Phase II study of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as second-line treatment for metastatic colorectal cancer and exploratory analysis of associations between DNA methylation status and the efficacy of the anti-EGFR antibody: T-CORE1201.

Background: Little is known about the biweekly combined use of cetuximab and chemotherapy as second-line treatment of metastatic colorectal cancer (mCRC). Recently, DNA methylation status has been reported to be a new possible predictor of the efficacy from the anti-epidermal growth factor receptor (EGFR) antibody treatment. The purpose of this study was to examine the efficacy and safety of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as a second-line treatment for KRAS exon 2 wild-type mCRC. We also investigated the predictability of DNA methylation status on the efficacy of the EGFR antibody-containing treatment. Methods: Patients who were refractory or intolerant to the first-line chemotherapy were enrolled and received biweekly cetuximab plus mFOLFOX6 or mFOLFIRI. The primary endpoint was progression-free survival (PFS). Tumor evaluations were performed every 2 months using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. DNA methylation status of colorectal cancer cells was defined by a modified MethyLight assay. Results: Sixty-six cases were enrolled. The median PFS (mPFS) was 5.1 [95% confidence interval (CI), 3.8-7.6] months. The median overall survival (mOS) was 12.7 (95% CI, 7.5-15.3) months. Grade 3 or higher neutropenia occurred in 53.0% of patients, whereas skin disorders with a grade 3 or higher occurred in <15% of patients. In multivariate analysis, DNA methylation status could not be an independent predictor of PFS [hazard ratio (HR), 1.43; P=0.39] and OS (HR, 2.13; P=0.086). However, in RAS/BRAF wild-type patients, the mPFS and mOS in the low-methylated colorectal cancer (LMCC) group was numerically better than those in the highly-methylated colorectal cancer (HMCC) group, although the difference was not statistically significant [mPFS: 8.5 (95% CI, 6.1-10.9) vs. 3.3 (95% CI, 1.2-not reached) months, P=0.79; ΔmPFS, 5.2 months; mOS: 15.3 (95% CI, 11.9-23.5) vs. 6.5 (95% CI, 3.1-not reached) months, P=0.53; ΔmOS, 8.8 months]. Conclusions: Biweekly cetuximab plus mFOLFOX6 or mFOLFIRI is a useful second-line therapy for mCRC. DNA methylation status warrants further exploration as a predictive biomarker for anti-EGFR efficacy in mCRC.

[Two Cases of Long-Term Control of Advanced Gastric Cancer Treated with>35 Cycles of Low-Dose Nab-Paclitaxel].

Nanoparticle albumin-bound paclitaxel(nab-PTX)is effective as second-line chemotherapy for advanced gastric cancer. Long-term administration is generally impossible because of peripheral sensory neuropathy. However, we report 2 cases that were treated with>35 cycles of nab-PTX with dose reduction to control disease progression, which appears to be the highest number cycles so far reported. Case 1 was a male patient in his 70s, with distant lymph node metastases and an advanced primary lesion(tub2). He received 6 cycles S-1/CDDP and achieved a partial response; however, the treatment was changed to second-line chemotherapy with nab-PTX because of adverse effects; the dose of nab-PTX was reduced by 60% every 3 weeks. At the time of writing, 36 cycles have been administered and disease control has been maintained, with Grade 2 peripheral sensory neuropathy. Case 2 was another male patient in his 70s, who underwent total gastrectomy for gastric cancer(mucinous adenocarcinoma). Virchow metastasis was detected 6months after surgery. He received 1 cycle S-1/CDDP and achieved a partial response; however, treatment was changed to second-line chemotherapy with nab-PTX because of adverse effects; the dose of nab-PTX was reduced by 60% every 3 weeks. At the time of writing, 41 cycles have been administered and disease control has been maintained, with Grade 2 peripheral sensory neuropathy.

[A Case of Large-Cell Neuroendocrine Carcinoma of the Stomach with Multiple Liver Metastases That Show Complete Response to Multidisciplinary Therapy].

