High dose chemoradiotherapy increases chance of organ preservation with satisfactory functional outcome for rectal cancer.

BACKGROUND: High dose chemoradiotherapy offers a curative chance for patients with rectal cancer that are unfit or unwilling to undergo surgical resection, yet its long-term survival and functional outcomes have been rarely investigated. METHODS: Patients with non-metastatic rectal adenocarcinoma who received pelvic radiation for curative intent from April 2006 to July 2017 were retrospectively investigated. Survival rates were analyzed using the Kaplan-Meier method. Quality of life and functional outcomes were evaluated using the EORTC quality of life questionnaire. RESULTS: A total of 57 patients were included, with a median age of 59.0 (range, 29-84) years. The numbers of patients who were diagnosed as stage I, II and III were 5 (8.8%), 16 (28.1%) and 36 (63.2%), respectively. 53 (93.0%) patients had tumor located within 5 cm from the anal verge. All patients received fluorouracil-based concurrent chemoradiotherapy with a median radiation dose of 80 (range, 60-86) Gy. All kinds of grade 3-4 adverse events occurred in 18 (31.6%) patients. 42 (73.7%) patients achieved a clinical complete response after chemoradiotherapy. After a median follow-up of 43.5 (range 14.9-163.2) months, 12 (21.1%) patients had local progression and 11 (19.3%) developed distant metastasis. The 3-year local recurrence-free survival and distant metastasis-free survival were 77.3% (95% CI, 65.7-88.8%) and 79.2% (95% CI, 68.2-90.2%), while the 3-year progression-free survival, cancer-specific survival, overall survival were 61.9% (95% CI, 48.8-75.0%), 93.1% (95% CI, 85.8-100.0%) and 91.4% (95% CI, 83.6-99.2%), respectively. For patients who had tumor located within 3 cm from the anal verge, the sphincter preservation rate was 85.3% at last follow-up. Long-term adverse events mainly were anal blood loss. 21 patients completed the quality-of-life questionnaire and had a score of the global health status of 78.57 ± 17.59. Of them, 95.2% reported no urinary incontinence and 85.7% reported no fecal incontinence. CONCLUSIONS: High dose chemoradiation demonstrated promising survival outcomes with acceptable short-term and long-term side effects, and satisfying long-term functional outcomes and quality of life. It could be considered as a non-invasive alternative for rectal cancer patients who refuse surgery.

Voltage-gated sodium channel Nav1.5 promotes tumor progression and enhances chemosensitivity to 5-fluorouracil in colorectal cancer.

Nav1.5, encoded by SCN5A, has been associated with metastasis in colorectal cancer (CRC). Here, we investigated the mechanism by which Nav1.5 regulates tumor progression and whether Nav1.5 influences chemosensitivity to 5-fluorouracil (5-FU) in CRCs. CRC cases were evaluated for Nav1.5 expression. Elevated Nav1.5 expression was associated with poor prognosis in CRCs, whereas stage II/III patients with upregulated SCN5A expression could have better survival after receiving 5-FU-based adjuvant chemotherapy. In CRC cells, SCN5A knockdown reduced the proliferation, migration and invasion. According to RNA sequencing, SCN5A knockdown inhibited both the cell cycle and epithelial-mesenchymal transition. In addition, Nav1.5 stabilized the KRas-calmodulin complex to modulate Ras signaling, promoting Ca2+ influx through the Na+-Ca2+ exchanger and Ca2+ release-activated calcium channel. Meanwhile, SCN5A knockdown increased the 50% inhibitory concentration to 5-FU by upregulating 5-FU-stimulated apoptosis in CRCs. In conclusion, Nav1.5 could progress to proliferation and metastasis through Ca2+/calmodulin-dependent Ras signaling in CRC, and it could also enhance 5-FU-stimulated apoptosis. Clinically, patients with stage II/III CRCs with elevated SCN5A expression demonstrated poor prognosis, yet those patients could benefit more from 5-FU-based chemotherapy than patients with lower SCN5A expression.

Phase III randomized, placebo-controlled, double-blind study of monosialotetrahexosylganglioside for the prevention of oxaliplatin-induced peripheral neurotoxicity in stage II/III colorectal cancer.

