Adjuvant Oxaliplatin Research Articles

Neuropathy severity at the time of oxaliplatin treatment alteration in patients with colon cancer (Alliance A151912).

12090 Background: Clinical guidelines recommend altering chemotherapy treatment by decreasing, delaying, or discontinuing dosing in patients (pts) experiencing chemotherapy-induced peripheral neuropathy (CIPN). There are few data available on clinical use of treatment alteration including the severity of CIPN at the time of alteration. Our objective was to investigate the incidence of oxaliplatin treatment alterations and CIPN severity at that time. Methods: This was a retrospective analysis of pts with colon cancer scheduled to receive oxaliplatin-containing combination chemotherapy on the N08CB trial of intravenous calcium and magnesium for prevention of CIPN. Dose alterations were not mandated by the N08CB protocol. Clinicians assessed CIPN using NCI-CTCAE V.4.0; pts used the sensory subscale of the EORTC-QLQ Chemotherapy-Induced Peripheral Neuropathy 20 (CIPN8). Pts were classified as 1) completed oxaliplatin treatment without alteration, 2) dose reduction or delay due to CIPN, 3) discontinuation due to CIPN, 4) discontinuation due to other AE, or 5) discontinuation for another reason. Comparisons focused primarily on pts with alteration due to CIPN (groups 2 and/or 3) compared with pts completing treatment without alteration (group 1) using chi-squared and Kruskal-Wallis tests. Results: In this analysis of 350 N08CB pts, 135 (39%) completed oxaliplatin without treatment alteration, 70 (20%) had a dose reduction (n=66) or delay (n=4) due to CIPN and 35 (10%) discontinued early due to CIPN. Pts who experienced alterations due to CIPN were younger (p=0.0249) and more likely to be female (p=0.008). Clinician-assessed CIPN severity was greater in pts at the time of dose reduction or delay compared with CIPN severity at the end of treatment in pts with no alteration (p<0.0001). Pt-assessed CIPN severity was not different in pts who completed treatment without alteration compared to pts who had a dose reduction or delay (p=0.88) or a discontinuation (p=0.37). CIPN8 scores at cycle 4 were higher (worse) in pts who eventually had any alteration (i.e., reduction, delay, or discontinuation) compared to pts who completed treatment without any alteration (median CIPN8 11.5 vs. 7.7, p=0.023). Conclusions: Treatment alterations due to CIPN are relatively common in pts receiving adjuvant oxaliplatin for colon cancer and are associated with clinician-assessed but not pt-reported CIPN severity. Rapid CIPN8 increases early in treatment are indicative of increased likelihood of a future oxaliplatin treatment alteration, indicating a potential use of early monitoring and intervention. Support: UG1CA189823; https://acknowledgments.alliancefound.org. Clinical trial information: NCT01099449 (NCCTG N08CB).

Review and Updates on Approaches to Neoadjuvant Chemotherapy in Rectal Cancer

The currently established standard of care treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) and adjuvant fluorouracil and oxaliplatin. The body of evidence that supports this treatment has grown over the last 20 years. However, recent advances and ongoing studies seek to further evaluate the role of neoadjuvant chemotherapy with and without radiation and total neoadjuvant therapy (TNT). In this article, we review the current literature as well as investigate the emerging role of TNT for patients with LARC and comment on updates utilizing combination neoadjuvant chemotherapy in early-stage rectal cancer. Evidence for the current standard of neoadjuvant CRT comes from well-established randomized phase III trials as well as emerging evidence on merits of TNT. There is a growing body of literature including retrospective analysis and ongoing clinical trials that look at upfront induction chemotherapy in addition to CRT prior to surgical resection leading to more effective delivery of systemic therapy and increases in response to treatment. Neoadjuvant combination chemotherapy is also being investigated in early-stage low rectal tumors to see if rates of local excision will increase compared to radical excision. Current evidence continues to support neoadjuvant CRT as the standard treatment for LARC. There is an increasing body of evidence to support TNT in LARC as an effective treatment strategy that better ensures delivery of systemic therapy leading to higher rates of complete response (CR) and is encouraging for the development of non-operative protocols. There is ongoing evaluation looking at the benefit of novel sensitizers added to neoadjuvant therapy and ongoing investigation into upfront combination chemotherapy with selective use of radiation in upper rectal cancers.

