Phase II trial of second-line bendamustine chemotherapy in relapsed small cell lung cancer patients

1. Introduction 

Small cell lung cancer (SCLC) is sensitive to chemotherapy and radiotherapy. The first-line treatment in SCLC with polychemotherapy is associated with high response rates and prolonged survival. However, the majority of patients will relapse within the first year after diagnosis. Patients who relapse earlier than 3 months after first-line chemotherapy are commonly termed “refractory” and have a poor prognosis with very low response rates to subsequent treatment. Prognosis and response rates are more favorable in patients with sensitive disease, which is defined as a relapse more than 2–3 months after initial therapy.

Two prospectively randomized phase III trials have assessed the efficacy of second-line treatments of SCLC. The first trial demonstrated equivalent efficacy, when comparing topotecan monotherapy to the combination of cyclophosphamide, adriamycin and vincristine (CAV). Toxicity profile favoured the topotecan regimen [1]. A second randomized phase III trial demonstrated a survival benefit for patients treated with second-line topotecan when compared to best supportive care only [2].

Bendamustinehydrochloride is a cytotoxic agent combining a purine-like benzimidazol and a bifunctionally alkylating nitrogen mustard group. After intravenous application bendamustinehydrochloride binds to proteins and is selectively taken up by the liver and the kidney. It becomes hydrolysed to its mono- and dihydroxy derivates with a half-life of about 10min. The elimination pathway is renal and to a lower extend biliary. The main side effect is myelosuppression [3], [4]. The drug has antitumour activity in lymphoma, myeloma and a variety of solid tumours including breast cancer and germ cell cancer [5], [6].

Single-agent acitivity of bendamustine has been demonstrated in first-line treatment of SCLC. Reck et al. investigated 70mg/m2 of bendamustine administered on Days 1–4 every 4 weeks and reported an objective response in 9 out of 22 (41%) patients. Grade III leucopenia and thrombocytopenia was observed in 5% and 2.4%, respectively [7]. Another group investigated bendamustine in a dose of 120mg/m2 on Days 1 and 2 every 3 weeks and found a response rate of 46% in 22 patients treated first-line, no toxicity data were reported from this trial [8].

The trial reported here investigated the efficacy and toxicity of bendamustine chemotherapy in patients with SCLC relapse after first-line chemotherapy.

2. Patients and methods 

3. Results 

3.1. Patient characteristics 

Between February 2001 and December 2004, 21 patients were treated within the trial. Median time to relapse after the end of first-line chemotherapy was 6 months, time to relapse ranged from 2 to 16 months. Median age was 59 years, the majority of patients was male. Ten out of 21 patients had a Karnofsky performance status of 90% or 100% (Table 1).

Table 1. Patient characteristics

		Number of patients
	All patients	21
	Female	4
	Male	17
	Median age (range)	59 years (47–76)
	Karnofsky PS
	100%	3
	90%	7
	80%	8
	70%	2
	60%
	Median time between end of first-line therapy and relapse (range)	6 months (2–16)
	Disease stage at initial diagnosis
	Limited disease	2
	Extensive disease	19
	First-line chemotherapy
	Carbo/etoposide followed by RT	2
	Carbo/etoposide	11
	Carbo/irinotecan	6
	Carbo/paclitaxel	2
	Response to first-line therapy
	CR	3
	PR	17
	SD	1

PS, performance status; carbo, carboplatin; RT, radiotherapy; CR, complete remission; PR, partial remission; SD, stable disease.

Two patients had limited disease and 19 extensive disease according to Veterans Administration Cancer Study Group (VALG) classification at initial diagnosis. First-line treatment of patients with limited disease consisted of six cycles of carboplatin/etoposide chemotherapy followed by thoracic radiotherapy. Patients with extensive disease had carboplatin/etoposide (n=11) or carboplatin/irinotecan (n=6) or carboplatin/paclitaxel (n=2) as first-line therapy. Three patients had a complete and 17 patients a partial remission after first-line treatment. One patient had a disease stabilization lasting for more than 2 months (Table 1).

3.2. Response to treatment 

All patients were evaluable for response assessment. Six of 21 (29%) had a confirmed partial remission, 6 (29%) had stable disease and 9 (42%) progressed. The objective response rate for patients who received bendamustine was 29% (Table 2). Because the minimal recommendation of six objective responses had already been observed after 21 patients had been treated within step 1, we stopped accrual at this time point.

Table 2. Response to treatment

	Number of patients	N=21 (100%)
	Complete remission	0 (0%)
	Partial remission	6 (29%)
	Stable disease	6 (29%)
	Progressive disease	9 (42%)

3.3. Time to progression and overall survival 

The median time to progression was 4 months (95% CI 0.7–7.3) (Fig. 1). Median overall survival was 7 months (95% CI 5.8–8.2). One- and 2-year survival rates were 16% and 8%, respectively (Fig. 2).

