Capecitabine and oxaliplatin combined with bevacizumab are feasible for treating selected Japanese patients at least 75 years of age with metastatic colorectal cancer

A single-arm multicenter phase II trial (ASCA trial, Avastin plus XELOX Strategy for elderly patients with metastatic colorectal cancer) was planned to evaluate the safety and efficacy of XELOX plus bevacizumab for patients with mCRC ≥75 years of age [32]. The scientific and ethical validity of the study protocol was reviewed and approved by an internal review board of each participating facility (the Institutional Review Board at Osaka National Hospital, Osaka City General hospital, Osaka Rosai Hospital, Kitakyushu General Hospital, Kinki University, Kochi University, Fukui-ken Saiseikai Hospital, Saitama Medical Center, Jichi Medical University, Izumisano Municipal Hospital, Sakai City Hospital, Toyonaka Municipal Hospital, Dongo Hospital, Nara Social Insurance Hospital, Hakodate Goryoukaku Hospital, Fukuiken Saiseikai Hospital, Minoh City Hospital and Mimihara General Hopital). Written informed consent was obtained from all patients before enrollment. This study was conducted in accordance with the Declaration of Helsinki (2008) and registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry as UMIN000003500 (http://​www.​umin.​ac.​jp/​ctr/​index.​htm).

Patients from 18 institutes were included in this study if they met all eligibility criteria as follows: (1) written informed consent before treatment; (2) age ≥75 years when informed consent was granted; (3) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1; (4) life expectancy >3 months; (5) histologically confirmed colorectal adenocarcinoma; (6) measurable disease consistent with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; (7) no prior chemotherapy (adjuvant chemotherapy included fluorouracil and/or oxaliplatin was allowed, but the last course of adjuvant chemotherapy must have concluded more than six months prior to colorectal cancer recurrence); (8) adequate function of vital organs, including liver and kidney (total bilirubin ≤1.5-times the institutional upper normal limit, aspartate aminotransferase and alanine aminotransferase ≤2.5-times the institutional upper normal limit, and serum creatinine ≤ institutional upper normal limit or creatinine clearance (CCr, calculated using the Cockcroft–Gault formula) ≥50 ml/min); adequate bone marrow function (leucocyte count ≥3000/mm³, neutrophil count ≥1500/mm³, platelet count ≥100,000/mm³, and hemoglobin ≥9.0 g/dl).

Key exclusion criteria included uncontrolled pleural effusion or ascites, brain metastasis, presence of other active malignancies, present or past (within the past 1 year) clinically significant cerebrovascular disease or thromboembolism, surgery planned during the course of the trial, anticoagulant treatment, coagulation disorder, nephropathy requiring medication or transfusion, uncontrolled hypertension or diabetes mellitus, uncontrolled diarrhea, history of bevacizumab treatment, and inability to take drugs orally [32].

Treatment consisted of intravenous administration of 7.5 mg/kg of bevacizumab and 130 mg/m² of oxaliplatin on day 1 of each cycle combined with 2000 mg/m² oral capecitabine per day on days 1–14 of each cycle [32]. The end of the protocol treatment period was not prescribed. Treatment was repeated every 3 weeks until disease progression or termination of the study. The study protocol had no provisions regarding the second-line treatment. When patients exhibited adverse effects (AEs), the dose of each drug was reduced as specified in the study protocol that provided detailed algorithms to manage drug-specific toxicities such as oxaliplatin-related neuropathy, capecitabine-related diarrhea, hand–foot syndrome, bevacizumab-related hypertension, bleeding, and thromboembolism as well as other treatment-related toxicities. The dose reduction or stopping criteria of drugs due to adverse events is defined based on the haematological toxicity (Grade 4 neutropenia, Grade 3 febrile neutropeni a or Grade 3 or more decrease in platelets) and Grade 3 non-haematological toxicity. Dose reduction due to adverse events was performed for each drug as specified in the study protocol, which provided detailed algorithms to manage drug-specific toxicities such as oxaliplatin-related neuropathy as follows; G1, continue administration; G2/3, until recovery to G1 or less and resume oxaliplatin with the reduction dose (for the first time 100 mg/m², for the second time 85 mg/m²); G4, discontinuation of oxaliplatin.

Screening and baseline evaluations included assessing ECOG PS and conducting blood tests and physical examinations. Baseline tumor status with prospective identification of index lesions that were followed over the course of the study, was assessed using computed tomography (CT) studies of the chest, abdominal, and pelvis as well as determination of serum tumor-marker levels (carcinoembryonic antigen and carbohydrate antigen 19–9). During treatment, tumor status was assessed at the completion of each 8-week cycle. RECIST ver. 1.1 was used to evaluate responses and determine disease progression. Response rate assessment was done locally. Toxicities, graded according to the criteria of the National Cancer Institute Common Terminology for Adverse Events (version 4.0), were evaluated during the study period and for 28 days after the last dose administered during the study by conducting physical examinations and laboratory tests (hematology, chemistry and electrolytes, and urinalysis), and evaluating ECOG PS. Patients who discontinued the protocol treatment were followed every 2 months until death or loss to follow-up. Neurotoxicity was graded as follows: G1 (asymptomatic) loss of deep tendon reflexes or paresthesia, G2 (moderate symptoms) limiting instrumental activities of daily living, G3 (severe symptoms) limiting daily self-care activities; G4 (life-threatening consequences) urgent intervention indicated, and G5 (death). Patients were questioned about their use of concomitant medication and AEs. Association between the incidence of AEs ≥ G3 and baseline CCr, American Society of Anesthesiologists (ASA) score (comorbidity index), ASA Physical Status Classification System score, age, body mass index (BMI), and sex were evaluated as potential risk factors for severe AEs.

