Kurata, Takayasu MD, PhD; Kashii, Tatsuhiko MD, PhD; Takeda, Koji MD; Seki, Nobuhiko MD, PhD; Tsuboi, Masahiro MD, PhD; Kobayashi, Masashi MD; Satoh, Taroh MD; Nakagawa, Kazuhiko MD, PhD; Fukuoka, Masahiro MD, PhD
Small cell lung cancer (SCLC) accounts for 15 to 20% of all lung cancers. As SCLC is highly sensitive to chemotherapy and radiation, chemotherapy plays a central role in the treatment of SCLC. Although initial standard chemotherapies such as cisplatin plus etoposide1 or cisplatin plus irinotecan2 yield high response rates, especially in terms of complete remission, in SCLC, the majority of patients experience relapse and the 5-year survival rate is disappointing, at 20 to 25% for patients with limited disease and only 1 to 2% for those with extensive disease. Moreover, the outcome for patients who receive second-line chemotherapy after relapse is generally poor, depending on the interval from the day of the last administration of first-line chemotherapy to the day of relapse.3,4 It seems that the response rate of second-line chemotherapy with an interval of 90 days or more for “sensitive cases” is higher than that of chemotherapy with an interval of less than 90 days for “refractory cases.”
Topotecan targets DNA topoisomerase I. Recently, two randomized phase III studies on the effect of topotecan, as a single agent and second-line chemotherapy, for relapsed SCLC were performed.5,6 The first randomized study showed that topotecan alone had an equivalent effect to the combination chemotherapy (cyclophosphamide, doxorubicin, and vincristine: CAV) in sensitive cases. In this study, topotecan achieved a response rate of 24% (CAV, 18%) and a median survival time (MST) of 25 weeks (CAV, 24.7 weeks), with significantly better symptom relief.5 The second randomized study demonstrated that oral topotecan prolonged overall survival more significantly than best supportive care (25.9 weeks versus 13.9 weeks) in relapsed SCLC patients, who were not considered as candidates for standard intravenous chemotherapy, including refractory cases. Moreover, patients receiving oral topotecan also showed better quality of life and greater symptom control.6 Based on these results, it would seem that topotecan alone should be the standard of care for relapsed SCLC; however, as there have been few randomized trials in the second-line setting, whether results of combination chemotherapy can exceed those of the single agent is not yet well known.
We planned combination chemotherapy using carboplatin with the present standard of care, topotecan. Cisplatin is a platinum preparation that has an important role in the treatment of SCLC, but its cumulative toxicity such as neural and renal toxicities from first-line therapy was a matter of concern. We thus chose carboplatin rather than cisplatin. However, until now, combination chemotherapy of topotecan and carboplatin for relapsed SCLC had not been fully evaluated. Trials on ovarian cancer demonstrated that the toxicity of combination therapy for carboplatin on day 5 with topotecan on days 1 to 5 was significantly milder than that of carboplatin on day 1 with topotecan. Therefore, we chose a schedule in which carboplatin was administered on day 5 in combination with topotecan on days 1 to 5 every 3 weeks.7 As both carboplatin and topotecan have overlapping toxicities, neutropenia and leucopenia, we decided to give granulocyte colony-stimulating factor (G-CSF) prophylaxis.
The purposes of this study were to establish the toxicity and maximum tolerated dose (MTD) of this combination, to determine the recommended dose for further studies, and to assess the antitumor activity.
PATIENTS AND METHODS
Patients with histologic or cytologic confirmation of SCLC who had received one previous chemotherapy regimen were eligible. The eligibility criteria were as follows (1): measurable lesions (2); age 20–75 years (3); Eastern Cooperative Oncology Group performance status 0–1 (4); life expectancy of at least 3 months (5); adequate organ function (12,000/μl ≥ white blood cell count (WBC) ≥4000/μl, absolute neutrophil count ≥2000/μl, platelet count ≥100,000/μl, hemoglobin count ≥9.5 g/dl, serum total bilirubin ≤1.5 mg/dl, serum transaminase ≤2.5 × upper normal limits, serum creatinine ≤ upper normal limits, PaO2 ≥60 torr). At least 4 weeks had to have passed after completion of the previous chemotherapy. Prior radiotherapy and surgery were allowed. The exclusion criteria were as follows (1): pulmonary fibrosis or interstitial pneumonitis with symptoms or apparent abnormalities on chest radiograph (2); massive pleural effusion, pericardial effusion, or ascites (3); pregnancy (4); lactation (5); fertile men with no intention of using contraception (6); symptomatic brain metastases (7); active concurrent malignancies (8); patients who had received a bone marrow transplantation or peripheral blood stem cell transplantation (9); severe drug allergies (10); severe comorbidities. Prior topotecan chemotherapy was not allowed. This study was approved by the Institutional Review Board at each institute, and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients.