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Fig. 1. Kaplan–Meier estimates for progression free survival (PFS).

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Fig. 2. Kaplan–Meier estimates for overall survival (OS).

3.4. Toxicity analysis 

Three patients had grade III or IV neutropenia, of which one patient developed fever and a lethal Gram-negative sepsis. Two patients developed grade III anemia. No grade III or IV thrombocytopenia was observed. Non-hematologic toxicities were grade II and III nausea and vomiting and two cases of grade III pneumonia in the absence of neutropenia (Table 3). No alopecia occurred.

Table 3. Toxicities

		n=21 (100%)
	Anemia
	Grade III	2 (10%)
	IV	0
	Neutropenia
	Grade III	2 (10%)
	IV	1 (5%)
	Thrombopenia
	Grade III	0
	IV	0
	Nausea
	Grade II	4 (19%)
	III	2 (10%)
	IV	0
	Vomiting
	Grade II	5 (14%)
	III	2 (10%)
	IV	0
	Infection
	Grade III	2 (10%)
	IV	1 (5%)
	Febrile neutropenia
	Grade III	0
	IV	1 (5%)
	Treatment-related death	1 (5%)

4. Discussion 

We investigated bendamustine chemotherapy in patients with “sensitive” relapse, because non-hematologic toxicity is mild and activity had been demonstrated in first-line chemotherapy of SCLC. In phase II studies response rates in first-line treatment were 41% and 46% with a frequency of grade III neutropenia and thrombopenia in 5% and 2.4%. Non-hematologic toxicity was mild [7], [8]. Our trial demonstrated a response rate of 29%, a median survival of 7 months and grade III/IV neutropenia and anemia in 15% and 10%, respectively.

Recently, a randomized phase III trial comparing topotecan chemotherapy to best supportive care demonstrated a significant prolongation of survival in patients with relapsed SCLC [2]. Patients treated in the topotecan arm had a median survival of 6.0 months compared to 3.5 months in the best supportive care arm. Response rate was 7% and the rate of disease stabilizations was 44%. Patients with refractory and sensitive disease had been included into that trial [2]. Another randomized phase III study compared topotecan monotherapy to CAV combination consisting of cyclophosphamide, doxorubicin and vincristine [1]. Topotecan and CAV demonstrated response rates of 24% and 18% and median time to progression of 13 and 12 weeks and median survival of 25 and 24.7 weeks, respectively [1]. Bendamustine treatment in our trial resulted in a response rate of 29% and a median progression free survival (PFS) of 4 months and a median survival of 7 months, which is comparable to the results of the larger phase III trial. Grade III and IV neutropenia/thrombopenia occurred in 88.3%/57.6% in the topotecan arm versus 86.9%/14.9% in the CAV arm of the randomized trial [1]. In our study hematologic toxicity was much lower with grade III and IV neutropenia and thrombocytopenia in 15% and 0%. Nevertheless one grade IV neutropenia was associated with a fatal Gram-negative sepsis. Therefore, the treatment-related mortality of our trial was 5% (1 out of 21 patients). Treatment-related mortality was 4% in the topotecan arm and 3% in the CAV arm [1] and 4% in the study of O’Brien et al. [2].

Combination regimens like carboplatin/irinotecan or carboplatin/paclitaxel demonstrated overall response rates of 68% and 69% and a median overall survival of 6.5 and 7 months, respectively [11], [12]. Although the survival in these trials is comparable to our trial an unfavourable toxicity has been reported with these combination regimens. The rates of grade III and IV neutropenia were 63% and 55%, grade III and IV thrombocytopenias occurred in 58% and 3% and grade III and IV anemias in 67% and 36% of patients [11], [12].

Gemcitabine mono-chemotherapy had also been investigated in relapsed or refractory disease. Overall response rate was 11.9% and median survival 7.1 months. Toxicity was modest with grade III/IV neutropenia and thrombopenia in 27%, respectively [13].

Taken these phase II and III trials together response rates expectedly vary considerably between studies, which might be due to selection of patients. Nevertheless median survival in all studies is about 7 months. The major difference between the protocols is toxicity, which is more frequent when chemotherapy combinations are used. However, there is currently no evidence that combination therapy is superior to single-agent chemotherapy, which should be considered for future trials. Our current trial was able to prove a 29% response rate and a median survival of 7 months. Therefore, bendamustine should be compared to other single-agent treatments in future randomized trials in relapsed SCLC.

Conflict of interest statement 

The authors indicate no potential conflict of interest.