Combination chemotherapy with bevacizumab and S-1 for elderly patients with metastatic colorectal cancer (BASIC trial)

European Journal of Cancer (2015) 51, 935– 941

Available at www.sciencedirect.com

ScienceDirect journal homepage: www.ejcancer.com

Clinical Trial

Combination chemotherapy with bevacizumab and S-1 for elderly patients with metastatic colorectal cancer (BASIC trial) M. Yoshida a,⇑, K. Muro b, A. Tsuji c, Y. Hamamoto d, T. Yoshino e, K. Yoshida f, K. Shirao g, Y. Miyata h, D. Takahari b, T. Takahashi f, A. Ohtsu e a

Cancer Chemotherapy Center, Osaka Medical College Hospital, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681, Japan c Department of Medical Oncology, Kochi Health Sciences Hospital, 2125-1 Ike, Kochi 781-8555, Japan d Department of Medical Oncology, Tochigi Cancer Center, Utsunomiya, 4-9-13 Yonan, Utsunomiya, Tochigi 320-0834, Japan e Department of Gastrointestinal Oncology/Gastroenterology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan f Department of Surgical Oncology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan g Department of Medical Oncology, Oita University Faculty of Medicine, 1-1, Idaigaoka, Hasamacho, Yufu, Oita 879-5543, Japan h Department of Gastroenterology, Saku Central Hospital, 197 Usuda, Saku, Nagano 384-0393, Japan b

Received 24 October 2014; received in revised form 17 February 2015; accepted 8 March 2015 Available online 30 March 2015

KEYWORDS Bevacizumab Colorectal cancer Elderly S-1

Abstract Background: Chemotherapeutic regimens for elderly patients with metastatic colorectal cancer (mCRC), such as bevacizumab combined with 5-fluorouracil (5-FU) and leucovorin, often exclude oxaliplatin and irinotecan owing to the risk of toxicity. However, treatment with infusional 5-fluorouracil and leucovorin requires percutaneous port-catheter placement and other precautions, causing unnecessary stress for patients as well as healthcare workers. Methods: We conducted a phase II study to evaluate the efficacy and safety of bevacizumab plus S-1 in elderly patients with previously untreated mCRC. Bevacizumab was given intravenously every two weeks, and S-1 was administered orally on days 1–28 of a 42-day cycle. The primary end-point was progression-free survival (PFS). The secondary end-points were time to treatment failure, response rate (RR), overall survival (OS), treatment completion status and safety.

⇑ Corresponding author at: ESMO ID: 42465, Division of Cancer Chemotherapy Center, Osaka Medical College Hospital, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan. Tel.: +81 72 683 1221; fax: +81 72 684 6778. E-mail address: [email protected] (M. Yoshida).

http://dx.doi.org/10.1016/j.ejca.2015.03.007 0959-8049/Ó 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

936

M. Yoshida et al. / European Journal of Cancer 51 (2015) 935–941

Results: From October 2007 through March 2010, 56 patients were enroled. The median PFS was 9.9 months, the median OS was 25.0 months, and the RR was 57%. The main adverse events of grade 3 or higher were hypertension (11%), diarrhoea (9%) and neutropenia (7%). Conclusion: Our results suggest that combination chemotherapy with S-1 and bevacizumab can be administered safely and continuously on an outpatient basis and is therapeutically effective in elderly patients with mCRC. Ó 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

