Multi-institutional phase II trial of irinotecan, cisplatin, and etoposide for sensitive relapsed small-cell lung cancer

Article metrics

Abstract

Irinotecan (CPT-11) has been shown to exhibit excellent antitumour activity against small-cell lung cancer (SCLC). A multi-institutional phase II study was therefore conducted to evaluate the efficacy and toxicity of CPT-11 combined with cisplatin (CDDP) and etoposide (ETOP) (PEI regimen) for the treatment of sensitive relapsed SCLC. Patients who responded to first-line chemotherapy but relapsed more than 8 weeks after the completion of first-line therapy (n=40) were treated using the PEI regimen, which consisted of CDDP (25 mg m−2) weekly for 9 weeks, ETOP (60 mg m−2) for 3 days on weeks 1, 3, 5, 7, and 9, and CPT-11 (90 mg m−2) on weeks 2, 4, 6, and 8 with granulocyte colony-stimulating factor support. Five complete responses and 26 partial responses were observed, and the overall response rate was 78% (95% confidence interval 61.5–89.2%). The median survival time was 11.8 months, and the estimated 1-year survival rate was 49%. Grade 3/4 leucocytopenia, neutropenia, and thrombocytopenia were observed in 55, 73, and 33% of the patients, respectively. Nonhaematological toxicities were mild and transient in all patients. In conclusion, the PEI regimen is considered to be highly active and well tolerated for the treatment of sensitive relapsed SCLC.

Main

Small-cell lung cancer (SCLC) is one of the most chemosensitive solid tumours, and first-line combination chemotherapy improves survival. However, despite a high response rate to chemotherapy, the majority of SCLC patients relapse. At the time of recurrence, the tumour is broadly resistant to second-line chemotherapy and is lethal within a few to several months (Glisson, 2003). The further development of not only first-line chemotherapy but also of effective salvage chemotherapies is needed.

In predicting the efficacy of salvage chemotherapy, two major factors are important: the response to the initial chemotherapy and the duration of time between the last exposure to chemotherapy and the confirmation of recurrence (Postmus et al, 1987; Giaccone et al, 1988; Ardizzoni et al, 1997; Ebi et al, 1997). Based on these factors, relapsed SCLC is now commonly classified into two main groups. Patients who both respond to the initial chemotherapy and relapse more than 2 or 3 months after the completion of chemotherapy are considered to be ‘sensitive relapse’ patients, while patients whose tumour is stable or progresses during the initial chemotherapy or who have a recurrence within 2 or 3 months after the completion of chemotherapy are considered to be ‘refractory relapse’ patients (Giaccone et al, 1988). Since the outcomes of salvage chemotherapy for relapsed SCLC patients are different between these two groups, the ratios of sensitive and refractory cases must be carefully considered when evaluating the results of clinical trials for second-line chemotherapy.

The combination of cisplatin (CDDP) and etoposide (ETOP) (PE regimen) has been the standard chemotherapeutic regimen for SCLC (Fukuoka et al, 1991; Ihde, 1992; Roth et al, 1992; Aisner, 1996). Moreover, PE is a reasonable second-line chemotherapy for relapsed SCLC after combination chemotherapy consisting of cyclophosphamide, doxorubicin (ADM), and vincristine (VCR) (CAV regimen); the likelihood of a response to this regimen is 40–50% (Evans et al, 1984; Porter et al, 1985). Since PE has a relatively mild toxicity profile, other cytotoxic agent can be combined with PE.

Irinotecan (CPT-11), a camptothecin derivative topoisomerase I inhibitor, has been shown to exhibit excellent antitumour activity against SCLC in monotherapy and in combination with CDDP (Masuda et al, 1992; Kudoh et al, 1998). Based on these results, the Japan Clinical Oncology Group (JCOG) conducted a randomised phase III trial comparing CPT-11 and CDDP (IP regimen) with standard PE for previously untreated extensive stage (ED) SCLC (JCOG 9511) (Noda et al, 2002). The response rates were significantly higher for IP than for PE, and overall survival was also significantly better for IP than for PE. This was the first study to show the superiority of any one regimen over PE for the treatment of ED SCLC, and IP has become one of the standard regimens for ED SCLC in Japan. Thereafter, several clinical trials of CPT-11-containing regimens for patients with limited disease (LD), ED, and relapsed SCLC have been conducted by Japanese clinical study groups (Masuda et al, 1998; Mori et al, 2002; Sekine et al, 2002).

