated at intervals of six weeks or more (often necessitated by the use of nitrosoureas) or several successive cycles of one regimen were administered before the switch to another was made. Assuming that small cell lung cancer is composed of tumor cell subpopulations that are intrinsically resistant to either drug regimen A or drug regimen 6 (but not both), the mathematical model of Goldie et al [15] predicts that prolonged intervals between administration of regimens A and B, or administration of two or more courses of one regimen before administration of another regimen greatly favors the spontaneous emergence of tumor cells resistant to both regimens (doubly-resistant tumor cells). We designed the present study to test the feasibility of alternating two highly and independently active combination drug regimens as rapidly as possible. Combination CAV is an established standard treatment regimen with high activity in small cell lung cancer and acute toxicity that is sufficiently short-lived to allow treatment with another regimen within at least three weeks of administration. Combination cisplatin and VP-16 has been shown to possess high activity both in previously untreated small cell lung cancer [l] and in small cell lung cancer refractory to combination CAV [ 16,171. In our study, CAV was alternated with cisplatin plus VP-16 every two weeks in 80 percent of the patients entered. The 67 percent complete remission rate obtained after four courses of therapy (CAV for courses 1 and 3; cisplatin plus VP-16 for courses 2 and 4) appears to be higher than the 47 percent complete remission rate obtained in our previous study when two successive courses of cisplatin plus VP-16 were followed by four successive courses of CAV [ 11. This suggested therapeutic advantage of rapidly alternating CAV and cisplatin plus VP-16 requires testing in an appropriately designed prospective randomized trial. The respectable medial survival (18.5 months) and incidence of long-term survival (17 percent alive and disease-free more than 5 years after diagnosis) among patients with limited disease that was achieved in this study with chemotherapy induction and involved-field radiotherapy alone suggests that maintenance chemotherapy may not be necessary in small cell lung cancer after induction regimens that yield a high complete remission rate. These results confirm the original experience of Johnson et al [ 181 and are in agreement with the recent preliminary studies of Feld et al [ 191 and Holoye et al [20] that show that long-term disease-free survival in patients with limited disease is achievable without prolonged cyclic maintenance chemotherapy. However, since six of 12 patients with limited disease and relapse from complete remission status in our study 1995
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obtained temporary objective disease regression following re-induction with CAV and cisplatin plus VP-16, more than four courses of chemotherapy are probably required to eradicate drug-sensitive tumor populations. Whether this should be in the form of prolonged induction therapy or several intermittent courses of intensive maintenance or “re-induction” chemotherapy requires further study. The precise value of radiotherapy to the primary disease complex in small cell lung cancer remains unclear. Our study demonstrates that locoregional high-dose radiotherapy with careful treatment planning is well tolerated and effective in increasing the complete remission rate. The fact that fewer relapses occurred at the primary disease site in this study compared with our previous trial that did not include radiotherapy [l] suggests that improved locoregional control can be achieved in some patients. That two of the four longterm disease-free survivors had only partial responses with induction chemotherapy and subsequently had complete remissions with radiotherapy adds to this impression.
ET AL
The serum carcinoembryonic antigen value was a useful adjunctive parameter in monitoring disease response in many patients. However, it was not useful in assessment of the quality (complete remission versus partial response) or duration of response. A rising carcinoembryonic antigen value during apparent clinical remission was predictive of subsequent disease recurrence but occurred infrequently and was not clinically useful. In summary, this study suggests that the use of rapidly alternating courses of combination drug regimens remains a hopeful treatment strategy in small cell lung cancer and deserves further investigation. Combination CAV and cisplatin plus VP-16 are two highly active drug regimens that are suitable for intensive administration in rapidly alternating sequence and on an outpatient basis. Locoregional radiotherapy delivered via multiple fields is effective in increasing the complete remission rate in patients with limited disease and is probably less toxic than conventional delivery schemes. Maintenance chemotherapy is not required for prolonged survival in all patients and requires critical re-evaluation.
REFERENCES
4.
5. 8. 7.
8.
9.
10.
