Phase III chemotherapy trials in small cell lung cancer

Lung Cancer, 5 (1989) 178-185 Elsevier

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Phase III chemotherapy trials in small cell lung cancer Mark R. Green University of California a~ San Diego, San Diego, CA (USA.) (Acceped 18 June 1989)

Introduction Several phase III trial designs have been employed to assess optimal treatment approaches to chemotherapy management of small cell lung cancer. Studies of duration of treatment, dose intensity, alternation or sequential use of two potentially non-cross-resistant combinations, timing of drug administration, addition of new agents to an established combination (including use of biochemical modulation), and simple direct comparison of two active single- or multi-drug regimens have all been pursued. Separate reviews of dose intensity, alternating versus continuous schedules, and duration of therapy trials have been presented by others as part of this workshop. This manuscript will therefore focus on trials utilizing several of the other strategies which have been tested in this disease.

Direct agent or regimen comparisons Single agent trials: etoposide(VP-l@ The epipodophylotoxin VP-16 is among the most active single agents available for small cell lung cancer. It is a cell cycle specific agent with major activity against cells in S and GZ The impact of VP-16 schedule on efficacy was tested by Slevin et al. [l] in 40 previously untreated small cell patients with extensive disease. Individuals were randomized to either 500 mg/m2 over 24 h by continuous infusion or 100 mg/m2 as a 2-h infusion given daily for 5 days. Cycles were repeated every 3 weeks. At progression or relapse all patients were given cyclophosphamide, doxorubicin, and vincristine. Pharmacokinetic studies revealed an equivalent area under the curve for exposure to active VP-16 using either schedule. The overall response rate to VP16 for 20 patients receiving drug by 24-h infusion was 10% compared to 78% for 18 patients Median survivals were 167 and 294 days, respectreated on the daily x5 schedule (P=O.OOOl). tively (P=O.O3. In a subsequent trial [21, the same group tested VP-16 100 mg/m2/day x5 versus 62.5 mg/m 1/day x8 (total dose=500mg/m2/cycle in each group) in a total of 77 patients with small cell. No differences were seen in overall response rate, median remission duration, or survival. Correspondence: M.R. Gmen. Director, UCSD Canar Center, 225 Dickinsat Sttut, H811K. University of California at San Diego, San Diego, CA 92103. U.S.A. 0169-5002 / 89/$03.50 (B 1989 Elsevier Science Publishers B.V. (Biomedical Division)

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Recent phase II data [31 indicate that teniposide (VM-26) also has substantial single agent activity against small cell lung cancer. A phase III trial comparing VP-16 and VM-26 has been completed by Bork et al. [4]. Ninety-two previously untreated patients with good performance status (O-2) but age greater than 70 years were randomized to either VP-16 70 mg/m*/day x5 or VM-26 at the same dose and schedule. After an initial cohort of patients received these doses, myelosuppression was found to be modest enough to permit dose escalation. Subsequent patients received VP-16 90 mg/m2/day or VM-26 80 mg/m2/day on the same daily x5 schedule. The overall complete plus partial response rate for VP-16 was 66% versus 77% for VM-26. The complete response rate was 25% in each group. Median survivals were 8.5 and 11 months for VP-16 and VM-26, respectively. None of the differences between the two agents was statistically significant. A follow-up trial testing 75 mg/m2/day x5 of VM-26 versus 100 mg/m2/day x5 of VP- 16 has been implemented. Multi-agenttrials: etoposide(VP-16) The work of Slevin et al. [l] demonstrated enhanced single agent efficacy for VP-16 on a daily x 5 schedule. However, a small phase III trial by Mead et al. [5], evaluating two VP-16 schedules in combination with cyclophosphamide and doxorubicin, failed to confii the single agent data. In the Mead trial all patients got cyclophosphamide 600 mg/m2 and doxorubicin 50 mg/m2 intravenously on day 1 of each cycle. Patients were randomly assigned to also receive etoposide orally either 500 mg/m2 day 3 (CAVl) or 100 mg/m2 days 3-7 (CAV5). Among 54 evaluable patients, the CR+PR rates (82.5% versus 76%), median survival times (8 versus 9 months) and percent of 2-year survivors (8% versus 9%) were not impacted by the VP-16 schedule. The optimum timing of VP-16 administration during a cycle of chemotherapy has also been explored. Hirsch et al. [6] treated 285 patients with extensive small cell with one of the 3 treatment regimens. All patients received CCNU 70 mg/m2 orally plus cyclophosphamide 1000 mg/m2 and vincristine 1.3 mg/m2 intravenously on day 1 of each course. During the first cycle additional doses of vincristine were given weekly. Patients assigned to regimen A also received methotrexate 20 mg/m2 orally on days 14 and 17. Patients on regimen B received VP-16 70 mg/m2 orally on days 14-17 while regimen C patients received the same dose of VP-16 on days 3-6. Previous work by the Copenhagen group had suggested that tumor cell rebound put a major fraction of cells within the VP-16 vulnerable S-Gz window 3-6 days after CCV chemotherapy [7]. Thus, this trial was devised to assess the relative contribution of methotrexate and VP-16 to combination chemotherapy and possible increased efficacy (and/or toxicity) based on the timing of VP-16 administration. The median survival times of the three groups were A 23 weeks, B 27 weeks, and C 33 weeks. The overall survival curves for groups A and C were different, P&OS. There were no significant survival differences between groups A and B (P=O.l 1) or B and C (P=O.O9).When the subset of patients of favorable performance status (PS 0.1) was probed, the median survival time of group C patients, 51 weeks, was superior to that of either Group A patients, 32 weeks (P=O.OOl),or Group B patients, 36 weeks (P=O.O3)Phis subset analysis must be interpreted cautiously since it cuts the study data using groupings not based on a stratification variable utilized during initial randomization.] Group C patients experienced enhanced myelosuppression compared to groups A and B, perhaps due to a marrow rebound effect after day 1 chemotherapy analogous to the tumor cell recruitment. Whether giving an increased dose of VP-16 on a day 14-17 schedule, sufficient to create a program equimyelosuppressive to regimen C

