Etoposide Plus Cisplatin With or Without the Combination of 4'-Epidoxorubicin Plus Cyclophosphamide in Treatment of Extensive Small-Cell Lung Cancer: a French Federation of Cancer Institutes Multicenter Phase III Randomized Study

Pujol, Jean-Louis; Daurès, Jean‐Pierre; Rivière, Alain; Quoix, Élisabeth; Westeel, Virginie; Quantin, Xavier; Breton, Jean-Luc; Lemarié, É.; Poudenx, M.; Milleron, B.; Moro, D.; Debieuvre, D.; Chevalier, Thierry Le

doi:10.1093/jnci/93.4.300

Cited by 155 publications

(66 citation statements)

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“…The infection rates seen in both arms of this study were substantially higher than the 14-15% reported for ACE and 16% for VICE -toxicity data were not reported for the Sundstrom study. Thatcher et al, 2000) However, the toxic death rate (1%) is lower than the 4 -10% reported in other comparable studies (Thatcher et al, 2000;Pujol et al, 2001;Ardizzoni et al, 2002). The likely explanation for the high-recorded infection rate but low toxic death rate in both arms was that patients were seen weekly and clinical teams had a low threshold for responding to neutropenia.…”

Section: Discussionmentioning

confidence: 78%

“…Subsequently, an overview of US National Cancer Institute sponsored trials for ED patients conducted between 1972 and 1990 demonstrated that cisplatin-based regimens were associated with an improved median survival (Chute et al, 1999) and a metaanalysis of 19 trials published between 1981 and 1999 showed a small survival benefit for patients receiving cisplatin-based chemotherapy (Pujol et al, 2001). Etoposide-containing regimens, with or without cisplatin, were also shown to be associated with a significant survival benefit (Mascaux et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

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Phase III randomised trial of doxorubicin-based chemotherapy compared with platinum-based chemotherapy in small-cell lung cancer

et al. 2008

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This randomised trial compared platinum-based to anthracycline-based chemotherapy in patients with small-cell lung cancer (limited or extensive stage) and p2 adverse prognostic factors. Patients were randomised to receive six cycles of either ACE (doxorubicin 50 mg/m 2 i.v., cyclophosphamide 1 g/m 2 i.v. and etoposide 120 mg/m 2 i.v. on day 1, then etoposide 240 mg/m 2 orally for 2 days) or PE (cisplatin 80 mg/m 2 and etoposide 120 mg/m 2 i.v. on day 1, then etoposide 240 mg/m 2 orally for 2 days) given for every 3 weeks. For patients where cisplatin was not suitable, carboplatin (AUC6) was substituted. A total of 280 patients were included (139 ACE, 141 PE). The response rates were 72% for ACE and 77% for PE. One-year survival rates were 34 and 38% (P ¼ 0.497), respectively and 2-year survival was the same (12%) for both arms. For LD patients, the median survival was 10.9 months for ACE and 12.6 months for PE (P ¼ 0.51); for ED patients median survival was 8.3 months and 7.5 months, respectively. More grades 3 and 4 neutropenia (90 vs 57%, Po0.005) and grades 3 and 4 infections (73 vs 29%, Po0.005) occurred with ACE, resulting in more days of hospitalisation and greater i.v. antibiotic use. ACE was associated with a higher risk of neutropenic sepsis than PE and with a trend towards worse outcome in patients with LD, and should not be studied further in this group of patients.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Phase III randomised trial of doxorubicin-based chemotherapy compared with platinum-based chemotherapy in small-cell lung cancer

et al. 2008

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“…The issue of adding further agents to the standard doublet regimen has been investigated in patients with ED-SCLC. The addition of ifosfamide or cyclophosphamide and epirubicin to the cisplatin and etoposide combination produced a slight survival benefit, but at the expense of greater toxicity (Loehrer et al, 1995;Pujol et al, 2001). Phase III trials of cisplatin and etoposide with or without paclitaxel showed unacceptable toxicity with 6 -13% toxic deaths in the paclitaxel-containing arm (Mavroudis et al, 2001;Niell et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Randomised phase II trial of irinotecan plus cisplatin vs irinotecan, cisplatin plus etoposide repeated every 3 weeks in patients with extensive-disease small-cell lung cancer

