- Email: [email protected]
Extensive small cell lung cancer
Lung Cancer, 1993; 9 (Suppl. 1): S27-S39 0 1993 Elsevier Scientific Publishers Ireland
LUNG
s21 Ltd. All rights reserved.
0169-5002/93/$06.00
00202
Extensive small cell lung cancer Robert L. Comis Vice President, Medical Science, Fox Chase Cancer Center, Philadelphia, PA, USA
Summary Despite significant advances in the treatment of small cell lung cancer (SCLC), complete response and survival rates have remained essentially stable, and a variety of strategies have been implemented in attempts to improve therapeutic impact. Increasing dose intensity, for example, has been evaluated in studies of dose escalation, alternating combinations of drugs, and weekly dose-intensive regimens. Although there has been some indication that etoposide/cisplatin may provide a small, reproducible benefit in the treatment of limited SCLC, there is no evidence that such is the case in the extensive-disease setting. With currently available drugs, extensive SCLC remains a disease not curable by chemotherapy. In fact, studies combining agents with proven single-agent activity suggest the existence of a resistant core of SCLC cells that are insensitive to current therapies. Thus, it is essential that new agents with truly unique mechanisms of action be developed. It is also imperative that the role of biologic tools, such as the interferons, interleukin-2, monoclonal antibodies and anti-growth factor strategies, be aggressively studied if we are to improve the current climate of treatment for extensive SCLC.
Key words: Extensive SCLC; Dose intensity
Introduction Lung cancer is one of the most important public health problems in the world, as a result of cigarette smoking. Approximately 25% of all lung cancer cases are of the small cell variety. In the United States alone there have been over 40 000 patients with newly diagnosed SCLC, approximately 60%, or 24 000, will have presented with extensive disease, 99% of whom will die of their disease within 2 years. Correspondence to: Robert L. Conk, M.D., Vice President, Burholme Ave, Philadelphia, PA 19111, USA.
Medical
Science, Fox Chase Cancer
Center,
7701
S28 TABLE 1 Extensive SCLC: past to present. Reference
Regimen
No. patients
Response %
CR %
Median Survitil (weeks)
Green et al. [I]
Placebo Cyclophosphamide
-
-
-
331 1286 630 211
11 55 70 82
25 14 23 30
-6 -12 33 31 39 31
Bunn et al. [2] Klasa et al. [3]
CAV CAE Etoposide/cisplatin
CAV, cyclophosphamide/doxorubicin/vincristine;
CAE, cyclophosphamide/doxorubicin/etoposide.
SCLC has been the focus of intensive clinical research for the last two decades (Table 1). During that time, significant therapeutic progress has been made with combination chemotherapy. In 1969, Green et al. [l] first reported that cyclophosphamide could extend survival in patients with extensive disease from approximately 6 weeks to 12 weeks. In 1917, Bunn [2] reviewed then-extant studies employing a variety of combinationchemotherapy regimens, generally doxorubicin or nitrosourea based. By that time, investigators were reporting an increase in the complete response (CR) rate to approximately 25% and an extended median survival of 33 weeks. The following decade was highlighted by an extension of the CAV (cyclophosphamide/doxorubicin/vincristine) experience and the introduction of etoposide into combination therapy programs, as well as by the development of the etoposide/cisplatin regimen. Although composite data from a review by Klasa et al. [3] show that there has been little advance during the last 10 years in increasing the CR rate or the median survival of patients with extensive SCLC, a variety of strategies have been implemented in attempts to increase our therapeutic power over this disease.
Dose Intensity
Recently Klasa et al. [3] conducted a dose-intensity meta-analysis of doxorubicin-based regimens but found no clear-cut association between dose intensity and either CR or survival. It should be noted, though, that the studies analyzed were conducted when the clinical research community accepted the dictum that therapy should be delivered intensively, so the splay in dose is much less than has been seen in similar evaluations [3]. Nevertheless, within this fairly narrow range of dose intensity, no demonstrable effect was apparent. Increasing drug doses
Cohen et al. [4] reported one of the few trials in which the dose of an individual agent in a combination was found to be effective. In this study, a relatively low dose of cyclophosphamide (500 mg/m2) was found to be less effective than a full dose (1000 mg/m2), both given as part of a nitrosourea-based regimen. Cyclophosphamide [5] has been
S29
evaluated extensively in bone marrow transplant support studies at dose levels up to 4800 mg/m2 and, overall, there has been no evidence that dose escalations of this drug provides any therapeutic advance in either extensive- or limited-stage SCLC [5]. Souhami et al. [6] have shown that clinical resistance to cyclophosphamide, evidenced by a decreasing incremental change in tumor volume, occurs within two doses of cyclophosphamide 120 mg/kg in untreated patients. Most high-dose cyclophosphamide late-intensification efforts, however, have used this agent after treatment with other regimens that included the drug, i.e, in potentially resistant situations. More recent studies have evaluated dose escalation of etoposide or etoposide/cisplatin combinations (Table 2). Ihde et al. [7] recently reported results of a study in which a 67%dose escalation of etoposide/cisplatin was attempted in patients with extensive disease. The actual increase in intensity achieved was 47% during the first two cycles of therapy. As shown in Table 2, no alteration in overall response, CR rate, or median survival was noted in this group of patients. Investigators from Vanderbilt [g-10] have reported a series of nonrandomized studies evaluating the response of patients with extensive disease to high-dose etoposide (1200 mg/m2) alone, the same etoposide dose combined with highdose cyclophosphamide (100 mg/kg), or these doses of both drugs combined with cisplatin (120 mg/m2). As shown in Table 2, the latter combination appeared to produce a substantial increase in CR but had no significant impact on median survival. Neither autologous bone marrow support nor treatment with colony-stimulating factors (CSFs) was used in this progression of studies. As expected, profound but transient aplasia was induced in the latter two trials [9,10]. Taken at face value, the Vanderbilt studies indicate that the addition of cisplatin to high-dose etoposide/cyclophosphamide provides entry into a moderately resistant cellular domain, effectively increasing the CR rate. In spite of
TABLE 2 Extensive SCLC: dose escalation
studies.
Regimen
No. patients
per day per day 50 mg/kg per day 50 mg/kg per day
(‘VU)
Median survival (months)
Overall
CR
39
85
24
12
42
81
21
11
x 3 13 x 3 17 per day x 2 x 3 18 per day x 2 x 3
62 92
31 29
I.5 IO
90
65
High- vs. standard-dose etoposide” Etoposideb 80 mgim* per day x 5 Cisplatin 27.5 mgim* per day x 5 Etoposide 50 mgim* per day x 3 Cisplatin 80 mgim* Vanderbilt trialsC Etoposide 400 mg/m2 Etoposide 400 mg/m* Cyclophosphamide Etoposide 400 mgim* Cyclophosphamide Cisplatin 40 mg/m*
Response
“Adapted from Ihde et al. [7]. b47% Increase in dose rate, median potential follow-up was 53 months. ‘Adapted from Wolff et al. [S] and Johnson et al. [9,10].
no evidence
9.5+
for increased
effect
s30
this benefit, however, no substantial alteration in overall survival was observed in these studies. Obviously, randomised studies would be necessary to address these issues precisely, but the lack of a clear-cut signal in either the short- (median survival) or long-term result, even in this Phase II setting, is sobering. Research into dose-escalation regimens involving etoposide and platinum continues, with the associated use of autologous bone marrow support with or without hematopoietic CSFs. Shea et al. [ 1l] have shown that with autologous bone marrow support, carboplatin can be escalated to levels of 2000-2400 mg/m* before nonhematologic toxicity supervenes. It has not been determined whether such doses, either alone or combined with high-dose etoposide, will substantially alter the CR rate or the duration of survival in patients with extensive SCLC. Dose escalation of etoposide/platinum-based programs also has been attempted with the addition of hematopoietic CSFs. Liukart et al. [12] have recently reported a maximally tolerated dose (MTD) of etoposide (750 mg/m2) and carboplatin (375 mg/m2) administered over 3 days when combined with lo-20 &kg per day of granulocyte-macrophage (GM)-CSF. It is unlikely that further escalation of drug levels will be possible without the addition of autologous bone marrow or peripheral blood stem cell support. The addition of ifosfamide to etoposide/platinums
The preliminary results have been reported of two recent trials of extensive disease patients treated with ifosfamide added to full-dose etoposide/platinum regimens, with Smith et al. [ 131employing a single dose of carboplatin 400 mg/m2 and Miller et al. [4] using cisplatin 100 mg/m2 delivered over 5 days. The latter study reported a complete remission rate of 57% in 40 patients. Confirmation of results of this study, reported by the Hoosier Oncology Group, is currently under way in a randomised setting in which this regimen is being compared with etoposide/cisplatin. We have recently attempted to escalate the dose intensity of ifosfamide/carboplatin/etoposide (ICE) in combination with GM-CSF (5 pg/kg per day, days 4 through 11). In this study, the doses of ifosfamide and carboplatin were maintained at 5 g/m2 and 400 mg/m2, respectively, and etoposide was escalated to an MTD of 1200 mg/m2. Alternating combinations
During the 198Os, the concept of increasing therapeutic intensity by alternating noncross-resistant combination therapies was spurred by the mathematical model of drug resistance proposed by Goldie et al. [15] Numerous attempts at alternating treatment with existing drugs and drug combinations had been made by the early 198Os, at which time extensive analyses of the subject indicated that no consistent effect had been produced [ 16,171. In general, however, these alternating combinations did not include etoposide or etoposide combined with cisplatin. To put subsequent trials, which did include etoposide-based alternatives, into perspective, certain data need to be addressed. First, a series of trials initiated in the early 1980s was designed to assess the relative value of etoposide, either substituted for vincristine or doxorubicin in the prevalent CAV program or added to the CAV combination [ 18-201. In each of these trials, the addition of etoposide to front-line therapy yielded a 6- to 8-week
s3
TABLE 3 Extensive SCLC: alternating Regimen
CAV CAVIEP EP SEC. Southern
Overall
drug trials.
response
Median
CR (‘ih)
(Y0)
survival
(weeks)
NCIC
SEC
NCIC
SEC
NCIC
SEC
63 80
58 58 59
21 39
12 17 17
32 38
38 39 38
Oncology
Group;
EP, etoposide/cisplatin.
