Impact of early tumor shrinkage on quality of life in patients treated with first-line cetuximab plus chemotherapy for unresectable metastatic colorectal cancer: results of Phase II QUACK trial.

PURPOSE: Although early tumor shrinkage (ETS) is a predictor of improved overall survival (OS), the association between ETS and health-related quality of life (HRQOL) remains unclear for patients with metastatic colorectal cancer (mCRC) treated with first-line cetuximab plus chemotherapy. METHODS: The data were collected from a prospective trial that assessed HRQOL using the EORTC QLQ-C30. The impact of ETS on HRQOL was estimated using a linear mixed-effects model for repeated measures. RESULTS: ETS was achieved in 82 (64.1%) of 128 mCRC patients treated with first-line cetuximab plus chemotherapy, and these patients had a significantly longer OS than those without ETS (HR, 0.38; 95% CI, 0.20-0.72; P = .002). Asymptomatic patients with ETS had a favorable OS, while symptomatic patients without ETS had a worse OS (2-year OS rates, 77.8% vs. 42.5%). Symptomatic patients with ETS had similar outcomes as asymptomatic patients without ETS (2-year OS rates, 64.1% vs. 67.0%). For symptomatic patients, ETS was associated with improved HRQOL scores between baseline and 8 weeks: the mean changes for patients with and without ETS were 5.86 and -4.94 for global health status (GHS)/QOL, 26.73 and 3.79 for physical functioning, and 13.58 and -3.10 for social functioning, respectively. The improved HRQOL was comparable to that of asymptomatic patients without ETS. For asymptomatic patients, ETS showed a decreased deterioration in HRQOL. CONCLUSION: Our findings highlight the importance of ETS for HRQOL and prognostic estimates, and assessing ETS may provide clinically useful information for physicians and patients to make more informed decisions.

Efficacy of celecoxib as preemptive analgesia for patients undergoing laparoscopic inguinal hernia repair: a randomized trial.

PURPOSE: To investigate the efficacy and safety of preemptive analgesia with a transversus abdominis plane (TAP) block versus celecoxib for patients undergoing laparoscopic transabdominal preperitoneal inguinal hernia repair (LTAPP). METHODS: Sixty patients scheduled for LTAPP were randomized into three groups: a celecoxib group, given 200 mg celecoxib 2 h before surgery; a celecoxib/diclofenac group, given 200 mg celecoxib 2 h before surgery and 50 mg rectal diclofenac sodium on recovery from general anesthesia; and a block group, given a TAP block with 60 mL 0.25% levobupivacaine after general anesthesia. We assessed the numerical rating scale (NRS) scores for pain at rest and with movement 24 h after surgery. Postoperative analgesia use and adverse events were also evaluated. RESULTS: The NRS scores for pain at rest and with movement were lower in the celecoxib group than in the block group, 24 h postoperatively. The time to first request for analgesia tended to be longer in the block group than in the celecoxib group. No significant between-group differences were noted in analgesic use or adverse events. CONCLUSIONS: Celecoxib was not inferior to the TAP block as preemptive analgesia. Thus, celecoxib could be given as simple preemptive analgesia for LTAPP by considering a multimodal analgesic strategy in the early postoperative period.

Phase II study of 5-fluorouracil-leucovorin plus bevacizumab for chemotherapy-naïve older or frail patients with metastatic colorectal cancer (OGSG 0802).

BACKGROUND: Older or frail patients are often underrepresented in clinical trials for metastatic colorectal cancer (mCRC). We here assessed the efficacy and safety of 5-fluorouracil (5-FU)-leucovorin plus bevacizumab in such patients. METHODS: The study (OGSG 0802) was designed as a single-arm, open-label, multicenter phase II trial. Eligible patients had mCRC and at least one of the following: an age of ≥ 65 years, an Eastern Cooperative Oncology Group performance status of 1 or 2, a serum albumin level of ≤ 3.5 g/dL, incompatibility with oxaliplatin or irinotecan, and a history of abdominal or pelvic radiotherapy. Patients received 5-FU (600 mg/m2) and l-leucovorin (200 mg/m2) on days 1, 8, and 15 together with bevacizumab (5 mg/kg) on days 1 and 15 every 4 weeks. The primary end point was objective response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty-one patients were enrolled and eligible. Median age was 76 years (range 56-90 years), and 51% of patients had a performance status of 0. The ORR was 36.6% [95% confidence interval (CI) 22.1-53.1%], median PFS was 9.4 months (95% CI 7.4-17.7 months), and median OS was 24.0 months (95% CI 19.9 months-not reached). The most common treatment-related adverse events of grade ≥ 3 were neutropenia (24%), anorexia (10%), leukopenia (7%), and mucositis/stomatitis (7%). There were no treatment-related deaths. CONCLUSION: Weekly 5-FU-leucovorin with biweekly bevacizumab may be a tolerable and effective treatment option for older or frail patients with mCRC.