1. Introduction The recent introduction of molecularly targeted chemotherapeutic agents has improved the outcomes of patients with advanced and recurrent colorectal cancer. Recent phase III clinical trials have reported a median survival time of longer than 2 years [1,2]. Combination regimens such as FOLFOX or FOLFIRI are similarly effective in younger patients, but tend to be associated with higher incidences of bone-marrow toxicity in elderly patients with advanced or recurrent colorectal cancer [3–8], requiring that these treatments are used with caution in older patients. Combination therapy with 5-fluorouracil (5-FU) and bevacizumab has been demonstrated to be safe and effective. In the AVF0780 g trial, a randomised phase II study comparing 5-FU plus leucovorin (5-FU/LV) with 5-FU/LV plus bevacizumab [9,10], the progression-free survival (PFS) was 9.0–9.2 months in the 5-FU/LV plus bevacizumab group despite the absence of oxaliplatin, compared with 5.2–5.5 months in the 5-FU/LV group. While no study has directly compared FOLFOX plus bevacizumab with 5-FU/LV plus bevacizumab, the results of previous clinical trials [3,9,10] indicate that the median PFS is similar with these regimens, and that 5-FU/LV plus bevacizumab is better tolerated, with a lower incidence of adverse events. These clinical results suggest that it may be unnecessary to use oxaliplatin or irinotecan in combination with 5-FU as first-line treatment and that sequential chemotherapy based on 5-FU is useful. In the phase III AVEX trial in elderly patients, bevacizumab and capecitabine were shown to be superior to capecitabine alone with PFS as the primary end-point. The main toxic effect of capecitabine is known to be frequent hand-foot syndrome [11]. S-1 (Taiho Pharmaceutical Co., Ltd., Tokyo, Japan) is an anticancer preparation that is widely used in Japan to treat advanced gastric, colon, pancreatic and lung cancer. S-1 combines the 5-FU prodrug tegafur (FT) with 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate [12]. Phase II studies of S-1 reported a response rate (RR) of 40%, a median PFS of 5.4 months and high safety in Japanese patients with unresectable or recurrent colorectal cancer [13,14]. The SOFT study showed S-1 and oxaliplatin plus bevacizumab to be non-inferior to mFOLFOX6 plus

bevacizumab, in terms of PFS, as first-line treatment for metastatic colorectal cancer (mCRC) [15]. To confirm and extend these results, we conducted a phase II study of S-1 plus bevacizumab in elderly patients with metastatic colorectal cancer. 2. Patients and methods 2.1. Patients Patients with histologically confirmed colorectal cancer and measurable metastatic disease were eligible for enrolment in this study. Patients who had previously received chemotherapy, radiotherapy, or both for metastatic disease were excluded. Patients who had received oral adjuvant fluorouracil-based chemotherapy with drugs other than S-1 were eligible, provided that they had remained disease-free for at least 6 months after the completion of such therapy. Other eligibility criteria were as follows: age P65 years; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2; treatment with FOLFIRI or FOLFOX was not indicated; ability to tolerate oral drug administration; electrocardiographic results within normal limits; adequate baseline bone-marrow function (white cell count, >3500/mL to <12,000/ mL; neutrophil count, >1500/mL; haemoglobin concentration, >9.0 g/dL; and platelet count, >100,000/mL); adequate hepatic function (serum total bilirubin level, <1.5 mg/dL; serum aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels, <100 U/L); adequate renal function (serum creatinine, <1.2 mg/dL; creatinine clearance estimated by the Cockcroft–Gault equation, >50 mL/min); a life expectancy of at least 90 days; and written informed consent from the patient. The main exclusion criteria were as follows: surgical procedures or open biopsy performed <28 days before study entry; current use of anticoagulant or thrombolytic therapy; severe drug allergy; treatment with aspirin (>325 mg/day) or non-steroidal anti-inflammatory drugs, except as required for cancer pain; treatment with steroids; the concurrent presence of another cancer, infection, serious pleural effusion or ascites. The study was approved by the institutional review board of each participating centre and was registered in the Clinical Trials Government Registry (NCT00569699).