Adapted
from Evans et al. [24] and Roth et al. [25].
increase in the median survival of patients with extensive disease [18,19] or a comparable increase in the duration of response [20]. Second, it became clear that etoposide/cisplatin was active in patients who had failed therapy with CAV, yet the reverse did not appear to hold true. It is suggested that the best design for testing the role of etoposide/cisplatin would be a three-arm study comparing CAV with etoposide/cisplatin and with alternating these two regimens. Since 1984, eight major trials have evaluated alternating chemotherapy regimens that included etoposide in the alternating scheme [21-231. Seven studies have shown a statisticaly significant increase in median survival in extensive-disease patients, but this increase generally has been in the aforementioned 6- to g-week range. Each of these trials compared an etoposide-based alternation with a non-etoposide-containing control arm.
TABLE 4 Schedules during
weekly regimens. Weeks
1
2
3
4
5
6
7
8
9
Cisplatin
0 X
0
0 X
0
0 X
0
0
0 X
Etoposide
0 X
0 X + 0 X +
Vincristine
0
Doxorubicin
0 +
Ifosfamide Cyclophosphamide Methotrexateileucovorin 0 = Murray et al. [28] X = Miles et al. [29] + = Taylor et al. [27]
0 X +
; X + 0 +
0 +
0 X
+
0 +
0 +
X +
+
+
0 + 0
0
X
X
S32
The one study in which etoposide was included both in the control arm and in the alternating sequence yielded no significant difference in median survival. Thus, these studies may signal only that early use of etoposide provides small increment of cell kill that consistently produces the 6- to 8-week increase in median survival observed in these substitution studies. It was hoped that the addition of etoposide/cisplatin to the CAV-based therapeutic arsenal would provide a significant increase in activity. Evans et al. [24] reporting for the National Cancer Institute of Canada (NCIC), were the first to evaluate a fixed alternating schedule of CAV and etoposide/cisplatin, compared with a CAV control arm in patients with extensive disease. This study was followed by a three-arm randomised trial that also included an etoposide/cisplatin control arm 1251.The contrasting results of these two trials are presented in Table 3. Over 300 patients were randomised and evaluated in each study. The two-arm trial reported a statistically significant increase in both overall response and CR in favor of the alternating regimen. The approximately 6-week increase in median survival also was statistically significant. The three-arm study did not show a significant difference in any parameter. The survival times cited in Table 3 are well within those anticipated for the treatment of extensive disease patients, as noted in Table 1. In summary, alternating combinations of drugs has not led to any clinically significant advance in the therapy of extensive SCLC, although the results of several studies imply that etoposide or etoposide/cisplatin should be employed early in the course of therapy for extensive disease. Weekly dose-intense regimens
Another method of increasing dose intensity is to alter the time-dose relationship of the drugs delivered. This approach reportedly has been successful in the treatment of diffuse large cell lymphoma [26]. Klastersky et al. [5] reviewed the study data on SCLC as of 1989, and three of the studies assessed have since reached the publication stage [27-291. Common to each is the rapid sequencing of drugs over a 9- to 16-week period. A composite of the drug and scheduling parameters used in these studies is presented in Table 4 and eligibility and exclusion criteria are presented in Table 5. Two of the studies were performed in highly selected patients with extensive disease, with 52 and 29% of available extensive-disease patients participating in the studies by Murray et al. [28] and Miles et al. [29], respectively. Of note, approximately 20% of the patients in the trial represented
TABLE 5 Selection factors: exterpive disease. Reference
Age (years)
Taylor et al. [27] Murray et al. [28] Miles et al. [29]
< 66
Performance status (%) o-1 (84) 2-4 (17) o-2 o-1
Proximity
Other
Eligible (%)
< lh -
20% thoracic
52 (48/92) 29
s33
TABLE 6 Extensive SCLC: response
to weekly alternating
therapy
Reference
No. patients
Overall (%) response
CR (‘G/u)
Median survival (months)
Dose intensity achieved (X)
Taylor et al. [27] Murray et al. [28] Miles et al. [29]
76 48 25
81 94 92
38 40 48
II.4 I5 10.5
80 90 15
by Murray et al. [28] had intrathoracic disease. The study reported by Taylor et al. [27] for the Southwest Oncology Group (SWOG) was conducted with a less selected group of patients in a Phase II cooperative group setting. Results of the three trials are shown in Table 6. The CR rates ranged from 38 to 48%, and the median survival times reported were 10.5-15 months. The delivery of the planned dose intensity ranged from 75 to 90%. Of interest is the 20-25% 2-year survival projected in the studies by Murray et al. [28] and Miles et al. [29] The less selected group of patients treated in the SWOG study [27] did not attain this plateau in survival, although the survival characteristics of both the poor and good performance status groups in that study were favourable compared with historical data. A major drawback of this approach to therapy is that growth factor support is difficult to incorporate into rapidly sequenced drug programs because of the dictum that growth factors and chemotherapy should not be administered concomitantly. However, a randomized study reported by Masuda et al. [30] questions this issue. Although final results of the trial have not been reported, preliminary data comparing patients randomised to CODE (cyclophosphamide/vincristine/doxorubicin/etoposide) chemotherapy, as used by Murray et al. [28] with or without GM-CSF indicate that with supportive therapy the dose intensity delivered can be increased and hematologic toxicity decreased despite administration of concomitant and continuous GM-CSF. The potential advantages of weekly intensive therapy relate to the finite duration of treatment and the hint of greater efficacy with this approach. The former point is supported by studies showing that protracted maintenance therapy is of little benefit in the setting of extensive SCLC. All told, the preliminary data on weekly intensive therapy demand evaluation in properly designed randomised settings. Such studies are now under way in Europe, Canada, and the United States.