401MO OS and long-term DFS with 3- vs. 6-month adjuvant oxaliplatin and fluoropyrimidine-based therapy for stage III colon cancer patients: A randomized phase III ACHIEVE trial

401MO OS and long-term DFS with 3- vs. 6-month adjuvant oxaliplatin and fluoropyrimidine-based therapy for stage III colon cancer patients: A randomized phase III ACHIEVE trial

Long-Term Prevalence of Sensory Chemotherapy-Induced Peripheral Neuropathy for 5 Years after Adjuvant FOLFOX Chemotherapy to Treat Colorectal Cancer: A Multicenter Cross-Sectional Study.

(1) Background: Oxaliplatin is among the most neurotoxic anticancer drugs. Little data are available on the long-term prevalence and consequences of chemotherapy-induced peripheral neuropathy (CIPN), even though the third largest population of cancer survivors is made up of survivors of colorectal cancer. (2) Methods: A multicenter, cross-sectional study was conducted in 16 French centers to assess the prevalence of CIPN, as well as its consequences (neuropathic pain, anxiety, depression, and quality of life) in cancer survivors during the 5 years after the end of adjuvant oxaliplatin chemotherapy. (3) Results: Out of 406 patients, the prevalence of CIPN was 31.3% (95% confidence interval: 26.8–36.0). Little improvement in CIPN was found over the 5 years, and 36.5% of patients with CIPN also had neuropathic pain. CIPN was associated with anxiety, depression, and deterioration of quality of life. None of the patients with CIPN were treated with duloxetine (recommendation from American Society of Clinical Oncology), and only 3.2%, 1.6%, and 1.6% were treated with pregabalin, gabapentin, and amitriptyline, respectively. (4) Conclusions: Five years after the end of chemotherapy, a quarter of patients suffered from CIPN. The present study showed marked psychological distress and uncovered a failure in management in these patients.

Survival benefit of surgical resection after first-line triplet chemotherapy and bevacizumab in patients with initially unresectable metastatic colorectal cancer

BackgroundSurgical resection of metastatic disease in patients with initially non-resectable colorectal cancer (CRC) has improved overall survival. Intensified chemotherapy regimens have increased the probability of converting unresectable metastasis to resectable. Here, we report the result of combining intensive chemotherapy (triplet) and surgical resection of metastatic lesions in patients with metastatic CRC.Patients and methodsPatients with unresectable metastatic CRC were enrolled in phase I/II trial of triplet chemotherapy consisting of capecitabine, oxaliplatin, irinotecan, and bevacizumab. Patients were given 5–8 cycles induction chemotherapy of the above regimen followed by maintenance capecitabine and bevacizumab until disease progression, unacceptable toxicity, or patient request. All patients were assessed at a multidisciplinary conference for possible surgical resection of their metastatic disease at the time of inclusion in the trial and 2 monthly intervals thereafter.Patients who underwent R0 resection of their metastatic disease received adjuvant oxaliplatin and capecitabine to complete a total of 6 months of chemotherapy.ResultsFifty-three patients were enrolled. The median age was 52 years (range 23–74), 29 (55%) were males, ECOG PS 0-1 was 13 (66%), 11 (42%) had a right-sided tumor, 29 (55%) had resection of their primary tumor, 22 (42%) had a single metastatic site, and 8 (15.1%) had a liver-limited disease.Thirteen patients (24.5%) underwent surgical resection of residual metastatic disease +/− the primary tumor with 10 (18.9%) of them were R0.The surgical group had a higher incidence of males compared to the non-surgical group (69.3% vs 47.2%, p = 0.2), equal performance status, lower median number of metastatic sites (1 vs 2, p = 0.09), higher mutant Kras (53.8% vs 34.2%, p = 0.3), and higher response rate (84.6% vs 56.2%, p = 0.3).With a median follow-up duration of 89 months, the median PFS for the whole group was 16.1 months [95% confidence interval (CI) 9.1–20] and the median OS was 28.2 months (95% CI 22.5–53.3).The median PFS for the surgery group was 18.9 months (95% CI 12.6–not reached) compared to 9.6 months (95% CI 7.0–18.3) for the non-surgical group, log-rank p = 0.0165. The median OS for both groups was not reached (95% CI 53.3–not reached) and 23.2 months (95% CI 17.0–28.4) respectively, log-rank p = 0.0006. Five-year PFS and OS for the surgery group were 46.2% and 67.6% respectively.ConclusionsPatients with unresectable metastatic CRC and fit for triplet chemotherapy should have the benefit of combining this intensified regimen and surgical resection of their metastatic disease if possible.Trial registrationClinicaltrials.gov, NCT01311050, registered March 6, 2011, retrospectively registered.