M. Yoshida et al. / European Journal of Cancer 51 (2015) 935–941

2.2. Treatment Bevacizumab (5 mg/kg) was administered as a 90-, 60- or 30-min intravenous infusion every 2 weeks. The infusion time was chosen based on whether the patient showed any infusion-site reaction. S-1 was available in capsule and granule preparations containing 20 or 25 mg of tegafur, respectively. Patients received S-1 orally twice daily (after breakfast and dinner) from the evening of day 1 to the morning of day 29, followed by a 14-day rest. The dose of S-1 was based on body surface area (40 mg for <1.25 m2; 50 mg for 1.25–1.50 m2; or 60 mg for >1.50 m2). This 6-week cycle was repeated until onset of disease progression or a severe adverse event. No patient received premedication with a 5-hydroxytryptamine-3-receptor antagonist. All treatments were routinely given on an outpatient basis. In patients with laboratory abnormalities, subsequent treatment was withheld until the neutrophil and platelet counts were >1500/mL and >75,000/mL, respectively; the AST or ALT was <100 IU/L; the total bilirubin level was <2.0 mg/dL; the serum creatinine level was <1.2 mg/dL; and any diarrhoea, stomatitis or hand-foot syndrome (HFS) had resolved to grade 0 or 1. The dose of S-1 was reduced by one step if the neutrophil count was less than 500/mL, the platelet count was less than 50,000/mL, the AST was 200 IU/L or higher, the ALT was 200 IU/L or higher or the serum creatinine level was 1.5 mg/dL or higher. In the event of grade 3 or higher non-haematological toxicity (excluding constipation, anorexia, fatigue and nausea), the dose of S1 was reduced by one step. The protocol treatment was repeated until the onset of disease progression or a severe adverse event. Treatment with bevacizumab was withdrawn if patients developed bevacizumab-induced uncontrolled hypertension, proteinuria, bleeding, thrombosis, gastrointestinal perforation or hypersensitivity of grade 3 or higher.

2.3. Toxicity and response evaluation Before enrolment, all patients underwent a physical examination, complete blood cell count (CBC) with differential counts, serum chemical analysis, electrocardiography, and computed tomography scanning or magnetic resonance imaging, including documentation of measurable disease. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE v3.0) [16]. During the study, all patients were evaluated weekly for signs and symptoms of toxicity. CBC and differential counts, liver function tests, measurements of blood urea nitrogen, creatinine, and electrolyte levels, and urinalysis were performed weekly. All toxic effects were evaluated weekly during the first cycle, and then every 2 weeks from the second cycle onward. Any serious adverse

937

events or deaths were reported by the investigators, and the factors responsible were analysed. CT or MRI scans were performed every 8 weeks to evaluate lesions. Responses were evaluated according to the RECIST criteria, version 1.0 [17]. Treatment response and safety were assessed by the trial committee. 2.4. Statistical methods The primary end-point was PFS. The secondary endpoints were safety, RR, overall survival (OS), relative dose intensity (RDI) and time to treatment failure (TTF). We calculated the required sample size for this study on the basis of a target PFS of 8.5 months and a minimum PFS of 5 months, with a one-sided a error of 0.05 and a b error of 0.2, and estimated that we needed to enrol 50 patients. Therefore, the required sample size for analysis, to compensate for mid-trial exclusions or ineligibility, was 55. OS was calculated as of September 2012. TTF, PFS and OS were analysed by the Kaplan–Meier method. RDI was calculated for each drug on the basis of four treatment cycles. The association of PS (0 versus 1), alkaline phosphatase activity (ALP) (<300 versus P300) and the number of organs involved (1 versus P2) with PFS and OS were evaluated by univariate and multivariate analyses using a proportional hazards model as described by Ko¨hne et al. [18]. 3. Results 3.1. Patient characteristics Between October 2008 and March 2010, we enroled 56 patients with advanced colorectal carcinoma at eight hospitals in Japan. This study was approved by the institutional review board of each hospital. All patients gave written informed consent. The clinical characteristics of the eligible patients are shown in Table 1. The median age was 75 years (range, 66–85). The ECOG PS was 0 in 28 patients and 1 in 28 patients. The median follow-up time was 34.6 months (range, 1.1–54.0 months). 56 patients received a total of 329 treatment courses (median, 5; range, 1–17). Thirty-five patients (63%) received second-line chemotherapy based on oxaliplatin (20 patients, 36%), irinotecan (10 patients, 18%), or combination therapy including bevacizumab (13 patients, 23%). After second-line therapy, nine patients (16%) received anti-epidermal growth factor receptor antibodies. Three patients received surgery for metastases after the completion of the study treatment. 3.2. Efficacy Median PFS, the primary end-point of the study, was 9.9 months (95% confidence interval [CI], 7.9–