New Directions in Scheduling and Evaluation Etoposide
Over 20 years ago, Cavalli et al. [31] were the first to show that etoposide, administered by either-the intravenous (IV) or oral route, was active against SCLC and that the benefit provided might be schedule dependent. Since then, multiple-day dosing schedules have
s34
been implicitly employed, although it is only recently that the schedule dependency of etoposide activity has been proven in a randomized controlled trial. As reported by Slevin et al. [32] 39 previously untreated patients with extensive SCLC were randomized to treatment with the same total dose of etoposide (500 mg/m2 i.v.), given either as a single 24hour infusion or in lOO-mg/m2 doses for 5 days. The objective response rates were 10% in the single-day and 84% in the 5-day arm, with a 4.5-month median duration of response in the patients treated over 5 days. Interestingly, crossover to CAV occurred in about half of the patients in each arm, yielding a comparable number of partial responders. The overall median survival was 10 vs. 6.3 months, favoring those who were treated initially with the daily x 5 dosage regimen. Subsequent studies by the same group of investigators [33] have extended these observations and attempted both to increase the duration of daily administration to 8 days and to evaluate the potential pharmacologic differences that might explain the scheduledependent effect of etoposide. As expected, peak drug levels were higher with the shorter administration schemes. Aside from this observation, the only statistically significant difference in pharmacokinetics was the area under the curve for low concentrations obtained in the 5-day schedule (> 1 to < 5 j&ml per h), which implies that continuous exposure to low concentrations is more important than peak levels. In addition, it can be seen in this series of trials that a moderate increase in the duration of therapy from 5 to 8 days did not significantly alter objective response rates. Formulation problems complicate further protraction of the schedule of daily i.v. administration. Low-dose protracted
therapy
Hainsworth et al. [34] were the first to report a Phase I study of protracted low-dose oral etoposide therapy. The MTD was shown to be 50 mg/m2 per day x 21 days, with transient myelotoxicity as the dose-limiting factor. Activity was documented against a variety of refractory tumors. Subsequently, Johnson et al. [35] reported a formal Phase II trial in which this dose of etoposide was administered to 22 evaluable patients with refractory SCLC, for an overall response rate of 45% and a CR rate of 9%. In contrast, a response rate of approximately 12% was reported previously when conventional etoposide doses were used in patients with refractory SCLC [36]. Certain critical features were correlated with response in this trial and included response to previous chemotherapy and duration of time from previous treatment. Objective response, for example, was significantly higher when the time since previous therapy was greater than (64%) compared with less than (12.5%) 90 days. Myriad clinical questions arise from these observations: what is the maximal and optimal duration of therapy? What is the optimal dose of administration? Can effective protracted administration be integrated effectively into combination programs? Is protracted therapy truly superior to more conventional dosing approaches? It is hoped protracted administration represents a new facet of one of the stalwarts of the chemotherapeutic armamentarium. The next several years will undoubtedly emphasize the issues raised by these observations. Other drugs
Agents shown to be active against previously untreated extensive SCLC are listed in Table 7. Although these drugs are substantially active as single agents, reported CR rates
s35
TABLE 7 SCLC: contemporary
single-agent
studies -
drugs with > 50% response
Drug
No. patients
Overall response (% CR)
Etoposide Teniposide Carboplatin Ifosfamide
138 101 101 217
79 88 55 54
Epirubicin
176
51 (8)
(IO) (23) (II) -
are somewhat less than might be achieved with combination regimens. Also of note, these agents are generally analogues of existing drugs that are known to be active against SCLC, and prior exposure to chemotherapy reduces their level of activity to the lo-20% range [37]. Given that the parent compounds are active, the question remains whether the newer agents provide greater efficacy or a greater potential for response when used in combination programs. The answer appears to be nugatory. Bork et al. [38] have directly compared etoposide with teniposide in a randomized controlled fashion in previously untreated patients with limited or extensive SCLC. No difference in objective response, CR, or survival in either group was discerned. The survival of the 26 patients with extensive disease, randomised equally to either etoposide or teniposide, was 8.5 and 11.3 months, respectively. The sample size precludes any comment relative to the absolute difference reported in survival. Table 8 presents the extant data on extensive-disease patients treated with etoposide/carboplatin, two of the most active agents available to treat SCLC [39-441. None of the studies indicates a substantial increment in efficacy when these agents are combined. On the other hand, the expected decrease in nonhematologic side effects was apparent. What is the biologic meaning of such data? It appears that the ‘sensitive’ cell population in extensive SCLC is collaterally sensitive to a variety of drugs including the epipodophyl-
TABLE 8 Extensive SCLC: carboplatinietoposide. Reference
Total dose (mgim*)
No. evaluable
Overall response (%)
CR (Vi)
13 9 16 15 14 22
Etoposide
Carboplatin
Smith et al. [39]
300
300
24
88
Bishop et al. [40] Evans et al. [41] Liukart et al.” [42] Eberhardt et aLb [43] Evans et akc [44]
300 300 600 420 700
360 300 375 300 150
55 32 13 36 25
58 56 53 61 72
“With GM-CSF. bWith vincristine ‘Oral etoposide.
days 1, 8, 15 and 22
Median survival (months) 9.5 8.3 8.1 11
S36
lotoxins, platinums, alkylating agents, and certain anthracyclines. If each class of agent selected out a uniquely sensitive population of cells, one would anticipate at least an additive effect, which clearly has not been observed. This suggests a core of resistant cells that, in their unperturbed state, are insensitive to the available agents. A more fruitful area of investigation, therefore, would be to evaluate unique compounds. Such studies are under way.
Evaluation of New Compounds Several compounds of unique structure have been evaluated against SCLC and shown to be inactive. The list includes amonafide, menogaril, idarubicin, mitoxantrone, and sulofenur. Interestingly, this group includes DNA active agents considered a priori to be potentially active. A major milestone was the trial design established by the Eastern Cooperative Oncology Group (ECOG) to evaluate a new agent yet protect the patient from a potentially adverse effect on palliation and survival. In this study patients were randomly allocated to treatment with CAV or menogaril. On progression or after two cycles without response to menogaril, patients were immediately crossed over to etoposide/cisplatin. Ettinger et al. [45] have reported the preliminary results of this trial. Fortuitously, although menogaril turned out to be inactive against extensive SCLC (response rate, 5O), there was no significant difference in median survival for the two groups of patients (41.7 weeks for CAV vs. 38.3 weeks for the inactive compound). Thus, with an appropriate study design, new agents can be evaluated safely in patients with extensive disease. New agents with activity The camptothecin derivative CPT-11 and taxol, two agents with unique mechanisms of action, have been reported to be active against SCLC. The former compound inhibits topoisomerase I. Negoro et al. [46] have recently reported on 41 patients treated with CPT-11 100 mg/m’ delivered over 90 min. Overall, 13 of 35 (37%) patients responded, including 33% who had received prior therapy and 50% who had not. Further studies of this compound, and other camptothecin analogues such as hycamptomine, should be a top priority. Preliminary taxol data are available from the ECOG. To date, objective response has been attained in 8 of 18 (44%) subjects with previously untreated extensive disease (D.C. Ettinger, M.D., October 1991, personal communication). Further studies with this agent are under way. Whether these agents induce response in the same responsive pool of cells affected by other, currently available agents against SCLC or whether they may provide the first approach in decades with activity against a previously unassaulted cell population remains to be determined.
Conclusions Tremendous effort has been directed to the therapy of extensive SCLC over the last two decades. The halcyon days occurred in the late 1970s and early 198Os, during which a
s37
previously unprecedented degree of responsiveness was found in this clinical setting. Since then, however, there has been little therapeutic advance. Although the integration of etoposidekisplatin into limited-disease treatment strategies appears to have provided an incremental, reproducible advantage, such has not occurred in the extensive-disease setting. Once SCLC becomes metastatic, as with many other malignancies, the cure boundary with existing programs is eclipsed. With existing drugs, extensive SCLC is a chemoresponsive but chemoincurable disease. The development of truly new agents, with different mechanisms of action from those available currently, must be a top priority. Combined with this effort, the realization that extensive SCLC is a chemoresistant disease demands that strategies to avert or circumvent drug resistance should be immediately directed to this setting. Additionally, further exploration of the role of biologic tools, such as the interferons, interleukin-2, monoclonal antibodies, and anti-growth factor strategies, should be pursued aggressively in the hope that future patients may be treated with more than palliative intent.