P-214 A single-centre experience of adjuvant oxaliplatin based chemotherapy in elderly stage II-III colorectal cancer patients

The MOSAIC trial showed the benefit of adding oxaliplatin to fluorouracil plus leucovorin with a 78.2% 3-year survival, however, patients > 75 years old were not included. The SCOT trial found that 3 months of treatment with oxaliplatin-containing chemotherapy was not inferior to 6 months, with a 3-year disease free survival of 76.6% and 77.1% respectively. There is a paucity of published data for adjuvant doublet chemotherapy within elderly (>70 years old) colorectal patients. We aimed to assess whether 3 months of adjuvant doublet chemotherapy in elderly patients with stage II-III colorectal cancer is tolerated.

Long-term symptoms of polyneuropathy in breast and colorectal cancer patients treated with and without adjuvant chemotherapy.

BackgroundThe aim of this study was to assess chemotherapy‐induced polyneuropathy (CIPN) 5 years after adjuvant chemotherapy in patients with breast and colorectal cancer. The association of CIPN with quality of life, anxiety, and depression was analyzed.MethodsOf a set of 100 patients with breast cancer and of 74 with colorectal cancer who had undergone surgery and adjuvant chemotherapy in 2011‐2012, 80 and 52 patients alive, respectively, were included together with two reference groups of 249 breast cancer patients and 83 colorectal cancer patients who had undergone surgery only. All patients were sent a questionnaire on alcohol consumption, smoking habits, comorbidity, medicine consumption, and oxaliplatin‐specific questions, as well as the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), the Douleur Neuropathique 4 Questions (DN4q), the EQ‐5D, and the Hospital Anxiety and Depression Scale. Possible polyneuropathy was defined as the presence of numbness and/or tingling in the feet, secondly as a score of ≥4 on the MNSIq. Possible painful polyneuropathy was defined as pain in both feet and a score ≥3 on the DN4q.ResultsThe prevalence of possible polyneuropathy defined by numbness and/or tingling in the feet was 38.8% (28.1‐50.3) after adjuvant docetaxel and 57.7% (43.2‐71.3) after adjuvant oxaliplatin, with no significant difference from a previous 1‐year follow‐up (P >.35). Fewer had possible polyneuropathy as defined by the MNSIq. Patients with possible polyneuropathy after adjuvant chemotherapy reported significantly lower quality of life than patients treated with surgery only.ConclusionSymptoms of polyneuropathy following adjuvant docetaxel and oxaliplatin persist 5 years after treatment and affect quality of life negatively.

Postoperative XELOX therapy for patients with curatively resected high-risk stage II and stage III rectal cancer without preoperative chemoradiation: A prospective, multicenter, open-label, single arm phase II study.

e16039 Background: Preoperative 5-FU-based chemoradiation is currently a standard treatment for advanced rectal cancer, particularly in Western countries. Although it reduced the local recurrence, it could not necessarily improve overall survival. Furthermore, it can also produce adverse effects and long-term sphincter function deficiency. Adjuvant oxaliplatin plus capecitabine (XELOX) is a recommended regimen for patients with curatively resected colon cancer. However, the efficacy of postoperative adjuvant therapy for rectal cancer patients who have not undergone preoperative chemoradiation remains unknown. We aimed to evaluate the efficacy of surgery and postoperative XELOX without preoperative chemoradiation for treating rectal cancer. Methods: We performed a prospective, multicenter, open-label, single arm phase II study. Patients with curatively resected high-risk stages II and III rectal cancer who had not undergone preoperative therapy were treated with a 120 min intravenous infusion of oxaliplatin (130 mg/m2) on day 1 and capecitabine (2,000 mg/m2/day) in 2 divided doses for 14 days of a 3-week cycle, for a total of 8 cycles (24 weeks). The primary endpoint was 3-year disease-free survival (DFS). Results: Between August 2012 and June 2015, 60 men and 47 women with a median age was 63 years (range: 29–77 years) were enrolled. Ninety-three patients had Eastern Cooperative Oncology Group performance status scores of ‘0’ and 14 had scores of ‘1’. Tumors were located in the upper and lower rectums in 54 and 48 patients, respectively; 8 patients had stage II disease and 99 had stage III. The 3-year DFS was 70.1% (95% confidence interval, 60.8–78.0%) and 33 patients (31%) experienced recurrence, most commonly in the lung (16 patients) followed by local recurrence (9) and hepatic recurrence (7). Conclusions: Postoperative XELOX without preoperative chemoradiation is effective for rectal cancer and provides good 3-year DFS prospects.And this is probably the first and last report in the world for such cases. Trial registration: This clinical trial was registered in the University Hospital Medical Information Network registry system as UMIN000008634 at Aug 06, 2012.

