Randomized phase III trial in extended stage small cell lung cancer comparing first line platinum in combination with etoposide or topotecan

Background

Small cell lung cancer (SCLC) comprises 15% of newly diagnosed lung cancers with approximately two thirds of cases having extended stage (ES) at time of diagnosis [1]. For the last four decades, progress in the treatment of ES SCLC has been limited. Recently, the addition of an immune checkpoint inhibitor to standard platin-based chemotherapy in fit patients has yielded a modest increase in median survival from approximately 10.3 to 13.0 months [2,3]. Hence, platinum-based chemotherapy in combination with etoposide remains the core of treatment of choice in the first line setting of ES SCLC. A meta-analysis published in 2000 showed that regimens containing cisplatin are superior to regimens without [4]. Afterwards efforts were therefore made to develop agents to combine with cisplatin to improve outcome. The topoisomerase I inhibitor topotecan was identified as such an agent based on its efficacy in second line treatment of SCLC [5,6]. Initially, the combination yielded a high rate of fatal toxicity when cisplatin was administered on day 1 followed by 5 days of topotecan, but the regime became tolerable when cisplatin was administered on day 5 instead [7–9]. Subsequently, a phase II study using a 3-day regimen with cisplatin administered on day 3 was compared to the 5-day regimen, which demonstrated similar response rates of 60% and 62%, respectively [10]. The regimen has been further explored in a phase II trial, where the same sequence of cisplatin and topotecan was given to patients, but with a higher dose of topotecan. The study yielded an even higher overall response rate (ORR) of 72%, warranting further investigation [11]. Accordingly, we initiated a multicentre randomized phase III study comparing topotecan/cisplatin with etoposide/carboplatin for ES SCLC, which we previously have reported [12]. Platin-irinotecan is considered an equivalent option to platin-etoposide for the initial treatment of SCLC. The investigation of the closely related compound, topotecan, is particularly intriguing due to variations in metabolism (liver vs. renal) and toxicity (diarrhea and the cholinergic syndrome associated with irinotecan). Here, we present the final results of the trial with long-term follow-up.

Methods

The study included treatment naïve patients with ES SCLC with adequate bone marrow function, normal renal clearance, and serum bilirubin levels lower than 40 mmol/L. Initially, the study included patients from the age of 18 to 75 with WHO performance status of 2 or less. Patients with raised levels of lactate dehydrogenase (LDH) more than 2.5 times the upper normal limit (ULN) were excluded. Due to low accrual rate, an amendment implemented in December 2010 removed these exclusion criteria and extended the inclusion to all patients with age 18 and above with no upper age limit. Restrictions on performance status were also removed. Prior radiotherapy for brain metastases or spinal compression was allowed. Exclusion criteria included previous malignant disease within 5 years (except for basal or squamous carcinoma of the skin or carcinoma in situ of the cervix), active uncontrolled infection, serious medical condition, pregnancy, and lactation.

Patients were randomized 1:1 to arm E or arm T. Arm E consisted of six cycles of etoposide intravenously (IV) 120 mg/m² day 1 to 3 and carboplatin IV area under the curve (AUC) 5 on day 1. Arm T consisted of six cycles of topotecan IV 2 mg/m² day 1 to 3 and cisplatin 50 mg/m² IV on day 3. In both arms, treatment cycles were repeated every 3 weeks and without concomitant administration of granulocyte-colony stimulating factor (G-CSF).

The primary endpoint of the study was overall survival (OS) and secondary endpoints included progression free survival (PFS), objective response rate (RR) according to the RECIST criteria version 1.0, and toxicity according to the National Cancer Institute Common Toxicity Criteria version 2.

Recruitment of patients was expected to last 2 years with a 2-year follow-up period. The survival rate at 2 years was expected to be 7.5% in arm E and 15% in arm T. The risk of a type 1 error was set at 5%, and the risk of a type 2 error was 20%. Based on these assumptions, a sample size of 380 patients was needed. OS and PFS were assessed by use of the Kaplan-Meier method. Survival rates were compared by means of the log-rank test. Differences between categorial variables were tested with the use of Fishers exact test. All analyses were done per intention-to-treat. Three interim analyses were planned. The first analysis was to be performed after 60 patients had completed 2 cycles (endpoint: toxicity). The second and third analysis were planned to be executed when 25% and 50% of expected events had occurred (endpoint: survival).