References 1 Green RA, Humphrey E, Close H, Patno ME. Alkylating agents in bronchogenic carcinoma. Am J Med 1969; 46: 516-525. 2 Bunn PA, Cohen MH, Ihde DC, Fossieck BE, Mathews J, Minna JD. Advances in small cell bronchogenic carcinoma. Cancer Treat Rep 1977; 61: 333-342. 3 Klasa RJ, Murray N, Coldman AJ. Dose-intensity meta-analysis of chemotherapy regimens in small cell carcinoma of the lung. J Clin Oncol 1991; 9: 499-508. 4 Cohen MH, Creaven PJ, Fossieck BE, Broder LE, Selawry OS, Johnston AV, Williams CL, Minna JD. Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 1977; 61: 349-354. 5 Klastersky JA, Scullier JP. Intensive chemotherapy of small cell lung cancer. Lung Cancer 1989; 5: 196-206. 6 Souhami RL, Harper PG, Linch D, Trask C, Goldstone AH, Tobias J, Spiro SG, Geddes DM, Richards JDM. High-dose cyclophosphamide with autologous bone marrow transplantation as initial treatment of small cell carcinoma of the lung. Cancer Chemother Pharmacol 1982; 8: 31-34. 7 Ihde DC, Mulshine JL, Kramer BS, Steinberg SM, Edison M, Phelps R, Lesar M, Phares JC, Minna JD, Johnson BE. Randomized trial of high versus standard dose etoposide (VP-16) and cisplatin in extensive stage small cell lung cancer (SCLC) [abstract 8191. Proc Am Sot Clin Oncol 1991; 10: 240. 8 Wolff SN. High dose etoposide as a single agent chemotherapy for small cell carcinoma of the lung. Cancer Treat Rep 1983; 67: 957-958. Johnson DH, Wolff SN, Hainsworth JD, Porter LL, Grosh WW, Hande KR, Greco FA. Extensive stage small cell bronchogenic carcinoma: intensive induction chemotherapy with high-dose etoposide. J Clin Oncol 1985; 3: 170-175. Johnson DH, DeLer MJ, Kande KR, Wolff SN, Hainsworth JD, Greco FA. High-dose induction chemotherapy with cyclophosphamide, etoposide, and cisplatin for extensive stage small cell lung cancer. J Clin Oncol 1987; 5: 703-709. Shea TC, Flaherty M, Elias A, Eder JP, Antman K, Begg L, Schnipper L, Frei E, Henner WD. A phase I clinical and pharmacokinetic study of carboplatin and autologous bone marrow support. J Clin Oncol 1989; 7: 651-661. Liukart SD, MacDonald M, Huezan D, Modeas C, Perry MC, Green MR. Ability of daily or twice daily granulocyte-macrophage colony-stimulating factor (GM-CSF) to support dose escalation of etoposide (VP16) and carboplatin (CBDCA) in extensive small cell lung cancer (SCLC) [abstract A825]. Proc Am Sot Clin Oncol 1991; 10: 242. Smith IE, Perren TJ, Ashley SA, Woodiwiss J, Forgeson GV, Yarnold JR, Ford HT. Carboplatin,
S38
14
15
16 17
18
19 20 21 22
23
24 25
26 27
28 29 30
31
32 33
etoposide, and ifosfamide as intensive chemotherapy for small cell lung cancer. J Clin Oncol 1990; 8: 899-905. Miller JC, Loehrer PJ, Songer J, Pennington K, Ansari R, Turner S, Einhorn LH. VP-16, ifosfamide, and cisplatin (VIP) in extensive small cell lung cancer (SCLC). A Hoosier Oncology Group Study [abstract A962]. Proc Am Sot Clin Oncol 1990; 9: 248. Goldie JH, Coldman JA, Gudauskas GA. Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat Rep 1982; 66: 439-449. Elliot JA, Osterlind K, Hansen HH. Cyclic alternating non-cross-resistant chemotherapy in the management of small cell anaplastic carcinoma of the lung. Cancer Treat Rev 1984; 11: 103-l 13. Aisner J, Albert0 P, Bitran J, Comis R, Daniels J, Hansen H, Ikegami H, Smyth J. Role of chemotherapy in small cell lung cancer: a consensus report of the International Association for the Study of Lung Cancer workshop. Cancer Treat Rep 1983; 67: 37-43. Hong WK, Nicaise C, Lauson R, Maroun JA, Comis RL, Speer J, Luedke D, Rozencweig M. Etoposide combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high dose cyclophosphamide plus vincristine in the treatment of small cell carcinoma of the lung: randomised trial of the Bristol Lung Cancer Study Group. J Clin Oncol 1989; 7: 450-456. Bunn PA Jr, Greco FA, Einhorn L. Cyclophosphamide, doxorubicin, and etoposide as first-line therapy in the treatment of small-cell lung cancer. Semin Oncol 1986; 13(3): 63-74. Jackson DV, Case LD, Zekan PJ, Powell BL, Capizzi RL. Improvement of long-term survival in extensive small cell lung cancer. J Chn Oncol 1988; 6: 1161-1169. Osterlind K. Alternating or sequential chemotherapy in small cell lung cancer? Lung Cancer 1989; 5: 173-177. Ettinger DS, Finkelstein DM, Abeloff MD, Ruckdeschel JC, Aisner SC, Eggleston JC. A randomised comparison of standard chemotherapy versus alternating chemotherapy and maintenance versus no maintenance therapy for extensive stage small cell lung cancer: a phase III study of the Eastern Cooperative Oncology Group. J Clin Oncol 1990; 8: 230-240. Wampler GL, Heim WJ, Ellison NM, Ahlgren JD, Fryer JG. Comparison of cyclophosphamide, doxorubicin, and vincristine with an alternating regimen of methotrexate, etoposide, and cisplatin/cyclophosphamide, doxorubicin, and vincristine in the treatment of extensive-disease small-cell lung carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol 1991; 9: 1438-1445. Evans WK, Feld R, Murray N, Willan A, Coy P. Superiority of alternating non-cross-resistant chemotherapy in extensive small cell lung cancer. Ann Intern Med 1987; 107: 451-458. Roth BJ, Johnson DH, Greco FA, Einhorn LH, Goodlow JL, Cheung N, Randolph JA, Schacter LP. A phase III trial of etoposide (E) and cisplatin (P) versus cyclophosphamide (C), doxorubicin (A), and vincristine (V), versus alternation of the two therapies for patients (pts) with extensive small cell lung cancer (SCLC): preliminary results [abstract 8751. Proc Am Sot Clin Oncol 1989; 8: 225. Klimo P, Connors JM. MACOP-B chemotherapy for the treatment of diffuse large cell lymphoma. Ann Intern Med 1985; 102: 596-602. Taylor CW, Crowley J, Williamson SK, Miller TP, Livingston RB. Treatment of small cell lung cancer with an alternating chemotherapy regimen given at weekly intervals: a Southwest Oncology Group Pilot Study. J Clin Oncol 1990; 8: 1811-1817. Murray N, Shah A, Osoba D, Page R, Voss N. Intensive weekly chemotherapy for the treatment of extensive stage small cell lung cancer. J Clin Oncol 1991; 9: 1632-1638. Miles DW, Earl HM, Souhami RL, Harper PG, Rudd R, Ash CM, Sprio SG. Intensive weekly chemotherapy for good prognosis patients with small cell lung cancer. J Chn Oncol 1991; 9: 280-285. Masuda N, Fukuoka M, Negoro N, Takada M, Nakagaura K, Kodama N, Kawahara M, Furuse K. CODE chemotherapy with or without recombinant human granulocyte colony-stimulating factor (rhG-CSF) in extensive stage (ES) small cell lung cancer (SCLC) [abstract 8731. Proc Am Sot Clin Oncol 1991; 10: 254. Cavalli F, Sonntag RW, Jungi F, Senn HJ, Brunner KW. VP16-213 monotherapy for remission induction of small cell lung cancer: a randomised trial using three dosage schedules. Cancer Treat Rep 1978; 62: 473-475. Slevin ML, Clark PI, Joel SP, Malik S, Osborne RJ, Wrigley PFM. A randomised trial to evaluate the effect of schedule on the activity of etoposide in small cell lung cancer. J Clin Oncol 1989; 7: 1333-1340. Clark PI, Joel SP, Slevin ML. A pharmacokinetic hypothesis for the clinical efficacy of etoposide in small cell lung cancer [abstract A257]. Proc Am Sot Clin Oncol 1989; 8: 66.
s39
34 35
36 31 38 39 40
41 42
43
44 45
46
Hainsworth DJ, Johnson DH, Frazier SR, Greco FA. Chronic daily administration of oral etoposide a phase I trial. J Clin Oncol 1989; 7: 396-401. Johnson DH, Greco FA, Strupp J, Hande KR, Hainsworth JD. Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: a phase II trial. J Clin Oncol 1990; 8: 1613-1617. Issell BF, Einhorn LH, Comis RL, Lawson RD, Baker LH, Rosenbaum PF. Multicenter phase II trial of etoposide in refractory small cell lung cancer. Cancer Treat Rep 1985; 69: 127-131. Johnson DH. New drugs in the management of small cell lung cancer. Lung Cancer 1989; 5: 221-231. Bork E, Ersboll P, Dombernowsky B, Bergman B, Hansen M, Hansen HH. Teniposide and etoposide in previously untreated small cell lung cancer: a randomised study. J Clin Oncol 1991; 9: 1627- 1631. Smith IE, Evans BD. Carboplatin as a single agent and in combination in the treatment of small cell lung cancer. Cancer Treat Rev 1985; 12 Suppl A: 73-75. Bishop JF, Raghavan D, Stuart-Harris R, Morstyn G, Aroney R, Kefford R, Yuen K, Lee J, Giantousos P, Olver IN, Zalcberg J, Ball D, Bull C, Fox R. Carboplatin and VP-16-213 in previously untreated patients with small cell lung cancer. J Clin Oncol 1987; 5: 1574-1578. Evans WK, Eisenhauer E, Hughes P, Maroun JA, Ayoob J, Shepherd FA, Feld R. VP-16 and carboplatin for previously untreated extensive small cell lung cancer [abstract]. Lung Cancer 1988; 4 Suppl: Al04 Luikart SD, Mitchell EP, Van Echo DA, Propert K, Modeas C, Perry MC, Green M, for the Cancer and Leukemia Group B. Phase I/II trial of etoposide (VP-16) and carboplatin (CBDCA) in untreated extensive small cell lung cancer (SCLC) [abstract 7541. Proc Am Sot Clin Oncol 1988; 7: 195. Eberhardt W, Ochel HJ, Grabke I, Moritz T, Achterrath W, Konietzko N, Niederle N. Carboplatin, etoposide, vincristine (CEV) plus/minus CM-CSF in the treatment of small cell lung cancer (SCLC): a phase II study [abstract A947]. Proc Am Sot Clin Oncol 1990; 9: 245. Evans WK, Stewart DJ, Marion J, Logan D, Martins H, Tomiak E, Dahrough S. Oral VP-I 6 and carboplatin for small cell lung cancer [abstract A847]. Proc Am Sot Clin Oncol 1991; 10: 247. Ettinger DS, Finkelstein DM, Abeloff MD, Bonomi P. Justification for evaluating new anticancer drugs in selected untreated patients with a chemotherapy-sensitive advanced cancer: an ECOG randomised study [abstract A864]. Proc Am Sot Clin Oncol 1990; 9: 224. Negoro S, Fukuoka M, Niitani H, Taguchi T. Phase II study of CPT-11, new camptothecin derivative, in small cell lung cancer (SCLC) [abstract 8221. Proc Am Sot Clin Oncol 1991; IO: 241.