Overall survival (OS) and long-term disease-free survival (DFS) of three versus six months of adjuvant (adj) oxaliplatin and fluoropyrimidine-based therapy for patients (pts) with stage III colon cancer (CC): Final results from the IDEA (International Duration Evaluation of Adj chemotherapy) collaboration.

4004 Background: In overall population, IDEA pooled analysis did not demonstrate non-inferiority (NI) regarding 3y DFS in pts with stage III CC receiving 3m vs. 6m of adj FOLFOX/CAPOX. However, in pts treated with CAPOX (especially in low-risk pts), 3m of therapy was as effective as 6m. Results of OS and 5y DFS are reported. Methods: OS was defined as time from enrollment to death due to all causes. OS NI margin was conservatively set to be Hazard Ratio (HR) = 1.11, which is equivalent to: the maximum acceptable loss of OS efficacy, by shortening treatment to 3m, was half of the OS efficacy gained in MOSAIC trial (i.e., 2.26% absolute reduction in 5y OS rate). Pre-planned sub-group analyses included by regimen and risk group for both OS and 5y DFS. NI was to be declared if the one-sided false discovery rate adjusted (FDRa) NI p-value < 0.025. Results: With an overall median survival follow-up of 72 m (range per study, 62 to 84 m), 2584 deaths and 3777 DFS events among 12,835 pts from six trials were observed. Across 6 studies, 39.5% of pts received CAPOX (rate by study, 0% to 75.1%). Overall, the 5y OS rate was 82.4% (3m) and 82.8% (6m), with estimated OS HR of 1.02 (95% confidence interval [CI], 0.95-1.11; FDRa NI p, 0.058) and absolute 5-y OS rate difference of -0.4% (95% CI, -2.1 to 1.3%). Overall, the 5y DFS rate was 69.1% (3m) and 70.8% (6m), with estimated DFS HR of 1.08 (95%CI, 1.01-1.15, FDRa NI p, 0.22). HRs (95% CI) within subgroups see table. Conclusions: 5y OS rate reported in IDEA trials was higher than historical rates, regardless of duration of therapy. While overall survival in IDEA did not meet prior statistical assumptions for NI in overall population, the 0.4% difference in 5y OS should be placed in clinical context. OS and 5y DFS results continue to support the use of 3m adjuvant CAPOX for the vast majority of stage III colon cancer pts. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies and cost associated with shorter treatment duration. Clinical trial information: NCT01150045; 2009-010384-16; NCT00749450; ISRCTN59757862; 2007-003957-10; UMIN000008543; 2007-000354 . [Table: see text]

Adjuvant chemotherapy (AC) for stage III colorectal cancer (CRC) in the elderly: An Irish experience.

54 Background: Since 2004 6 months of adjuvant Oxaliplatin containing regimens (OCR) has been standard of care for Stage III CRC despite cumulative neurotoxicity. The IDEA collaboration evaluated 3 versus 6 months of OCR in high/low risk pts with regard to peripheral neuropathy (PN) and efficacy.The median pt age was 64; individual studies included pts ≤85. Methods: This study is part of a retrospective review of the clinicopathological records of consecutive CRC pts referred to the multi-disciplinary CRC team at an Irish tertiary referral centre from 2002-2018. We recorded pt characteristics, Rx received and outcomes. Overall Survival (OS) was assessed using Kaplan-Meier analysis. Results: 869 pts were identified; 37% (328) female. 63% (551/869) < 70 and 37% (318/869) ≥ 70. Median OS for < 70 cohort was 31.5 months versus 19 months in ≥ 70 cohort (p < 0.0001).Stage distribution in < 70: ≥70 cohorts was Stage II 14%( 79/551):20% (63/318), Stage III 47% (260/55):46% (142/318) and Stage IV 38% (207/551):34% (111/318). In < 70 Stage III cohort 7% (37/551) pts received no AC, 42%(230/551) received FOLFOX, 3%(16/551) received FLOX or XELOX, 7%(38/551) received 5FU/LEU. 32%(78/246) of pts < 70 developed PN with persistence at 6 months in 18%(44/256). In ≥ 70 Stage III cohort 58%(83/142) did not received AC. 23%(32/142) received an OCR and 16%(23/142) received 5FU/LEU; there was a statistically significant survival difference with an OCR. 47% (15/32) of pts ≥70 receiving OCR developed PN which persisted at 6 months in 28% (9/32). In < 70 cohort there was no significant survival difference in the IDEA-trial-defined low risk group between 12 versus < 12 FOLFOX. There was a numerical survival difference in the < 70 high risk group between 12 versus < 12 FOLFOX; this was not statistically significant. In the ≥70 age group there was no survival difference in either IDEA risk groups for 12 versus < 12 FOLFOX. Conclusions: > 50% of Stage III CRC patients ≥ 70 did not receive AC. OCRs were associated with a significant OS improvement but with higher PN than in < 70 cohort and higher persistence at 6 months. Irrespective of IDEA-defined risk groups,there was no statistically significant survival difference for Stage III CRC ≥70 receiving 12 versus < 12 FOLFOX.

