Clinical significance of enterocyte-specific gene polymorphisms as candidate markers of oxaliplatin-based treatment for metastatic colorectal cancer.

Colorectal cancer (CRC) can be classified into subtypes based on gene expression signatures. Patients with stage III enterocyte subtype of the CRC Assigner classifier have been shown to benefit from oxaliplatin adjuvant therapy. Here, we investigated whether single nucleotide polymorphisms (SNPs) in two enterocyte subtype-related genes, MS4A12 and CDX2, could predict the efficacy of oxaliplatin in first-line treatment for patients with metastatic CRC (mCRC). Three cohorts of patients were included: a discovery cohort receiving FOLFOX ± bevacizumab (BEV) (n = 146), a validation cohort receiving FOLFOXIRI + BEV (n = 230), and a control cohort receiving FOLFIRI + BEV (n = 228). SNPs were analyzed by PCR-based direct sequencing. In the discovery cohort, MS4A12 rs4939378 and CDX2 rs3812863 were identified as potential markers of efficacy. In the validation cohort, any G allele of MS4A12 rs4939378 was associated with longer progression-free survival (PFS) than the A/A variant in both univariate analysis (12.4 vs. 10.9 months, hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49-0.99, P = 0.033) and multivariable analysis (HR 0.65, 95%CI 0.44-0.97, P = 0.035) in patients expressing wild-type KRAS, but not mutant KRAS. In contrast, longer PFS was observed for patients expressing the CDX2 rs3812863 G/G variant than any A allele in univariate analysis (32.3 vs. 10.3 months, HR 0.39, 95%CI 0.19-0.81, P = 0.004) only in patients expressing mutant KRAS. These findings were not observed in the control cohort. Thus, MS4A12 and CDX2 SNPs may have utility as predictive biomarkers of response to oxaliplatin-based treatment in mCRC patients.

Role of enterocyte-specific gene polymorphisms in response to adjuvant treatment for stage III colorectal cancer.

OBJECTIVES: The enterocyte subtype of colorectal cancer (CRC) responds favorably to oxaliplatin-based adjuvant treatment for stage III CRC. We examined the clinical significance of single-nucleotide polymorphisms (SNPs) in enterocyte-related genes MS4A12 and CDX2 in response to adjuvant treatment for stage III CRC. PATIENTS AND METHODS: A total of 350 patients with stage III CRC were included: 274 received adjuvant treatment with surgical resection (discovery cohort) and 76 received surgery alone (control cohort). In the discovery cohort, 68 patients received FOLFOX and 206 received oral fluoropyrimidine. SNPs were analyzed by PCR-based direct sequencing. RESULTS: In the discovery cohort, the MS4A12 rs4939378 G/G variant was associated with lower 5-year survival than any A allele [70% vs. 90%, univariate: hazard ratio (HR) 2.29, 95% confidence interval (CI) 1.03-5.06, P = 0.035; multivariate: HR 2.58, 95% CI 1.15-5.76, P = 0.021]. Patients with the CDX2 rs3812863 G/G variant had better overall survival than those with any A allele, although this was not significant in multivariate analysis (5 year-survival: 95% vs. 82%, univariate: HR 0.34, 95% CI 0.12-0.97, P = 0.034; multivariate: HR 0.39, 95% CI 0.13-1.11, P = 0.078). The SNPs did not show significant association with overall survival in the control cohort, and significant interaction was observed between MS4A12 genotypes and groups (P = 0.007). CONCLUSIONS: Our findings suggest that MS4A12 and CDX2 gene polymorphisms may predict outcome in stage III CRC. However, the clinical significance of SNPs for response to oxaliplatin may differ by tumor stage.

Self-Reported Adherence to Capecitabine on XELOX Treatment as Adjuvant Therapy for Colorectal Cancer.

Adherence has become an important issue in modern oncology treatment. Most studies have included heterogeneous target tumor types, regimens, and therapy settings. Our study focused on capecitabine during capecitabine plus oxaliplatin (XELOX) treatment as an adjuvant therapy for colorectal cancer. The main aims of this study were to evaluate real-life adherence to capecitabine and to investigate candidate factors that might decrease adherence. We studied 338 consecutive patients who received XELOX treatment between December 1, 2011, and April 30, 2015, at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. Our study assessed adherence to capecitabine through patient-reported treatment diaries and interviewed nonadherents to determine the reasons for not taking capecitabine at a pharmaceutical outpatient clinic. We calculated the adherence rate in a cycle as: number of times the patient took capecitabine/28. Relative dose intensities and factors associated with deteriorating adherence to capecitabine were retrospectively surveyed from electronic patient records. Uni- and multivariate logistic regression analyses were used to investigate factors associated with optimal adherence. The study covered 282 patients who received 2,055 cycles of XELOX. Median adherence rate was 94.0% in the first cycle, and median relative dose intensity of capecitabine was 77.8%. The most common reasons for nonadherence were nausea/vomiting and diarrhea. The presence of the following factors was not significantly associated with adherence: ECOG performance status ≥1 (p = 0.715), clinical stage (p = 0.408), primary tumor site (p = 0.576), age ≥70 years at study entry (p = 0.757), female gender (p = 0.504), and not living alone (p = 0.579). The adherence rate from this study was significantly higher than the adherence from metastatic settings. Adherence-enhancing interventions for capecitabine in XELOX treatment as adjuvant therapy comprised management of nausea/vomiting and diarrhea.

