Update on the treatment of small cell lung cancer (SCLC)

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1 Update on the treatment of small cell lung cancer (SCLC) Andrea Ardizzoni a and Francesco Grossi b 1 Istituto Nazionale per la Ricerca sul Cancro, Oncologia Medica I, Geneva, Italy b University of Udine, Clinica Oncologica, Udine, Italy First line treatment Chemotherapy represents a standard first line treatment option in virtually all patients with SCLC regardless of disease extent, performance status and age. Thoracic radiotherapy (TRT) and prophylactic cranial irradiation (PCI) are a valuable addition in selected patients. In rare circumstances, up-front surgery may still play a role in the management of patients with very limited disease such as those with mediastinoscopically proven stage I II. Chemotherapy Combination chemotherapy is the cornerstone of SCLC treatment. With the use of current chemotherapy regimens, survival outcome of SCLC patients has improved 4-5-fold compared with patients who are given no therapy. Combination chemotherapy is superior to single agent therapy in terms of both survival and symptom palliation, even in patients with advanced disease, poor performance status and old age as demonstrated by two British randomised studies [1,2]. Standard chemotherapy regimens Chemotherapy regimens most widely used for first line treatment of SCLC include: cisplatin/carboplatin and etoposide (PE), cyclophosphamide, doxorubicin and vincristine (CAST), cyclophosphamide, doxorubicin, and etoposide (CAE), ifosfamide, carboplatin and etoposide (ICE) (Table 1). Survival outcomes with all these regimens appear similar. Regimens including three or more drugs do not seem to offer any advantage as compared to standard doublets. However, in only one randomised study, a three-drug regimen including cisplatin, ifosfamide and etoposide was found superior to the cisplatin-etoposide doublet [3] and preliminary results of a French study would also indicate superiority of a four-drug regimen including cisplatin, etoposide, cyclophosphamide and epidoxorubicin over the standard doublet. A Medical Table 1 Most commonly employed chemotherapy regimens PE Cisplatin mg/m 2 or Carboplatin AUC 6 dl Etoposide mg/m 2 dl-3 CAE Cyclophosphamide 1000 mg/m 2 dl Doxorubicin mg/m 2 dl Etoposide mg/m 2 dl-3 CAV Cyclophosphamide 1000 mg/m 2 dl Doxorubicin mg/m 2 dl Vincristine 2 mg dl ICE Ifosfamide 5 g/m 2 dl Carboplatin mg/m 2 dl Etoposide mg/m 2 dl-3 Research Council (MRC) British study testing the possible superiority of a four-drug regimen with midcycle vincristine (VICE) over standard chemotherapy is still underway. New drugs Among new drugs with activity in SCLC, the most promising are taxanes, camptothecins and gemcitabine (Table 2). Paclitaxel, as a single agent, has been evaluated in two phase II studies involving a total of 71 previously untreated patients with extensive-stage small cell lung cancer (ED-SCLC). Response rates were reported to be 34 and 41%, respectively [4,5]. Two studies have explored the activity of docetaxel in previously untreated patients; results were contradictory with only one partial response among 12 evaluable patients in one study [6] and 12 out of 46 partial responses in the other [7]. CPT-11 was evaluated as a first line treatment in only 8 patients with a response rate of 50% [8]. In one phase II study of single agent topotecan, previously untreated patients with extensive disease were reported to have a response rate of 39% [9]. Gemcitabine was tested in only one trial in previously untreated patients resulting in a 27% response rate [10]. 101

2 102 A. Ardizzoni and F. Grossi Table 2 New chemotherapeutic agents for the treatment of SCLC Authors), reference Smit [72] Ettinger [4], Jett [5] Smyth [74] Latreille [6], Bums [7] Le Chevalier [8], De Vore [64], Masuda [63], Negoro [62] Le Chevalier [8] Ardizzoni [65], Eckardt [66], Depierre [67], von Pawel [70], Perez-Soler [68], Schiller [9] Van der Lee [77] Cormier [10] Drug Paclitaxel Paclitaxel Docetaxel Docetaxel CPT-11 CPT-11 Topotecan Topotecan Gemcitabine Gemcitabine Furuse [76], Jassem [75] Vinorelbine Fokkemafll] Oral Platinum (JM216) Previous CT RR(%) ^ ^* Recently, an oral formulation of cisplatin (JM216) has been tested in patients considered unfit for intensive combination chemotherapy with a response rate of 38% and mild toxicity [11]. The future of these new active agents in the treatment of SCLC is their incorporation into combination chemotherapy regimens for first line therapy. A number of new combination chemotherapy regimens are presently under evaluation, including regimens which incorporate old and new drugs or new agents only. Preliminary results of some of these regimens are promising [12-15]. Whether these new regimens would represent a step forward for the first line treatment of SCLC is still subject of intensive investigation. Preliminary results of three randomised studies, presented at the ASCO 2000 