Abstract
Background Etoposide and irinotecan are key drugs in the treatment of small-cell lung cancer. We did this study to investigate whether combined chemotherapy with cisplatin, etoposide, and irinotecan was superior to topotecan monotherapy as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer. Methods We did this open-label, multicentre, randomised phase 3 trial at 29 institutions in Japan. Patients with small-cell lung cancer that responded to first-line treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment were eligible to participate. Enrolled patients were randomly assigned (1:1) to receive combination chemotherapy with cisplatin plus etoposide plus irinotecan or topotecan alone. Randomisation was done via the minimisation method with biased-coin balancing for Eastern Cooperative Oncology Group performance status, disease stage at enrolment, and institution. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m2 on days 1 and 8, intravenous etoposide 60 mg/m2 on days 1–3, and intravenous irinotecan 90 mg/m2 on day 8, with granulocyte colony-stimulating factor given by hypodermic injection every day starting from day 9 of the first course (except on the days anticancer drugs were given). Topotecan therapy consisted of four courses of intravenous topotecan 1·0 mg/m2 on days 1–5, every 3 weeks. The primary endpoint was overall survival in the intention-to-treat population, which was analysed with a one-sided α of 5%, and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000000828. Findings Between Sept 20, 2007, and Nov 30, 2012, 180 patients were enrolled, with 90 assigned to each treatment group. The median follow-up for censored patients was 22·7 months (IQR 20·0–35·3). Overall survival was significantly longer in the combination chemotherapy group (median 18·2 months, 95% CI 15·7–20·6) than in the topotecan group (12·5 months, 10·8–14·9; hazard ratio 0·67, 90% CI 0·51–0·88; p=0·0079). The most common grade 3 or 4 adverse events were neutropenia (75 [83%] patients in the combination chemotherapy group vs 77 [86%] patients in the topotecan group), anaemia (76 [84%] vs 25 [28%]), and leucopenia (72 [80%] vs 46 [51%]). Grade 3 or 4 febrile neutropenia was more common in the combination chemotherapy group than in the topotecan group (28 [31%] vs six [7%]), as was grade 3 or 4 thrombocytopenia (37 [41%] vs 25 [28%]). Serious adverse events were reported in four (4%) patients in the topotecan group and nine (10%) in the combination chemotherapy group. Two treatment-related deaths (one each of pneumonitis and pulmonary infection) occurred in the topotecan group and one (febrile neutropenia with sepsis) occurred in the combination chemotherapy group. Interpretation Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed small-cell lung cancer. Funding National Cancer Center and the Ministry of Health, Labour and Welfare of Japan.
| Original language | English |
|---|---|
| Pages (from-to) | 1147-1157 |
| Number of pages | 11 |
| Journal | The Lancet Oncology |
| Volume | 17 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Aug 1 2016 |
ASJC Scopus subject areas
- Oncology
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Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605) : a multicentre, open-label, randomised phase 3 trial. / for the; JCOG0605 investigators.
In: The Lancet Oncology, Vol. 17, No. 8, 01.08.2016, p. 1147-1157.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605)
T2 - a multicentre, open-label, randomised phase 3 trial
AU - for the
AU - JCOG0605 investigators
AU - Goto, Koichi
AU - Ohe, Yuichiro
AU - Shibata, Taro
AU - Seto, Takashi
AU - Takahashi, Toshiaki
AU - Nakagawa, Kazuhiko
AU - Tanaka, Hiroshi
AU - Takeda, Koji
AU - Nishio, Makoto
AU - Mori, Kiyoshi
AU - Satouchi, Miyako
AU - Hida, Toyoaki
AU - Yoshimura, Naruo
AU - Kozuki, Toshiyuki
AU - Imamura, Fumio
AU - Kiura, Katsuyuki
AU - Okamoto, Hiroaki
AU - Sawa, Toshiyuki
AU - Tamura, Tomohide
N1 - Funding Information: In this study of second-line chemotherapy for sensitive relapsed small-cell lung cancer, overall survival was significantly longer in patients who received the combination of cisplatin plus etoposide plus irinotecan than in those who received topotecan alone. To our knowledge, this is the first time that any regimen has been shown to yield a survival benefit compared with topotecan in relapsed small-cell lung cancer. Although only selected patients in good physical condition with sensitive relapsed small-cell lung cancer (ie, those 75 years old or younger who had a good ECOG performance status [mainly 0–1] and no symptomatic brain metastasis) were included in this study, it is notable that, in the combination chemotherapy group, median survival was 18·2 months and 84% of patients achieved an objective response. Salvage chemotherapy might be possible and could prolong the survival of patients with sensitive relapsed small-cell lung cancer who are in good physical condition. Moreover, similar to that reported in the first-line setting, 23 our results show that intensive combination chemotherapy was more effective than palliative single-agent chemotherapy in patients with sensitive relapsed small-cell lung cancer. Response and survival results from clinical trials for relapsed small-cell lung cancer in Japan have generally been better than those reported from the USA and Europe. The better survival data reported in Japanese trials might be related to the difference in follow-up intervals between Japan and western countries. Since intensive follow-up is common after completion of first-line treatment in Japan, relapses can be detected by CT or MRI at a very early stage, before the patient becomes symptomatic. 