Evaluation of FOLFOX or CAPOX reintroduction with or without bevacizumab in relapsed colorectal cancer patients treated with oxaliplatin as adjuvant chemotherapy (REACT study).

BACKGROUND: Chemotherapy in relapsed colorectal cancer patients treated with oxaliplatin as adjuvant chemotherapy is under debate. REACT study aimed to investigate the efficacy of reintroducing modified FOLFOX6 (mFOLFOX6) or CAPOX with or without bevacizumab in recurrent colorectal cancer patients after oxaliplatin adjuvant chemotherapy. METHODS: Patients that participated in this trial had a medical history of adjuvant chemotherapy, including oxaliplatin with a cumulative dose greater than 400 mg/m2, and recurrence that was diagnosed more six months post adjuvant chemotherapy. Primary endpoints were response rate (RR) and disease control rate (DCR), while key secondary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 31 patients were enrolled between October 2012 and October 2016. Of the 29 eligible patients, 7 received mFOLFOX6 and 22 received CAPOX. The RR was 62.1% (95% confidence interval 42.3-79.3) and the DCR was 82.8% (95% confidence interval 64.2-94.2). The RR for oxaliplatin-free interval was 100.0% in months 6-12 and 56.0% after 12 months. Median TTF, PFS, and OS were 6.3, 10.8, and 28.7 months, respectively. Grade 3 or worse peripheral sensory neuropathy developed in 6.5%. Allergic reactions occurred in 12.9% of the patients, with one (3.2%) grade 3 episode. There were no other severe treatment-related adverse events. CONCLUSION: Reintroduction of oxaliplatin was feasible and achieved high RR or DCR in patients after more than 6 months post oxaliplatin adjuvant chemotherapy.

[A Study on the Status of End-of-Life Chemotherapy for Solid Cancer after the Introduction of New Anti-Cancer Drugs].

BACKGROUND: In recent years, the decision to discontinue chemotherapy has become more difficult, and there is a tendency for chemotherapy to continue until just before death. We investigated the current state of end-of-life(EOL)chemotherapy for solid cancer patients. METHODS: Patients who died of cancer during hospitalization between January and November 2018 were included. Patients were divided into 2 groups, those who received EOL chemotherapy within 30 days of death(Near group: NG)and those who did not receive it(Far group: FG). The contents of each treatment were compared retrospectively. RESULTS: The number of patients were 46(32%)in the NG and 96(68%)in the FG. As EOL chemotherapy, the number of patients received cytotoxic drugs were 27(59%)and 68(71%), molecular targeted drugs were 6(13%)and 16(16%), immune-checkpoint inhibitors were 8(18%)and 12(12%), and hormone drugs were 0(0%)and 5(5%)in patients with NG and FG respectively(p<0.05). DISCUSSION: Minimally invasive drugs were often selected for EOL chemotherapy. It was suggested that the advent of new drugs has expanded the options for EOL chemotherapy.

[A Case of Intra-Abdominal Desmoid Tumor with Abacterial Peritonitis].

A woman in her 50s visited our hospital in February 2015 with a complaint of dull abdominal pain in the right lower quadrant. She had a medical history of appendectomy for appendicitis in her 20s. Computed tomography(CT)revealed a tumor 90 mm in diameter near the ileocecum. Elective surgery was planned under the suspicion of gastrointestinal tumor, malignant lymphoma, or ileal cancer. She was emergently hospitalized 1 day earlier than scheduled because of high fever and severe abdominal pain. CT revealed that the tumor had increased to 120 mm in diameter without free air. Her white blood cell count was not elevated, and her symptoms improved readily with medical treatment. Thus, we performed the operation as scheduled. A tumor with a dark red recess on the surface had invaded the transverse colon intraoperatively, and a small amount of purulent ascites was present at the pouch of Douglas. We performed ileocecal resection with partial transverse colectomy. Histopathological examination led to the diagnosis of desmoid tumor in the mesentery of the terminal ileum. The surgical margins were negative for tumor cells. The tumor surface around the recess showed peritonitis, and the ascites showed no bacteria or tumor cells. The patient had been doing well without recurrence after discharge. Some cases of desmoid tumor with peritonitis have been reported, but most were caused by tumor penetration into the intestinal tract. We report herein a rare case of intra-abdominal desmoid tumor with abacterial peritonitis.