LUNG
s21 Ltd. All rights reserved.
0169-5002/93/$06.00
00202
Extensive small cell lung cancer Robert L. Comis Vice President, Medical Science, Fox Chase Cancer Center, Philadelphia, PA, USA
Summary Despite significant advances in the treatment of small cell lung cancer (SCLC), complete response and survival rates have remained essentially stable, and a variety of strategies have been implemented in attempts to improve therapeutic impact. Increasing dose intensity, for example, has been evaluated in studies of dose escalation, alternating combinations of drugs, and weekly dose-intensive regimens. Although there has been some indication that etoposide/cisplatin may provide a small, reproducible benefit in the treatment of limited SCLC, there is no evidence that such is the case in the extensive-disease setting. With currently available drugs, extensive SCLC remains a disease not curable by chemotherapy. In fact, studies combining agents with proven single-agent activity suggest the existence of a resistant core of SCLC cells that are insensitive to current therapies. Thus, it is essential that new agents with truly unique mechanisms of action be developed. It is also imperative that the role of biologic tools, such as the interferons, interleukin-2, monoclonal antibodies and anti-growth factor strategies, be aggressively studied if we are to improve the current climate of treatment for extensive SCLC.
Key words: Extensive SCLC; Dose intensity
Introduction Lung cancer is one of the most important public health problems in the world, as a result of cigarette smoking. Approximately 25% of all lung cancer cases are of the small cell variety. In the United States alone there have been over 40 000 patients with newly diagnosed SCLC, approximately 60%, or 24 000, will have presented with extensive disease, 99% of whom will die of their disease within 2 years. Correspondence to: Robert L. Conk, M.D., Vice President, Burholme Ave, Philadelphia, PA 19111, USA.
Medical
Science, Fox Chase Cancer
Center,
7701
S28 TABLE 1 Extensive SCLC: past to present. Reference
Regimen
No. patients
Response %
CR %
Median Survitil (weeks)
Green et al. [I]
Placebo Cyclophosphamide
-
-
-
331 1286 630 211
11 55 70 82
25 14 23 30
-6 -12 33 31 39 31
Bunn et al. [2] Klasa et al. [3]
CAV CAE Etoposide/cisplatin
CAV, cyclophosphamide/doxorubicin/vincristine;
CAE, cyclophosphamide/doxorubicin/etoposide.
SCLC has been the focus of intensive clinical research for the last two decades (Table 1). During that time, significant therapeutic progress has been made with combination chemotherapy. In 1969, Green et al. [l] first reported that cyclophosphamide could extend survival in patients with extensive disease from approximately 6 weeks to 12 weeks. In 1917, Bunn [2] reviewed then-extant studies employing a variety of combinationchemotherapy regimens, generally doxorubicin or nitrosourea based. By that time, investigators were reporting an increase in the complete response (CR) rate to approximately 25% and an extended median survival of 33 weeks. The following decade was highlighted by an extension of the CAV (cyclophosphamide/doxorubicin/vincristine) experience and the introduction of etoposide into combination therapy programs, as well as by the development of the etoposide/cisplatin regimen. Although composite data from a review by Klasa et al. [3] show that there has been little advance during the last 10 years in increasing the CR rate or the median survival of patients with extensive SCLC, a variety of strategies have been implemented in attempts to increase our therapeutic power over this disease.
Dose Intensity
Recently Klasa et al. [3] conducted a dose-intensity meta-analysis of doxorubicin-based regimens but found no clear-cut association between dose intensity and either CR or survival. It should be noted, though, that the studies analyzed were conducted when the clinical research community accepted the dictum that therapy should be delivered intensively, so the splay in dose is much less than has been seen in similar evaluations [3]. Nevertheless, within this fairly narrow range of dose intensity, no demonstrable effect was apparent. Increasing drug doses
Cohen et al. [4] reported one of the few trials in which the dose of an individual agent in a combination was found to be effective. In this study, a relatively low dose of cyclophosphamide (500 mg/m2) was found to be less effective than a full dose (1000 mg/m2), both given as part of a nitrosourea-based regimen. Cyclophosphamide [5] has been
S29
evaluated extensively in bone marrow transplant support studies at dose levels up to 4800 mg/m2 and, overall, there has been no evidence that dose escalations of this drug provides any therapeutic advance in either extensive- or limited-stage SCLC [5]. Souhami et al. [6] have shown that clinical resistance to cyclophosphamide, evidenced by a decreasing incremental change in tumor volume, occurs within two doses of cyclophosphamide 120 mg/kg in untreated patients. Most high-dose cyclophosphamide late-intensification efforts, however, have used this agent after treatment with other regimens that included the drug, i.e, in potentially resistant situations. More recent studies have evaluated dose escalation of etoposide or etoposide/cisplatin combinations (Table 2). Ihde et al. [7] recently reported results of a study in which a 67%dose escalation of etoposide/cisplatin was attempted in patients with extensive disease. The actual increase in intensity achieved was 47% during the first two cycles of therapy. As shown in Table 2, no alteration in overall response, CR rate, or median survival was noted in this group of patients. Investigators from Vanderbilt [g-10] have reported a series of nonrandomized studies evaluating the response of patients with extensive disease to high-dose etoposide (1200 mg/m2) alone, the same etoposide dose combined with highdose cyclophosphamide (100 mg/kg), or these doses of both drugs combined with cisplatin (120 mg/m2). As shown in Table 2, the latter combination appeared to produce a substantial increase in CR but had no significant impact on median survival. Neither autologous bone marrow support nor treatment with colony-stimulating factors (CSFs) was used in this progression of studies. As expected, profound but transient aplasia was induced in the latter two trials [9,10]. Taken at face value, the Vanderbilt studies indicate that the addition of cisplatin to high-dose etoposide/cyclophosphamide provides entry into a moderately resistant cellular domain, effectively increasing the CR rate. In spite of
TABLE 2 Extensive SCLC: dose escalation
studies.
Regimen
No. patients
per day per day 50 mg/kg per day 50 mg/kg per day
(‘VU)
Median survival (months)
Overall
CR
39
85
24
12
42
81
21
11
x 3 13 x 3 17 per day x 2 x 3 18 per day x 2 x 3
62 92
31 29
I.5 IO
90
65
High- vs. standard-dose etoposide” Etoposideb 80 mgim* per day x 5 Cisplatin 27.5 mgim* per day x 5 Etoposide 50 mgim* per day x 3 Cisplatin 80 mgim* Vanderbilt trialsC Etoposide 400 mg/m2 Etoposide 400 mg/m* Cyclophosphamide Etoposide 400 mgim* Cyclophosphamide Cisplatin 40 mg/m*
Response
“Adapted from Ihde et al. [7]. b47% Increase in dose rate, median potential follow-up was 53 months. ‘Adapted from Wolff et al. [S] and Johnson et al. [9,10].
no evidence
9.5+
for increased
effect
s30
this benefit, however, no substantial alteration in overall survival was observed in these studies. Obviously, randomised studies would be necessary to address these issues precisely, but the lack of a clear-cut signal in either the short- (median survival) or long-term result, even in this Phase II setting, is sobering. Research into dose-escalation regimens involving etoposide and platinum continues, with the associated use of autologous bone marrow support with or without hematopoietic CSFs. Shea et al. [ 1l] have shown that with autologous bone marrow support, carboplatin can be escalated to levels of 2000-2400 mg/m* before nonhematologic toxicity supervenes. It has not been determined whether such doses, either alone or combined with high-dose etoposide, will substantially alter the CR rate or the duration of survival in patients with extensive SCLC. Dose escalation of etoposide/platinum-based programs also has been attempted with the addition of hematopoietic CSFs. Liukart et al. [12] have recently reported a maximally tolerated dose (MTD) of etoposide (750 mg/m2) and carboplatin (375 mg/m2) administered over 3 days when combined with lo-20 &kg per day of granulocyte-macrophage (GM)-CSF. It is unlikely that further escalation of drug levels will be possible without the addition of autologous bone marrow or peripheral blood stem cell support. The addition of ifosfamide to etoposide/platinums
The preliminary results have been reported of two recent trials of extensive disease patients treated with ifosfamide added to full-dose etoposide/platinum regimens, with Smith et al. [ 131employing a single dose of carboplatin 400 mg/m2 and Miller et al. [4] using cisplatin 100 mg/m2 delivered over 5 days. The latter study reported a complete remission rate of 57% in 40 patients. Confirmation of results of this study, reported by the Hoosier Oncology Group, is currently under way in a randomised setting in which this regimen is being compared with etoposide/cisplatin. We have recently attempted to escalate the dose intensity of ifosfamide/carboplatin/etoposide (ICE) in combination with GM-CSF (5 pg/kg per day, days 4 through 11). In this study, the doses of ifosfamide and carboplatin were maintained at 5 g/m2 and 400 mg/m2, respectively, and etoposide was escalated to an MTD of 1200 mg/m2. Alternating combinations
During the 198Os, the concept of increasing therapeutic intensity by alternating noncross-resistant combination therapies was spurred by the mathematical model of drug resistance proposed by Goldie et al. [15] Numerous attempts at alternating treatment with existing drugs and drug combinations had been made by the early 198Os, at which time extensive analyses of the subject indicated that no consistent effect had been produced [ 16,171. In general, however, these alternating combinations did not include etoposide or etoposide combined with cisplatin. To put subsequent trials, which did include etoposide-based alternatives, into perspective, certain data need to be addressed. First, a series of trials initiated in the early 1980s was designed to assess the relative value of etoposide, either substituted for vincristine or doxorubicin in the prevalent CAV program or added to the CAV combination [ 18-201. In each of these trials, the addition of etoposide to front-line therapy yielded a 6- to 8-week
s3
TABLE 3 Extensive SCLC: alternating Regimen
CAV CAVIEP EP SEC. Southern
Overall
drug trials.
response
Median
CR (‘ih)
(Y0)
survival
(weeks)
NCIC
SEC
NCIC
SEC
NCIC
SEC
63 80
58 58 59
21 39
12 17 17
32 38
38 39 38
Oncology
Group;
EP, etoposide/cisplatin.