938

M. Yoshida et al. / European Journal of Cancer 51 (2015) 935–941

Table 1 Patient baseline characteristics. Variable

Type

No. (%) of patients (N = 56)

Age, years

Median [range] 65–69 70–74 75–79 80– Male/Female 0/1 Colon/Rectum Liver Lung Lymph nodes Peritoneal 1/2 or more Liver Lung Lymph nodes Well differentiated Moderately differentiated Poorly differentiated Others Yes/No

75 [66–85] 7 (12.5) 19 (33.9) 19 (33.9) 11 (19.6) 32 (57.1)/24 28 (50.0)/28 34 (60.7)/22 35 (62.5) 22 (39.3) 25 (44.6) 15 (26.8) 23 (41.1)/33 9 (16.1) 8 (14.3) 6 (10.7) 17 (30.4) 34 (60.7) 4 (7.1) 1 (1.8) 10 (17.9)/46

Gender Eastern Cooperative Oncology Group performance status (ECOG PS) Tumour site Metastasis

No. of tumour sites One organ only

Histopathological diagnosis

Adjuvant chemotherapy

11.1 months) (Fig. 1). Results for the secondary endpoints were as follows: the median OS was 25.0 months (range, 19.4–31.6 months) (Fig. 2) and the median TTF was 7.5 months (95% CI, 5.9–9.1 months). The response rate was 57% (95% CI, 43.2–70.3), with a disease control rate (DCR) of 96%. The confirmed response rate was 43%, with an associated confirmed DCR of 89%. The response was evaluated according to the protocol in all patients, but the confirmed response could not be evaluated in four patients (two who refused to continue treatment and two who discontinued treatment because of grade 1 or 2 gastrointestinal toxicity after evaluation of the initial response). All 56 patients had at least one measurable lesion. The responses to treatment are shown in Table 2. One patient had a complete response (CR), 31 had an unconfirmed partial response and 22 had stable disease. The CR was achieved after 14 cycles of the protocol treatment in a patient with liver metastasis. (%)

100 Median PFS: 9.9 months (95% CI: 7.9 11.1)

80 60 40 20

(42.9) (50.0) (39.3)

(58.9)

(82.1)

(%)

100 Median OS: 25.0 months (95% CI: 19.4 31.6)

80 60 40 20

0 0

6

12

18

24

30

36

42

48

54

Number at risk 56 55

48

36

28

20

6

3

3

1

(M)

Fig. 2. Overall survival.

3.3. Toxicity Toxicity was classified according to the worst grade per patient across the 329 courses of treatment (Table 3). The most common toxic effects were neutropenia, hypertension and diarrhoea, which were generally mild. With the exception of hypertension, the incidence of grade 3 or 4 toxicity was less than 10%. One patient had thalamic haemorrhage (not shown in the table). There was no treatment-related death. The treatment protocol was discontinued owing to toxicity in 18 of the 56 patients. 3.4. Dose intensity

0 4

8

12

16

20

24

28

32

Number at risk 56 51

0

33

17

10

3

2

1

0

Fig. 1. Progression-free survival.

36

(M)

The median number of treatment cycles was five (range, 1–17). The mean RDI for both S-1 and bevacizumab was 80% (range, 8.9–100% and 33.3–100%, respectively).

M. Yoshida et al. / European Journal of Cancer 51 (2015) 935–941

939

Table 2 Response rates. No. (%) of patients (N = 56)

CR

PR

SD

PD

NE

RR (%)

DCR (%)

Unconfirmed Confirmed*

1 (2) 1 (2)

31 (55) 23 (41)

22 (39) 26 (46)

2 (4) 2 (4)

0 (0) 4 (7)

57 43

96 89

Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluated; RR, response rate; DCR, disease control rate. * Not prespecified in the study protocol because the primary end-point in this study was progression-free survival.