Results

From June 2006, 281 patients from nine Danish oncology centres were randomised to either arm T (n = 138) or arm E (n = 136), 7 patients were incorrectly randomised. The trial was prematurely closed in December 2013 following the third interim analysis due to low accrual rate. Patient characteristics were well balanced between the two arms (Table 1).

Table 1. Patient characteristics.

	Topotecan + cisplatin N(%)	Etoposide + carboplatin N(%)	Total N(%)	P value
Gender
Female	69 (50%)	68 (50%)	137 (50%)	NS
Male	69 (50%)	68 (50%)	137 (50%)
Performance status
PS ≤1	111 (82%)	100 (74%)	211 (78%)	NS
PS ≥ 2	24 (18%)	36 (26%)	60 (22%)
Median Age (range)	63 (42–82)	65 (40–78)	64 (40–82)	NS

N: number; P: Probability; PS: Performance status; NS: Not significant.

Median overall survival in arm T was 10.2 months and 9.6 months in arm E (Figure 1). Overall survival at 1, 2, and 5 years was 42.8%, 8.0%, and 2.2%, respectively, for arm T and 30.1%, 7.4%, and 2.9%, respectively, for arm E. At 10 years, no patients in arm T remained alive and 2 patients (1.5%) were alive in arm E. The difference in survival between the arms was not significant (HR = 0.90, 95% CI: 0.71–1.15, p = 0.40).

Figure 1. Kaplan-Meyer curves comparing survival probability after treatment with etoposide/carboplatin vs topotecan/cisplatin.

Subsequent systemic treatment was administered to less than 10%, with no apparent differences between the treatment arms. The predominant regimen employed was cyclophosphamide and adriamycin, with no significant variation between the arms. PS had no impact on efficacy or toxicity (data not shown).

Progression free survival (PFS) rates were not different (HR = 0.95, 95% CI: 0.75–1.21, p = 0.67). Median PFS was 6.9 months vs 6.6 months in arm T and E, respectively. Response rates showed a non-significant difference in favour of arm E (ORR: 57% vs 69%, p = 0.08) between the two treatment arms. Disease control rates did not differ (DCR: 75% vs 79%, p = 0.31).

Hematological toxicity was significantly more frequent in arm E with higher incidences of grade 3/4 anemia (6% vs 14%, p = 0.006), leucocytopenia (49% vs 58%, p = 0.009), and thrombocytopenia (13% vs 38%, p = 0.0001) in arm T and E, respectively (Table 2). More episodes of febrile neutropenia were recorded in arm E (17% vs 27%, p = 0.048).

Table 2. Hematological and non-hematological toxicity.

	Topotecan + cisplatin N(%)		Etoposide + carboplatin N(%)
Non-hematological	Gr 1 + 2	Gr 3 + 4	Gr 1 + 2	Gr 3 + 4	P-value
Hematological
Anemia	127 (94%)	8 (6%)	115 (86%)	18 (14%)	0.006
Leuco-cytopenia	53 (39%)	67 (49%)	47 (35%)	77 (58%)	0.009
Thrombo-cytopenia	87 (64%)	17 (13%)	64 (48%)	51 (38%)	0.0001
Alopecia	119 (89%)	–	118 (93%)	–	NS
Auditory	45 (34%)	2 (1%)	32 (26%)	2 (2%)	NS
Fatigue	114 (78%)	17 (13%)	98 (77%)	18 (14%)	NS
Fever	31 (23%)	7 (5%)	27 (21%)	9 (7%)	NS
Infection	18 (14%)	16 (12%)	24 (19%)	22 (17%)	NS
Cardiac	15 (11%)	1 (1%)	11 (9%)	2 (2%)	NS
Nausea	77 (58%)	1 (1%)	71 (55%)	1 (1%)	NS
Vomiting	32 (24%)	3 (2%)	35 (27%)	1 (1%)	NS
Stomatitis	35 (26%)	0 (0%)	36 (28 %)	1 (1%)	NS
Obstipation	51 (46%)	0 (0%)	62 (48%)	2 (2%)	NS
Renal	5 (4%)	0 (0%)	5 (4%)	0 (0%)	NS
Neuropathy	53 (40%)	2 (2%)	43 (34%)	1 (1%)	NS

N: Number; P: Probability; Gr: Grade.