Quattro-II study: A multicenter randomized phase II study comparing capoxiri plus bevacizumab with FOLFOXIRI plus bevacizumab in patients with metastatic colorectal cancer as the first-line treatment.

TPS267 Background: The first-line FOLFOXIRI with Bevacizumab (BEV) is highly effective and regarded as one of standard-of-care treatments in patients (pts) with metastatic colorectal cancer (mCRC) despite a high incidence of adverse events (AEs) such as neutropenia and diarrhea. The AXEPT, Asian Phase III study showed CAPIRI+BEV [Capecitabine (CAP: 1600 mg/m2), Irinotecan (IRI: 200 mg/m2) and BEV (7.5 mg/m2)] q3wk was non-inferior to FOLFIRI+BEV in pts with the second-line mCRC, with a lower incidence hematologic toxicity favoring CAPIRI+BEV over FOLFIRI+BEV. Based on these, a reduced dose of CAP and IRI regimen in combination with Oxaliplatin (OX) and BEV, CAPOXIRI+BEV may be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods: QUATTRO-II is an open-label, multicenter, randomized phase II study. Key eligibility criteria are as follows; age ≥20 years, ECOG performance status (PS) 0-1 (≥71 years age: PS 0), adequate organ function, and UGT1A1 single-heterozygous (UGT1A1*1/*6 or *1/*28) or wild-type (*1/*1) genotype. Pts are randomized to either the recommended dose of CAPOXIRI+BEV or FOLFOXIRI+BEV (OX: 85 mg/m2, IRI: 165 mg/m2, l-leucovorin: 200 mg/m2, 5-FU: 3200 mg/m2), with the strata of RAS/ BRAF status, previous adjuvant OX, tumor sidedness, and UGT1A1 status. Induction triplet chemotherapy plus BEV treatments are administered for up to 4 months followed by fluoropyrimidine plus BEV maintenance. The recommended dose of CAPOXIRI+BEV will be determined as a safety-lead-in before moving forward to the phase II main part. The primary endpoint is progression-free survival (PFS). The similarity of PFS between the two arms is evaluated by observing whether the point estimate of hazard ratio (HR) for PFS falls in between 0.80 and 1.25. Ensuring 70% probability that the observed HR will be “0.8<HR<1.25” under the assumption of the true HR of 1.0, a total of 100 patients will be needed with 3-year study period. Secondary endpoints included overall survival, overall response rate, safety, and patient-reported outcome (FACT/GOG-Ntx4). The enrollment started in October 2019. Clinical trial information: NCT04097444.

91P - Adjuvant therapy for high-risk stage II or stage III colon adenocarcinoma: A propensity score-matched, nationwide, population-based cohort study