A 64-year-old man was diagnosed with advanced gastric cancer based on an endoscopic examination in June 2009; histological findings indicated poorly differentiated adenocarcinoma.Computed tomography revealed multiple liver metastases and bulky lymph node metastases of LN#7.The multiple liver metastases of the gastric cancer were not considered to be candidates for surgical resection, and S-1/CDDP chemotherapy was initiated in July 2009. After 6 courses of this regimen, liver and lymph node metastases showed partial response(PR), but the gastric tumor showed progressive disease(PD).Therefore, we switched this regimen to bi-weekly CPT-11/CDDP in March 2010. However, because the gastric tumor had increased in size and presented with bleeding, we performed distal gastrectomy.The pathological diagnosis based on the resected speci- men was large-cell neuroendocrine carcinoma.After surgery, CPT-11/CDDP was continued but was switched to CPT-11 in June 2011 because of induced renal dysfunction.In November 2011, the regimen was switched to weekly paclitaxel because of a progressive increase in size of a solitary liver metastatic lesion located in S4-5.Two courses of this regimen were administered, but they were ineffective; therefore, we performed partial hepatectomy.No other recurrent lesions were observed during the surgery, and the patient was estimated to have achieved complete response(CR).After the surgery, no further adjuvant chemotherapy was administered.Four years after hepatectomy, the patient was diagnosed with esophageal cancer but exhibited no recurrence of the gastric cancer.We performed esophagectomy for the esophageal cancer in May 2016.T he patient is currently well without any relapse.

Intermittent Withdrawal of Oxaliplatin for Alleviating Neurotoxicity during Oxaliplatin-Based Chemotherapy for Japanese Patients with Inoperable or Metastatic Colorectal Cancer: A Phase 2 Multicenter Study.

Oxaliplatin-based chemotherapy is a well-established regimen for patients with inoperable and metastatic colorectal cancer. However, one of the major limitations of oxaliplatin-based chemotherapy is sensory neuropathy. It was previously reported that introduction of intermittent oxaliplatin treatment to an oxaliplatin-based regimen has a significant benefit on efficacy or safety. Here, we prospectively assessed whether efficacy and safety of first-line chemotherapy for advanced colorectal cancer are achieved by introduction of withdrawal of oxaliplatin treatment for a certain period (intermittent oxaliplatin treatment). The primary endpoint of the present study is to assess the progression free survival time on patients treated with chemotherapy (mFOLFOX6 (levofolinate, 5-fluorouracil and oxaliplatin combination therapy) plus bevacizumab or CapeOX (oxaliplatin and capecitabine combination therapy) plus bevacizumab) with intermittent oxaliplatin treatment. Bevacizumab is a humanized anti-vascular endothelial growth factor antibody. Median progression-free survival by the mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or the CapeOX plus bevacizumab with intermittent oxaliplatin treatment were 10.6 months (95% confidential interval [CI], 8.3-13.4 months) or 8.0 months (95% CI, 4.2-16.8 months), respectively. Overall response rate by the mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or CapeOX plus bevacizumab with intermittent oxaliplatin treatment was 55.1% or 42.1%, respectively. Grade 3 or 4 neuropathy was observed in 4.1% or 10.5% of patients treated with mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or CapeOX plus bevacizumab with intermittent oxaliplatin treatment, respectively. Introduction of intermittent oxaliplatin treatment has improved severe neuropathy in mFOLFOX6 plus bevacizumab regimen without reducing treatment efficacy.

Phase II trial of cetuximab plus irinotecan for oxaliplatin- and irinotecan-based chemotherapy-refractory patients with advanced and/or metastatic colorectal cancer: evaluation of efficacy and safety based on KRAS mutation status (T-CORE0801).