17 Therefore, patients with relapse show a relatively good performance status and good responses to salvage chemotherapy, as well as better survival results than in other countries. Since second-line chemotherapy for patients with relapsed small-cell lung cancer is a palliative treatment, a reasonable toxicity profile is essential. Severe adverse events were more common in the combination chemotherapy group than in the topotecan group. Although G-CSF was routinely given to patients in the combination chemotherapy group, grade 3 or worse neutropenia and febrile neutropenia were reported in 75 (83%) and 28 (31%) patients receiving combination chemotherapy, respectively. Grade 3 or worse anaemia and thrombocytopenia were also noted. Non-haematological adverse events were mild and transient in the combination chemotherapy group. However, these adverse events were easily managed through modification of irinotecan dose. Although the severe toxicity of cisplatin plus etoposide plus irinotecan must be taken into account, the 6-month increased survival compared with topotecan represents a substantial benefit for patients with relapsed small-cell lung cancer. Repeat use of the first-line regimen is one of the most popular treatments for patients with sensitive relapsed small-cell lung cancer. In two previous studies, 46% and 62% of patients achieved responses with repeated induction chemotherapy. 5,24 Such high proportions of patients achieving a response seem to be attributable to the residual chemosensitivity of the tumour cells that were not eradicated by the initial therapy, suggesting that this approach might be a promising treatment alternative for patients with sensitive relapsed small-cell lung cancer. However, these reports were published in the 1980s and were based on studies of small-cell lung cancer in patients who developed relapse 30–34 weeks after the end of the initial therapy. The effectiveness of this approach for patients with sensitive relapse that develops 90 days or more after the end of the initial therapy—a situation that is often encountered during clinical practice—remains to be established. Thus, although repeated induction chemotherapy seems to be effective, it is unknown to what extent such an approach can contribute to improving patient survival. The combination chemotherapy regimen in our study consists of alternating weeks of the two two-drug combinations, cisplatin plus etoposide and cisplatin plus irinotecan. Both cisplatin plus etoposide and cisplatin plus irinotecan have been reported to show promising activity in patients with small-cell lung cancer and they are regarded as standard first-line chemotherapy regimens. 25–27 Cisplatin plus etoposide plus irinotecan is therefore a combination chemotherapy regimen with two platinum re-challenges. The efficacy of this regimen might depend partly on this repeated use of the first-line cisplatin plus etoposide and cisplatin plus irinotecan regimens. Initially, the weekly regimen of the combination chemotherapy was chosen to increase the overall relative dose intensity of the chemotherapeutic drugs. 28 However, several phase 3 trials have shown that intensive weekly chemotherapy does not necessarily improve the survival of patients with small-cell lung cancer. 29,30 On the positive side, drug dosages and treatment schedules are easy to modify in weekly chemotherapy regimens. Moreover, the individual dosages of each drug are within the commonly used dose ranges and the doses given each time in the weekly regimen are lower than those in a standard regimen with 3-week cycles. Therefore, the weekly design affords greater flexibility in dosage adjustment and treatment delays, which can be based on laboratory data or the physical condition of the patient. 