BackgroundTo estimate the optimal adjuvant chemotherapy in patients with high-risk stage II and III colon adenocarcinoma, we use a propensity score-matched (PSM), nationwide, population-based cohort study to estimate different adjuvant treatments in high-risk stage II or stage III colon adenocarcinoma. MethodsWe minimized the confounding effects with PSM of sex, age, pathologic stages, tumor locations, total cycles of chemotherapy, and Charlson comorbidity index in various adjuvant treatments outcomes in patients with high-risk stage II and III resctable colon adenocarcinoma from the Taiwan Cancer Registry database by dividing them as follows: group 1, those undergoing surgery alone; group 2, those undergoing adjuvant fluoropyrimidine alone; group 3, those receiving adjuvant oxaliplatin, fluoropyrimidine, and leucovorin (FOLFOX) and group 4 those receiving adjuvant folinic acid, fluorouracil, irinotecan (FOFIRIL). ResultsIn both univariate and multivariate Cox regression analyses, adjusted HRs (aHRs) derived for mortality and 95% confidence intervals (CIs), reported as aHR (95% CI), derived for surgery alone, adjuvant fluoropyrimidine alone, and adjuvant FOLFIRI groups compared with the adjuvant FOLFOX group were 1.55 (1.32-1.82), 1.22 (1.05-1.43), and 2.97 (2.43-3.63), respectively. After stratified subgroup analysis, at high-risk stage II, the aHR (95% CI) derived for mortality was 0.52 (0.30-0.89) for the adjuvant fluoropyrimidine alone group compared with the group 3. ConclusionsAdjuvant fluoropyrimidine alone were more suitable for patients with high-risk stage II colon adenocarcinoma rather than other adjuvant chemotherapy regimens. Adjuvant FOLFOX could be the optimal regimen for patients with pathologic stage III colon adenocarcinoma whatever elderly, sex, or tumor locations. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

556P - Sex hormones and sperm parameters after adjuvant oxaliplatin-based treatment for colorectal cancer

BackgroundThe occurrence of colorectal cancer in individuals with potentially reproductive age has increased. Oxaliplatin is a cornerstone treatment in the adjuvant setting for stage III and high-risk stage II colorectal cancer in patients up to 70 years of age. The aim of this study was to investigate sex hormones and sperm function after oxaliplatin-based chemotherapy to clarify the risk for hypogonadism and infertility. MethodsThrough 2006-2013 20 males (aged ≤55 and younger) and 16 females (aged ≤40 and younger) were included. All had undergone radical surgery due to colorectal cancer, and were planned for adjuvant oxaliplatin in combination with 5-fluorouracil. Measurement of LH, FSH, testosterone, SHBG and sperm analysis was done in males. LH, FSH and estradiol was measured in females. Measurements were done after surgery, after cessation of adjuvant cytostatic treatment and at follow-up 1-5 years after end of treatment. ResultsFSH and testosterone levels increased in males, but were restored at follow-up. No patients went from normal gonadal function to hypogonadism. There was a tendency towards a decrease in sperm concentration, (p=0.,063). When comparing sperm concentration and rapid progressive motility before treatment and at follow-up, there was no differences, and we observed no patients that turned overtly infertile by treatment. No distinct altering of gonadal function could be observed in the females. ConclusionsFrom the results of this study, oxaliplatin seems to incur transient decrease in sperm concentration with recovery, and some but not pronounced increase in FSH in males. The risk for infertility and hypogonadism in males and females after adjuvant oxaliplatin-based chemotherapy seems to be low to moderate, but the general recommendation of appropriate fertility conserving measures shall should not be changed. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureP. Österlund: Honoraria (self): Amgen; Honoraria (self): Bayer; Honoraria (self): Celgene; Honoraria (self): Eli Lilly; Honoraria (self): Merck; Honoraria (self): Nordic Drugs; Honoraria (self): Roche; Honoraria (self): Sanofi; Honoraria (self): Servier; Travel / Accommodation / Expenses: Pierre Fabre; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: AbbVie. E. Hofsli: Honoraria (self): Amgen. H. Sorbye: Honoraria (self): Novartis; Honoraria (self): Ipsen; Honoraria (self): Pfizer; Honoraria (self): Keocyt; Honoraria (self): AstraZeneca; Honoraria (self): Roche; Honoraria (self): Amgen; Honoraria (self): Merck; Honoraria (self): Shire; Honoraria (self): Celgene; Honoraria (self): Nordic Drugs. All other authors have declared no conflicts of interest.