Consequently, a phase I trial of CPT-11 combined with weekly CDDP (25 mg m−2) and biweekly ETOP (60 mg m−2) (PEI regimen) was conducted, and the recommended dose of 90 mg m−2 of CPT-11 was repeated every 2 weeks (JCOG 9507) (Sekine et al, 2003). This regimen showed promising antitumour activity in patients with untreated ED SCLC (response rate, 91%, 1-year survival rate 46%). Moreover, since the drug dose and treatment schedule can be easily modified in a weekly regimen, this protocol is considered to be suitable for relapsed SCLC patients, who usually present with severe haematological toxicities during salvage chemotherapy because of poor bone marrow reserve (Masuda et al, 1990; Faylona et al, 1995).

Based on these results, we conducted two phase II trials to evaluate the efficacy and toxicities of PEI in patients with sensitive and refractory relapsed SCLC, separately. In this paper, the final results for the sensitive relapsed SCLC group are reported.

Patients and methods

Patient selection

Patients with histologically or cytologically confirmed SCLC who respond to first-line chemotherapy or chemoradiotherapy and relapsed more than 8 weeks after the completion of first-line treatment were candidates for the present study. Additional eligibility criteria were as follows: (1) age of 75 years or younger; (2) performance status of 0–2 on the Eastern Cooperative Oncology Group scale; (3) measurable disease; (4) adequate organ function as documented by a 4.0 × 109 l−1WBC count12.0 × 109 l−1, haemoglobin level of 9.0 g dl−1, platelet count of 100 × 109 l−1, total serum bilirubin level of 1.5 mg dl−1, a hepatic transaminase level of 2 times the institutional upper limit of normal, a serum creatinine level of 1.5 mg dl−1; and (5) written informed consent. Patients were not eligible for the study if they had experienced any of the following events: (1) massive pleural effusion requiring drainage; (2) prior radiotherapy with an irradiated area larger than one-third of the bone marrow volume; (3) active infection; (4) contraindications for the use of CPT-11, including diarrhoea, ileus, interstitial pulmonary fibrosis, massive ascites, or hypersensitive reaction to CPT-11; (5) serious concomitant medical illness, including severe heart disease, uncontrollable diabetes mellitus or hypertension; or (7) pregnancy or lactation. This study was approved by the institutional review board at each participating institution.

Treatment schedule

Figure 1 shows the treatment schema of the PEI regimen. CDDP (25 mg m−2) was administered intravenously (i.v.) over 60 min on day 1 and at 1-week intervals for 9 weeks; ETOP (60 mg m−2) was administered i.v. over 60 min on days 1–3 of weeks 1, 3, 5, 7, and 9; and CPT-11 (90 mg m−2) was administered i.v. over 90 min on day 1 on weeks 2, 4, 6, and 8. Hydration (2000 ml) and granisetron (40 μg kg−1) were given on day 1. After day 1 on week 2, granulocyte colony-stimulating factor (G-CSF) (50 μg m−2) was administered routinely according to JCOG 9507 on days when the cytotoxic drugs were not given, unless the WBC count exceeded 10.0 × 109 l−1. Patients were expected to complete at least six cycles of this regimen; if the toxicities were acceptable and the tumour responded to the treatment, a maximum of nine cycles of chemotherapy were performed.

Figure 1
figure1

Treatment schedule.

Toxicity assessment and treatment

During the course of treatment, complete blood cell counts and differential counts were analysed twice a week, and routine chemistry measurements and a chest X-ray were performed once a week. Toxicity was graded according to the toxicity criteria of the JCOG (Tobinai et al, 1993), a modified version of the NCI Common Toxicity Criteria issued in 1991. Grade 4 neutropenia was defined as <0.5 × 109 l−1, and grade 3 neutropenia was defined as between (and including) 0.5–1.0 × 109 l−1, according to the JCOG criteria. The second and subsequent cycles of chemotherapy were delayed for 1 week if one of the following toxicities was noted on day 1: a WBC count of <2.0 × 109 l−1, a platelet count of <50 × 109 l−1, a serum creatinine level of 2.0 mg dl−1, an elevated hepatic transaminase level or total serum bilirubin of grade 2 or higher, diarrhoea of grades 1–2, fever 38°C, or a performance status of 3. The treatment was terminated if the above-mentioned criteria did not disappear in 3 weeks or if one of the following severe nonhaematological toxicities was noted: diarrhoea of grade 2 lasting for more than 1 week, diarrhoea of grade 3, neurotoxicity of grade 3, or drug-induced pneumonitis.