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.

BACKGROUND: Studies done in Asia have shown that a regimen of S-1 plus oxaliplatin (SOX) has promising efficacy and safety in patients with metastatic colorectal cancer. We aimed to establish whether SOX plus bevacizumab is non-inferior to mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer. METHODS: We undertook an open-label, non-inferiority, randomised phase 3 trial in 82 sites in Japan. We enrolled individuals aged 20-80 years who had metastatic colorectal cancer, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had assessable lesions, had received no previous chemotherapy or radiotherapy, could take drugs orally, and had adequate organ function. Eligible patients were randomly assigned (1:1) to receive either mFOLFOX6 plus bevacizumab (on day 1 of each 2-week cycle, 5 mg/kg intravenous infusion of bevacizumab and a simultaneous intravenous infusion of 85 mg/m(2) oxaliplatin, 200 mg/m(2)l-leucovorin, 400 mg/m(2) bolus fluorouracil, and 2400 mg/m(2) infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7·5 mg/kg intravenous infusion of bevacizumab and 130 mg/m(2) intravenous infusion of oxaliplatin; assigned dose of S-1 twice a day from after dinner on day 1 to after breakfast on day 15, followed by 7-day break). Randomisation was done centrally with the minimisation method, with stratification by institution and whether postoperative adjuvant chemotherapy had been given. Participants, investigators, and data analysts were not masked to treatment assignment. The primary endpoint was progression-free survival (PFS), which was defined as the interval between enrolment and progressive disease (≥20% increase in sum of longest dimensions of target lesions from baseline, or appearance of new lesions) or death, whichever came first. The primary analysis was done by modified intention to treat. This trial is registered with the Japan Pharmaceutical Information Center, number JapicCTI-090699. FINDINGS: Between Feb 1, 2009, and March 31, 2011, 512 patients underwent randomisation. 256 patients assigned to receive SOX plus bevacizumab and 255 assigned to receive mFOLFOX6 plus bevacizumab were included in the primary analysis. Median PFS was 11·5 months (95% CI 10·7-13·2) in the group assigned to mFOLFOX6 plus bevacizumab and 11·7 months (10·7-12·9) in the group assigned to SOX plus bevacizumab (HR 1·04, 95% CI 0·86-1·27; less than non-inferiority margin of 1·33, pnon-inferiority=0·014). The most common haematological adverse events of grade 3 or higher were leucopenia (21 [8%] of 249 patients given mFOLFOX6 plus bevacizumab included in safety analysis vs six [2%] of 250 given SOX plus bevacizumab; p=0·0029) and neutropenia (84 [34%] vs 22 [9%]; p<0·0001). Grade 3 or higher anorexia (13 [5%] vs three [1%]; p=0·019) and diarrhoea (23 [9%] vs seven [3%]; p=0·0040) were significantly more common in patients given SOX plus bevacizumab than in those given mFOLFOX6 plus bevacizumab. We recorded seven treatment-related deaths (three in the group given mFOLFOX6 plus bevacizumab; four in that given SOX plus bevacizumab). INTERPRETATION: SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab with respect to PFS as first-line treatment for metastatic colorectal cancer, and could become standard treatment in Asian populations. FUNDING: Taiho.

[A case of a colon cancer patient with liver metastasis subjected to hepatectomy after achieving radiographic complete response with preoperative chemotherapy].