Postoperative XELOX therapy for patients with curatively resected high-risk stage II and stage III rectal cancer without preoperative chemoradiation: a prospective, multicenter, open-label, single-arm phase II study

BackgroundPreoperative 5-FU-based chemoradiation is currently a standard treatment for advanced rectal cancer, particularly in Western countries. Although it reduced the local recurrence, it could not necessarily improve overall survival. Furthermore, it can also produce adverse effects and long-term sphincter function deficiency. Adjuvant oxaliplatin plus capecitabine (XELOX) is a recommended regimen for patients with curatively resected colon cancer. However, the efficacy of postoperative adjuvant therapy for rectal cancer patients who have not undergone preoperative chemoradiation remains unknown. We aimed to evaluate the efficacy of surgery and postoperative XELOX without preoperative chemoradiation for treating rectal cancer.MethodsWe performed a prospective, multicenter, open-label, single arm phase II study. Patients with curatively resected high-risk stage II and stage III rectal cancer who had not undergone preoperative therapy were treated with a 120 min intravenous infusion of oxaliplatin (130 mg/m2) on day 1 and capecitabine (2000 mg/m2/day) in 2 divided doses for 14 days of a 3-week cycle, for a total of 8 cycles (24 weeks). The primary endpoint was 3-year disease-free survival (DFS).ResultsBetween August 2012 and June 2015, 60 men and 47 women with a median age was 63 years (range: 29–77 years) were enrolled. Ninety-three patients had Eastern Cooperative Oncology Group performance status scores of ‘0’ and 14 had scores of ‘1’. Tumors were located in the upper and lower rectums in 54 and 48 patients, respectively; 8 patients had stage II disease and 99 had stage III. The 3-year DFS was 70.1% (95% confidence interval, 60.8–78.0%) and 33 patients (31%) experienced recurrence, most commonly in the lung (16 patients) followed by local recurrence (9) and hepatic recurrence (7).ConclusionsPostoperative XELOX without preoperative chemoradiation is effective for rectal cancer and provides adequate 3-year DFS prospects.Trial registrationThis clinical trial was registered in the University Hospital Medical Information Network registry system as UMIN000008634 at Aug 06, 2012.

Comprehensive assessment of HER2 alteration in a colorectal cancer cohort: from next-generation sequencing to clinical significance.

PurposeHuman epidermal growth factor receptor 2 (HER2) is an emerging therapeutic target in colorectal cancer (CRC). Currently, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) have been used to determine HER2-positive CRCs; however, the clinical utility of next-generation sequencing (NGS)-based techniques for determining HER2 status in CRC has been limited. Here, we detail our experience regarding the assessment of HER2 alterations in a CRC cohort.Materials and methodsWe prospectively enrolled 73 CRC patients who underwent surgery and received adjuvant oxaliplatin treatment. We then examined HER2 alterations using the Oncomine Comprehensive Assay version 1, as well as clinical outcomes, in this cohort.ResultsUsing the NGS-based assay, HER2 copy number gains in 12 of 73 CRCs were determined to range from 2.74 to 92.62. Of these 12 tumors, 6 had HER2 high-level copy number gain (92.6, 57.9, 57.0, 52.0, 35.2, and 8.42) and were all defined as HER2-positive CRC using HERACLES Diagnostic Criteria. Nevertheless, other 6 patients with low-level copy number gain (ranging from 2.74 to 3.04) and the remaining 61 patients without increase in HER2 copy number were all HER2-negative. Among the 6 HER2-positive CRCs, KRAS and PIK3CA mutations were detected in 1 (17%; G13D) and 2 (33.3%; 1 Q546R and 1 H1047R) patients, respectively. Moreover, 2 of the 6 (33.3%) HER2-positive patients had recurrent disease, while one patient had a partial response after anti-HER2 therapy.ConclusionNGS-based tools could assist in the simultaneous detection of HER2 and other genomic alterations in patients with CRC. Only CRCs with HER2 high-level copy number gain were HER2-postive by current diagnostic criteria.

Adjuvant Capecitabine After Biliary Cancer Resection

A recent phase III trial showed that adding adjuvant gemcitabine and oxaliplatin chemotherapy to surgical resection did not improve survival in

Adjuvant Gemcitabine and Oxaliplatin for Resected Biliary Cancer

After complete resection of a locally advanced biliary cancer, standard adjuvant therapy with 6 months of capecitabine has been shown to improve

Genetic polymorphisms of vascular endothelial growth factor (VEGF) associated with gastric cancer recurrence after curative resection with adjuvant chemotherapy.