Dose modifications for toxicity

The CPT-11 dosage was reduced to 67.5 mg m−2 (25% reduction) in subsequent cycles if one of the following toxicities was noted: a WBC count of <1.0 × 109 l−1, or a platelet count of <25 × 109 l−1. If the above-mentioned toxicities reappeared after a 25% reduction in the dosage, the CPT-11 dosage was further reduced to 50 mg m−2 (44% reduction). Since CDDP (25 mg m−2) and ETOP (60 mg m−2) in this regimen were relatively low dose, no dose modifications for these drugs were permitted.

Pretreatment evaluation

Pretreatment assessment included a complete blood cell count, differential counts, routine chemistry measurements, creatinine clearance, blood gas analysis, electrocardiogram, chest X-rays, computed tomography (CT) scan of the chest, brain CT scan or magnetic resonance imaging (MRI), abdominal CT scan or ultrasound sonography, radionuclide bone scan, and bone X-rays, if indicated.

Response evaluation

Objective tumour responses were evaluated in all enrolled patients according to the WHO criteria issued in 1979 (WHO, 1979). A complete response (CR) was defined as the disappearance of all known disease for at least 4 weeks with no new lesions appearing. A partial response (PR) referred to a decrease in the total tumour size of at least 50% for at least 4 weeks without the appearance of new lesions. No change (NC) was defined as the absence of a partial or complete response and the appearance of no progressive or new lesions for at least 4 weeks. Progressive disease (PD) was defined as a 25% or greater increase in the size of any measurable lesion or the appearance of new lesions. Patients whose responses were not evaluated were included in the analysis as not evaluable (NE).

Statistical methods

The primary end point of this study was the response rate, defined as the proportion of patients whose best response was CR or PR among all eligible patients, and its confidence interval was based on an exact binomial distribution. Simon's two-stage minimax design was used to determine the sample size and decision criteria. Assuming that a response rate of 40% in eligible patients would indicate a potential usefulness of the regimen while a rate of 20% would be the lower limit of interest and that alpha=0.05 and beta=0.20, the estimated number of required patients was 33 (Simon, 1989). Finally, this regimen would be considered worthy of further testing if 11 (33%) or more eligible patients showed an objective response. At the first stage decision, this regimen would be rejected if four (22%) or fewer of 18 eligible patients had an objective response. Thus, we determined that the sample size would be 35 registered patients. The planned accrual period was 2 years, and the follow-up period was set as 1 year after the completion of accrual. Secondary end points were toxicity and overall survival. The duration of overall survival was measured from the date of registration to the date of death from any cause or the last follow-up examination. Progression-free survival was calculated from the date of registration until evidence of PD. All patients started the treatment within 1 week of registration. The survival distribution was estimated by the method of Kaplan and Meier (1958).

Results

Patient characteristics

From October 1998 to March 2001, 40 patients were enrolled in this study. The first-stage decision was made in October 1999, when 22 patients were registered. Three CRs and 13 PRs were observed in 18 analysed patients, resulting in a response rate of 89% (95% confidence interval (CI), 65.3–98.6%). This result did not meet the criteria for stopping the study as defined in the protocol, and the study was continued. At the time of the final analysis, there were three censored cases (8%). The median follow-up period for these cases was 25.5 months (range, 4.4–46.1 months).

The clinical characteristics of the enrolled patients are listed in Table 1. Of the 40 patients in the total, 29 (73%) were male and 11 (27%) were female; the median age was 67 years. A total of 39 patients (97%) had a good performance status of 0 or 1. The extent of the disease at the time of recurrence was LD in five patients (12%) and ED in 35 (88%). All 40 patients had been previously treated using platinum-based chemotherapy, such as PE in 11 patients, carboplatin plus ETOP in 11, PE plus weekly CDDP/VCR/ADM/ETOP (CODE) in six, CDDP plus CPT-11 in six, PEI in two, and other regimens in four. Eight (20%) of these patients received thoracic radiotherapy. All patients were eligible, and the toxicity and efficacy of the regimen was evaluated in all 40 patients.