Table 3 Adverse events (worst grades). Event

Grade

Neutropenia Thrombocytopenia Anaemia Leukopenia Diarrhoea Fatigue Anorexia Hyperbilirubinemia Stomatitis Hyperpigmentation Rash Hypertension Proteinuria Epistaxis

1

2

3

4

1 20 14 11 24 24 29 18 20 24 12 9 8 16

12 3 24 14 6 11 9 18 5 1 3 5 23 0

4 1 1 0 5 1 3 1 0 0 1 6 0 0

0 1 0 0 0 0 0 0 0 0 0 0 0 0

3.5. Survival according to Ko¨hne’s index Fig. 3 shows the Kaplan–Meier curves of OS and median OS according to risk group as defined by Ko¨hne’s index [18], based on PS (0 versus 1), ALP (<300 versus P300) and the number of organs involved (%)

100

Low risk Intermediate risk High risk

80 60 40 20

Any grade (%)

Grade P3 (%)

30 45 70 45 63 64 73 66 45 45 29 36 55 29

7 4 2 0 9 2 5 2 0 0 2 11 0 0

(1 versus P2), which have been reported to be predictors of the response to fluoropyrimidine therapy. PS was 0 in 28 patients and one in 28. ALP was <300 in 32 patients and P300 in 24. The number of organs involved was one in 23 patients and P2 in 33. Our results showed that median OS according to Ko¨hne’s index was longer in the low-risk group (35.3 months [95% CI: 22.3–notreached]) than in the high-risk group (14.4 months [95% CI: 7.5–25.0], hazard ratio 4.21 [95% CI: 1.83–9.91], P < 0.001; Fig. 3). Second-line chemotherapy was given to 12 (86%) of the 14 patients in the high-risk group, 10 (53%) of the 19 patients in the intermediate-risk group and 13 (57%) of the 23 patients in the low-risk group. 4. Discussion

0

0

12

24

36

48

High risk

14

10

4

0

0

Intermediate risk

19

18

9

1

0

Low risk

23

20

15

5

3

Number at risk

Risk group

Median OS (months)

95% CI

(M)

HR p value vs. low risk group

High (n=14)

14.4

7.5 - 25.0

4.21

<0.001

Intermediate (n=19)

28.5

18.5 - 32.3

1.63

0.237

Low (n=23)

35.3

22.3 - NR

1

Fig. 3. Overall survival (OS) according to risk group.

We conducted a phase II study to evaluate the efficacy and safety of combination chemotherapy with bevacizumab plus S-1 in elderly patients with untreated unresectable or recurrent colorectal cancer. Toxicity was tolerable, and efficacy outcomes in terms of RR and PFS were comparable to those reported for combination chemotherapy with 5-FU or capecitabine in combination with bevacizumab in a phase 3 trial [10,11]. This phase II trial may be considered as further confirmation that the S-1 compound can replace 5-FU or capecitabine in combination with bevacizumab, with or