In 2006, a 70-year-old man who underwent low anterior resection for rectal cancer (SS, N0, H1, Stage IV)at a nearby hospital was referred to our hospital. He was noted to have multiple liver metastases of approximately 1 cm in diameter in S2, S3, S6, and S7, and was subsequently treated with chemotherapy for 5 courses of mFOLFOX6 regimen. He achieved a complete response radiographically. Thereafter, he underwent lateral segmentectomy of the liver and was noted to have residual tumor cells by histopathological examination of the resected tissue. Seven months after the hepatectomy, recurrence occurred in S6 and S7 and a new lesion in S8 was noted. He then underwent 12 courses of mFOLFOX6. As of June 2012, the patient is alive without recurrence. A prolonged survival may be possible if downstaging is achieved with successful chemotherapy. However, similar to the present case, the detection of residual cancer cells during histopathological examination of the resected tissues has been reported in the literature. Thus, further investigation is needed to determine the optimal treatment of cases achieving a radiographic complete response.

The importance of evaluation of DNA amplificability in KRAS mutation testing with dideoxy sequencing using formalin-fixed and paraffin-embedded colorectal cancer tissues.

OBJECTIVE: We evaluated DNA amplificability to achieve a 100% success rate in KRAS mutation testing with dideoxy sequencing using formalin-fixed and paraffin-embedded colorectal cancer tissue samples obtained from a recent clinical trial. METHODS: We evaluated the effects of deparaffinization, formalin fixation or storage time, and amplicon size on the amplificability of DNAs extracted from 19 formalin-fixed and paraffin-embedded colorectal cancer tissue samples. We subjected to KRAS mutation analysis 112 samples from metastatic colorectal cancer patients in 31 hospitals enrolled in a Phase II trial of a second-line FOLFIRI (5-fluorouracil+ leucovorin + irinotecan) + cetuximab regimen. RESULTS: Deparaffinization, formalin fixation and storage times did not appear to affect the recovery and amplificability of DNAs. However, amplicon size had a remarkable effect on the amplificability of DNAs. The smaller fragments with a size of ≤278 bp (96-278 bp) were successfully amplified with polymerase chain reaction in all samples tested, whereas the larger fragments with a size of ≥298 bp (298-565 bp) were not amplified. All samples from our clinical trial were successfully analyzed using three sets of primers with the amplicon sizes of 201, 221 and 240 bp, and KRAS mutations in exons 2 and 3 were detected in 49 of the 112 cases (43.8%). CONCLUSIONS: These data suggest that the evaluation of DNA amplificability and amplicon size is important for the success of mutation detection tests such as the KRAS test with dideoxy sequencing using formalin-fixed and paraffin-embedded tissue samples in the clinical setting.

Timing of resection for synchronous liver metastases from colorectal cancer.

BACKGROUND: This study aimed to compare the surgical outcome and long-term survival between simultaneous and delayed resection of liver metastases from colorectal cancer (LM), and to identify the factors influencing hepatic disease-free survival in patients with synchronous LM. METHODS: Seventy-four patients with LM were divided into two groups, i.e., 32 patients who underwent hepatectomy at the time of colorectal surgery (simultaneous group) and 42 patients who underwent delayed liver resection (delayed group). RESULTS: The hepatic disease-free survival rates of patients from the delayed group with either ≥ 3 or <3 liver metastases were significantly better than that of the simultaneous group. Multivariate analysis showed that simultaneous resection was one of three independent prognostic indicators with an influence on hepatic disease-free survival. In 13 of the 42 (31%) patients from the delayed group, new metastatic lesions were found in the same and/or different segments after re-evaluation during the interval between operations. These patients had a higher incidence of poorly differentiated or mucinous adenocarcinoma, shorter interval between procedures, and larger tumors than patients without tumor progression. CONCLUSIONS: Tumor progression could be recognized and occult metastases were detected during the interval between operations. Delayed resection of synchronous LM may be useful to reduce the risk of rapid recurrence in the remnant liver. Patients with poorly differentiated or mucinous adenocarcinoma and those with larger tumors who undergo delayed liver resection should receive neoadjuvant chemotherapy during the interval between operations.

[Delayed hepatic resection for synchronous liver metastases from colorectal cancer].

BACKGROUND: This study aimed to compare the surgical outcome and long-term survival between simultaneous and delayed resection of liver metastases from colorectal cancer (LM). METHODS: Seventy-four patients with LM were divided into two groups, i. e., 32 patients who underwent hepatectomy at the time of colorectal surgery (simultaneous group) and 35 patients who underwent delayed liver resection (delayed group). RESULTS: In 12 of the 35 (34%) patients from the delayed group, new metastatic lesions were found in the same and/or different segments after re-evaluation during the interval between operations. These patients had a shorter interval between procedures, and larger tumors than patients without tumor progression. There were significant differences (p=0.0454 and 0.0077) of hepatic disease-free survival between the metachronous or delayed groups and the simultaneous group. Multivariate analysis showed that simultaneous resection was one of three independent prognostic indicators with an influence on hepatic disease-free survival. CONCLUSIONS: Tumor progression could be recognized and occult metastases were detected during the interval between operations. Delayed resection of synchronous LM may be useful to reduce the risk of rapid recurrence in the remnant liver.