Pretreatment and Follow-Up Studies
Prior to entry, complete history-taking and physical examination were performed regarding age, height, weight, performance status, histologic diagnosis, tumor stage, details of previous treatment, and presence of complication. The pretreatment laboratory investigations included complete blood cell count, differential WBC, platelet count, serum electrolytes, total protein, albumin, total bilirubin, transaminase, alkaline phosphatase, lactate dehydrogenase, BUN, creatinine, creatinine clearance, and urinalysis. After initiation of therapy, blood count was repeated twice per week, and blood chemistry and urinalysis were repeated weekly. Lesions were measured in every second course at minimum. Toxicity was evaluated in accordance with the National Cancer Institute Common Toxicity Criteria version 2. Tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.8 Time to progression was measured from the date of registration to the date of first progression or death from any cause. Survival time was also measured from the date of registration to the date of death or latest follow-up, and was calculated using the Kaplan-Meier method.9
Drug Administration, Dose Escalation, and Sample Size
The treatment schedule included topotecan, diluted with 100 ml of normal saline, given intravenously as a 30-minute infusion on days 1 through 5, and carboplatin with 250 to 500 ml of normal saline, given intravenously over 60 minutes after completion of topotecan infusion on day 5 every 3 weeks. All patients were allowed to receive antiemetics with dexamethasone, metoclopramide, or 5HT3 antagonists at the treating physician’s discretion. G-CSF prophylaxis was administered from day 8 until WBC recovered to more than 10,000/μl or absolute neutrophil count to more than 5000/μl. The subsequent courses were delayed if any of the following parameters were not met: WBC ≥3000/μl, platelet count ≥100,000/μl, or recovery to at least grade 1 nonhematological toxicity. If dose-limiting toxicities (DLTs) occurred, the patient was withdrawn from the study in principle, but when an antitumor effect could be expected, the dose of topotecan was decreased by one dose level and that of carboplatin was reduced to area under curve (AUC) 4. At the initial dose level, dose reduction was not permitted and when it was required the patient was withdrawn from this study.
The starting dose of topotecan was 0.50 mg/m2 and the targeted AUC of carboplatin was 5. In the dose escalation method, the AUC of carboplatin was fixed at 5, and only the dose of topotecan was increased, by 0.10 mg/m2 or by 0.05 mg/m2 (topotecan: level 1, 0.50 mg/m2; level 2, 0.60 mg/m2; level 3, 0.65 mg/m2; level 4, 0.70 mg/m2; level 5, 0.75 mg/m2; level 6, 0.85 mg/m2). Intrapatient dose escalation was not allowed. At least three patients were treated at each dose level, and three additional patients were entered at the same dose level if DLT was observed in one or two of the first three patients. The MTD was defined as the dose level at which all three of the first three patients, or three of any six patients, experienced DLT. The definitions of DLT were as follows (1): grade 4 neutropenia for more than 4 days (2); thrombocytopenia <20,000/μl (3); grade 3 febrile neutropenia (4); grade 3 nonhematological toxicity except nausea/vomiting, appetite loss, constipation, hyponatremia, and weight loss (5); grade 2 interstitial pneumonitis or pulmonary fibrosis (6); grade 4 constipation, and hyponatremia (7); delayed administration of the subsequent course by more than 2 weeks.
Patients were registered from six institutions that were members of the West Japan Thoracic Oncology Group. Between October 2002 and January 2006, 32 patients (dose level- number of patients: 1–6, 2–3, 3–8, 4–3, 5–6, 6–6) were enrolled. The total and median number of courses were 90 and 2.5 (range, 1–6), respectively. The patients’ characteristics are shown in Table 1. Nine patients were female. The median age was 64 (range, 43–74). The regimen most often given as first-line chemotherapy was cisplatin or carboplatin plus etoposide, which 18 patients (56.3%) received. Twelve patients (37.5%) had received a regimen including CPT-11. Fourteen patients (43.8%) had had prior radiotherapy and no patient had had prior surgery.
All 32 patients were evaluable for toxicity. The major toxicities following all courses are listed in Table 2. The most frequent toxicities were hematological toxicities. Grade 3 thrombocytopenia occurred in 17 of 32 patients (53.1%), and 6 patients (18.8%) received platelet transfusions (one patient at level 1, one at level 5, and 4 at level 6); however, no patient had hemorrhagic complications. Grade 3/4 leukopenia, neutropenia, and anemia occurred in 34.4/0%, 37.5/9.4%, and 34.4/3.1%, of patients, respectively. There were fewer cases with grade 3/4 leukopenia or neutropenia than expected, owing to G-CSF prophylaxis. Two patients (6.3%) received blood transfusions (one at level 1 and the other at level 6). Nonhematological toxicities were generally mild. The most frequent grade 3 nonhematological toxicities were constipation, nausea, and appetite loss. No patient experienced pneumonitis or neutropenic fever, and there was no treatment-related death. One patient at level 2 underwent dose reduction after the third course by judgment of the treating physician owing to grade 3 nausea and vomiting, and the dose for one patient at level 3 was also reduced after the second course because of delayed administration of the subsequent course by more than 2 weeks. Moreover, the dose was reduced in one patient at level 5 and 2 patients at level 6 after their first course because of thrombocytopenia. The median length of the delay before starting the subsequent course was 28 days (21–49 days). Among 90 courses, only 14 courses (15.6%) proceeded to the next course without delay, as is stipulated in the protocol.
