Phase II study on early start of chemotherapy after excising primary colorectal cancer with distant metastases (Pearl Star 02)

Abstract Initiating chemotherapy usually requires a delay of more than 4 weeks after surgically resecting colorectal cancer. However, there is little evidence regarding the required delay interval. We have previously reported a pilot study to determine the safety and feasibility of early initiation of chemotherapy after resecting primary colorectal cancer with distant metastases. We aimed to determine the safety and efficacy of early initiation of chemotherapy after resecting colorectal cancer with distant metastases. This phase II study (trial number UMIN000006310) was a prospective, single‐arm trial. A total of 20 patients (men, 15 and women, 5) were enrolled. They underwent XELOX therapy (130 mg/m2 oxaliplatin on day 1+1000 mg/m2 capecitabine twice daily on days 1‐4) on postoperative day 7 and XELOX+bevacizumab (7.5 mg/kg bevacizumab on day 1) after the second chemotherapy cycle. Baseline characteristics included a median age of 64 (range, 43‐72) years. Surgical procedures included right hemicolectomy in six patients, sigmoidectomy in three, anterior resection in five, and Hartmann procedure in six. All patients started chemotherapy on postoperative day 7. Median progression‐free survival was 14.9 months; overall response rate was 80%. Disease control rate was 100%. Grade 3 or higher hemotoxicity and grade 3 or higher non‐hematological toxicity was noted in 5.0% and 25.0% of patients, respectively. Postoperative complications were observed in two patients (superficial incisional surgical site infection and ileus). Early initiation of chemotherapy after surgery is feasible. These findings suggest future changes of the start time of chemotherapy after surgery.


| INTRODUCTION
The National Comprehensive Cancer Network recommends that patients with metastatic colorectal cancer (CRC) undergo primary tumor resection if they have impending obstruction, bowel obstruction, or potentially resectable metastases. There is no doubt that resection or stoma placement is mandatory before starting systemic chemotherapy among patients with severe intestinal symptoms. [1][2][3] Palliative resection of primary tumors reportedly improves systemic chemotherapy efficacy 4 and prolongs time to treatment failure. 5 In many cases, it is not possible for patients to continue chemotherapy because of complications, such as bleeding, perforation and bowel obstruction, if chemotherapy is started without surgical resection of the symptomatic primary tumor. Therefore, surgical resection of the primary tumor is apparently necessary to utilize chemotherapy with few complications. However, surgical resection may delay chemotherapy initiation. 6 In general, a post-surgical period longer than 4 weeks is standard until starting chemotherapy, 6,7 such as treatment with folinic acid, fluorouracil (5-FU), and oxaliplatin; folinic acid, 5-FU, and irinotecan; and capecitabine and oxaliplatin (XELOX).
However, there is no positive evidence for this delay. In stage III disease, the time to start adjuvant therapy is an important prognostic factor for both colon and rectal cancers. [8][9][10][11] Early adjuvant therapy initiation is most often defined as starting therapy within 8 weeks after surgery, and it reportedly reduces the risks of recurrence and increases overall survival (OS) and disease-free survival. 8,9 Metastatic tumors may rapidly enlarge before starting chemotherapy and may lead to patient death. It is unclear whether an even earlier initiation, such as within 1 week after surgery, may provide additional improvements. We conducted a clinical trial to prevent the early growth of metastatic lesions after primary resection. Because we previously reported that early initiation of chemotherapy after surgery is feasible, 12  This study evaluated the efficacy of early initiation of chemotherapy after resecting colorectal cancer with distant metastases. Primary endpoint was disease control rate (DCR), whereas secondary endpoints were objective tumor response rate (RR), progression-free survival (PFS), overall survival (OS), and safety. The target sample size was 18 patients, assuming that the expected DCR and threshold DCR were 95% and 75%, respectively, with a onesided alpha level of 5% and a power of 80%. The expected DCR was decided based on past experience of the Pearl Star 01 trial at our hospital. 12

| Patients and eligibility criteria
In the present study, 20 patients were enrolled between September 2011 and June 2015. Eligibility criteria for selecting subjects were as follows: (i) age 20-75 years; (ii) Eastern Cooperative Oncology Group performance status of 0 or 1; (iii) histologically confirmed CRC without prior chemo-or radiotherapy for metastatic disease; (iv) unresectable synchronous distant metastases; (v) adequate hematological (absolute leukocyte count, 4000-12 000 leukocytes/mm 3 ; neutrophil count, Written informed consent was obtained from each patient.
Patients with any of the following conditions were excluded: history of serious hypersensitivity to drugs, active infection, symptomatic brain metastases, uncontrolled hypertension, uncontrolled diabetes, cirrhosis, clinically significant cardiovascular disease, history of myocardial infarction within the previous 3 months, uncontrolled angina pectoris or arrhythmia, multiple primary cancers within the past 5 years, pleural effusion requiring drainage, ascites or pericardial effusion, clinically significant mental or psychological disease, or any other condition that made the patient unsuitable for this study.

| Baseline patient characteristics
Characteristics of the study patients are presented in Table 1.

| Treatment
All patients successfully started chemotherapy on postoperative day 7 ( Figure 1). Median number of chemotherapy cycles was 14 (range, . Median cumulative dose of oxaliplatin was 1751 mg/m 2 . Fifteen patients (75.0%) continued treatment for more than eight cycles, whereas three discontinued treatment for adverse events and two discontinued treatment because of refusal or personal reasons.
Four patients (20.0%) required dose reduction at least once within the eight cycles: two because of fatigue, one as a result of diarrhea, and one owing to thrombocytopenia.

| Safety
Adverse events for 20 patients are summarized in Table 2  future takedown of colostomy, or even death. It has been estimated that one of every three postoperative deaths after colonic surgery was because of a leaking anastomosis. 28 Several animal researchers have revealed that anastomoses were weaker and that there was a high risk of anastomotic leakage when systemic 5-FU was given as a bolus immediately after surgery. 29,30 Immediate i.p.

5-FU also causes anastomotic leakage. 31 Continuous 5-FU infusions
enabled the use of greater daily dosages and appeared safer than injecting a bolus of 5-FU. 32