BACKGROUND: Monosialotetrahexosylganglioside (GM1) is a neuroprotective glycosphingolipid that repairs nerves. Oxaliplatin-based chemotherapy is neurotoxic. This study assessed the efficacy of GM1 for preventing oxaliplatin-induced peripheral neurotoxicity (OIPN) in colorectal cancer (CRC) patients receiving oxaliplatin-based chemotherapy. METHODS: In total, 196 patients with stage II/III CRC undergoing adjuvant chemotherapy with mFOLFOX6 were randomly assigned to intravenous GM1 or a placebo. The primary endpoint was the rate of grade 2 or worse cumulative neurotoxicity (NCI-CTCAE). The secondary endpoints were chronic cumulative neurotoxicity (EORTC QLQ-CIPN20), time to grade 2 neurotoxicity (NCI-CTCAE or the oxaliplatin-specific neuropathy scale), acute neurotoxicity (analog scale), rates of dose reduction or withdrawal due to OIPN, 3-year disease-free survival (DFS) and adverse events. RESULTS: There were no significant differences between the arms in the rate of NCI-CTCAE grade 2 or worse neurotoxicity (GM1: 33.7% vs placebo: 31.6%; P = .76) or neuropathy measured by the EORTC QLQ-CIPN20 or time to grade 2 neurotoxicity using NCI-CTCAE and the oxaliplatin-specific neuropathy scale. GM1 substantially decreased participant-reported acute neurotoxicity (sensitivity to cold items [P < .01], discomfort swallowing cold liquids [P < .01], throat discomfort [P < .01], muscle cramps [P < .01]). The rates of dose reduction or withdrawal were not significantly different between the arms (P = .08). The 3-year DFS rates were 85% and 83% in the GM1 and placebo arms, respectively (P = .19). There were no differences in toxicity between the arms. CONCLUSION: Patients receiving GM1 were less troubled by the symptoms of acute neuropathy. However, we do not support the use of GM1 to prevent cumulative neurotoxicity. (ClinicalTrials.gov number, NCT02251977).

Neoadjuvant sandwich treatment with oxaliplatin and capecitabine administered prior to, concurrently with, and following radiation therapy in locally advanced rectal cancer: a prospective phase 2 trial.

PURPOSE: Systemic failure remains the major challenge in management of locally advanced rectal cancer (LARC). To optimize the timing of neoadjuvant treatment and enhance systemic control, we initiated a phase 2 trial to evaluate a new strategy of neoadjuvant sandwich treatment, integrating induction chemotherapy, concurrent chemoradiation therapy, and consolidation chemotherapy. Here, we present preliminary results of this trial, reporting the tumor response, toxicities, and surgical complications. METHODS AND MATERIALS: Fifty-one patients with LARC were enrolled, among which were two patients who were ineligible because of distant metastases before treatment. Patients were treated first with one cycle of induction chemotherapy consisting of oxaliplatin, 130 mg/m² on day 1, with capecitabine, 1000 mg/m² twice daily for 14 days every 3 weeks (the XELOX regimen), followed by chemoradiation therapy, 50 Gy over 5 weeks, with the modified XELOX regimen (oxaliplatin 100 mg/m²), and then with another cycle of consolidation chemotherapy with the XELOX regimen. Surgery was performed 6 to 8 weeks after completion of radiation therapy. Tumor responses, toxicities, and surgical complications were recorded. RESULTS: All but one patent completed the planned schedule of neoadjuvant sandwich treatment. Neither life-threatening blood count decrease nor febrile neutropenia were observed. Forty-five patents underwent optimal surgery with total mesorectal excision (TME). Four patients refused surgery because of clinically complete response. There was no perioperative mortality in this cohort. Five patients (11.1%) developed postoperative complications. Among the 45 patients who underwent TME, pathologic complete response (pCR), pCR or major regression, and at least moderate regression were achieved in 19 (42.2%), 37 (82.2%), and 44 patients (97.8%), respectively. CONCLUSIONS: Preliminary results suggest that the strategy of neoadjuvant sandwich treatment using XELOX regimen as induction, concomitant, and consolidation chemotherapy to the conventional radiation is well tolerated. The strategy is highly effective in terms of pCR and major regression, which warrants further investigation.

[Prognostic analysis of 443 cases of stage II colorectal cancer and the value of adjuvant chemotherapy].