Adapted
from Evans et al. [24] and Roth et al. [25].
increase in the median survival of patients with extensive disease [18,19] or a comparable increase in the duration of response [20]. Second, it became clear that etoposide/cisplatin was active in patients who had failed therapy with CAV, yet the reverse did not appear to hold true. It is suggested that the best design for testing the role of etoposide/cisplatin would be a three-arm study comparing CAV with etoposide/cisplatin and with alternating these two regimens. Since 1984, eight major trials have evaluated alternating chemotherapy regimens that included etoposide in the alternating scheme [21-231. Seven studies have shown a statisticaly significant increase in median survival in extensive-disease patients, but this increase generally has been in the aforementioned 6- to g-week range. Each of these trials compared an etoposide-based alternation with a non-etoposide-containing control arm.
TABLE 4 Schedules during
weekly regimens. Weeks
1
2
3
4
5
6
7
8
9
Cisplatin
0 X
0
0 X
0
0 X
0
0
0 X
Etoposide
0 X
0 X + 0 X +
Vincristine
0
Doxorubicin
0 +
Ifosfamide Cyclophosphamide Methotrexateileucovorin 0 = Murray et al. [28] X = Miles et al. [29] + = Taylor et al. [27]
0 X +
; X + 0 +
0 +
0 X
+
0 +
0 +
X +
+
+
0 + 0
0
X
X
S32
The one study in which etoposide was included both in the control arm and in the alternating sequence yielded no significant difference in median survival. Thus, these studies may signal only that early use of etoposide provides small increment of cell kill that consistently produces the 6- to 8-week increase in median survival observed in these substitution studies. It was hoped that the addition of etoposide/cisplatin to the CAV-based therapeutic arsenal would provide a significant increase in activity. Evans et al. [24] reporting for the National Cancer Institute of Canada (NCIC), were the first to evaluate a fixed alternating schedule of CAV and etoposide/cisplatin, compared with a CAV control arm in patients with extensive disease. This study was followed by a three-arm randomised trial that also included an etoposide/cisplatin control arm 1251.The contrasting results of these two trials are presented in Table 3. Over 300 patients were randomised and evaluated in each study. The two-arm trial reported a statistically significant increase in both overall response and CR in favor of the alternating regimen. The approximately 6-week increase in median survival also was statistically significant. The three-arm study did not show a significant difference in any parameter. The survival times cited in Table 3 are well within those anticipated for the treatment of extensive disease patients, as noted in Table 1. In summary, alternating combinations of drugs has not led to any clinically significant advance in the therapy of extensive SCLC, although the results of several studies imply that etoposide or etoposide/cisplatin should be employed early in the course of therapy for extensive disease. Weekly dose-intense regimens
Another method of increasing dose intensity is to alter the time-dose relationship of the drugs delivered. This approach reportedly has been successful in the treatment of diffuse large cell lymphoma [26]. Klastersky et al. [5] reviewed the study data on SCLC as of 1989, and three of the studies assessed have since reached the publication stage [27-291. Common to each is the rapid sequencing of drugs over a 9- to 16-week period. A composite of the drug and scheduling parameters used in these studies is presented in Table 4 and eligibility and exclusion criteria are presented in Table 5. Two of the studies were performed in highly selected patients with extensive disease, with 52 and 29% of available extensive-disease patients participating in the studies by Murray et al. [28] and Miles et al. [29], respectively. Of note, approximately 20% of the patients in the trial represented
TABLE 5 Selection factors: exterpive disease. Reference
Age (years)
Taylor et al. [27] Murray et al. [28] Miles et al. [29]
< 66
Performance status (%) o-1 (84) 2-4 (17) o-2 o-1
Proximity
Other
Eligible (%)
< lh -
20% thoracic
52 (48/92) 29
s33
TABLE 6 Extensive SCLC: response
to weekly alternating
therapy
Reference
No. patients
Overall (%) response
CR (‘G/u)
Median survival (months)
Dose intensity achieved (X)
Taylor et al. [27] Murray et al. [28] Miles et al. [29]
76 48 25
81 94 92
38 40 48
II.4 I5 10.5
80 90 15
by Murray et al. [28] had intrathoracic disease. The study reported by Taylor et al. [27] for the Southwest Oncology Group (SWOG) was conducted with a less selected group of patients in a Phase II cooperative group setting. Results of the three trials are shown in Table 6. The CR rates ranged from 38 to 48%, and the median survival times reported were 10.5-15 months. The delivery of the planned dose intensity ranged from 75 to 90%. Of interest is the 20-25% 2-year survival projected in the studies by Murray et al. [28] and Miles et al. [29] The less selected group of patients treated in the SWOG study [27] did not attain this plateau in survival, although the survival characteristics of both the poor and good performance status groups in that study were favourable compared with historical data. A major drawback of this approach to therapy is that growth factor support is difficult to incorporate into rapidly sequenced drug programs because of the dictum that growth factors and chemotherapy should not be administered concomitantly. However, a randomized study reported by Masuda et al. [30] questions this issue. Although final results of the trial have not been reported, preliminary data comparing patients randomised to CODE (cyclophosphamide/vincristine/doxorubicin/etoposide) chemotherapy, as used by Murray et al. [28] with or without GM-CSF indicate that with supportive therapy the dose intensity delivered can be increased and hematologic toxicity decreased despite administration of concomitant and continuous GM-CSF. The potential advantages of weekly intensive therapy relate to the finite duration of treatment and the hint of greater efficacy with this approach. The former point is supported by studies showing that protracted maintenance therapy is of little benefit in the setting of extensive SCLC. All told, the preliminary data on weekly intensive therapy demand evaluation in properly designed randomised settings. Such studies are now under way in Europe, Canada, and the United States.