Meeting, assessing the possible added value of paclitaxel in first line chemotherapy regimens, are still inconclusive. A Dutch study is randomising patients with extensive disease between ACE and carboplatin-paclitaxel while another European cooperative group is running a prospective randomised study comparing cisplatinetoposide versus a regimen of paclitaxel-topotecan. Finally, the preliminary results of a Japanese randomised trial, presented at the ASCO 2000 Meeting, would suggest superiority of a regimen of cisplatin- CPT-11 as compared to standard PE chemotherapy. Chemotherapy dose intensity Given the high response rates seen in SCLC with conventional chemotherapy, the use of more intensive 38 chemotherapy treatments to overcome drug resistance has been intensively studied. However, the contribution of chemotherapy dose size or dose intensity to response and survival remains still controversial. A meta-analysis has evaluated the effect of dose intensity on response and survival in limited and extensivestage patients [16]. This retrospective study showed that increasing the planned dose intensity of CAE, but not of other regimens, improved survival. Dose intensity can be increased either by increasing dose size or by shortening the interval between doses, and the effects of these two different approaches may not be the same. Two prospective randomised studies assessing the role of dose size increase of PE and CAV led to negative results [17,18]. On the contrary, another French study in which dose size at the first cycle was only moderately increased showed an improved outcome [19]. Recently, the MRC has published the results of a randomised trial comparing six cycles of CAE at conventional 3-week interval to the same regimen plus G-CSF at 2-week interval (chemotherapy acceleration). The results of this study demonstrate that increasing the dose intensity of CAE with G-CSF support improved survival while maintaining acceptable toxicity [20]. An important feature of this trial is that among the three variables of cytotoxic drug delivery (individual dose size, interval between dose cycles and total dose) only one differed between the regimens, i.e., the interval between cycles. The results of this study are in keeping with that of another British study of chemotherapy acceleration [21]. On the contrary, a Canadian trial addressing a similar concept with cisplatin, vincristine, doxorubicin and etoposide (CODE) weekly regimen could not show any benefit over standard 3-weekly CAV/PE chemotherapy [22]. A recently completed EORTC study [23] has assessed the role of doubling CAE chemotherapy dose intensity by either dose size increase and chemotherapy acceleration. Final results of this study should shed further light on this controversial area of research. Radiotherapy SCLC is highly sensitive to radiotherapy and both thoracic and cranial irradiation have a crucial role in the multidisciplinary treatment of limited disease. Thoracic irradiation Two meta-analysis have indicated a small but statistically significant improvement of survival in patients treated with thoracic radiotherapy in addition to chemotherapy [24,25]. At the present time, combined chemotherapy and TRT represent a standard practice for most patients with SCLC limited to one

3 Update on the treatment of small cell lung cancer (SCLC) 103 Table 3 Randomised studies of early (E) versus late (L) thoracic irradiation (RT) in SCLC Author, reference Pts RT start RT dose 2-Year S. (%) Perry [30,31] 270 EweekO 50 Gy 23 L week 9 30 Murray [26] 308 E week 3 40 Gy 40* L week Work [29] 199 EweekO 45 Gy 20 L week Jeremic[27] 103 EweekO 54 Gy 34* L week 6 BID 26 Goto [28] 228 EweekO 45 Gy 55* L week 9 35 * Statistically significant difference. hemithorax. However, many aspects of TRT delivery remain less than adequately defined. For example, the optimal timing of TRT is still subject for debate. The meta-analysis could not identify any significant difference between early and late TRT. There have been only few randomised trials that prospectively addressed the importance of TRT timing with conflicting results (Table 3), some studies showing a benefit of early radiation [26-28] while others showing no difference [29-31]. Overall, these randomised studies along with a number of phase II trials consistently reporting 40 to 50% 2-year survival rates [32-34] seem to suggest that early TRT administered concurrently with PE might be the optimal treatment. At the present time there is a dichotomy in standard practice between USA, where PE with concurrent TRT is standard practice for limited disease small cell lung cancer (LD-SCLC), and Europe, where CAE or PE followed by TRT is still broadly used. Since concurrent chemoradiation is more toxic and less practical compared to the sequential approach, further studies are needed to confirm its superiority and make it standard practice worldwide. The other most important issues relate to the optimal dose and