Table 1 Patient characteristics

Compliance with treatment

A total of 251 treatment cycles were administered, with a median of six cycles per patient (range, 1–9 cycles). A total of 32 patients (80%) completed six or more cycles of chemotherapy, and the median number of weeks for completing six cycles of chemotherapy was 7 weeks (range 6–10 weeks). Eight patients could not complete the planned six or more cycles for the following reasons: toxicities in four cases (grades 4 and 3 diarrhoea, grade 3 liver dysfunction, and grade 3 erythema); patient refusal in three cases; and PD in one case. Six patients (15%) had their dosage of CPT-11 reduced because of leucocytopenia in three, thrombocytopenia in two, and both in one.

Clinical response and survival

All the patients were included in the analyses of tumour response and survival. Five CRs (13%) and 26 PRs (65%) were observed, for an overall response rate of 78% (31 out of 40 patients; 95% CI, 61.5–89.2%). Four NC, four PD, and one NE were also observed. One patient was lost to follow-up and only two patients were still alive as of April 16, 2003. The median survival time (MST) was 11.8 months (95% CI, 10.1–13.5 months), and the estimated 1-year survival rate was 49% (Figure 2).

Figure 2
figure2

Overall survival (n=40).

Site of first relapse and progression-free survival

The majority of patients (n=30, 75%) experienced a systemic relapse after completing PEI, including 17 patients (43%) with central nerve metastases. Six patients (15%) developed only a locoregional recurrence, and one had no recurrence and died of acute myocardial infarction. No data on recurrence patterns were available in three patients because these patients were followed up at other hospitals. In all, 13 patients received additional chemotherapy treatment after recurrence (no data on response to third-line chemotherapy were available), while four patients underwent palliative chest radiotherapy and 18 underwent whole-brain irradiation for cerebral metastases. One patient, who achieved a CR by this regimen, developed a locoregional recurrence and underwent a right upper lobectomy. He has not experienced any further relapse and is still alive. The median progression-free survival period was 5.0 months (95% CI, 4.1–5.9 months) (Figure 3).

Figure 3
figure3

Progression-free survival (n=40).

Toxicities

All the patients were included in the toxicity analysis. Severe toxicities were mainly haematological. Grades 3–4 leucopenia, neutropenia, and thrombocytopenia were observed in 22 (55%), 29 (73%), and 13 (33%) patients, respectively (Table 2). Nonhaematological toxicities were mild and transient in all patients. Grades 3–4 diarrhoea was noted in only three patients (8%) (Table 3). No treatment-related deaths occurred.

Table 2 Haematological toxicities (JCOG toxicity criteria)
Table 3 Nonhaematological toxicities (JCOG toxicity criteria)

Discussion

Despite a high response rate to first-line chemotherapy, most patients with SCLC experience a relapse within a year of the completion of therapy (Hansen, 1992). Although many relapsed patients in good physical condition undergo second-line chemotherapy, the results are disappointing. The obtained response is usually brief, and the median survival period is generally less than 4 months (Albain et al, 1993; Glisson, 2003).

Although one phase III trial for patients with relapse SCLC comparing the use of topotecan with CAV has been reported (von Pawel et al, 1999), a standard treatment for relapsed SCLC has not been agreed upon. However, the repeated use of the original induction regimen is the most popular treatment for sensitive relapsed patients. Reinduction chemotherapy has been reported to produce a response rate of 50%, and patients who relapsed more than 3 months after the end of their previous chemotherapy regimen were sensitive to reinduction chemotherapy (Giaccone et al, 1987; Postmus et al, 1987). Giaccone et al (1988) suggested that sensitive tumour cells, which were not completely eradicated by the induction chemotherapy, regrow spontaneously after the suspension of chemotherapy, eventually constituting a clinically significant part of the tumour burden. In the present study, two patients received the PEI regimen as a reinduction chemotherapy, and both patients showed PRs.

Many clinical trials of salvage chemotherapy for relapsed SCLC have been reported. In these studies, the single administration of CPT-11 or ETOP produced good results, with response rates of 16–47% and an MST of 3.5–6.2 months (Einhorn et al, 1990; Johnson et al, 1990; Masuda et al, 1992; Le Chevalier et al, 1997). Moreover, CPT-11 or ETOP-containing combined chemotherapy regimens showed favourable results, with response rates of 20–88% and an MST of 4.7–8.7 months (Table 4) (Evans et al, 1985; Masuda et al, 1990; Sculier et al, 1990; Gridelli et al, 1991; Roth et al, 1992; Faylona et al, 1995; Kubota et al, 1997; Masuda et al, 1998; Groen et al, 1999; Nakanishi et al, 1999; von Pawel et al, 1999; Domine et al, 2001; Kosmas et al, 2001). Therefore, these two drugs are considered to be key drugs for the treatment of relapsed SCLC. In particular, the combination of CPT-11 and ETOP (a combination of topoisomerase I and II inhibitors) produced a high response rate (71%) and the best survival results (MST, 8.7 months) (Masuda et al, 1998). In addition, a weekly chemotherapy regimen containing ETOP (CODE) was highly active in patients with relapsed SCLC, with a favourable response rate (88%) and survival duration (MST, 8.2 months) (Kubota et al, 1997). In the two studies mentioned above, four patients (16%) with refractory relapsed SCLC were included in the CPT-11 and ETOP study, and six patients (35%) with refractory relapsed SCLC were included in the CODE study. Three and five of these patients achieved PR, respectively.