Patient-reported symptom burden as a prognostic factor in treatment with first-line cetuximab plus chemotherapy for unresectable metastatic colorectal cancer: Results of Phase II QUACK trial.

BACKGROUND: It remains unclear whether patients' self-perceptions of symptoms at baseline clinically impact the prognostic relevance, treatment efficacy, or toxicity profiles in metastatic colorectal cancer (mCRC) patients treated with the first-line cetuximab and standard chemotherapy. METHODS: The data were collected from a prospective trial that assessed the relationships between quality of life (QOL), treatment efficacy, and adverse events (AEs). RESULTS: The analysis of 137 mCRC patients revealed a significant association between the presence of baseline tumor-related symptoms and a lower overall survival (OS) compared to the absence of symptoms (HR, 2.49; 95% CI, 1.37-4.62; P = .003). The asymptomatic responders had favorable outcomes compared to the symptomatic nonresponders (2-year OS rates: 83.6% and 35.9%, respectively), while the symptomatic responders had similar outcomes to the asymptomatic nonresponders. The median postprogression survival differed significantly: 10.2 months for the symptomatic patients and 15.9 months for the asymptomatic patients (HR, 2.29; 95% CI, 1.25-4.29, P = .008). The objective response rates and patient toxicity profiles were similar irrespective of the severity of baseline symptoms. CONCLUSION: Baseline symptoms were associated with worse OS but not with impaired treatment efficacy or more frequent AEs in mCRC patients treated with cetuximab in addition to chemotherapy.

Disagreement between patient- and physician-reported outcomes on symptomatic adverse events as poor prognosis in patients treated with first-line cetuximab plus chemotherapy for unresectable metastatic colorectal cancer: Results of Phase II QUACK trial.

The status and prognostic value of the disagreement between physician and patient assessments of symptomatic adverse events (AEs) remain unclear for patients with metastatic colorectal cancer treated with first-line cetuximab plus chemotherapy. Paired data on patient-reported outcomes using the EORTC QLQ-C30 and physician-reported outcomes using the NCI-CTCAE for eight symptomatic AEs (fatigue, pain, insomnia, dyspnea, constipation, appetite loss, nausea/vomiting, and diarrhea) were collected from a prospective trial assessing the relationships between treatment efficacy, AEs, and quality of life. The overall agreement rates between patient and physician reporting at 4 weeks ranged from 40.2% to 76.5% for 129 patients. The level of agreement based on Cohen's κ statistics was slight to poor for dyspnea, pain, fatigue, and insomnia, while it was moderate to fair for the remaining AEs. No clinicopathological characteristics of disagreement were found. The underreporting by physicians ranged from 12.5% (nausea/vomiting) to 56.7% (fatigue). The 2-year overall survival (OS) rate was more favorable for patients with high agreement than for those with low agreement (71.2% vs. 46.5%, p = .016), and the agreement status was an independent factor of OS (HR, 2.31; 95% CI, 1.13-4.71; p = .022). For patients who were reported as asymptomatic by the physician, the presence of patient-reported symptoms resulted in a trend toward poor prognostic outcomes for appetite loss, dyspnea, diarrhea, and constipation. These findings provide the clinical importance of the monitoring of patient-reported symptoms that can be complementary to physician-reported data to ensure more accurate clinical outcomes.

[Hepatic resection after neoadjuvant therapy for initially unresectable colorectal liver metastases].