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would eliminate the survival differences noted in this trial is indeterminate. The addition of etoposide to CAV has been studied by several grouts. Nikkanen 181treated 80 limited disease patients using CAV (750 mg/m2; 50 mg/m2; 1 mg/m q 3 weeks x9)* etoposide 80 mg/m2 intravenously days 2-4. Overall response rates were CAV 84%, CAVE 74%. There were no significant differences in median survival or overall 2-year survival. Myelosuppression was increased in the 4-drug arm. The Piedmont Oncology Association [91 randomized 259 patients to a somewhat more dose intensive CAVf E trial (cyclophosphamide 1 g/m2, doxorubicin 50 mg/m2, vincristine 2.0 mg with or without etoposide 60 mg/m2/day x5 for three cycles, then 250 mg/m2 day 1 of subsequent cycles). In this trial, there was an increased overall response rate in the CAVE arm (84% versus 64%; P=O.OOl) but no significant difference in overall response duration (9.4 versus 8.2 months) or survival (11.2 months versus 9.4 months; P=O.3). Jackson [lo] has published a recent final update on the extensive disease only groups from the Piedmont trial (139 patients). An increased overall response rate (70% versus 46%; P=O.O08), increased CR rate (29% versus 12%; P=O.O3) and prolongation of time to disease progression (9.6 versus 6.5 months; P=O.Ol) were seen for CAVE-treated patients. However, even in this subgroup analysis, no overall survival difference was demonstrated. The North Central Cancer Treatment Group (NCCTG) evaluated CAW E in 236 limited disease small cell patients [ 111. This trial differed from the Nikkanen and Jackson studies because the cyclophosphamide dose in the CAV regimen was revised downward (750 mg/m2+500 mg/m2) when VP-16 60 mg/m2/day x3 was added. Overall response rates were CAV 78%, CAVE 84%. Median response duration was significantly prolonged in CAVE responders (363 days versus 292 days; Pti.03). There were no significant survival differences. The substitution of etoposide for doxorubicin or vincrktine in front line small cell regimens has been studied by Hong [12] and coworkers and Einhom et al. [ 133. Hong et al. [12] treated 353 newly diagnosed small cell patients with a standard CAV schedule (1000/m2; 50/m’; 1.4/m2 [2.0 max]) repeated every 3 weeks or CEV (C, 1000 mg/m2; V, 1.4 mg/m2 [2.0 max]; E, 50 mg/m2 i.v. day 1 followed by 100 mg/m2 p.o. days 2-5). A third group received cyclophosphamide 2000 mg/m2 and vincristine 1.4 mg/m2 [2.0 max] alone. Results were reported separately for limited and extensive disease subgroups. For limited disease patients there were no significant differences in overall response rates (CAV 68%, CEV 66%, CV SOS), median duration of response (44 weeks, 48 weeks, 35 weeks), median survival times (55 weeks, 58 weeks, 41 weeks), or overall survival. In extensive disease, however, the CEV regimen produced a prolonged response duration (CEV 32 weeks, CAV 24 weeks, CV 23 weeks; P
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evaluated by Jackson et al. 1141.One hundred reviously untreated patients were randomized to CAVE alone or CAVE plus cisplatin 20 mg/mE:/day x 4 cycles 1.2,6,7 and 20 mg/m2/day x 3 cycles 3,4,5. The CAVE doses were the same in both arms. The CAVE-P regimen produced a higher overall response rate (83% versus 48%; P=O.O017) and a longer time to treatment failure (8.3 months versus 4.8 months; P=O.Ol) than CAVE alone. Median survivals of 10.3 months (CAVE-P) and 6.8 months (CAVE) were not statistically significantly different (Zsided ZYl.097). Red cell and platelet toxicity were significantly enhanced in the cisplatin group which also had a 10% septic death rate. The differences in response rate and time to treatment failure, which significantly favor CAVE-P, must be interpreted cautiously in light of the relatively poor CAVE alone results in this trial compared to Jackson et al’s previously reported CAVE alone experiences in extensive disease patients (response rate 70%; time to disease progression 9.6 months) discussed above [ 101. The EORTC Lung Cancer Working Party has evaluated the impact of adding cisplatin to a 2drug regimen of vindesine and etoposide [15]. Patients received vindesine 3 mg/m2 day 1 and etoposide 120 mg/m2 days l-3 with or without cisplatin 60 mg/m2 day 1. Cycles were repeated every 3-4 weeks. Among 181 patients eval~ble for response, the CEV response rate was 76% compared to 55% for EV (P&01). No differences were seen in median survival time or the percent of 2-year survivors (CEV 42 weeks/8%; EV 39 weeks/4%).