17 Thus, based on our results, we consider the weekly cisplatin plus etoposide plus irinotecan regimen to be suitable for the treatment of patients with relapsed small-cell lung cancer who have lower bone marrow reserves. Four randomised phase 3 studies in patients with sensitive relapsed small-cell lung cancer have been reported, 6,7,19,20 and all showed the effectiveness of topotecan compared with other treatments such as best supportive care, the combination of cyclophosphamide plus doxorubicin plus vincristine, oral topotecan, or amrubicin. On the basis of these results, single-agent topotecan has been regarded as the standard second-line chemotherapy for sensitive relapsed small-cell lung cancer and is now the most commonly used treatment for relapsed small-cell lung cancer in the USA and EU. However, since the efficacy of topotecan (7–24% of patients reported as achieving a response and reported median survival of 25–35 weeks) was much lower in everyday practice than expected, there is not yet a consensus as to whether topotecan monotherapy should actually be the standard treatment for relapsed small-cell lung cancer. However, it is generally agreed that, at present, there is no established superior chemotherapy for patients with relapsed small-cell lung cancer. Our study had several limitations. First, the topotecan dose of 1·0 mg/m 2 was lower than the approved topotecan dose of 1·5 mg/m 2 used in the USA. However, 1·5 mg/m 2 topotecan is regarded as very toxic, and in a randomised trial 19,20,31 of intravenous topotecan at 1·5 mg/m 2 in patients with relapsed small-cell lung cancer, reduction of the topotecan dose was needed in 35–45% of patients because of the development of haematological adverse events. This result suggests that 1·5 mg/m 2 of topotecan might represent an overdose of the drug in patients with relapsed small-cell lung cancer who have lower bone marrow reserves, and that the recommended dose should be reduced to the lower dose range of 1·0–1·25 mg/m 2 . Huber and colleagues 32 did a prospective study of topotecan at the reduced dose of 1·25 mg/m 2 and reported the efficacy of the drug at the lower dose to be equivalent to that of the standard dose of 1·5 mg/m 2 . Additionally, results from a meta-analysis of four multicentre trials of topotecan at a starting dose of 1·5 mg/m 2 in patients with relapsed small-cell lung cancer suggested that the dose reductions due to haematological adverse events were not associated with decreased efficacy. 33 These data suggest that the higher dose of topotecan might only be associated with an increase in the frequency of haematological adverse events without any improvement in efficacy. A Japanese phase 2 study of topotecan was started with a dose of 1·2 mg/m 2 in patients with small-cell lung cancer. 34 Since the dose of 1·2 mg/m 2 was still toxic and one treatment-related death occurred, the dose was further reduced to 1·0 mg/m 2 . Based on these safety and efficacy data, 1·0 mg/m 2 was selected as the recommended dose in Japan. In this phase 2 study 34 with a 1·0 mg/m 2 dose of topotecan, 26% of patients had a response and progression-free survival was 19·0 weeks. In our phase 3 study, among those who received 1·0 mg/m 2 topotecan, 27% of patients had a response and progression-free survival was 15·7 weeks. This suggests that the dose of topotecan did not affect the results of this phase 3 study. Second, because second-line chemotherapy for relapsed small-cell lung cancer is a palliative treatment, and severe adverse events were reported frequently in the combination chemotherapy group, it is a major limitation of our trial that we did not include quality of life as one of the endpoints. Since the JCOG has now established a system for the assessment of quality of life, we will investigate this outcome in future clinical trials for relapsed small-cell lung cancer. Third, in this study, use of subsequent intensive chemotherapy with three or more drugs was prohibited in the topotecan group. This restriction could have contributed to overall survival being better in the combination chemotherapy group than in the topotecan group, although the better progression-free survival in the combination chemotherapy group might have had a greater contribution. In conclusion, the combination of cisplatin, etoposide, and irinotecan resulted in longer overall survival and greater response than single-agent topotecan for the treatment of sensitive relapsed small-cell lung cancer. Therefore, this combination chemotherapy could be regarded as the standard second-line chemotherapy for patients with sensitive relapsed small-cell lung cancer who are in good general physical condition. Contributors All authors were involved in the conception and design of the study, and the provision of study material, patients, and data acquisition. KG, YO, TSh, and TTam were responsible for data management, statistical analysis, and data interpretation. All authors were involved in the writing of the report and approved the final version. Declaration of interests KG reports grants and personal fees from AstraZeneka, Taiho Pharmaceutical, Chugai Pharmaceutical, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Pfizer, Kyowa Hakko Kirin, Eli Lilly Japan, Novartis Pharma, and Daiichi Sankyo; grants from Quintiles, GlaxoSmithKline, OxOnc, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Astellas Pharma, Eisai, Amgen, Astellas BioPharma, and MSD; and personal fees from Yakult Honsha and Bristol-Myers Squibb, outside the submitted work. YO reports grants and personal fees from BMS and personal fees from Nipponkayaku during the conduct of the study, as well as grants and personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Ono Pharmaceutical, BMS, Daiichi