et al. 2008

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Patients with previously untreated extensive-disease small-cell lung cancer were treated with irinotecan 60 mg m À2 on days 1 and 8 and cisplatin 60 mg m À2 on day 1 with (n ¼ 55) or without (n ¼ 54) etoposide 50 mg m À2 on days 1 -3 with granulocyte colonystimulating factor support repeated every 3 weeks for four cycles. The triplet regimen was too toxic to be considered for further studies. Small-cell lung cancer (SCLC), which accounts for approximately 14% of all malignant pulmonary tumours, is an aggressive malignancy with a propensity for rapid growth and early widespread metastases (Jackman and Johnson, 2005). A combination of cisplatin and etoposide (PE) has been the standard treatment, with response rates ranging from 60 to 90% and median survival times (MSTs) from 8 to 11 months in patients with extensive disease (ED)-SCLC (Fukuoka et al, 1991;Roth et al, 1992). A combination of irinotecan and cisplatin (IP) showed a significant survival benefit over the PE regimen (MST: 12.8 vs 9.4 months, P ¼ 0.002) in a Japanese phase III trial for ED-SCLC (Noda et al, 2002), although another phase III trial comparing these regimens failed to show such a benefit (Hanna et al, 2006). Thus, irinotecan, cisplatin and etoposide are the current key agents in the treatment of SCLC. A phase II trial of the three agents, IPE combination, in patients with ED-SCLC showed a promising antitumour activity with a response rate of 77%, complete response (CR) rate of 17% and MST of 12.9 months (Sekine et al, 2003).We have developed these IP and IPE regimens in a 4-week schedule where irinotecan was given on days 1, 8 and 15. The dose of irinotecan on day 15, however, was frequently omitted because of toxicity in both regimens (Noda et al, 2002;Sekine et al, 2003).The objectives of this study were to evaluate the toxicities and antitumour effects of IP and IPE regimens in the 3-week schedule in patients with ED-SCLC and to select the right arm for subsequent phase III trials. PATIENTS AND METHODS Patient selectionPatients were enrolled in this study if they met the following criteria: (1) a histological or cytological diagnosis of SCLC; (2) no prior treatment; (3) measurable disease; (4) ED, defined as having distant metastasis or contralateral hilar lymph node metastasis; (5) performance status of 0 -2 on the Eastern Cooperative Oncology Group (ECOG) scale; (6) predicted life expectancy of 3 months or longer; (7) age between 20 and 70 years; (8) adequate organ function as documented by a white blood cell (WBC) count X4.0 Â 10 3 ml À1 , neutrophil count X2.0 Â 10 3 ml À1 , haemoglobin X9.5 g dl À1 , platelet count X100 Â 10 3 ml À1 , total serum bilirubinp1.5 mg dl À1 , hepatic transaminasesp100 IU l À1 , serum creatinine p1.2 mg dl À1 , creatinine clearance X60 ml min À1 , and PaO 2 X60 torr; and (9) providing written informed consent.Patients were not eligible for the study if they had any of the following: (1) uncontrollable pleural, pericardial effusion or ascites; (2) symptomatic brain metastasis; (3) active infection; (4) contr...

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“…However, response to treatment, in particular, complete response, has been suggested as the major indicator of long-term survival (Paesmans et al, 2000). In ED patients the doublet PE produced complete response rates ranging from 4 to 23% (Evans et al, 1985;Roth et al, 1992;Pujol et al, 2001) and the triplets CDE (cyclophosphamide, doxorubicin and i.v. etoposide) and CAV yielded similar figures (Ettinger et al, 1990;Roth et al, 1992;Ardizzoni et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Epirubicin/paclitaxel/etoposide in extensive-stage small-cell lung cancer: a phase I–II study

et al. 2006

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The aim of this study was to evaluate feasibility and toxicity of escalating doses of epirubicin and paclitaxel plus fixed dose of etoposide and to define the activity of the triplet in extensive disease small-cell lung cancer. Thirteen patients entered the phase I study: the maximum tolerated doses were epirubicin (EpiDX) 90 mg m À2 and paclitaxel (P) 175 mg m À2 with febrile neutropenia as dose-limiting toxicity. The recommended schedule for this regimen for the phase II study was EpiDX 75 mg m À2 , P 175 mg m À2 , etoposide (E) 100 mg m À2 intravenous (fixed dose) days 1 -3 with courses repeated every 21 days. The prophylactic use of colonystimulating factors (CSFs) was not allowed. Twenty patients entered the phase II trial: median age was 61 years (range 50 -70), median Eastern Cooperative Oncology Group performance status 0 (0 -2); nine patients had visceral disease and 17 had more than two metastatic sites. A total of 100 courses were administered with a median of 5 (range 1 -6) per patients. Main toxicity (NCI-CTC) was myelosuppression: neutropenia grades 3 and 4 in 16 and 35% of the courses, respectively. Seven episodes of febrile neutropenia were documented and one patient required hospital admission. Nonhaematological toxicity was moderate. Seven out of 19 evaluable patients achieved a complete response (37%), nine patients (47.3%) a partial response with an overall response rate of 84.2% ((95% confidence interval ¼ 60.4 -96.6)). In this poor prognostic population of patients the triplet epirubicin/paclitaxel/ etoposide showed high antitumour activity with mild nonhaematological side effects. The use of CSFs should be able to improve the haematological profile.

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Etoposide Plus Cisplatin With or Without the Combination of 4'-Epidoxorubicin Plus Cyclophosphamide in Treatment of Extensive Small-Cell Lung Cancer: a French Federation of Cancer Institutes Multicenter Phase III Randomized Study

Abstract: Compared with the EP regimen, the PCDE regimen yielded higher response rates and better survival rates in patients with extensive SCLC without affecting the quality of life of the patients during chemotherapy.

Cited by 155 publications

References 25 publications

Phase III randomised trial of doxorubicin-based chemotherapy compared with platinum-based chemotherapy in small-cell lung cancer

Phase III randomised trial of doxorubicin-based chemotherapy compared with platinum-based chemotherapy in small-cell lung cancer

Randomised phase II trial of irinotecan plus cisplatin vs irinotecan, cisplatin plus etoposide repeated every 3 weeks in patients with extensive-disease small-cell lung cancer

Epirubicin/paclitaxel/etoposide in extensive-stage small-cell lung cancer: a phase I–II study

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