940

M. Yoshida et al. / European Journal of Cancer 51 (2015) 935–941

without other drug combinations. Although as yet there has been no phase III trial of S-1 plus bevacizumab alone, the above conclusion is supported by the results of three randomised phase III trials in Asia, comparing S-1 plus oxaliplatin with capecitabine plus oxaliplatin [19], FOLFIRI with S-1 plus irinotecan [20], and FOLFOX plus bevacizumab with S-1/oxaliplatin plus bevacizumab [15]. All these trials demonstrate the non-inferiority of S1 combination therapy compared with drug combinations containing 5-FU or capecitabine, suggesting that S-1 can replace 5-FU or capecitabine, at least in Asia. The therapeutic usefulness of sequential chemotherapy with molecularly targeted drugs has yet to be validated in well-designed clinical trials. However, the FOCUS [21], CAIRO [22], and FFCD2000-05 [23] studies showed that OS does not differ significantly between sequential chemotherapy (with fluoropyrimidines alone as first-line therapy and oxaliplatin or irinotecan as second-line therapy) and combination chemotherapy (with fluoropyrimidines and oxaliplatin or irinotecan as firstline therapy), suggesting the non-inferiority of sequential chemotherapy. 5-FU monotherapy may be particularly useful in elderly or frail patients because of its low toxicity. Many patients with colorectal cancer are elderly (aged P65 years) and thus tend to have greater morbidity and a higher risk of adverse reactions [24]. Poor tolerability and severe adverse reactions may therefore preclude aggressive chemotherapy. Our study group is likely to have many subjects with reduced tolerance to chemotherapy because the protocol required that patients were 65 years or older. The proportion of the elderly patients enroled in our study who were frail is unclear because detailed data on physical status were not collected. While the median OS obtained in the studies on 5-FU/LV + bevacizumab therapy (AVF2192g trial) and capecitabine + bevacizumab therapy (AVEX trial) was 16.6 and 20.7 months, respectively, our study achieved a considerably longer median OS of 25.0 months. However, while 8% and 9% of patients included in the AVF2192g and AVEX studies, respectively, had a PS P 2, this particular group of patients was not included in our study [10,11]. It is therefore likely that this difference in patient background is a contributing factor in our favourable OS. The eligibility criteria required that treatment with FOLFOX and FOLFIRI was not indicated. However, our subjects included patients who did not want to receive intensive chemotherapy, as well as those who were ‘frail.’ Although treatment with FOLFOX and FOLFIRI was not indicated in our subjects, 30 patients subsequently received second-line chemotherapy with oxaliplatin- or irinotecan-based regimens after the protocol treatment. The reasons for using these second-line regimens are unfortunately not available for all patients. However, it is possible that some patients who refused

FOLFOX or FOLFIRI as first-line therapy consented to second-line therapy with oxaliplatin- or irinotecanbased regimens because their physical and mental condition had improved. Since PS and other data were not collected at the initiation of second-line therapy, this can only be a supposition; however, such differences in patient status between the time of enrolment and the start of second-line therapy may have allowed patients to receive regimens including oxaliplatin or irinotecan. Among patients’ demographic characteristics at enrolment, PS, WBC, ALP, and the number of organs involved, which are collectively known as Ko¨hne’s index, have been reported to be predictors of the response to fluoropyrimidine therapy. Although none of our subjects had a PS of two or higher, our results are generally consistent with those reported by Ko¨hne et al. regarding the prognostic factors for fluoropyrimidine therapy, suggesting that these factors may apply not only to 5-FU-based chemotherapy but also to other therapies. However, it should be noted that the correlation of OS with ALP and the number of organs involved might be a reflection of tumour burden rather than a direct effect of treatment. The fact that 86% of high-risk patients received second-line chemotherapy suggests that such patients may require intensive chemotherapy. The results of a riskstratified analysis based on the aforementioned prognostic factors suggested that the outcomes of combination therapy with fluoropyrimidines and bevacizumab agree with those of a previous study [18]. However, large prospective clinical studies and additional analyses may be necessary to verify this conclusion. Combination chemotherapy with fluoropyrimidine and bevacizumab is currently positioned as one treatment option for elderly patients with metastatic or unresectable colorectal cancer, and new trials of this regimen are being performed by the North Central Cancer Treatment Group and Japanese Clinical Oncology Group [25]. Standard chemotherapy for elderly patients may change on the basis of the findings of these trials. In conclusion, our results suggest that combination therapy with S-1 plus bevacizumab can be administered safely and continuously on an outpatient basis and may be therapeutically effective in elderly patients with advanced or recurrent colorectal cancer. Funding This work was supported by Taiho Pharmaceutical Co., Ltd., Tokyo, Japan. Conflict of interest statement Kazuhiro Yoshida is a member of Taiho advisory boards. All remaining authors have declared no conflicts of interest.