Table 4 Combination chemotherapy studies for relapsed small-cell lung cancer

The response and survival data from Japanese clinical trials for relapsed SCLC were generally better than those obtained in western countries. We have no proof that this difference depends on either drug metabolism or tumour sensitivity. It is possibly related to the difference in patient follow-up interval between Japan and western countries. Since intensive follow up after completion of first-line treatment is common in Japan, relapses can be detected in the early stage by CT or MRI before becoming symptomatic. Therefore, relapsed patients had a relatively good performance status, and showed good responses to second-line chemotherapy as well as better survival results.

The weekly regimen was designed to increase the overall relative dose intensity of the chemotherapeutic drugs (Murray et al, 1991). However, several phase III trials have made it clear that intensive weekly chemotherapy does not improve the survival of patients with SCLC (Furuse et al, 1998; Murray et al, 1999). On the other hand, drug dosages and treatment schedules are easy to modify in weekly chemotherapy regimens. Since patients with relapsed SCLC may have lower bone marrow reserve, a high-dose regimen or intensified dosage can lead to treatment-related death (Masuda et al, 1990; Faylona et al, 1995). In the PEI regimen, the individual dosage of each drug is within the commonly used range and the dose given at one time is lower than that of a standard 3-week cycle regimen. The PEI regimen therefore permits greater flexibility in dosage adjustment and treatment delays based on laboratory data or the physical condition of patients. Thus, this regimen is considered to be suitable for the treatment of patients with relapse SCLC. In addition, this weekly schedule may be of great advantage for enabling the synergistic effects of ETOP (a topoisomerase II inhibitor) and CPT-11 to be realised because the development of resistance to topoisomerase II inhibitors has been reported to increase tumour sensitivity to subsequent treatment with topoisomerase I inhibitors (Vasey and Kaye, 1997).

Three cytotoxic drugs were used in this PEI regimen. However, three-drug combination chemotherapy was reportedly associated with more severe toxicity and showed no survival benefit as compared with the two-dug combination (Mavroudis et al, 2001; Niell et al, 2002). The main reason for mild toxicities was that the PEI regimen consists of a weekly schedule. With a weekly chemotherapy regimen, drug dosages and treatment schedules can easily be adjusted according to haematological data and the patient's physical condition. These careful modifications resulted in a mild toxicity profile with the PEI regimen. Moreover, the PEI regimen did not consist of concomitant administration of three drugs but rather weekly alternative administration of a two-drug combination chemotherapy, that is, PE and IP. As a result, the toxicity profile was similar with that of two-drug combination chemotherapy.

Although all the patients in this study were sensitive relapsed cases, the overall response rate of 78% is one of the best results reported for relapsed SCLC. Moreover, although only selected patients with a good performance status were included in this study, it is notable that the median survival time was 11.8 months and the 1-year survival rate was 49%. In JCOG- 9511, the MST was 12.8 months in the IP arm and 9.4 months in the PE arm for chemotherapy naive ED SCLC patients (Noda et al, 2002). Our survival data for PEI is almost equivalent to that of first-line treatment. Salvage chemotherapy may be possible to prolong the survival of sensitive relapsed SCLC patients who are in good physical condition.

Since second-line chemotherapy for relapsed SCLC patients is a palliative treatment, a reasonable toxicity profile is essential. The main toxicities of the PEI regimen were haematological. Although G-CSF was routinely administered, Grades 3–4 leucopenia and neutropenia were observed in 55 and 73% of patients, respectively. Grades 3–4 thrombocytopenia was observed in 33% of patients. However, the frequencies of these haematological toxicities were approximately equal to that of first-line PE treatment (Noda et al, 2002). Nonhaematological toxicities were mild and transient in all patients. Grades 3–4 diarrhoea was noted in only three patients (8%). Irinotecan dose modifications as a result of haematological toxicities were only performed in six patients (15%). All toxicities were easily manageable, and no treatment-related deaths occurred.