BACKGROUND: Recently, an increased number of reports have been published on liver resection following neoadjuvant chemotherapy ( NAC) in patients with initially unresectable colorectal liver metastases (IUCLM). However, the definition of unresectable liver metastases differs among institutions. The size of liver tumor B5 cm and number of tumors B5 is commonly a contraindication for resection of liver metastases. The present study was performed to compare the short and longterm results between patients who underwent liver resection following NAC for IUCLM and those with multiple bilobar metastases for initially resectable liver metastases. METHODS: Twenty-seven patients with multiple bilobar liver metastases between 1994 and 2007 were divided into two groups, i. e. 11 patients who underwent liver resection following NAC for IUCLM and 16 patients who initially underwent liver resection. NAC was used in three in J-IFL and eight cases in mFOLFOX6. RESULTS: All eleven patients with IUCLM were H3/grade C. The median course of NAC was 6 (4-6 courses, Mean+/-SD: 6+/-2 courses). The objective overall response rate was 100% (11/11). H3 of eleven patients was changed to two in H1 and nine in H2 after chemotherapy. Grade C of 11 patients was down-staged in 4 in grade Band 2 in grade A. The H factors and grade of 16 patients who initially underwent liver resection were H16H28H32 and grade A4/B6/C6, respectively. The disease-free and overall survival after resection of colorectal liver metastases between patients with initially unresectable and resectable liver metastases were not significantly different. CONCLUSIONS: NAC enables liver resection in some patients with IUCLM. It should be performed not only preoperatively but also postoperatively for IUCLM because of better survival after surgery.

Association between polymorphisms in EGFR and tumor response during cetuximab and oxaliplatin-based combination therapy in metastatic colorectal cancer: Analysis of data from two clinical trials.

Predicting tumor response prior to starting anti-epidermal growth factor receptor (EGFR) antibody therapy would benefit patients with advanced/metastatic colorectal cancer (mCRC). The present study investigated the association between efficacy of cetuximab treatment and gene polymorphisms of fragment C γ receptor (FcγR) 2A, FcγR3A and EGFR in patients with extended RAS/BRAF wild-type mCRC. Clinical data and specimens were obtained from 90 patients who participated in either of two clinical studies evaluating the first-line, cetuximab plus oxaliplatin-based treatment. It was hypothesized that polymorphisms H/H of FcγR2A, V/V of FcγR3A, K/K of EGFR and <36 CA repeats in the EGFR gene may be associated with a favorable tumor response. Multivariate analysis demonstrated that patients with the H/H polymorphism tended to have an improved tumor response compared with the non-H/H population, although the result was not significant [odds ratio, 2.25; 95% confidence interval (CI), 0.89-5.66; P=0.09]. Univariate analysis revealed increased tumor shrinkage in patients with the K/K polymorphism of EGFR compared with the other polymorphisms (mean ± standard deviation, -55.3±28.4 vs. -39.6±40.8%; P=0.04). Subsequent multivariate analysis confirmed that the K/K polymorphism of EGFR predicted greater tumor shrinkage (multiple linear regression analysis estimate, -19.3; 95% CI, -35.5 to 3.0; P=0.02), with the tendency toward a preferable response in patients with <36 CA EGFR gene repeats (estimate, -16.9; 95% CI; -34.4 to 0.6; P=0.06). However, other polymorphisms and clinical variables did not predict tumor shrinkage. In conclusion, the present study demonstrated that polymorphisms of EGFR, FcγR2A and FcγR3A may differentiate the patients that obtain the maximum benefit from cetuximab treatment.

Multicenter open-label randomized phase II study of second-line panitumumab and irinotecan with or without fluoropyrimidines in patients with KRAS wild-type metastatic colorectal cancer (PACIFIC study).

This phase II clinical trial compared the efficacy and safety of second-line irinotecan and panitumumab treatment (IRI + Pmab) with that of irinotecan, fluoropyrimidines and panitumumab treatment (control) in patients with KRAS wild-type mCRC. The primary endpoint was progression-free survival. In addition, early predictive markers of treatment efficacy were explored. Eighty patients were planned to be recruited. Due to a slow accrual rate, only 48 patients were recruited from 2012 to 2016, of which 23 were allocated to the control group and 25 were allocated to the IRI + Pmab group. The median progression-free survival was 254 days (95% confidence interval, 159-306) for control, and 190 days (95% confidence interval, 159-213) for IRI + Pmab (log-rank test, P = 0.26). The response rate without confirmation was 21.7% (5/23) for control and 40.0% (10/25) for IRI + Pmab. Neutropenia, leukopenia, and anorexia were the most common Grade 3/4 adverse events, and several early drop-outs from the treatment protocol were observed in the control group. As for the biomarkers, carcinoembryonic antigen and lactate dehydrogenase (LDH) smoothly declined immediately after the initial dosing in patients with a partial response or stable disease. After starting treatment, LDH-1 and - 2 increased, while LDH-4 and - 5 decreased, irrespective of tumor response. However, exceptions were frequent. In conclusion, this study failed to prove the safety and efficacy of irinotecan and panitumumab treatment due to insufficient patient accrual. Although LDH and its isozymes changed after initiation of treatment, their ability to predict the tumor response may not surpass that of carcinoembryonic antigen levels.The University Hospital Medical Information Network Clinical Trial Registry: UMIN000007658.