Sankyo, Pfizer, and Taiho; grants from Merck Serono, Dainippon-Sumitomo, Kyorin, and Esai; and personal fees from Nipponkayaku, Boehringer Ingelheim, Bayer, MSD, Clovis, Sanofi, and Novartis, outside the submitted work. TSe reports grants and personal fees from Chugai Pharmaceutical, AstraZeneca, Pfizer Japan, Taiho Pharmaceutical, and Nippon Boehringer Ingelheim; grants from Astellas Pharma, Novartis Pharma, MSD, Bayer Yakuhin, and Yakult Honsha; and personal fees from Eli Lilly Japan, Ono Pharmaceutical, Fuji Pharma, Eisai, Takeda Pharmaceutical, Dainippon Sumitomo Pharma, Kyowa Hakko Kirin, and Hisamitsu Pharmaceutical. TTak reports grants and personal fees from AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, and Ono Pharmaceutical; and personal fees from Boehringer Ingelheim Japan, outside the submitted work. KN reports personal fees and research funding from Daiichi Sankyo, during the conduct of the study. HT reports grants and personal fees from Eli Lilly, AstraZeneca, Ono Pharmaceutical, and Chugai; and grants from MSD, Takeda Bio, Daiichi Sankyo, Pfizer, Taiho Pharmaceutical, and Boehringer Ingelheim, outside the submitted work. MN reports fees for advisory roles or honoraria from AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Pfizer, Eli Lilly, Novartis, Daiichi Sankyo, and Bristol-Myers Squibb; and personal fees from Yakult Honsha, outside the submitted work. MS reports lecture fees and research expenses from Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly Japan, Pfizer Japan, AstraZeneca, Bristol-Myers Squibb, Ono Pharmaceutical, and Novartis Pharmaceutical; lecture fees from Boehringer Ingelheim; and research expenses from MSD, outside the submitted work. TH reports grants and personal fees from Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Novartis, Taiho Pharmaceutical, AstraZeneca, Nippon Boehringer Ingelheim, Pfizer, Bristol-Meyers Squibb, Clovis Oncology; and grants from Eisai, Takeda Bio, Dainippon Sumitomo Pharma, Abbvie, Merck Serono, Kyowa Hakko Kirin, Daiichi Sankyo, and Astellas, outside the submitted work. TK reports personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, Pfizer, Kyowa Hakko Kirin, Taiho Pharmaceutical, and Roche, outside the submitted work. KK reports speaking fees and research grants from Chugai Pharmaceutical, Ono Pharmaceutical, and Boehringer Ingelheim; and speaking fees from AstraZeneca and Eli Lilly, outside the submitted work. HO reports research funding from Takeda, MSD, Ono Pharmaceutical, AstraZeneca, Merck, Chugai Pharmaceutical, Taiho Pharmaceutical, other from Bristol-Myers Squibb, PAREXEL, and Eli Lilly, outside the submitted work. TTam reports grants from the National Cancer Center, during the conduct of the study, as well as honoraria Chugai Pharmaceutical, Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Eisai, Yakult, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Daiichi Sankyo, and Astellas, outside the submitted work. All other authors declare no competing interests. Acknowledgments This study was supported by the National Cancer Center Research and Development Fund ( 23-A-16 and 23-A-18, 26-A-4 ), a Grant-in-Aid for Cancer Research ( 17S-2, 17S-5, 20S-2 and 20S-6 ), and Health and Labour Sciences Research Grants for Clinical Cancer Research (H18-Gan-010, H21-Gan-013, and H24-Gan-008) from the Ministry of Health, Labour and Welfare of Japan. We sincerely thank all patients and their families. We especially thank the members of the Japan Clinical Oncology Group, Data Center and Operations Office for their support in article preparation (Kenichi Nakamura), statistical analysis support (Junki Mizusawa), data management (Tomoko Kazato), and oversight of the study management (Haruhiko Fukuda). Furthermore, we thank Nagahiro Saijo, Yutaka Nishiwaki, Ikuo Sekine, Fumiko Koh, and all the investigators of the Japan Clinical Oncology Group, Lung Cancer Study Group for their encouragement and for supporting this trial.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - Background Etoposide and irinotecan are key drugs in the treatment of small-cell lung cancer. We did this study to investigate whether combined chemotherapy with cisplatin, etoposide, and irinotecan was superior to topotecan monotherapy as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer. Methods We did this open-label, multicentre, randomised phase 3 trial at 29 institutions in Japan. Patients with small-cell lung cancer that responded to first-line treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment were eligible to participate. Enrolled patients were randomly assigned (1:1) to receive combination chemotherapy with cisplatin plus etoposide plus irinotecan or topotecan alone. Randomisation was done via the minimisation method with biased-coin balancing for Eastern Cooperative Oncology Group performance status, disease stage at enrolment, and institution. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m2 on days 1 and 8, intravenous etoposide 60 mg/m2 on days 1–3, and intravenous irinotecan 90 mg/m2 on day 8, with granulocyte colony-stimulating factor given by hypodermic injection every day starting from day 9 of the first course (except on the days anticancer drugs were given). Topotecan therapy consisted of four courses of intravenous topotecan 1·0 mg/m2 on days 1–5, every 3 weeks. The primary endpoint was overall survival in the intention-to-treat population, which was analysed with a one-sided α of 5%, and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000000828. Findings Between Sept 20, 2007, and Nov 30, 2012, 180 patients were enrolled, with 90 assigned to each treatment group. The median follow-up for censored patients was 22·7 months (IQR 20·0–35·3). Overall survival was significantly longer in the combination chemotherapy group (median 18·2 months, 95% CI 15·7–20·6) than in the topotecan group (12·5 months, 10·8–14·9; hazard ratio 0·67, 90% CI 0·51–0·88; p=0·0079). The most common grade 3 or 4 adverse events were neutropenia (75 [83%] patients in the combination chemotherapy group vs 77 [86%] patients in the topotecan group), anaemia (76 [84%] vs 25 [28%]), and leucopenia (72 [80%] vs 46 [51%]). Grade 3 or 4 febrile neutropenia was more common in the combination chemotherapy group than in the topotecan group (28 [31%] vs six [7%]), as was grade 3 or 4 thrombocytopenia (37 [41%] vs 25 [28%]). Serious adverse events were reported in four (4%) patients in the topotecan group and nine (10%) in the combination chemotherapy group. Two treatment-related deaths (one each of pneumonitis and pulmonary infection) occurred in the topotecan group and one (febrile neutropenia with sepsis) occurred in the combination chemotherapy group. Interpretation Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed small-cell lung cancer. Funding National Cancer Center and the Ministry of Health, Labour and Welfare of Japan.
AB - Background Etoposide and irinotecan are key drugs in the treatment of small-cell lung cancer. We did this study to investigate whether combined chemotherapy with cisplatin, etoposide, and irinotecan was superior to topotecan monotherapy as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer. Methods We did this open-label, multicentre, randomised phase 3 trial at 29 institutions in Japan. Patients with small-cell lung cancer that responded to first-line treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment were eligible to participate. Enrolled patients were randomly assigned (1:1) to receive combination chemotherapy with cisplatin plus etoposide plus irinotecan or topotecan alone. Randomisation was done via the minimisation method with biased-coin balancing for Eastern Cooperative Oncology Group performance status, disease stage at enrolment, and institution. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m2 on days 1 and 8, intravenous etoposide 60 mg/m2 on days 1–3, and intravenous irinotecan 90 mg/m2 on day 8, with granulocyte colony-stimulating factor given by hypodermic injection every day starting from day 9 of the first course (except on the days anticancer drugs were given). Topotecan therapy consisted of four courses of intravenous topotecan 1·0 mg/m2 on days 1–5, every 3 weeks. The primary endpoint was overall survival in the intention-to-treat population, which was analysed with a one-sided α of 5%, and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000000828. Findings Between Sept 20, 2007, and Nov 30, 2012, 180 patients were enrolled, with 90 assigned to each treatment group. The median follow-up for censored patients was 22·7 months (IQR 20·0–35·3). Overall survival was significantly longer in the combination chemotherapy group (median 18·2 months, 95% CI 15·7–20·6) than in the topotecan group (12·5 months, 10·8–14·9; hazard ratio 0·67, 90% CI 0·51–0·88; p=0·0079). The most common grade 3 or 4 adverse events were neutropenia (75 [83%] patients in the combination chemotherapy group vs 77 [86%] patients in the topotecan group), anaemia (76 [84%] vs 25 [28%]), and leucopenia (72 [80%] vs 46 [51%]). Grade 3 or 4 febrile neutropenia was more common in the combination chemotherapy group than in the topotecan group (28 [31%] vs six [7%]), as was grade 3 or 4 thrombocytopenia (37 [41%] vs 25 [28%]). Serious adverse events were reported in four (4%) patients in the topotecan group and nine (10%) in the combination chemotherapy group. Two treatment-related deaths (one each of pneumonitis and pulmonary infection) occurred in the topotecan group and one (febrile neutropenia with sepsis) occurred in the combination chemotherapy group. Interpretation Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed small-cell lung cancer. Funding National Cancer Center and the Ministry of Health, Labour and Welfare of Japan.
UR - http://www.scopus.com/inward/record.url?scp=84995934886&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84995934886&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(16)30104-8
DO - 10.1016/S1470-2045(16)30104-8
M3 - Article
C2 - 27312053
AN - SCOPUS:84995934886
VL - 17
SP - 1147
EP - 1157
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 8
ER -