M. Yoshida et al. / European Journal of Cancer 51 (2015) 935–941

Acknowledgements We thank Yuh Sakata, Masahiro Takeuchi, Masashi Fujii, Keisuke Aiba, and Hiroyuki Uetake for their kind advice and Mr. Ryutaro Yamagami and his clinical study team at Taiho Pharmaceutical Co., Ltd. for assistance with data collection. We also thank Professor J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University, a remunerated consultant of Taiho Pharmaceutical Co., Ltd., for his review of this manuscript. This article is dedicated to the memory of Prof. Hiroya Takiuchi, the principal investigator of this study who performed most of the work and would have been named first author but for his passing.

[12]

[13]

[14]

[15]

References [1] Heinemann V, von Weikersthal LF, Decker T, Kiani A, VehlingKaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, openlabel, phase 3 trial. Lancet Oncol 2014;15(10):1065–75. [2] Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 2014;371(17):1609–18. [3] Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26(12):2013–9. [4] Figer A, Perez-Staub N, Carola E, Tournigand C, Lledo G, Flesch M, et al. FOLFOX in patients aged between 76 and 80 years with metastatic colorectal cancer: an exploratory cohort of the OPTIMOX1 study. Cancer 2007;110(12):2666–71. [5] Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350(23):2335–42. [6] Jackson NA, Barrueco J, Soufi-Mahjoubi R, Marshall J, Mitchell E, Zhang X, et al. Comparing safety and efficacy of first-line irinotecan/fluoropyrimidine combinations in elderly versus nonelderly patients with metastatic colorectal cancer: findings from the bolus, infusional, or capecitabine with camptostar-celecoxib study. Cancer 2009;115(12):2617–29. [7] Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 2005;23(16):3706–12. [8] Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer–a GERCOR study. J Clin Oncol 2006;24(3): 394–400. [9] Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21(1):60–5. [10] Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005;23(16):3697–705. [11] Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, et al. Bevacizumab plus capecitabine versus capecitabine

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

941

alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol 2013;14(11):1077–85. Shirasaka T, Shimamato Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K, et al. Development of a novel form of an oral 5fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 1996;7(5):548–57. Shirao K, Ohtsu A, Takada H, Mitachi Y, Hirakawa K, Horikoshi N, et al. Phase II study of oral S-1 for treatment of metastatic colorectal carcinoma. Cancer 2004;100(11):2355–61. Ohtsu A, Baba H, Sakata Y, Mitachi Y, Horikoshi N, Sugimachi K, et al. Phase II study of S-1, a novel oral fluorophyrimidine derivative, in patients with metastatic colorectal carcinoma. S-1 Cooperative Colorectal Carcinoma Study Group. Br J Cancer 2000;83(2):141–5. Yamada Y, Takahari D, Matsumoto H, Baba H, Nakamura M, Yoshida K, et al. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol 2013;14(13):1278–86. [Japanese translation of common terminology criteria for adverse events (CTCAE), and instructions and guidelines]. Int J Clin Oncol 2004;9(Suppl. 3):1–82. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3):205–16. Kohne CH, Cunningham D, Di Costanzo F, Glimelius B, Blijham G, Aranda E, et al. Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal cancer: results of a multivariate analysis of 3825 patients. Ann Oncol 2002;13(2):308–17. Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, et al. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol 2012;13(11):1125–32. Muro K, Boku N, Shimada Y, Tsuji A, Sameshima S, Baba H, et al. Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 noninferiority study (FIRIS study). Lancet Oncol 2010;11(9):853–60. Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 2007;370(9582):143–52. Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 2007;370(9582):135–42. Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, et al. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000–05): an open-label, randomised, phase 3 trial. Lancet Oncol 2011;12(11): 1032–44. Yancik R, Wesley MN, Ries LA, Havlik RJ, Long S, Edwards BK, et al. Comorbidity and age as predictors of risk for early mortality of male and female colon carcinoma patients: a population-based study. Cancer 1998;82(11):2123–34. ClinicalTrials.gov. Combination Chemotherapy Plus Bevacizumab With or Without Oxaliplatin in Treating Older Patients With Metastatic Colorectal Cancer.