BACKGROUND: Mutations in the KRAS gene have been identified as negative predictors of response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy by patients with metastatic colorectal cancer (mCRC). However, it has been based on the study of mainly Caucasian mCRC patients. This prospective study investigated the relationship between the mutation status of EGFR-related genes including KRAS and the response rate (RR) to cetuximab plus irinotecan therapy in Japanese mCRC patients. METHODS: Samples taken from 43 chemotherapy-refractory mCRC patients who had undergone cetuximab plus irinotecan therapy at 11 medical centers in Japan were subjected to direct DNA sequencing to determine the KRAS, BRAF, PIK3CA, NRAS, and AKT1 mutation status. The clinical outcome after the treatment was evaluated for each mutation status. RESULTS: KRAS mutations were detected in 31.7% of 41 eligible patients. The RR to cetuximab plus irinotecan therapy was found to be 17.9 and 0% in the KRAS wild-type and mutant subgroups, respectively. CONCLUSION: Despite the identification of a lower-than-expected RR to treatment by the KRAS wild-type subgroup, KRAS mutation status appears to be a useful predictive marker of response to cetuximab plus irinotecan therapy in Japanese mCRC patients.

[Management of colorectal cancer in elderly patients over 80 years old].

AIM: The incidence of colorectal cancer is increasing. Surgery and chemotherapy for elderly patients are also increasing. We evaluated the characteristics of elderly colorectal cancer to clarify issues related to surgical therapy for elderly patients. METHOD: We studied 67 patients (38 men, 29 women) over 80 years old on whom we operated for colorectal cancer from 1990 to 2004. We compared them with 130 patients aged from 70 to 74 who were operated on in the same period, examining clinicopathological factors, operative methods, preoperative morbidity, postoperative complications, chemotherapy and postoperative survival ratio. RESULTS: In the elderly patients aged over 80, the rate of Dukes' B was high, whereas the rate of Dukes' A was high in patients aged from 70 to 74. No significant differences were observed in operative methods for colon cancer but Hartmann's operation and transanal local excision were frequent for rectal cancer in patients aged over 80. The rate of lymph node dissection was low in patients aged over 80 with rectal cancer. A significant difference was observed in lymph node dissection of rectal cancer between patients aged over 80 and those aged from 70 to 74, but there was no significant difference in curative ratio. Preoperative morbidity were recognized in 76% of patients aged over 80. Postoperative complications occurred in 51% of patients aged over 80. There were many cases showing delirium, but no differences in other complications between patients aged over 80 and those aged from 70 to 74. There was no operative mortality in patients aged over 80. CONCLUSION: Even elderly patients can anticipate safe operations without postoperative complications or decreased quality of life, if the appropriate operative procedure is selected with regard to their general condition.

[A case of liver metastasis from anorectal malignant melanoma on hemodialysis treated by chemotherapy].

We report a case on hemodialysis with liver metastases from anorectal malignant melanoma treated by dacarbazine (DTIC). A 61-year-old man presented with anal bleeding. An elastic soft mass was palpated in the anal canal, and a biopsy specimen was diagnosed as anorectal malignant melanoma histologically. After introducing hemodialysis for the chronic renal failure, abdominoperineal resection was performed. Two and a half years after surgery, computed tomography showed multiple liver metastases. We chose chemotherapy consisting of DTIC 100 mg for five consecutive days every 4 weeks in addition to hemodialysis (3 times a week). After three cycles of chemotherapy, liver metastases were stable, but new lung metastases were found. After 12 cycles of chemotherapy, liver metastases became stable, but lung metastases were progressive. Subsequently, the patient died of respiratory failure 4 years after surgery, 1 year and 7 months after the diagnosis of multiple liver metastases. No severe toxicity was observed during this period. We conclude that administration of DTIC undergoing hemodialysis for malignant melanoma with renal failure seems to be useful without severe adverse events.

[Clinical study of S-1 for advanced gastric cancer after reduction surgery].