In conclusion, PEI is a highly active and well-tolerated treatment for sensitive relapsed SCLC. Another phase II trial restricted to refractory relapsed SCLC patients is presently being performed by our clinical group. Further phase III studies comparing PEI regimen with rechallenges of the same drugs used in the first-line chemotherapy regimen should clarify the role of second-line chemotherapy for sensitive relapsed SCLC and are now being planned.

Change history

  • 16 November 2011

    This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication

References

  1. Aisner J (1996) Extensive-disease small-cell lung cancer: the thrill of victory; the agony of defeat. J Clin Oncol 14: 658–665

  2. Albain KS, Crowley JJ, Hutchins L, Gandara D, O'Bryan RM, Von Hoff DD, Griffin B, Livingston RB (1993) Predictors of survival following relapse or progression of small cell lung cancer. Southwest Oncology Group Study 8605 report and analysis of recurrent disease data base. Cancer 72: 1184–1191

  3. Ardizzoni A, Hansen H, Dombernowsky P, Gamucci T, Kaplan S, Postmus P, Giaccone G, Schaefer B, Wanders J, Verweij J (1997) Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 15: 2090–2096

  4. Domine M, Larriba J, Morales S, Gomez R, Isla D, Terrasa S, Giner V, Giron C, Andrade J, Maestu I, Lobo F, Diaz F (2001) Gemcitabine and paclitaxel as second line treatment in small cell lung cancer. A multicentric phase II study. Proc Am Soc Clin Oncol 20: 317a

  5. Ebi N, Kubota K, Nishiwaki Y, Hojo F, Matsumoto T, Kakinuma R, Ohmatsu H, Sekine I, Yokosaki M, Gotoh K, Yamamoto H, Kodama T (1997) Second-line chemotherapy for relapsed small cell lung cancer. Jpn J Clin Oncol 27: 166–169

  6. Einhorn LH, Pennington K, McClean J (1990) Phase II trial of daily oral VP-16 in refractory small cell lung cancer: a Hoosier Oncology Group study. Semin Oncol 17: 32–35

  7. Evans WK, Feld R, Osoba D, Shepherd FA, Dill J, Deboer G (1984) VP-16 alone and in combination with cisplatin in previously treated patients with small cell lung cancer. Cancer 53: 1461–1466

  8. Evans WK, Osoba D, Feld R, Shepherd FA, Bazos MJ, DeBoer G (1985) Etoposide (VP-16) and cisplatin: an effective treatment for relapse in small-cell lung cancer. J Clin Oncol 3: 65–71

  9. Faylona EA, Loehrer PJ, Ansari R, Sandler AB, Gonin R, Einhorn LH (1995) Phase II study of daily oral etoposide plus ifosfamide plus cisplatin for previously treated recurrent small-cell lung cancer: a Hoosier Oncology Group Trial. J Clin Oncol 13: 1209–1214

  10. Fukuoka M, Furuse K, Saijo N, Nishiwaki Y, Ikegami H, Tamura T, Shimoyama M, Suemasu K (1991) Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst 83: 855–861

  11. Furuse K, Fukuoka M, Nishiwaki Y, Kurita Y, Watanabe K, Noda K, Ariyoshi Y, Tamura T, Saijo N (1998) Phase III study of intensive weekly chemotherapy with recombinant human granulocyte colony-stimulating factor versus standard chemotherapy in extensive-disease small-cell lung cancer. The Japan Clinical Oncology Group. J Clin Oncol 16: 2126–2132

  12. Giaccone G, Donadio M, Bonardi G, Testore F, Calciati A (1988) Teniposide in the treatment of small-cell lung cancer: the influence of prior chemotherapy. J Clin Oncol 6: 1264–1270

  13. Giaccone G, Ferrati P, Donadio M, Testore F, Calciati A (1987) Reinduction chemotherapy in small cell lung cancer. Eur J Cancer Clin Oncol 23: 1697–1699

  14. Glisson BS (2003) Recurrent small cell lung cancer: update. Semin Oncol 30: 72–78

  15. Gridelli C, Contegiacomo A, Lauria R, Gentile M, Airoma G, De Placido S, Perrone F, Ferrante G, Bianco AR (1991) Salvage chemotherapy with CCNU and methotrexate for small cell lung cancer resistant to CAV/PE alternating chemotherapy. Tumori 77: 506–510