Direct combination comparisons The optimum combination chemotherapy program using currently available agents for treatment of small cell lung cancer remains indeterminate. Doses and schedules for commonly used drug combinations vary considerably. In many centers, the 2-drug etoposidecisplatin (EP) regimen has become the standard of care. Two recent randomized trials have provided direct comparative data on the efficacy of EP and CAV. Roth et al. [16] tested a 5&y EP schedule (E 80 mg/m2iday x5; P 20 mg/m2/day x5 q 3 weeks x4 cycles) versus CAV (C 1000/m2; A 40/m2; V l/m q 3 weeks x6) or an alternating regimen starting with CAV and administering 3 courses of each combination. Failing patients on non-alternating arms were crossed over. Three hundred and forty-four untreated patients with extensive small cell were entered with 3 12 evaluable. The initial response rates are essentially identical for the three groups (59%. 58%, 58%) as are the median survivals (38 weeks, 39 weeks, 38 weeks). Anemia and thmmbopenia were more severe in the EP-treated patients (alone plus alternating) compared to those getting CAV alone. A similar multi-center trial of EP versus CAV versu;EP/CAV has also been reprted by Tamura et al. [17]. Here the EP rel$men was E 100 mg/m days l-3 and P 80 mg/m day 1. CAV doses were: C 800/m2; A 50/m ; V 1.4/m2. Three hundred patients with limited or extensive disease were entered on trial between April 1985 and May 1988. The mix of limited and extensive disease cases is not provided. In the most recent report, the overall response rates were EP 78%. CAV 50.5%. EP/CAV 73.3% (P&01). Median response durations were EP 7.2 months, CAV 7.0 months, EP/CAV 11.3 months. Median survivals were 10.3,lO.O and 12.5 months, respectively. The median duration of response and overall survival were significantly better for the alternating arm than for either regimen alone. Neither the Roth nor the Tamura trial suggests that etoposide-cisplatin is clearly superior to CAV in the doses/schedules tested, especially in extensive disease patients. In limited disease patients, undesirable doxorubicin or desirable (cisplatin) radiation interactions may dictate a