BACKGROUND AND OBJECTIVE: Prognosis of stage II colorectal cancer varies. Whether or not to perform adjuvant chemotherapy on patients with stage II colorectal cancer is controversial. This study was to explore the prognostic factors for the patients with stage II colorectal cancer and evaluate the effect and the necessity of adjuvant chemotherapy. METHODS: Between January 2000 and January 2005, 443 patients with stage II colorectal cancer receiving radical surgery at Sun Yat-sen University Cancer Center were retrospectively analyzed. The overall survival rate and survival curve were analyzed using the Kaplan-Meier method and the log-rank test. The univariate and multivariate prognostic analyses were performed by the Cox regression model. Patients with or without chemotherapy (Xelox/Folfox regimen) with high-risk factors were analyzed respectively. RESULTS: The median follow-up time was 59 months, and the 3-and 5-year survival rates were 88.4% and 82.5%, respectively. Univariate analysis showed that intestinal obstruction or perforation, diabetes mellitus, inadequate surgical margin, and the number of sampled nodes < 9 were poor prognostic factors. Patients with intestinal obstruction or perforation, the number of sampled nodes < 9 achieved higher 5-year survival (80% and 86%) undergoing adjuvant chemotherapy than those receiving surgery alone (67% and 64%). CONCLUSIONS: The prognosis of colorectal cancer patients with intestinal obstruction or perforation, diabetes mellitus, inadequate surgical margin, and the number of sampled nodes < 9 are relatively poor. Adjuvant chemotherapy is recommended to patients with intestinal obstruction, perforation or sampled nodes < 9.

[Clinical analyses of 70 cases of multiple primary colorectal carcinoma].

BACKGROUND & OBJECTIVE: Multiple primary colorectal carcinoma (MPCC) is not rarely seen, but it possesses a unique biological characters. This study was to investigate the clinical characteristics, diagnosis, therapeutic principle and prognosis of MPCC. METHODS: Data of 70 MPCC patients, treated by operation from 1997 to 2003, were analyzed. Of the 70 patients, 61 had synchronous carcinoma (SC) and 9 had metachronous carcinoma (MC). RESULTS: Fifty-five patients were diagnosed by colonoscopy, barium enema or CT scan pre-operationally, while 15 were diagnosed intra-operationally due to the oversized tumor at the distal end of the colon. Thirty-three patients had colorectal carcinoma accompanying with adenoma and multiple polyps. All the patients underwent surgical resection except 3, who received short-circuit operation because of unresectable lesions. Fifty-two patients received radical resection, while 15 received palliative resection due to hepatic or peritoneal metastasis. The overall 3-and 5-year survival rates were 65.7% and 45.7%. In the patients who received radical resection, the 3-and 5-year survival rates were 78.1% and 59.3%. CONCLUSIONS: The occurrence of MPCC is largely related with adenomas and polyps. The extent of resection should be individually determined by the lesion location, range, the distance of lesions as well as the general condition of the patients. Prognosis of MPCC is relatively good. The patients accompanying with adenoma and multiple polyps should be followed up intensively.

[Comparing the effect of adjuvant chemotherapy by portal vein infusion with intraluminal chemotherapy for colorectal cancer].

OBJECTIVE: To compare the effect of 5-fluorouracil (5-FU) portal vein infusion (PVI) for 7 days after radical resection, with intraluminal chemotherapy during operation for eliminating liver metastasis and elevating long-term prognosis in colorectal cancer. METHODS: 162 colorectal cancer patients with radical resection were divided into portal vein chemotherapy group (group A, 82 cases) and intraluminal chemotherapy group (group B, 80 cases) randomly. In group A, 5-fluorouracil were infused with 1g per day constantly for 7 days after operation through portal vein catheters, which placed into greater omental vein and fixed on the abdominal wall. In group B, intraluminal chemotherapy was given and 5-fluorouracil 0.5 g was injected into the greater omental vein during operation. RESULTS: The short-term complications and long-term effect in the two groups were compared by statistical software SPSS 8.0. Group A had more operative complications, and no statistical differences was found in hospital time and survival rate of the two groups. The 5-year survival rate is 76.7% (group A: 74.3%, group B: 79.2%), and the liver metastasis rate is 19.8%. There is no significant difference between the two group-survival curves. Multiple variable analysis suggested that Dukes' stage was the prognosis factor (P < 0.05). CONCLUSIONS: The present study demonstrated that the two chemotherapy methods play an important role in preventing liver metastasis and improving the survival rate, and the intraluminal chemotherapy would be easier and simpler. The result should be further improved by using combined chemotherapy.