No significant differences in non-hematological toxicity were observed. The most common all grade toxicities were alopecia (89% vs 93%), fatigue (91% vs 90%), nausea (59% vs 58%) and constipation (46% vs 50%) in arm T and E, respectively. No episodes of grade 3 or 4 renal toxicity were observed. Grade 3/4 neuropathy was infrequent in both arms (2% vs 1% in arm T and E).

Discussion

Here we present the final data of multicentre prospectively randomized trial comparing topotecan/cisplatin with the standard treatment etoposide/carboplatin. No differences were found in terms of OS or PFS, although partial response was more often achieved in the etoposide arm (not significant).

After initiation of the trial, two larger randomised trials on topotecan + platin vs etoposide + platin and a meta-analysis of these two trials have been published [13–15]. These studies also failed to detect a survival benefit supporting the findings of the present study. The study reported by Fink et al. concluded that topotecan/cisplatin is non-inferior to etoposide/cisplatin in terms of overall survival (HR 0.99, 95% CI: 0.88–1.11, p = 0.87) [14].

Hematological toxicity was significantly lower in the topotecan arm, leading to fewer episodes of febrile neutropenia than the etoposide arm. In contrast, both the previously reported trials using topotecan reported significantly higher hematological toxicity compared to the etoposide arms [13,14]. The discrepancy could be explained by scheduling of topotecan over 3 days instead of 5 days and by the combination with carboplatin in instead of cisplatin in the present study.

The trial used carboplatin and not cisplatin in the comparator arm as etoposide-carboplatin is considered standard in Denmark. Thus, formally, the trial compares two drug combinations and not topotecan versus etoposide. However, a meta-analysis from 2012 including four randomized trials concluded that carboplatin and cisplatin were equally efficacious with regards to PFS or OS (OS 9.4 vs 9.6 months and PFS 5.3 vs 5.5 months, respectively) [16]. Toxicity profiles, however, were quite different. In the carboplatin containing regimens the high frequency of myelosuppression especially thrombocytopenia was confirmed which supports that carboplatin could be responsible for the increase in hematological toxicity in the etoposide arm. The cisplatin containing regimens had a higher frequency of non-hematologic toxicities such as neurotoxicity, renal toxicity, nausea, and vomiting. In the present trial no significant differences in non-hematologic toxicity were recorded, which could be due to the relatively low cisplatin dose used (50 mg/m²). However, this dose had previously been established as the maximum tolerable dose within this schedule [8,10].

Conclusion

This randomized study failed to demonstrate differences in survival between carboplatin-etoposide and cisplatin-topotecan in ES SCLC. Hematological toxicity and febrile neutropenia were more frequent in patients treated with etoposide and carboplatin. Long term survival was extremely rare.

Author contribution

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Morten Mau-Sørensen, Jonas Gerner-Rasmussen, Olfred Hansen, and Seppo W. Langer. The first draft of the manuscript was written by Morten Mau-Sørensen, Jonas Gerner-Rasmussen, and Seppo W. Langer, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics approval

The study protocol was approved by a national ethics committee. Written informed consent was required, and the study was conducted in accordance with the declaration of Helsinki. The study was registered in ClinicalTrials.gov, NCT 00812266.

Data availability statement

Data available on request from the authors.

Disclosure statement

SWL: Advisory board, research collaboration, speaker fee: Roche, Merck, Amgen, AbbVie, Jannsen Pharma, Boehringer-Ingelheim.

Additional information

Funding

The conduction of the study was supported by an unrestricted grant from Glaxo-Smith-Kline

The conduction of the study was supported by an unrestricted grant from Glaxo-Smith-Kline.