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&,a showing survival benefit for one or the other drug combination alone. TWO other drugs, carboplatin and ifosfamide, have single agent utility in the treatment of small cell. Two phase III trials from a German Multicenter Study Group have assessed the potential role of each as part of small cell combination chemotherapy. Wolf et al. 1181used doxofubicin, ifosfamide, vincristine (AIV) in alternation with either etoposide-cisplatin (BP) or etoposid&platin (EJ). The EP regimen was E 150 mg/m* i.v. days 1-3; P 90 mg/m* i.v. day 1 while EJ used E 120 mg/m* i.v. days l-3 and J (carboplatin, CBDCA, JM-8) 300 mg/m* i.v. day 1. Three hundred and fifty patients with previously untreated limited or extensive disease were entered. No significant differences have emerged overall, or in limited or extensive disease subgroups, for response rate, complete response rate, or median survival time. Gastrointestinal toxicity was diminished in the carboplatin group. Definitive determination of the relative efficacy of quitoxicity cisplatin and carboplatin regimens will require a direct comparative trial. Wolf et al. have also completed a trial comparing etoposidecisplatin to etoposide-ifosfamide [19]. Small cell patients less than 70 years of age with a performance status O-2 and no prior therapy were entered. The initial randomization assigned patients to either etoposidecisplatin (E 150 mg/m* days 3-5, and P 80 mg/m* day 1) or etoposideifosfamide (E 120 mg/m* days 3-5, and I 1500 mg/m* days l-5). Cycles were repeated every 3 weeks. Non-responders were switched to CAV salvage as were initital responders whose response plateaued prior to achieving complete response. One hundred and forty-one patients were evaluable, 73 on EP and 68 on EI. Overall response rates were comparable, 65% and 68%, respectively. Among the 51 limited disease patients, the CR rate for EP was 50% compared to 24% for EI (P
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in complete or partial response after completion of induction therapy were then re-randomized to observation or 2 cycles of consolidation cisplatin (20 mg/m2/day x4) and etoposide (100 mg/m2/day x4). One hundred and sixty patients entered the consolidation randomization. Onehundred and forty-eight are evaluable. The median duration of time to progression after entering the consolidation phase was 28 weeks in the observation group and 49 weeks for EP consolidation (P=O.OOOSfor comparison of the remission duration curves). The overall survival curves for the two groups were highly statistically significantly different, P=O.O094. The median survival times from start of therapy were 97.7 weeks and 68 weeks, respectively. A landmark analysis of survival from second randomization also showed the beneficial impact of the two cycles of etoposide-cisplatin chemotherapy, P=o.Ol. This positive impact of crossover consolidation with a new chemotherapy combination after intitial induction has precedent in other adult tumors. The addition of ABVD consolidation after full MOPP induction is superior to radiation consolidation in Hodgkin’s disease [22]. The use of VATH chemotherapy after 7 months of CMFVP induction improves at least disease free survival in patients receiving adjuvant chemotherapy for breast cancer [23]. ABVD now appears to be superior to MOPP as first line therapy and probably equivalent to an alternating MOPP/AEtVD program [24]. Doxorubicin-based adjuvant therapy is superior to L-PAM-SFU in breast cancer [25]. From available data, including some reviewed here and by analogy with the ABVD and adjuvant doxorubicin experience, it seems quite likely that EP alone would be at least as effective as CAV induction followed by EP consolidation. In each case, the therapeutic paradigm seems clear: truly effective new drugs can positively contribute to therapeutic outcome even when used as consolidation; however, up-front use of the most effective agents produces the greatest benefit at the least cost. Consolidation or maintenance therapy with allegedly non-cross-resistant second-line therapy after best available first-line therapy rarely enhances long-term outcome while contributing significantly to overall toxicity.

Conclusion Several conclusions pertinent to chemotherapy of small ceU hmg cancer can be drawn for the studies reviewed. (1) Etoposide and ten&side are both very active single agents against small cell lung cancer. (2) Divided dose etoposide appears more active than a single 24-h infusion schedule. (3) Early etoposide (day 3-6 after bolus cyclophosphamide, CCNU, vincristine) is more active but more toxic than delayed etoposide at equivalent doses. (4) Addition of etoposide to CAV produces increased toxicity with no significant survival benefit. (5) Substitution of etoposide for doxorubicin or for vincristine in the CAV combination may improve survival in extensive disease patients. (6) Addition of cisplatin to CAVE or to etoposide-vincristine produces increased toxicity without significantly improving survival. (7) Etoposide-cisplatin appears as active as any combination chemotherapy program for small cell lung cancer. Whether alternating etoposide+G@atin with CAV improves survival over EP alone is unsettled. Consolidation CAV adds nothing except toxicity to PE induction therapy (8) Etoposideifosfamide is inferior to etoposide-cisplatin as induction therapy.

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(9) Whether carboplatin, with its diminished gastrointestinal toxicity but increased myelosuppression, can supplant cisplatin in small cell therapy will require randomized comparative trials.

(lO)The optimum combination chemotherapy for small cell lung cancer remains undefined. While many take cisplatin-etoposide as the working ‘standard of care’, additional trials of equitonic regimens adding to or substituting in the EP regimen are appropriate. Issues of schedule (e.g. weekly versus every 34 week treatment), dose intensity (major augmentation with growth factor support), and biochemical modulation also present opportunities for fruitful investigation, many of which are currently being addressed. Bibliomauhv

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