New Directions in Scheduling and Evaluation Etoposide
Over 20 years ago, Cavalli et al. [31] were the first to show that etoposide, administered by either-the intravenous (IV) or oral route, was active against SCLC and that the benefit provided might be schedule dependent. Since then, multiple-day dosing schedules have
s34
been implicitly employed, although it is only recently that the schedule dependency of etoposide activity has been proven in a randomized controlled trial. As reported by Slevin et al. [32] 39 previously untreated patients with extensive SCLC were randomized to treatment with the same total dose of etoposide (500 mg/m2 i.v.), given either as a single 24hour infusion or in lOO-mg/m2 doses for 5 days. The objective response rates were 10% in the single-day and 84% in the 5-day arm, with a 4.5-month median duration of response in the patients treated over 5 days. Interestingly, crossover to CAV occurred in about half of the patients in each arm, yielding a comparable number of partial responders. The overall median survival was 10 vs. 6.3 months, favoring those who were treated initially with the daily x 5 dosage regimen. Subsequent studies by the same group of investigators [33] have extended these observations and attempted both to increase the duration of daily administration to 8 days and to evaluate the potential pharmacologic differences that might explain the scheduledependent effect of etoposide. As expected, peak drug levels were higher with the shorter administration schemes. Aside from this observation, the only statistically significant difference in pharmacokinetics was the area under the curve for low concentrations obtained in the 5-day schedule (> 1 to < 5 j&ml per h), which implies that continuous exposure to low concentrations is more important than peak levels. In addition, it can be seen in this series of trials that a moderate increase in the duration of therapy from 5 to 8 days did not significantly alter objective response rates. Formulation problems complicate further protraction of the schedule of daily i.v. administration. Low-dose protracted
therapy
Hainsworth et al. [34] were the first to report a Phase I study of protracted low-dose oral etoposide therapy. The MTD was shown to be 50 mg/m2 per day x 21 days, with transient myelotoxicity as the dose-limiting factor. Activity was documented against a variety of refractory tumors. Subsequently, Johnson et al. [35] reported a formal Phase II trial in which this dose of etoposide was administered to 22 evaluable patients with refractory SCLC, for an overall response rate of 45% and a CR rate of 9%. In contrast, a response rate of approximately 12% was reported previously when conventional etoposide doses were used in patients with refractory SCLC [36]. Certain critical features were correlated with response in this trial and included response to previous chemotherapy and duration of time from previous treatment. Objective response, for example, was significantly higher when the time since previous therapy was greater than (64%) compared with less than (12.5%) 90 days. Myriad clinical questions arise from these observations: what is the maximal and optimal duration of therapy? What is the optimal dose of administration? Can effective protracted administration be integrated effectively into combination programs? Is protracted therapy truly superior to more conventional dosing approaches? It is hoped protracted administration represents a new facet of one of the stalwarts of the chemotherapeutic armamentarium. The next several years will undoubtedly emphasize the issues raised by these observations. Other drugs
Agents shown to be active against previously untreated extensive SCLC are listed in Table 7. Although these drugs are substantially active as single agents, reported CR rates
s35
TABLE 7 SCLC: contemporary
single-agent
studies -
drugs with > 50% response
Drug
No. patients
Overall response (% CR)
Etoposide Teniposide Carboplatin Ifosfamide
138 101 101 217
79 88 55 54
Epirubicin
176
51 (8)
(IO) (23) (II) -
are somewhat less than might be achieved with combination regimens. Also of note, these agents are generally analogues of existing drugs that are known to be active against SCLC, and prior exposure to chemotherapy reduces their level of activity to the lo-20% range [37]. Given that the parent compounds are active, the question remains whether the newer agents provide greater efficacy or a greater potential for response when used in combination programs. The answer appears to be nugatory. Bork et al. [38] have directly compared etoposide with teniposide in a randomized controlled fashion in previously untreated patients with limited or extensive SCLC. No difference in objective response, CR, or survival in either group was discerned. The survival of the 26 patients with extensive disease, randomised equally to either etoposide or teniposide, was 8.5 and 11.3 months, respectively. The sample size precludes any comment relative to the absolute difference reported in survival. Table 8 presents the extant data on extensive-disease patients treated with etoposide/carboplatin, two of the most active agents available to treat SCLC [39-441. None of the studies indicates a substantial increment in efficacy when these agents are combined. On the other hand, the expected decrease in nonhematologic side effects was apparent. What is the biologic meaning of such data? It appears that the ‘sensitive’ cell population in extensive SCLC is collaterally sensitive to a variety of drugs including the epipodophyl-
TABLE 8 Extensive SCLC: carboplatinietoposide. Reference
Total dose (mgim*)
No. evaluable
Overall response (%)
CR (Vi)
13 9 16 15 14 22
Etoposide
Carboplatin
Smith et al. [39]
300
300
24
88
Bishop et al. [40] Evans et al. [41] Liukart et al.” [42] Eberhardt et aLb [43] Evans et akc [44]
300 300 600 420 700
360 300 375 300 150
55 32 13 36 25
58 56 53 61 72
“With GM-CSF. bWith vincristine ‘Oral etoposide.
days 1, 8, 15 and 22
Median survival (months) 9.5 8.3 8.1 11
S36
lotoxins, platinums, alkylating agents, and certain anthracyclines. If each class of agent selected out a uniquely sensitive population of cells, one would anticipate at least an additive effect, which clearly has not been observed. This suggests a core of resistant cells that, in their unperturbed state, are insensitive to the available agents. A more fruitful area of investigation, therefore, would be to evaluate unique compounds. Such studies are under way.
Evaluation of New Compounds Several compounds of unique structure have been evaluated against SCLC and shown to be inactive. The list includes amonafide, menogaril, idarubicin, mitoxantrone, and sulofenur. Interestingly, this group includes DNA active agents considered a priori to be potentially active. A major milestone was the trial design established by the Eastern Cooperative Oncology Group (ECOG) to evaluate a new agent yet protect the patient from a potentially adverse effect on palliation and survival. In this study patients were randomly allocated to treatment with CAV or menogaril. On progression or after two cycles without response to menogaril, patients were immediately crossed over to etoposide/cisplatin. Ettinger et al. [45] have reported the preliminary results of this trial. Fortuitously, although menogaril turned out to be inactive against extensive SCLC (response rate, 5O), there was no significant difference in median survival for the two groups of patients (41.7 weeks for CAV vs. 38.3 weeks for the inactive compound). Thus, with an appropriate study design, new agents can be evaluated safely in patients with extensive disease. New agents with activity The camptothecin derivative CPT-11 and taxol, two agents with unique mechanisms of action, have been reported to be active against SCLC. The former compound inhibits topoisomerase I. Negoro et al. [46] have recently reported on 41 patients treated with CPT-11 100 mg/m’ delivered over 90 min. Overall, 13 of 35 (37%) patients responded, including 33% who had received prior therapy and 50% who had not. Further studies of this compound, and other camptothecin analogues such as hycamptomine, should be a top priority. Preliminary taxol data are available from the ECOG. To date, objective response has been attained in 8 of 18 (44%) subjects with previously untreated extensive disease (D.C. Ettinger, M.D., October 1991, personal communication). Further studies with this agent are under way. Whether these agents induce response in the same responsive pool of cells affected by other, currently available agents against SCLC or whether they may provide the first approach in decades with activity against a previously unassaulted cell population remains to be determined.
Conclusions Tremendous effort has been directed to the therapy of extensive SCLC over the last two decades. The halcyon days occurred in the late 1970s and early 198Os, during which a
s37
previously unprecedented degree of responsiveness was found in this clinical setting. Since then, however, there has been little therapeutic advance. Although the integration of etoposidekisplatin into limited-disease treatment strategies appears to have provided an incremental, reproducible advantage, such has not occurred in the extensive-disease setting. Once SCLC becomes metastatic, as with many other malignancies, the cure boundary with existing programs is eclipsed. With existing drugs, extensive SCLC is a chemoresponsive but chemoincurable disease. The development of truly new agents, with different mechanisms of action from those available currently, must be a top priority. Combined with this effort, the realization that extensive SCLC is a chemoresistant disease demands that strategies to avert or circumvent drug resistance should be immediately directed to this setting. Additionally, further exploration of the role of biologic tools, such as the interferons, interleukin-2, monoclonal antibodies, and anti-growth factor strategies, should be pursued aggressively in the hope that future patients may be treated with more than palliative intent.