Efficacy of CapeOX plus Cetuximab Treatment as a First-Line Therapy for Patients with Extended RAS/BRAF/PIK3CA Wild-Type Advanced or Metastatic Colorectal Cancer.

Background: Oxaliplatin and capecitabine (CapeOX) combined with cetuximab is rarely used to treat advanced and metastatic colorectal cancer (mCRC). The present study aimed to clarify the clinical benefits of this treatment regimen when used as a first-line therapy in patients with expanded RAS/BRAF/PIK3CA wild-type mCRC, using the data and tumor specimens from two previously published Phase II clinical trials. Methods: The gene mutation status and clinical data of 102 patients with KRAS wild-type mCRC, who received either of CapeOX + cetuximab or FOLFOX + cetuximab, were analyzed. The primary endpoint was response rate (RR) of CapeOX + cetuximab treatment in patients with extended RAS/BRAF/PIK3CA wild-type mCRC. RR comparisons and maximum tumor size changes between different treatment regimens and gene mutation status were set as key secondary endpoints. Results: We identified 88 patients with extended RAS/BRAF/PIK3CA wild-type mCRC. Those treated with CapeOX + cetuximab (n = 52) had a 61.5% RR (95% CI, 47.0-74.7%), while those treated with FOLFOX + cetuximab (n = 36) had a 66.7% RR (95% CI, 49.0-81.4%). Patients with any mutation (n = 14) had a 42.9% RR (95% CI, 17.1-71.1%). There were no significant differences between these three groups (P = 0.298). The disease control rate was 86.5% (95% CI, 74.2-94.4%) in the CapeOX + cetuximab group, and 88.9% (95% CI, 73.9-96.9%) in the FOLFOX + cetuximab group. Maximum tumor size changes were largest in patients with wild-type mCRC treated with FOLFOX + cetuximab followed by patients with wild-type mCRC treated with CapeOX + cetuximab, and then by those with any mutation (-63.2%, -52.6%, and -27.3%, respectively; P = 0.035). Conclusions: Patients with RAS/BRAF/PIK3CA wild-type mCRC had a sufficient RR following first-line treatment with CapeOX + cetuximab. These results suggest that this combination therapy should be considered as a treatment option for patients with advanced mCRC.

A Multicenter Clinical Phase II Study of FOLFOXIRI Plus Bevacizumab as First-line Therapy in Patients With Metastatic Colorectal Cancer: QUATTRO Study.

BACKGROUND: FOLFOXIRI (Fluorouracil, folinate, oxaliplatin, and irinotecan) plus bevacizumab improved progression-free survival (PFS) and overall survival in patients with metastatic colorectal cancer (mCRC), compared with FOLFIRI (fluorouracil, folinate, and irinotecan) plus bevacizumab, but significantly increased the incidences of adverse events. The efficacy and safety profiles of FOLFOXIRI plus bevacizumab in ethnic Asian patients have not been established yet. PATIENTS AND METHODS: This study was an open-label, single-arm, multi-centered phase II prospective clinical trial in patients with mCRC who received FOLFOXIRI plus bevacizumab. The primary endpoint was the PFS rate at 10 months. Secondary endpoints included overall survival, response rate, and safety. RESULTS: A total of 69 patients received FOLFOXIRI plus bevacizumab as induction therapy and were assessed for efficacy and safety. The PFS rate at 10 months was 75.2% and the median PFS was 13.3 months. Complete response and partial response were achieved in 2 (2.9%) and 47 patients (69.1%), respectively. Grade 3 and 4 adverse events with incidence rates exceeding 20% were neutropenia (72.5%), hypertension (34.8%), leucopenia (33.3%), and febrile neutropenia (21.7%). Significantly more patients with grade 4 neutropenia had single-heterozygous UGT1A1*1/*6 or *1/*28 (46.2%) than UGT1A1 wild-type genotype (*1/*1) (13.3%) (P = .004). CONCLUSIONS: FOLFOXIRI plus bevacizumab is considered an effective first-line regimen that improves the outcome of patients with mCRC regardless of ethnicity. In Asian patients, utmost attention should be paid to the possible onset of severe neutropenia or febrile neutropenia attributed to different types of UGT1A1*6 and *28 polymorphism, when FOLFOXIRI plus bevacizumab is administered.