9 Background: The relationship between polymorphisms in vascular endothelial growth factor (VEGF) and gastric cancer is still inconclusive. We investigated whether there is an association between VEGF genetic polymorphisms and risk of gastric cancer, and evaluated the recurrence of advanced gastric cancer after curative resection with adjuvant chemotherapy according to VEGF genetic polymorphisms. Methods: The association of functional single nucleotide polymorphisms (SNPs) of the VEGF gene (+936C > T, -634G > C, -2578C > A, +1612G > A) were evaluated. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. A total of 151 patients with gastric cancer were enrolled, and the control group consisted of 413 individuals with esophago-gastroduodenoscopy who were randomly selected through health screening. All of the enrolled patients had curative resections with completion of adjuvant capecitabine and oxaliplatin combination chemotherapy and the initial metastatic cases were excluded. During the regular follow-up protocol, the episodes of the recurrence were documented and the specific genotype and allelic frequencies were evaluated. Results: As for the cancer risk, there were no significant differences in specific genotypes and allelic frequencies. The mean follow-up period was 28.82 ± 30.92 (12 ~ 72) months and the recurrence rate was 28.3%. In the patients carrying the 936-C allele, the recurrence rate of gastric cancer was high ( P = 0.02). Disease-free interval was significantly different between the patients carrying the 936-CC and 936-CT/TT genotype ( P = 0.02). Conclusions: VEGF +936 C > T genetic polymorphism is associated with poor prognosis, but not risk of gastric cancer. In the patients carrying the 936-C allele, more potent adjuvant treatment would be considered.

Refining the Use of Adjuvant Oxaliplatin in Clinical Stage II or III Rectal Adenocarcinoma.

Current guidelines include the use of adjuvant oxaliplatin in clinical stage II or III rectal adenocarcinoma. However, its efficacy is supported by a single phase II trial. We aimed to examine whether oxaliplatin confers survival benefit in this patient population. Using the National Cancer Database (2006-2013) we identified 6,868 individuals with clinical stage II or III rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy. We used multivariate Cox regression to evaluate survival differences according to treatment intensity and change from clinical to pathological stage. We demonstrated an association with improved overall survival with the use of doublet adjuvant chemotherapy in pathological stage III rectal adenocarcinoma (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67-0.92). This association was confirmed in patients with clinical stage III and subsequent pathological stage III disease (HR, 0.69; 95% CI, 0.57-0.83) and was not observed in patients who progressed from clinical stage II to pathological stage III disease. Doublet adjuvant chemotherapy was not associated with improved overall survival in patients with pathological stage 0 or I disease, regardless of their clinical stage. Adjuvant oxaliplatin following neoadjuvant chemoradiotherapy in rectal adenocarcinoma was confirmed in patients with clinical stage III and subsequent pathological stage III disease. Omission of oxaliplatin can be considered in pathological complete response or pathological stage I disease. Current guidelines include the use of oxaliplatin as part of adjuvant chemotherapy (AC) in patients with clinical stage II or III rectal adenocarcinoma (RAC). However, its efficacy is supported only by a single phase II trial. This study found an association with improved overall survival with the use of doublet AC in patients diagnosed with clinical stage III and subsequent pathological stage III, and not in patients with pathological stage 0 or I, regardless of their clinical stage. Therefore, omission of oxaliplatin can be considered in patients with either pathological complete response or pathological stage I RAC, thereby avoiding oxaliplatin-induced neuropathy.

SCOT: a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant Oxaliplatin combination chemotherapy for colorectal cancer

BACKGROUNDThe Short Course Oncology Therapy (SCOT) study is an international, multicentre, non-inferiority randomised controlled trial assessing the efficacy, toxicity, and cost-effectiveness of 3 months (3 M) versus the usually given 6 months (6 M) of adjuvant chemotherapy in colorectal cancer.METHODSIn total, 6088 patients with fully resected high-risk stage II or stage III colorectal cancer were randomised and followed up for 3–8 years. The within-trial cost-effectiveness analysis from a UK health-care perspective is presented using the resource use data, quality of life (EQ-5D-3L), time on treatment (ToT), disease-free survival after treatment (DFS) and overall survival (OS) data. Quality-adjusted partitioned survival analysis and Kaplan–Meier Sample Average Estimator estimated QALYs and costs. Probabilistic sensitivity and subgroup analysis was undertaken.RESULTSThe 3 M arm is less costly (-£4881; 95% CI: -£6269; -£3492) and entails (non-significant) QALY gains (0.08; 95% CI: −0.086; 0.230) due to a better significant quality of life. The net monetary benefit was significantly higher in 3 M under a wide range of monetary values of a QALY. The subgroup analysis found similar results for patients in the CAPOX regimen. However, for the FOLFOX regimen, 3 M had lower QALYs than 6 M (not statistically significant).CONCLUSIONSOverall, 3 M dominates 6 M with no significant detrimental impact on QALYs. The results provide the economic case that a 3 M treatment strategy should be considered a new standard of care.