References 1 Green RA, Humphrey E, Close H, Patno ME. Alkylating agents in bronchogenic carcinoma. Am J Med 1969; 46: 516-525. 2 Bunn PA, Cohen MH, Ihde DC, Fossieck BE, Mathews J, Minna JD. Advances in small cell bronchogenic carcinoma. Cancer Treat Rep 1977; 61: 333-342. 3 Klasa RJ, Murray N, Coldman AJ. Dose-intensity meta-analysis of chemotherapy regimens in small cell carcinoma of the lung. J Clin Oncol 1991; 9: 499-508. 4 Cohen MH, Creaven PJ, Fossieck BE, Broder LE, Selawry OS, Johnston AV, Williams CL, Minna JD. Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 1977; 61: 349-354. 5 Klastersky JA, Scullier JP. Intensive chemotherapy of small cell lung cancer. Lung Cancer 1989; 5: 196-206. 6 Souhami RL, Harper PG, Linch D, Trask C, Goldstone AH, Tobias J, Spiro SG, Geddes DM, Richards JDM. High-dose cyclophosphamide with autologous bone marrow transplantation as initial treatment of small cell carcinoma of the lung. Cancer Chemother Pharmacol 1982; 8: 31-34. 7 Ihde DC, Mulshine JL, Kramer BS, Steinberg SM, Edison M, Phelps R, Lesar M, Phares JC, Minna JD, Johnson BE. Randomized trial of high versus standard dose etoposide (VP-16) and cisplatin in extensive stage small cell lung cancer (SCLC) [abstract 8191. Proc Am Sot Clin Oncol 1991; 10: 240. 8 Wolff SN. High dose etoposide as a single agent chemotherapy for small cell carcinoma of the lung. Cancer Treat Rep 1983; 67: 957-958. Johnson DH, Wolff SN, Hainsworth JD, Porter LL, Grosh WW, Hande KR, Greco FA. Extensive stage small cell bronchogenic carcinoma: intensive induction chemotherapy with high-dose etoposide. J Clin Oncol 1985; 3: 170-175. Johnson DH, DeLer MJ, Kande KR, Wolff SN, Hainsworth JD, Greco FA. High-dose induction chemotherapy with cyclophosphamide, etoposide, and cisplatin for extensive stage small cell lung cancer. J Clin Oncol 1987; 5: 703-709. Shea TC, Flaherty M, Elias A, Eder JP, Antman K, Begg L, Schnipper L, Frei E, Henner WD. A phase I clinical and pharmacokinetic study of carboplatin and autologous bone marrow support. J Clin Oncol 1989; 7: 651-661. Liukart SD, MacDonald M, Huezan D, Modeas C, Perry MC, Green MR. Ability of daily or twice daily granulocyte-macrophage colony-stimulating factor (GM-CSF) to support dose escalation of etoposide (VP16) and carboplatin (CBDCA) in extensive small cell lung cancer (SCLC) [abstract A825]. Proc Am Sot Clin Oncol 1991; 10: 242. Smith IE, Perren TJ, Ashley SA, Woodiwiss J, Forgeson GV, Yarnold JR, Ford HT. Carboplatin,
S38
14
15
16 17
18
19 20 21 22
23
24 25
26 27
28 29 30
31
32 33
etoposide, and ifosfamide as intensive chemotherapy for small cell lung cancer. J Clin Oncol 1990; 8: 899-905. Miller JC, Loehrer PJ, Songer J, Pennington K, Ansari R, Turner S, Einhorn LH. VP-16, ifosfamide, and cisplatin (VIP) in extensive small cell lung cancer (SCLC). A Hoosier Oncology Group Study [abstract A962]. Proc Am Sot Clin Oncol 1990; 9: 248. Goldie JH, Coldman JA, Gudauskas GA. Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat Rep 1982; 66: 439-449. Elliot JA, Osterlind K, Hansen HH. Cyclic alternating non-cross-resistant chemotherapy in the management of small cell anaplastic carcinoma of the lung. Cancer Treat Rev 1984; 11: 103-l 13. Aisner J, Albert0 P, Bitran J, Comis R, Daniels J, Hansen H, Ikegami H, Smyth J. Role of chemotherapy in small cell lung cancer: a consensus report of the International Association for the Study of Lung Cancer workshop. Cancer Treat Rep 1983; 67: 37-43. Hong WK, Nicaise C, Lauson R, Maroun JA, Comis RL, Speer J, Luedke D, Rozencweig M. Etoposide combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high dose cyclophosphamide plus vincristine in the treatment of small cell carcinoma of the lung: randomised trial of the Bristol Lung Cancer Study Group. J Clin Oncol 1989; 7: 450-456. Bunn PA Jr, Greco FA, Einhorn L. Cyclophosphamide, doxorubicin, and etoposide as first-line therapy in the treatment of small-cell lung cancer. Semin Oncol 1986; 13(3): 63-74. Jackson DV, Case LD, Zekan PJ, Powell BL, Capizzi RL. Improvement of long-term survival in extensive small cell lung cancer. J Chn Oncol 1988; 6: 1161-1169. Osterlind K. Alternating or sequential chemotherapy in small cell lung cancer? Lung Cancer 1989; 5: 173-177. Ettinger DS, Finkelstein DM, Abeloff MD, Ruckdeschel JC, Aisner SC, Eggleston JC. A randomised comparison of standard chemotherapy versus alternating chemotherapy and maintenance versus no maintenance therapy for extensive stage small cell lung cancer: a phase III study of the Eastern Cooperative Oncology Group. J Clin Oncol 1990; 8: 230-240. Wampler GL, Heim WJ, Ellison NM, Ahlgren JD, Fryer JG. Comparison of cyclophosphamide, doxorubicin, and vincristine with an alternating regimen of methotrexate, etoposide, and cisplatin/cyclophosphamide, doxorubicin, and vincristine in the treatment of extensive-disease small-cell lung carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol 1991; 9: 1438-1445. Evans WK, Feld R, Murray N, Willan A, Coy P. Superiority of alternating non-cross-resistant chemotherapy in extensive small cell lung cancer. Ann Intern Med 1987; 107: 451-458. Roth BJ, Johnson DH, Greco FA, Einhorn LH, Goodlow JL, Cheung N, Randolph JA, Schacter LP. A phase III trial of etoposide (E) and cisplatin (P) versus cyclophosphamide (C), doxorubicin (A), and vincristine (V), versus alternation of the two therapies for patients (pts) with extensive small cell lung cancer (SCLC): preliminary results [abstract 8751. Proc Am Sot Clin Oncol 1989; 8: 225. Klimo P, Connors JM. MACOP-B chemotherapy for the treatment of diffuse large cell lymphoma. Ann Intern Med 1985; 102: 596-602. Taylor CW, Crowley J, Williamson SK, Miller TP, Livingston RB. Treatment of small cell lung cancer with an alternating chemotherapy regimen given at weekly intervals: a Southwest Oncology Group Pilot Study. J Clin Oncol 1990; 8: 1811-1817. Murray N, Shah A, Osoba D, Page R, Voss N. Intensive weekly chemotherapy for the treatment of extensive stage small cell lung cancer. J Clin Oncol 1991; 9: 1632-1638. Miles DW, Earl HM, Souhami RL, Harper PG, Rudd R, Ash CM, Sprio SG. Intensive weekly chemotherapy for good prognosis patients with small cell lung cancer. J Chn Oncol 1991; 9: 280-285. Masuda N, Fukuoka M, Negoro N, Takada M, Nakagaura K, Kodama N, Kawahara M, Furuse K. CODE chemotherapy with or without recombinant human granulocyte colony-stimulating factor (rhG-CSF) in extensive stage (ES) small cell lung cancer (SCLC) [abstract 8731. Proc Am Sot Clin Oncol 1991; 10: 254. Cavalli F, Sonntag RW, Jungi F, Senn HJ, Brunner KW. VP16-213 monotherapy for remission induction of small cell lung cancer: a randomised trial using three dosage schedules. Cancer Treat Rep 1978; 62: 473-475. Slevin ML, Clark PI, Joel SP, Malik S, Osborne RJ, Wrigley PFM. A randomised trial to evaluate the effect of schedule on the activity of etoposide in small cell lung cancer. J Clin Oncol 1989; 7: 1333-1340. Clark PI, Joel SP, Slevin ML. A pharmacokinetic hypothesis for the clinical efficacy of etoposide in small cell lung cancer [abstract A257]. Proc Am Sot Clin Oncol 1989; 8: 66.
s39
34 35
36 31 38 39 40
41 42
43
44 45
46
Hainsworth DJ, Johnson DH, Frazier SR, Greco FA. Chronic daily administration of oral etoposide a phase I trial. J Clin Oncol 1989; 7: 396-401. Johnson DH, Greco FA, Strupp J, Hande KR, Hainsworth JD. Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: a phase II trial. J Clin Oncol 1990; 8: 1613-1617. Issell BF, Einhorn LH, Comis RL, Lawson RD, Baker LH, Rosenbaum PF. Multicenter phase II trial of etoposide in refractory small cell lung cancer. Cancer Treat Rep 1985; 69: 127-131. Johnson DH. New drugs in the management of small cell lung cancer. Lung Cancer 1989; 5: 221-231. Bork E, Ersboll P, Dombernowsky B, Bergman B, Hansen M, Hansen HH. Teniposide and etoposide in previously untreated small cell lung cancer: a randomised study. J Clin Oncol 1991; 9: 1627- 1631. Smith IE, Evans BD. Carboplatin as a single agent and in combination in the treatment of small cell lung cancer. Cancer Treat Rev 1985; 12 Suppl A: 73-75. Bishop JF, Raghavan D, Stuart-Harris R, Morstyn G, Aroney R, Kefford R, Yuen K, Lee J, Giantousos P, Olver IN, Zalcberg J, Ball D, Bull C, Fox R. Carboplatin and VP-16-213 in previously untreated patients with small cell lung cancer. J Clin Oncol 1987; 5: 1574-1578. Evans WK, Eisenhauer E, Hughes P, Maroun JA, Ayoob J, Shepherd FA, Feld R. VP-16 and carboplatin for previously untreated extensive small cell lung cancer [abstract]. Lung Cancer 1988; 4 Suppl: Al04 Luikart SD, Mitchell EP, Van Echo DA, Propert K, Modeas C, Perry MC, Green M, for the Cancer and Leukemia Group B. Phase I/II trial of etoposide (VP-16) and carboplatin (CBDCA) in untreated extensive small cell lung cancer (SCLC) [abstract 7541. Proc Am Sot Clin Oncol 1988; 7: 195. Eberhardt W, Ochel HJ, Grabke I, Moritz T, Achterrath W, Konietzko N, Niederle N. Carboplatin, etoposide, vincristine (CEV) plus/minus CM-CSF in the treatment of small cell lung cancer (SCLC): a phase II study [abstract A947]. Proc Am Sot Clin Oncol 1990; 9: 245. Evans WK, Stewart DJ, Marion J, Logan D, Martins H, Tomiak E, Dahrough S. Oral VP-I 6 and carboplatin for small cell lung cancer [abstract A847]. Proc Am Sot Clin Oncol 1991; 10: 247. Ettinger DS, Finkelstein DM, Abeloff MD, Bonomi P. Justification for evaluating new anticancer drugs in selected untreated patients with a chemotherapy-sensitive advanced cancer: an ECOG randomised study [abstract A864]. Proc Am Sot Clin Oncol 1990; 9: 224. Negoro S, Fukuoka M, Niitani H, Taguchi T. Phase II study of CPT-11, new camptothecin derivative, in small cell lung cancer (SCLC) [abstract 8221. Proc Am Sot Clin Oncol 1991; IO: 241.