A prospective Phase II study to examine the relationship between quality of life and adverse events of first-line chemotherapy plus cetuximab in patients with KRAS wild-type unresectable metastatic colorectal cancer: QUACK trial.

A prospective trial has not been performed to investigate associations between quality of life (QOL), adverse events (AEs), and overall survival (OS) in the first-line treatment with cetuximab plus standard chemotherapy for advanced/metastatic colorectal cancer (mCRC). Associations between patient outcome and health-related QOL (HRQOL) together with skin toxicity-related QOL were prospectively evaluated using EORTC QLQ-C30 and DLQI questionnaires. One hundred and forty mCRC patients were analyzed in this study, and 87.8% received pre-emptive skin treatment. Skin toxicity had no clinical impact on HRQOL or skin-related QOL during the first 8 weeks and throughout the study period. An early skin reaction with a grade ≥2 at 8 weeks was significantly associated with a favorable OS compared with a grade of ≤1 (HR, 0.50; 95% CI, 0.24-0.95; P = .035) and was confirmed to be an independent predictor of OS (HR, 0.48; 95% CI, 0.21-0.97; P = .040). Patients symptomatic at baseline who responded to treatment had improved HRQOL compared to nonresponding patients. Severe mucositis/stomatitis had a statistically significant and clinically meaningful negative impact on HRQOL (mean changes from baseline throughout the study period in global health status were -12.64 for a grade of ≥2 vs -0.35 for a grade of 0 or 1 (P = .005)). In conclusion, severe early skin reactions predict favorable OS for patients treated with cetuximab plus chemotherapy without impairing QOL. In addition, mucositis/stomatitis was the most substantial AE compromising both QOL and treatment compliance.

S-1 and oxaliplatin (SOX) plus bevacizumab versus mFOLFOX6 plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer: updated overall survival analyses of the open-label, non-inferiority, randomised phase III: SOFT study.

OBJECTIVE: The SOFT study previously demonstrated that S-1 and oxaliplatin (SOX) plus bevacizumab was non-inferior to l-leucovorin, fluorouracil and oxaliplatin (mFOLFOX6) plus bevacizumab in terms of the primary end point of progression-free survival (PFS) as first-line chemotherapy for metastatic colorectal cancer (mCRC). The overall survival (OS) data were immature at the time of the primary analysis. METHODS: A total of 512 patients were enrolled and randomly assigned to receive either mFOLFOX6 plus bevacizumab (5 mg/kg of bevacizumab, followed by 200 mg/m2 of l-leucovorin given simultaneously with 85 mg/m2 of oxaliplatin, followed by a 400 mg/m2 bolus of 5-FU on day 1 and then 2400 mg/m2 of 5-FU as an intravenous infusion over the course of 46 hours, every 2 weeks) or SOX plus bevacizumab (7.5 mg/kg of bevacizumab, 130 mg/m2 of oxaliplatin on day 1 and 40-60 mg of S-1 two times per day for 2 weeks, followed by a 1-week rest). The primary end point was PFS. After the primary analysis, the follow-up survey was cut-off on 30 September 2013, and the final OS data were analysed. RESULTS: With a median follow-up of 37.7 months, the median survival time (MST) was 29.7 months with mFOLFOX6 plus bevacizumab and 29.6 months with SOX plus bevacizumab (HR, 1.018; 95% CI 0.823 to 1.258). Median PFS was 11.7 months in the mFOLFOX6 plus bevacizumab group and 12.2 months in the SOX plus bevacizumab group (HR, 1.051; 95% CI 0.876 to 1.262; pnon-inferiority=0.0115). CONCLUSION: Our results reconfirmed that SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab in terms of PFS. MST did not differ between the groups. SOX plus bevacizumab is considered an effective regimen for first-line chemotherapy in patients with mCRC and can be used instead of mFOLFOX6 plus bevacizumab. TRIAL REGISTRATION NUMBER: JapicCTI-090699.