fractionation. Doses between 40 and 50 Gy in fractions of conventional fractionation TRT are most widely employed either concurrently or sequentially with chemotherapy. In a phase I study the MTD of hyperfractioned-accelerated twice daily TRT was determined to be 45 Gy in 30 fractions over 3 weeks, while it was judged to be at least 70 Gy in 35 fractions over 7 weeks for daily radiotherapy [35]. The ECOG/RTOG recently published a comparison of 45-Gy chest radiotherapy given daily over 5 weeks with that given twice daily over 3 weeks, both with concurrent PE chemotherapy, which showed an improvement in survival in favour of twice daily radiotherapy [36]. In a similar study, Bonner et al. [37] could not demonstrate any benefit with bifiractionation when thoracic irradiation was delayed until the fourth cycle of chemotherapy. Since twice-daily TRT is more toxic and allow a lower total dose to be administered compared to once-daily irradiation, further studies are planned to ascertain its role in the management of LD-SCLC. Prophylactic cranial irradiation Although only 10% of patients present with brain metastasis at the time of diagnosis, the cumulative incidence at two years is more than 50%, which is consistent with the rate found in autopsies series. In the early 1970s, the brain was assumed to be a pharmacological sanctuary where subclinical metastases were protected from cytotoxic drugs by the blood-brain barrier, and it was suggested that cranial irradiation might prevent the development of clinically evident brain metastases. These hypotheses led to several clinical trials which evaluated the role of PCI in patients with SCLC. Recently the Prophylactic Cranial Irradiation Overview Collaborative Group published the results of a meta-analysis of seven trials that compared PCI versus no PCI with the conclusion that PCI improves both overall survival and disease-free survival in patients with SCLC in complete remission [38]. PCI should now be considered as a part of the standard treatment in complete remission patients with LD-SCLC. The optimal radiation dose has not been determined; the most commonly used regimens in clinical practice range from 24 Gy, in eight fractions, to 30 Gy in 10 fractions. Aim of future clinical trials should be the establishment of the optimal dose and timing of treatment in order to further reduce the incidence of brain metastases with acceptable toxicity. A European Intergroup study (EULEN) has been recently launched to compare two different doses and schedules of PCI. Eradicating minimal residual disease Although frequent, responses to chemotherapy and radiation in SCLC are generally short-lasting. Developing strategies to maintain response after induction chemotherapy or chemo-radiotherapy has been therefore a major research focus. There are different strategies to achieve this goal such as maintenance chemotherapy, high dose chemotherapy and non-chemotherapeutic approaches including antimetastatic agents, drugs interfering with angiogenesis and manipulation of the host immune system.

4 104 A. Ardizzoni and F. Gmssi Table 4 Randomised trials evaluating the role of maintenance chemotherapy Author, ref. Induction regimen Maintenance regimen Pts PFS Survival Maurer [39] Cullen [40] Bleehen [41] Spiro [42] Byrne [44] Ettinger [45] Lebeau [46] Giaccone [47] Bleehen [48] Sculier [43] Sandier [49] CTX or CTX-MTX-VCR CTX-ADR-VCR VP-16-CTX-MTX-VCR CTX-VCR-VP-16 CDDP-VP-16/CTX-VCR-MTX CTX-ADR-VCR±HMM-VP-16-MTX CCNU-CTX-ADR-VP-16 ADR-VP-16-CTX VP-16-CTX-MTX-VCR IFO-VP-16-ADR or epirubicin VP-16-IFO-CDDP CTX-VCR-MTX VP-16-VDS VP-16 oral ?? S S 7 S SN Maintenance chemotherapy Maintenance chemotherapy is a controversial topic. Since 1980, 11 randomised trials addressing this issue have been published (Table 4). Although in the majority of studies a prolonged progression free survival was found with maintenance, only five reported some survival advantage in subgroups of patients [39-43], one [44] showed a significant shorter survival with maintenance and, in five studies [45-49], there was no difference between the two arms. The interpretation of these results is difficult because of several important methodological problems in the design of such studies. Consolidation non-cross resistant chemotherapy This strategy, which entails the administration of 2 or more cycles of a non-cross resistant regimen at the end of induction chemotherapy, has been evaluated in several studies [50-52]. In one of these, the survival of LD-SCLC patients treated with CAV (with or without thoracic radiotherapy) was improved with two cycles of PE consolidation therapy [50]. Whether this benefit is due to the consolidation strategy or simply to the fact that PE adds activity to CAV is still matter of discussion. The ECOG group has recently disclosed the results of a large randomised study assessing the role of topotecan chemotherapy consolidation after standard PE chemotherapy which indicate an impact of consolidation on