Exploratory phase II trial in a multicenter setting to evaluate the clinical value of a chemosensitivity test in patients with gastric cancer (JACCRO-GC 04, Kubota memorial trial).

BACKGROUND: Although postoperative adjuvant chemotherapy with S-1, an oral fluoropyrimidine, has become a standard of care for gastric cancer in Japan, nonresponders may suffer from the cost and adverse reactions without clinical benefit. This multicenter exploratory phase II trial was conducted to see whether a chemosensitivity test, the collagen gel droplet embedded culture drug sensitivity test (CD-DST), can adequately select patients for chemotherapy. METHODS: The CD-DST using four different concentrations of 5-fluorouracil was conducted with resected specimens from preregistered patients who underwent gastrectomy with D2 or more extensive lymphadenectomy. Patients who were histopathologically confirmed to have stage II or greater disease without distant metastasis were eligible for final enrollment. All patients underwent protocol-specified adjuvant chemotherapy with S-1. Three-year relapse-free survival was compared between patients determined as sensitive by the CD-DST (responders) and those deemed insensitive (nonresponders). Appropriate cutoff values for in vitro growth inhibition were defined when the hazard ratio for relapse in responders and the log-rank P values were at their minimum. RESULTS: Of the 311 patients enrolled, 14 were ineligible and 27 failed to start the protocol treatment. The CD-DST failed in 64 other patients, and survival analyses were conducted with the remaining 206 patients (39 stage II disease, 155 stage III disease, and 12 stage IV disease). The outcome of patients who were determined to be responders was significantly superior to that of nonresponders regardless of the 5-fluorouracil concentrations, although no differences in clinicopathologic characteristics were observed between the two groups, except for age. CONCLUSIONS: The CD-DST identified those who benefit from adjuvant chemotherapy. It deserves further evaluation in the setting of a prospective randomized trial. ClinicalTrials.gov identifier: NCT00287755.

Laparoscopic abdominosacral resection for locally advanced primary rectal cancer after treatment with mFOLFOX6 plus bevacizumab, followed by preoperative chemoradiotherapy.

Abdominosacral resection may be the only curative procedure for locally advanced rectal cancer involving the presacral fascia or sacrum. Multimodal therapy might be necessary to prevent local and distant recurrence for such tumors. A 67-year-old man was diagnosed with locally advanced rectal cancer widely involving the right pelvic sidewall and presacral fascia near the S4/5 junction on the right posterolateral side. We performed laparoscopic abdominosacral resection (S4/5) with en bloc right lateral lymph node dissection and seminal vesicle resection to obtain a clear resection margin after systemic chemotherapy with mFOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil) plus bevacizumab, followed by preoperative chemoradiotherapy. The total operative time was 660 min, and the estimated blood loss was 550 mL. The final pathological findings revealed no residual cancer cells (pathological complete response). Laparoscopic abdominosacral resection appears to be safe and feasible in selected patients.

How do we apply adjuvant FOLFOX to Japanese patients with curatively resected colorectal cancer?

AIM: In Japan the combination of fluorouracil (5-FU), leucovorin and oxaliplatin (FOLFOX) was approved as adjuvant therapy for stage III or high-risk stage II colon cancer only in September 2009. In this study we evaluated the safety and efficacy of FOLFOX as adjuvant chemotherapy for stage IIIb or IV colorectal cancer (CRC) patients in a Japanese group at a single institute. METHODS: A total of 45 consecutive patients received 12 cycles of adjuvant FOLFOX for stage IIIb (n = 31) or IV (n = 14) CRC. Toxicity and disease-free survival (DFS) were analyzed retrospectively. RESULTS: The median dose intensities of oxaliplatin and 5-FU were 0.7 and 0.74, respectively. Oxaliplatin was discontinued in 10 (22%) patients due to an allergic reaction in five, neurotoxicity in four and gastrointestinal toxicity in one. No severe neurotoxicity occurred. The median duration from completion of treatment until complete recovery from peripheral neuropathy was 582 days (95% CI, 486-678). Two-year DFS for stages IIIb and IV was 56.9% and 56.3%, respectively (log-rank, P = 0.533). Univariate analysis revealed that severe vessel invasion, liver metastasis and higher baseline levels of CA19-9 were associated with shorter DFS in stage IV patients. Multivariate analysis including the selected biomarkers revealed none as a significant prognostic factor. CONCLUSION: Adjuvant FOLFOX was well tolerated in a Japanese cohort of both stage IIIb and IV CRC patients.