  16. Groen HJ, Fokkema E, Biesma B, Kwa B, van Putten JW, Postmus PE, Smit EF (1999) Paclitaxel and carboplatin in the treatment of small-cell lung cancer patients resistant to cyclophosphamide, doxorubicin, and etoposide: a non-cross-resistant schedule. J Clin Oncol 17: 927–932

  17. Hansen HH (1992) Management of small-cell cancer of the lung. Lancet 339: 846–849

  18. Ihde DC (1992) Chemotherapy of lung cancer. N Engl J Med 327: 1434–1441

  19. Johnson DH, Greco FA, Strupp J, Hande KR, Hainsworth JD (1990) Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: a phase II trial. J Clin Oncol 8: 1613–1617

  20. Kaplan E, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481

  21. Kosmas C, Tsavaris NB, Malamos NA, Vadiaka M, Koufos C (2001) Phase II study of paclitaxel, ifosfamide, and cisplatin as second-line treatment in relapsed small-cell lung cancer. J Clin Oncol 19: 119–126

  22. Kubota K, Nishiwaki Y, Kakinuma R, Hojo F, Matsumoto T, Ohmatsu H, Sekine I, Yokozaki M, Goto K, Ebi N, Kodama T (1997) Dose-intensive weekly chemotherapy for treatment of relapsed small-cell lung cancer. J Clin Oncol 15: 292–296

  23. Kudoh S, Fujiwara Y, Takada Y, Yamamoto H, Kinoshita A, Ariyoshi Y, Furuse K, Fukuoka M (1998) Phase II study of irinotecan combined with cisplatin in patients with previously untreated small-cell lung cancer. West Japan Lung Cancer Group. J Clin Oncol 16: 1068–1074

  24. Le Chevalier T, Ibrahim N, Chomy P, Riviere A, Monnier A, Magherini E, Pujol J (1997) A phase II study of irinotecan in patients with small cell lung cancer progressing after initial response to first-line chemotherapy. Proc Am Soc Clin Oncol 16: 450a

  25. Masuda N, Fukuoka M, Kusunoki Y, Matsui K, Takifuji N, Kudoh S, Negoro S, Nishioka M, Nakagawa K, Takada M (1992) CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 10: 1225–1229

  26. Masuda N, Fukuoka M, Matsui K, Negoro S, Takada M, Sakai N, Ryu S, Takifuji N, Ito K, Kudoh S, Kusunoki Y (1990) Evaluation of high-dose etoposide combined with cisplatin for treating relapsed small cell lung cancer. Cancer 65: 2635–2640

  27. Masuda N, Matsui K, Negoro S, Takifuji N, Takeda K, Yana T, Kobayashi M, Hirashima T, Kusunoki Y, Ushijima S, Kawase I, Tada T, Sawaguchi H, Fukuoka M (1998) Combination of irinotecan and etoposide for treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 16: 3329–3334

  28. Mavroudis D, Papadakis E, Veslemes M, Tsiafaki X, Stavrakakis J, Kouroussis C, Kakolyris S, Bania E, Jordanoglou J, Agelidou M, Vlachonicolis J, Georgoulias V (2001) A multicenter randomized clinical trial comparing paclitaxel–cisplatin–etoposide versus cisplatin–etoposide as first-line treatment in patients with small-cell lung cancer. Ann Oncol 12: 463–470

  29. Mori K, Kubota K, Nishiwaki Y, Sugiura T, Noda K, Kawahara M, Negoro S, Watanabe K, Yokoyama A, Nakamura S, Fukuda H, Tamura T, Saijo N (2002) Updated results of a pilot study of etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy followed by three cycles of irinotecan and cisplatin for the treatment of limited-stage small cell lung cancer: Japan Clinical Oncology Group (JCOG9903). Proc Am Soc Clin Oncol 21: 294a

  30. Murray N, Livingston RB, Shepherd FA, James K, Zee B, Langleben A, Kraut M, Bearden J, Goodwin JW, Grafton C, Turrisi A, Walde D, Croft H, Osoba D, Ottaway J, Gandara D (1999) Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 17: 2300–2308

  31. Murray N, Shah A, Osoba D, Page R, Karsai H, Grafton C, Goddard K, Fairey R, Voss N (1991) Intensive weekly chemotherapy for the treatment of extensive-stage small-cell lung cancer. J Clin Oncol 9: 1632–1638