We investigated the clinical efficacy and safety of S-1 retrospectively for the treatment of 32 patients with advanced gastric cancer after reduction surgery (gastrectomy). S-1 was administered orally twice daily, at a standard dose of 80 mg/m(2) per day for 28 days, followed by a 14-day rest. There were 21 patients having only a single residual metastatic site and 11 with two or more metastatic sites. Major residual metastatic sites were peritoneum in 25 patients, lymph nodes in 7, liver in 4 and lung in 2. The response rate by target organ was 28.6% for lymph node metastasis, and 0% for liver and lung metastasis. Peritoneal metastasis was not considered measurable site. The median survival time (MST) after S-1 administration was 573 days (95% confidence interval, 439 to 707 days). The 1-, 2- and 3-year survival rates were 62.3%, 40.3% and 28.2%, respectively. Of the 32 patients, 14 received S-1 for more than a year, and the MST in these patients was 897 days (95% confidence interval, 255 to 1,539 days). The incidence of adverse events was 90.6%, but the incidence of grade 3 or 4 was 12.5%. Long-term administration of S-1 may serve to prolong the survival period of patients with gastric cancer after reduction surgery, particularly in peritoneal metastasis.

Surgical management for metastatic liver tumors.

BACKGROUND/AIMS: This study investigated the results of hepatectomy for multiple liver metastases and repeated hepatectomy for recurrent hepatic metastases. A proposed treatment strategy for liver metastases is discussed. METHODOLOGY: Fifty-seven consecutive cases of liver metastases were studied. The metastases originated from colon cancer (24 cases), rectal cancer (11 cases), gastric cancer (14 cases), or gastrointestinal stromal tumors (two cases). The other cases included one each of gastric carcinoid, carcinoma of the papilla of Vater, cystic duct cancer, esophageal cancer, choriocarcinoma and breast cancer. RESULTS: The overall 5-year survival rate for the 57 cases was 45.4%; there was no significant difference between patients with colon cancer (56.3%), rectal cancer (45.5%), or gastric cancer (41.6%). The cumulative 5-year survival rates for synchronous and metachronous metastases were 38.3% and 50.8%, respectively (difference not statistically significant; NS). The survival rates for single and multiple metastases were 56.0% and 31.3% (NS), and those for monolobar and bilobar metastases were 48.5% and 40.9% (NS), respectively. Concerning the operative procedure, the survival rates for partial resection and hemi-hepatectomy were 49.5% and 26.9%, respectively (NS). The survival rates for surgical margins <4mm and >5mm were 45.9% and 45.4%, respectively (NS), and those for single and repeat hepatectomy were 40.5% and 58.2% (NS). Preoperative portal embolization was performed in seven cases because of multiple metastases or a tumor located in a deeper site in the liver. There was no hospital death among the 57 cases. CONCLUSIONS: These results show that hepatectomy may offer longer survival, even in patients with multiple or bilobar metastases. Neither the operative procedure nor the size of the surgical margin had any influence on survival after hepatectomy. The prognosis was improved not only for metastases from colorectal cancer, but also for gastric cancer. An increased survival benefit was obtained by repeat hepatectomy for recurrent hepatic metastases. Preoperative portal embolization extended the indication for hepatectomy and provided postoperative safety.

Total papillectomy for borderline malignant tumor of papilla of Vater.

The therapies for treating tumors of the papilla of Vater remain controversial because accurate preoperative diagnosis is difficult. Treatments include endoscopic resection, pancreaticoduodenectomy and total papillectomy. We report the case of a 69-year-old man who underwent total papillectomy for a borderline malignant tumor of the papilla of Vater. In our institution, the decision to perform a total papillectomy for borderline malignant adenoma is based on whether it is intestinal type or pancreaticobiliary type. Carcinoma of the papilla of Vater is classified into two types: an intestinal type and a pancreaticobiliary type and the prognosis of the intestinal type is much better than that of the pancreaticobiliary type. We suggest that total papillectomy can be performed for an intestinal, borderline malignant tumor.