the time to progression but not on survival. Late intensification with high-dose chemotherapy As with other tumour types, such as lymphoma, myeloma, breast cancer, and nonseminomatous germ cell neoplasms, high dose chemotherapy has been used to overcome drug resistance and eradicate minimal residual disease. At least 36 studies have examined high-dose chemotherapy with autologous bone marrow or stem cell rescue in SCLC [53]. Among the studies in which high dose chemotherapy has been used as consolidation treatment, only one compared this novel approach to standard treatment in a randomised fashion [54]. Although median relapsefree survival improved from 10 to 28 weeks with high dose therapy, the median overall survival was not statistically improved. In addition, only a small fraction of patients could complete the high dose chemotherapy program and treatment-related mortality was significant. More recently, a regimen of multiple sequential courses of high-dose chemotherapy and peripheral-blood progenitor cells has been administered in a feasibility study by the European Bone Marrow Transplant (EBMT) group. The authors underline that this regimen is safe because 72% of all patients completed the treatment program and they conclude that the high rate of toxic death (9%) was within the range of other intensification regimen [55]. This pilot study served as background for an ongoing randomised EBMT study in which 6 courses of standard dose ICE chemotherapy are being compared with 2 courses of paclitaxel-epirubicin followed by 3 courses of high dose ICE with peripheral stem cell transplant. n-chemotherapeutic approaches Inhibitors of angiogenesis and of matrix metalloproteinases are among the most promising new agents to be tested as maintenance therapy in SCLC. Matrix metalloproteinase (MMP) are extracellular enzymes responsible for degradation of extracellular matrix involved in tumour progression and metastatic process. A series of agents which are able to inhibit MMP, such as the oral compound marimastat, are now available for investigation. Unpublished studies

5 Update on the treatment of small cell lung cancer (SCLC) 105 have shown activity of this class of compounds also in SCLC xenografts. Since this type of agents are not believed to produce an objective tumour shrinkage, randomised studies with survival as primary endpoint are needed to verify their role in the treatment of cancer. One of these randomised double-blind phase HI studies has been started in SCLC. The EORTC and NCIC are randomising SCLC patients in response after standard induction chemotherapy to marimastat 10 mg cps PO BID until progression or to placebo. More than 400 patients are expected to enter this important study which will probably clarify the potential role of this new class of agents in the treatment of SCLC. A number of immunotherapies have been attempted in SCLC particularly in patients with minimal residual disease. The drugs most extensively studied have been alpha and gamma interferon which, however, have not been found able to significantly prolong survival of SCLC patients in remission after first line therapy [51,56,57]. Among new immunological approaches, vaccination appears as one of the most promising. The objective is to sensitise patients to recognise an aspect of the tumour cell as foreign. Ganglioside GD3 expressed in all SCLC tumour samples tested is one potential target. Using an anti-idiotypic mouse mab (BEC-2), which mimics the structure of the SCLC-associated GD3 ganglioside, a pilot study was performed. Fifteen patients with SCLC who had a major response to induction chemotherapy were vaccinated with 5 injections of 2.5 mg BEC-2+ BCG (as an adjuvant). Of 6 evaluable patients all developed anti-bec-2 antibodies and 1 anti-gd3 antibodies also. Median overall survival was 21 months. These results demonstrated a significant improvement with respect to an historical control group receiving standard treatment [58]. These results have provided the rationale for designing a randomised prospective EORTC study, where patients with LD-SCLC are randomised to receive or not BEC-2 vaccination as maintenance therapy after standard induction treatment. Second line treatment The prognosis for patients submitted to second-line therapy after relapse is poor. The probability of response is influenced by the time to progression after cessation of first-line therapy. Patients who relapse less than three months after first-line therapy are commonly termed 'refractory' and have response rates that are lower than those of patients who relapse more than 3 months after the completion of first-line treatment, who are termed 'sensitive' [59]. There is no standard second-line therapy for SCLC. CAV is often used after first-line treatment based on PE. In two studies that included sensitive and refractory patients, CAV produced second-line response rates of 13% and 28% [60,61]. Camptothecin analogues offer a promising new treatment