The primary objective of the ASCA study was to determine PFS. Secondary endpoints were toxicity, overall response rate, time to treatment failure (TTF), and OS. Assuming a threshold PFS of 6.5 months and an estimated median PFS of 10.5 months, and referring to data from previous clinical trials we determined that a significance level = 95 %, an α-error = 0.05, and 32 patients were required. Estimating a loss as high as 10 % of the final subject population, 35 patients were required. The Kaplan–Meier method was used to estimate survival, and the Cox proportional hazards model was used to calculate confidence intervals (CI). PFS was defined as the interval from the time of enrolment to the date of the first documented disease progression or a patient’s death from any cause. OS was defined as the date of enrolment until the date of death from any cause. TTF was defined as the time from randomization to discontinuing treatment for any reason, including disease progression, treatment toxicity, patient preference, or death. The goodness-of-fit for AEs ≥ grade 3 was assessed by calculating the area under the curve (AUC), and optimal cutoff values were determined using the Youden index. The χ² test was used to compare the difference between the values of two patient groups. A statistically significant difference was defined as P < 0.05.

Thirty-seven patients treated between March 2010 and January 2012 at 18 institutes were screened and met all eligibility requirements. One patient withdrew from the study before receiving treatment. The 36 patients (male 58 %; median age 78 years; colon cancer 67 %) enrolled received at least one course of the planned treatment. Baseline patient characteristics are shown in Table 1.

Patients were treated with a median of five cycles of XELOX plus bevacizumab (range 1–17), and the median relative dose intensities during the initial protocol (XELOX plus bevacizumab) were 86, 89, and 100 % for capecitabine, oxaliplatin, and bevacizumab, respectively. There were 14 patients who continued to receive the protocol treatment after withdrawal of oxaliplatin (capecitabine with bevacizumab for 12 and capecitabine alone for two patients). The median TTF was 7.0 months (95 % CI 4.7–10.8 months) (Fig. 1a). The reasons for discontinuing treatment were disease progression (n = 14), AEs (n = 14), withdrawal (n = 6), and surgery for metastases (n = 2). AEs that prevented continuing were as follows: neutropenia (n = 3), thrombotic disease (n = 2), anorexia (n = 2), ileus (n = 2), heart failure (n =1), hand–foot syndrome (n = 1), cerebral bleeding (n = 1), neuropathy (n = 1), and fatigue (n = 1).

Treatment-related toxicities are listed in Table 2. Thirty-four (94.4 %), and 12 (33.3 %) patients experienced AEs or AEs ≥ grade 3, respectively, and one treatment-related death was caused by intracranial bleeding. The latter patient was a 77-year-old woman with liver and lung metastasis without serious comorbidities who received seven courses of protocol treatment (XELOX plus bevacizumab) using the regular dose. During the eighth course, she lost consciousness, was diagnosed with intracerebral bleeding according to the results of a CT scan, and chemotherapy was discontinued. Frequent adverse events (any grade) were as follows: neuropathy (83.3 %), anemia (80.5 %), thrombocytopenia (58.3 %), hand–foot syndrome (58.3 %), and neutropenia (55.6 %). Frequent AEs ≥ grade 3 were neutropenia (22.2 %) and neuropathy (13.9 %). Bevacizumab-related AEs, proteinuria (36.1 %), and hypertension (27.8 %), were frequently observed for all grades, and the most frequent ≥ grade-3 event was hypertension (11.1 %).

We evaluated the association between AEs ≥ G3 and baseline patient conditions including CCr, comorbidity index, ASA Physical Status Classification System score, age, BMI, and sex. These findings identified baseline CCr as a potential predictor of AEs ≥ grade 3. The AUC value of baseline CCr = 0.69, and the optimal cutoff value for predicting AEs ≥ grade 3 = 64 ml/min (sensitivity = 0.91, specificity = 0.50 (Additional file 1: Figure S1a). Further, patients with baseline CCr <64 ml/min had a significantly higher incidence of AEs ≥ G3 compared with those with baseline CCr ≥64 ml/min (77.8 % and 22.2 %, respectively, P = 0.018). No association was found between evaluated factors other than CCr (comorbidity index, ASA Physical Status Classification System score, age, BMI, and sex) and incidence of AEs ≥ G3.

The best radiographic response of each patient is presented in Additional file 1: Figure S1b. Responses to treatment were defined as follows: complete response (CR), partial response (PR), stable disease (SD), and progressive disease, according to the RECIST ver. 1.1 definitions. The rates for CR, PR, and SD were 2.8, 52.8, and 36.1 %, respectively, and the response and disease control rates were 55.6 and 91.7 %, respectively (Table 3). The median PFS was 11.7 months (95 % CI, 8.0–13.4 months (Fig. 1b), and the median OS was 22.9 months (95 % CI 17.6–33.0 months, Fig. 1c).