Laparoscopic assisted intersphincteric resection following preoperative chemoradiation therapy for locally advanced lower rectal cancer: report of a case.

Laparoscopy-assisted surgery for rectal surgery has been shown to be both technically feasible and a safe alternative to laparotomy. It can be combined with preoperative chemoradiation and sphincter preserving operation for advanced low rectal cancer. We report a case of advanced lower rectal cancer, which was treated with laparoscopy-assisted total mesorectal excision and intersphincteric resection (abdomino-anal resection with coloanal anastomosis) following preoperative chemoradiation. In this patient, preoperative chemoradiation was very effective and no cancer cells remained in resected specimens.

[Clinical genetics for hereditary cancers: from the viewpoint of physicians working at a hospital specialized in cancer].

In our daily practice, we provide clinical genetic consultation for patients at risk for hereditary cancers. The clinical characteristics of hereditary cancer syndromes in adults differ from those of hereditary diseases in children, although both involve genetic disease. One major difference is the difficulty in diagnosing hereditary cancers. Genetic testing has enabled us to diagnose HNPCC and familial breast and ovarian cancers. Another difference is the possibility to improve the outcomes of hereditary cancer syndromes by medical intervention. Intentional surveillance thus plays a key role in the management of hereditary cancer syndromes. These features make genetic counseling essential for hereditary cancer syndromes, including genetic testing and lifelong disease management. Networking among genetic disease specialists is particularly necessary. Clinical geneticists should be responsible for not only genetic disease but also for genomic information about cancer, with the ultimate goal of providing "order-made" medical consultation and services. Another important goal is the establishment of systems for the comprehensive care of patients and for the career development of specialists to provide regional-based care for persons who have or are at risk for hereditary cancers, including future generations.

[Prospective payment system of medical cost and surgical cancer treatment].

The process of introducing a prospective payment system after DRG or DPC in Japan was reviewed. The effect of DPC/PPS on surgical practice was discussed. Many problems resulted in the USA by introducing the DRG/PPS system. The rapid introduction of DPC/PPS in Japan only to reduce the total medical costs may bring about undesirable results for cancer patients.

Bloodless liver resection using the monopolar floating ball plus ligasure diathermy: preliminary results of 16 liver resections.

Blood loss during liver transection and ischemia-reperfusion injury associated with hepatic inflow occlusion are significant drawbacks during liver surgery. Sixteen patients underwent liver resection using the Monopolar Floating Ball (FB) plus LigaSure (LS) diathermy without occlusion of the hepatoduodenal ligament (group FB-LS). The liver parenchyma was precoagulated using the FB, and the uncovered tiny vessels were sealed using LS. Surgical outcomes were retrospectively compared with 16 well matched patients who underwent liver resection using the conventional clamp crushing method with Pringle's maneuver (group CC). The amount of blood loss during liver transection was significantly less in group FB-LS than in group CC [200 ml (0-990 ml) vs. 480 ml (120-1800 ml); p = 0.006]. The median time it took to complete the liver transection was significantly longer in group FB-LS than in group CC [144 minutes (43-335 minutes) vs. 58 minutes (18-94 minutes); p < 0.0001]. Hepatic inflow occlusion was temporally used in five patients in group FB-LS to achieve hemostasis in hepatic venous tributaries for 6, 10, 19, 26, and 61 minutes, respectively. Using these two electronic devices allows liver resection to be safely performed, with the advantage of minimal blood loss and a reduced inflow occlusion period compared to the conventional method. The major disadvantage may be a slower transection speed. A prospective randomized trial is needed to clarify the clinical benefits of liver resections performed using this novel technique.

[Progress in postoperative adjuvant chemotherapy in gastric cancer].

Clinical trials of adjuvant chemotherapy after surgery of gastric cancer have a long history dating since the late 1950s, but no standard regimen is yet established. Early studies included 5-FU- or TSPA-based regimens, sometimes combined with Me-CCNU or BCNU in Western countries, and resulted in a negative survival benefit, whereas 5-FU or MMC alone, or in combinations such as with MFC, were tried in Japan, and resulted in marginal survival benefit in the subset of moderately locally advanced diseases. Oral administration of 5-FU or its derivatives characterized Japanese trials in 1980s, though no definite benefit is yet established. Recent reports from Western countries regarding ELF, MMC + TGF, and FEM suggest significant or subsignificant survival benefit after curative gastrectomy. Meta-analysis of randomized trials also suggested marginal significant survival benefit, and these results encourage future trials with new drugs. The same regimens administered following surgery with different technical skill may result in different outcomes, and treatments in our country should be established based on our trials.