option for SCLC. CPT-11 was evaluated in four phase H studies with the majority of patients being previously treated; the response rates ranged from 16 to 47% [8,62-64]. Topotecan, as single agent, has been studied in several phase II trials as second-line therapy for SCLC. A study conducted by the EORTC reported a 21.7% overall response rate (38% among sensitive patients, 6.4% among refractory patients) and a 33-week median duration of response [65]. Two other phase II topotecan studies had response rates in sensitive patients of 14% (median survival, 25.7 weeks) and 19% (median survival, 26.6 weeks) and response rates in refractory patients of 2% (median survival, 16.3 weeks) and 3% (median survival, 20.4 weeks) [66,67]. One study, in 32 patient refractory to etoposide, show 11% of partial response with single agent topotecan, indicating that clinical resistance to the topoisomerase II inhibitor etoposide does not confer collateral sensitivity to the topoisomerase I inhibitor topotecan [68]. A meta-analysis of these three SCLC studies in sensitive patients reported an 18% response rate and median survival of 30 weeks [69]. A recent randomised trial of topotecan versus CAV reported a response rate of 24% for topotecan versus 18.3% for CAV with median survival of 25 weeks for topotecan and 24.7 weeks for CAV. In addition, topotecan appeared to be more effective than CAV in the palliation of major tumour-associated symptoms [70]. An oral formulation of topotecan which may increase the ease of administration of the 5-day regimen is under development. Preliminary data on a randomised phase II study of oral versus intravenous formulation of topotecan, for second line therapy in sensitive patients, suggest that the oral formulation has similar efficacy to the intravenous form [71]. A registration phase HI study comparing the two formulations in relapsed SCLC has been recently started. Taxoids were also evaluated as a second-line treatment in SCLC. In one study, paclitaxel has been given to patients refractory to first line chemotherapy, yielding an impressive response rate of 36% [72]. Paclitaxel was tested in combination with carboplatin in patients refractory to CAE yielding a very high response rate (73%) [73]. Docetaxel was evaluated by the EORTC in previously treated SCLC patients, and the response rate was 25% [74].

6 106 A. Ardizzoni and F. Grossi Vinorelbine, a vinca alkaloid, achieved response rates of 12% and 16% in second-line treatment of patients with sensitive disease [75,76]. Single agent gemcitabine showed only a moderate activity, 14% response rate, in a phase II trial in patients with resistant SCLC [77] (Table 1). Randomised studies comparing regimens including these new agents versus standard chemotherapy regimens in the second line treatment of SCLC are being planned. Treatment of brain metastases Cranial irradiation has been the standard therapeutic approach for established SCLC brain metastases. However, during the last decade, a number of small studies on systemic chemotherapy of brain metastases from SCLC have been published indicating antitumour activity similar to that observed in other tumour sites. The most important prospective study was conducted by the EORTC [78] which treated 80 patients with standard dose VM-26 and reported a 33% objective response rate. A follow-up EORTC study randomised 134 SCLC patients with cranial and extracranial metastases to receive either VM-26 alone or VM-26 plus combined whole brain cranial irradiation. Final results [79] show not only a better time to progression in the brain but also an improved survival duration in favour of the combined treatment indicating that whole brain irradiation still retains it fundamental role despite the availability of effective systemic chemotherapy. Recently, new active compounds have become available for the treatment of small cell lung cancer. The camptothecins have demonstrated a particular ability to cross the bloodrbrain barrier in a large fraction with clinical evidence of a significant rate of brain metastases regression. Topotecan is the drug most extensively studied for this aspect with a reported brain response rate >50% in two phase II studies including pretreated patients [66,80]. 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9 Educational Session NON-HODGKIN'S LYMPHOMA Chairperson Thomas Cerny Kantonsspital Medizinische Klinik C St. Gallen, Switzerland Co-Chairperson Nazli Gad-El-Mawla National Cancer Institute Cairo, Egypt Speakers "Follicle centre cell lymphoma: optimal use of therapeutic options" Ama Rohatiner St. Bartholomew's Hospital Department of Medical Oncology London, United Kingdom "Role of high-dose therapy in diffuse large B-cell lymphoma" Thomas Cemy Kantonsspital Medizinische Klinik C St. Gallen, Switzerland "Long-term survivors and adverse effect" Ron Epelbaum rthern Israel Oncology Center Rambam Medical Center Haifa, Israel

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