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Sierocki JS. Hilaris BS, Hopfan S, et al: Cisdiamminedichloroplatinum (II) and VP-18: an active induction regimen for small-cell carcinoma of the lung. Cancer Treat Rep 1979; 83: 1593-1597. Orton CG, Ellis F: A simplification in the use of the NSD concept in practical radiotherapy. Br J Radio1 1973; 48: 529-537. Wittes RE, Hopfan S, Hilaris B, Golbey RB, Melamed M, Martini N: Oat cell carcinoma of the lung-combination treatment with radiotherapy and cyclophosphamide, adriamycin, vincristine and methotrexate. Cancer 1977; 40: 853859. Bonadonna G: Chemotherapy strategies to improve the control of Hodgkin’s disease: the Richard and Hinda Rosenthal Foundation Award Lecture. Cancer 1982; 42: 43094320. Cohen MH, lhde DC, Bunn PA, et al: Cyclic alternating combination chemotherapy for small cell bronchogenic carcinoma. Cancer Treat Rep 1979; 83: 183- 170. Sierocki JS, Hilaris BS. Hopfan S, et al: Small cell carcinoma of the lung: experience with a sixdrug regimen. Cancer 1980; 45: 417-422. Aisner J, Whitacre M, Van Echo DA, Wiernik PH: Combination chemotherapy for small cell carcinoma of the lung: continuous versus alternating non-cross-resistant combinations. Cancer Treat Rep 1982; 88: 221-230. Mehta C, Vogl SE for ECOG: Cycling non-cross resistant combination chemotherapy for small cell lung cancer in remission-50% prolongation of remission duration without prolongation of survival and with enhanced toxicity (abstr). Proc Am Sot Clin Oncol 1982; 1: 152. Sikic BI, Daniels JR, Chak L, et al: PDCC versus PDCC/VAM therapy for small-cell anaplastic (oat cell) lung cancer. In: Prestayko AW, Crooke ST, Baker LH, Carter SK, Schein PS, eds. Nitrosoureas: current status and new developments. New York: Academic Press, 1981; 221-231. Osterlind K, Sorensen S, Hansen HH, et al: Continuous versus alternating combination chemotherapy for advanced small
September
1985
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Journal
of Medlclne
cell carcinoma of the lung. Cancer Res 1983; 43: 80858089. Brambilla C, Valagressa P, Bonnadonna G: Sequential combination chemotherapy in advanced breast cancer (abstr). Proc Am Assoc Cancer Res 1977; 18: 308. Tormey DC, Gelman R, Band P, et al: Comparison of single to alternating combination therapy in metastatic breast cancer (abstr). Proc Am Assoc Cancer Res Am Sot Clin Oncol 1980; 28: 888. Vogel C, Lefante J, East D, et al: Cyclophosphamide, adriamycin and 5-fluorouracil alternating with a cycle active regimen in metastatic breast cancer: a randomized cancer study group trial (abstr). Proc Am Assoc Cancer Res Sot Clin Oncol 1981; 22: 439. Bonadonna G, Monfardine S, Villa E: Non-cross resistant combinations in stage IV non-Hodgkin’s lymphomas. CancerTreat Rep 1977; 81: 1117-1123. Goldie JH, Coldman AJ, Gudauskas GA: Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat Rep 1982; 88: 439-449. Essers U, Knechten H, Seelis R, Ammon J: Etoposide after AC0 treatment for small-cell bronchogenic carcinoma. Cancer Treat Rev 1982; 9 (suppl A): 11 l-l 13. Evans WK. Feld R, Osoba D. et al: VP-18 alone and in combination with cisplatin in previously treated patients with small cell lung cancer. Cancer 1984; 53: 1481-1488. Johnson RE, Brereton HD, Kent CH: “Total” therapy for small cell carcinoma of the lung. Ann Thorac Surg 1978; 25: 5150-5154. Feld R, Evans WK, Yeoh JL. et al: Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung (abstr). Proc Am Assoc Cancer Res Am Sot Clin Oncol 1981; 22: 494. Holoye PY, Libnock JA, Byhardt RW, et al: Chemotherapy of small cell bronchogenic carcinoma with cytoxan, Adriamycin, methotrexate, high-dose vincristine and consolidation radiotherapy (abstr). Proc Am Assoc Cancer Res Am Sot Clin Oncol 1981; 22: 500.
11.
12.
13.
14.
15.
18.
17.
18.
19.
20.
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