  32. Nakanishi Y, Takayama K, Takano K, Inoue K, Osaki S, Wataya H, Takaki Y, Minami T, Kawasaki M, Hara N (1999) Second-line chemotherapy with weekly cisplatin and irinotecan in patients with refractory lung cancer. Am J Clin Oncol 22: 399–402

  33. Niell HB, Herndon JE, Miller AA, Watson DM, Sandler A, Kelly K, Marks R, Green MR (2002) Randomized phase III intergroup trial (CALGB 9732) of etoposide (VP-16) and cisplatin (DDP) with or without paclitaxel (TAX) and G-CSF in patients with extensive stage small cell lung cancer (ED-SCLC). Proc Am Soc Clin Oncol 21: 293a

  34. Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, Fukuoka M, Mori K, Watanabe K, Tamura T, Yamamoto S, Saijo N (2002) Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346: 85–91

  35. Porter III LL, Johnson DH, Hainsworth JD, Hande KR, Greco FA (1985) Cisplatin and etoposide combination chemotherapy for refractory small cell carcinoma of the lung. Cancer Treat Rep 69: 479–481

  36. Postmus PE, Berendsen HH, van Zandwijk N, Splinter TA, Burghouts JT, Bakker W (1987) Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur J Cancer Clin Oncol 23: 1409–1411

  37. Roth BJ, Johnson DH, Einhorn LH, Schacter LP, Cherng NC, Cohen HJ, Crawford J, Randolph JA, Goodlow JL, Broun GO, Omura GA, Greco FA (1992) Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 10: 282–291

  38. Sculier JP, Klastersky J, Libert P, Ravez P, Brohee D, Vandermoten G, Michel J, Thiriaux J, Bureau G, Schmerber J, Sergysels R, Coune A (1990) Cyclophosphamide, doxorubicin and vincristine with amphotericin B in sonicated liposomes as salvage therapy for small cell lung cancer. Eur J Cancer 26: 919–921

  39. Sekine I, Nishiwaki Y, Kakinuma R, Kubota K, Hojo F, Matsumoto T, Ohmatsu H, Goto K, Kodama T, Eguchi K, Shinkai T, Tamura T, Ohe Y, Kunitoh H, Yoshimura K, Saijo N (2003) Phase I/II trial of weekly cisplatin, etoposide, and irinotecan chemotherapy for metastatic lung cancer: JCOG 9507. Br J Cancer 88: 808–813

  40. Sekine I, Nishiwaki Y, Noda K, Kudoh S, Fukuoka M, Mori K, Negoro S, Yokoyama A, Matsui K, Ohsaki Y, Nakano T, Saijo N (2002) Randomized phase II study of cisplatin, irinotecan, and etoposide combinations administered weekly or every four weeks for extensive small cell lung cancer: JCOG9902-DI. Proc Am Soc Clin Oncol 21: 1223a

  41. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10: 1–10

  42. Tobinai K, Kohno A, Shimada Y, Watanabe T, Tamura T, Takeyama K, Narabayashi M, Fukutomi T, Kondo H, Shimoyama M, Suemasu K (1993) Toxicity grading criteria of the Japan Clinical Oncology Group. The Clinical Trial Review Committee of the Japan Clinical Oncology Group. Jpn J Clin Oncol 23: 250–257

  43. Vasey PA, Kaye SB (1997) Combined inhibition of topoisomerases I and II – is this a worthwhile/feasible strategy? Br J Cancer 76: 1395–1397

  44. von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, Stewart DJ, Clark PI, Palmer MC, Depierre A, Carmichael J, Krebs JB, Ross G, Lane SR, Gralla R (1999) Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17: 658–667

  45. World Health Organization (1979) World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment, Vol. WHO Offset Publication No. 48. Geneva, Switzerland: World Health Organization

Download references

Acknowledgements

This study was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health Labour and Welfare of Japan.

Author information

Correspondence to K Goto.

Rights and permissions

From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

Reprints and Permissions

About this article

Cite this article

Goto, K., Sekine, I., Nishiwaki, Y. et al. Multi-institutional phase II trial of irinotecan, cisplatin, and etoposide for sensitive relapsed small-cell lung cancer. Br J Cancer 91, 659–665 (2004) doi:10.1038/sj.bjc.6602056

Download citation

Keywords

  • irinotecan
  • etoposide
  • small-cell lung cancer
  • sensitive relapse
  • second line
  • salvage chemotherapy

Further reading