Maximum Tolerated Dose and Dose-Limiting Toxicities
At level 1, one patient suffered from grade 3 infection, which was considered a DLT. As 5 other patients at level 1 did not experience any DLTs, the dose was escalated to the next level. At level 2, none of the patients had a DLT. At level 3, one of six evaluable patients had a DLT, grade 3 diarrhea, during administration of topotecan; however, the other patients at levels 3 and 4 did not experience any DLTs, so we escalated the dose to level 5. At level 5, one patient had grade 3 thrombocytopenia, which was considered a DLT, and received platelet transfusion. At level 6, three of six patients also experienced the DLT, grade 3 thrombocytopenia, and all 3 patients received platelet transfusions. Therefore, dose level 6, 0.85 mg/m2 topotecan with AUC 5 carboplatin was regarded as the MTD, according to the protocol criteria. The recommended dose level for further phase II study was determined to be 0.75 mg/m2 topotecan with AUC 5 carboplatin.
Response and Survival
A total of 29 patients were evaluable for response (Table 3). There were 5 partial responses, with an overall response rate of 17.2% (5.8–35.8%). Among 21 patients who relapsed more than 90 days after completion of first-line chemotherapy, five had partial responses, with an overall response rate of 23.8%, and 8 patients had stable disease. Conversely, among seven patients who relapsed less than 90 days after completion of first-line chemotherapy, none had a complete or partial response, and four had stable disease. The median progression-free survival time was 3.2 months (Figure 1). The MST and 1-year survival rate were 11.3 months and 50.0%, respectively (Figure 2). In sensitive cases, the MST and 1-year survival rate were 10.6 months and 47.6%, respectively.
In this study, the overall response rate was 17.2%, which was significantly less than the 20% supposed to be invalid; however, the survival result in this study was excellent as compared with the results of previous phase III studies for relapsed SCLC. Moreover, the outcome of second-line chemotherapy highly depends on the interval between the day of the last administration of first-line chemotherapy and the day of recurrence. The shorter this interval, the lower the response rate. In clinical trials for relapsed SCLC, therefore, careful attention is required to evaluate the response. In the current study, the response rate for 21 patients who had disease progression more than 90 days after completion of first-line chemotherapy was 23.8%, whereas no response was observed among seven patients having disease progression less than 90 days later. The results of only sensitive cases were not necessarily disappointing, so additional studies in patients with sensitive relapsed SCLC may be warranted to evaluate the efficacy of this combination. In addition, the survival results of sensitive relapsed cases were very promising. However, from this study, this combination treatment was invalid for refractory relapsed cases.
Recently, a Japanese study showed that amrubicin, a topoisomerase II inhibitor, as a single agent, had an overall response rate of 50% in refractory cases and 52% in sensitive cases.10 If single agents such as amrubicin are really effective for both sensitive and refractory cases, the combination of carboplatin and topotecan would seem unnecessary; however, no conclusion can be drawn, because no results of randomized studies that evaluated the efficacy of amrubicin have been reported as of this writing. As there have been few such controlled trials, and the standard treatment has not been established in this setting, randomized trials to determine whether combination therapy is more useful than monotherapy are warranted.
Regarding toxicity, this carboplation-topotecan combination was generally well tolerated. The most frequent toxicity was thrombocytopenia. Grade 3 thrombocytopenia occurred in 17 of 32 patients (53.1%), and 6 patients received platelet transfusions. Thrombocytopenia became the decisive factor in determination of the MTD. However, only 3 patients had grade 4 neutropenia among all courses because of G-CSF prophylaxis. In contrast, no nonhematological toxicity was associated with dose escalation. In addition, the median interval between cycles was 28 days, and most patients had a delay of 21 days, as stipulated in the protocol. There is a possibility that decreased dose intensity led to the disappointing result of low response rate.
According to the design, prophylactic G-CSF was administered from day 8. Therefore, few patients had grade 4 neutropenia and none had neutropenic fever. However, skepticism has recently risen regarding dose-intensive chemotherapy in the treatment of SCLC, especially in the second-line setting. In addition, G-CSF administration is very expensive. There is thus a risk that compliance in therapy with prophylactic G-CSF would be low. Therefore, an additional phase I study without prophylactic G-CSF may be necessary before conduct of randomized studies.
In conclusion, the combination of carboplatin and topotecan was generally well tolerated, although most patients had a delay of 21 days, as stipulated in the protocol. The main DLT was thrombocytopenia. The recommended dose for further phase II and III studies is 0.75 mg/m2 topotecan on days 1 to 5 with AUC 5 carboplatin on day 5 with prophylactic G-CSF every 3 weeks. A phase III comparative study against single-agent topotecan for sensitive relapsed SCLC is warranted because the survival result of this combination is very promising, although the response rate was lower than expected.