Cycles Of Oxaliplatin Research Articles

Combined Transanal and Laparoscopic Approach for Full-Thickness Local Excision of Locally Advanced Rectal Cancer Following Near-Complete Response after Chemotherapy

Abstract Improving neoadjuvant therapies for locally advanced rectal cancer (LARC) has increased the rates of clinical complete response (cCR). The watch-and-wait approach has emerged as a viable strategy for patients with cCR, avoiding the potential morbidity of radical surgery. However, the management of near-complete response (nCR) remains controversial. We present a case of a 46-year-old male with cT4, node indeterminate, mid-to-upper rectal adenocarcinoma. The patient declined radical resection and radiotherapy. Clinical nCR of the tumor was confirmed on imaging and endoscopy following six cycles of oxaliplatin and capecitabine (chemotherapy only). He underwent full-thickness local excision of the remnant lesion using a combined transanal and laparoscopic approach. Histopathological examination revealed high-grade dysplasia without residual malignancy. There has been no evidence of tumor recurrence at nine months post-surgery. This case demonstrates the safety and feasibility of minimally invasive local excision in selected patients with nCR following neoadjuvant therapy for LARC.

Prevention of allergic reactions during oxaliplatin desensitization through inhibition of Bruton tyrosine kinase

BackgroundAcute infusion reactions to oxaliplatin, a chemotherapeutic used to treat gastrointestinal cancers, are observed in about 20% of patients. Rapid drug desensitization (RDD) protocols often allow the continuation of oxaliplatin in patients with no alternative options. Break-through symptoms including anaphylaxis can still occur during RDDs. ObjectiveTo evaluate if pretreatment with acalabrutinib, a Bruton’s tyrosine kinase inhibitor, can prevent anaphylaxis during a RDD in a patient sensitized to oxaliplatin. MethodsA 52-year-old male with locally advanced gastric carcinoma developed anaphylaxis during his 5th cycle of oxaliplatin. As he required 6 additional cycles to complete his curative-intent treatment regimen, he underwent RDD to oxaliplatin but still developed severe acute reactions. The risks and benefits of adding acalabrutinib prior to and during a RDD, were reviewed and he elected to proceed. ResultsWith acalabrutinib taken prior to and during the RDD, the patient was able to tolerate oxaliplatin RDDs without complication. Consistent with its mechanism of action, acalabrutinib completely blocked the patient’s positive skin prick response to oxaliplatin. Acalabrutinib did not alter the percentage of circulating basophils (1.24% versus 0.98%) prior to the RDD but protected from basopenia (0.74% versus 0.09%) after the RDD. Acalabrutinib was associated with a drastic reduction in the ability of basophils to upregulate CD63 in vitro following incubation with oxaliplatin (0.11% versus 2.38%) or polyclonal anti-human IgE antibody (0.08% versus 44.2%). ConclusionsFive doses of acalabrutinib 100mg orally twice daily starting the evening 2 days before and continuing through a RDD allowed a sensitized patient to successfully and safely receive oxaliplatin.

Induction chemotherapy plus concomitant oxaliplatin-based chemoradiotherapy for locally advanced rectal cancer: A real world experience at San Raffaele Hospital.

144 Background: The standard treatment of locally advanced rectal cancer (LARC) consists of giving preoperative chemoradiation therapy (CT/RT) followed by surgery. Recently, total neoadjuvant therapy (TNT) has shown greater efficacy in terms of increasing the rate of complete pathological response (pCR) and reducing local and systemic relapse. However, based on the proposed therapy scheme, the risk of overtreatment and side effects is not negligible. The objective of this study was to evaluate the efficacy and safety of neoadjuvant doublet with oxaliplatin-based CT and concomitant RT. Methods: Patients with clinically staged II-III rectal cancer were treated with preoperative CT/RT using up to 3 cycles of oxaliplatin and fluoropyrimidine plus pelvic radiation daily, for a total dose of 46.2 Gy in 18 fractions. The first cycle of mXELOX (oxaliplatin 85 mg/m2 D1 Q14 plus capecitabine 825 mg/m2 BID) was administrated before RT (as induction CT); the other 2 cycles of mXELOX were administrated concurrent with RT, with capecitabine continued until the end of RT. Radical resection was performed within median 11 weeks of the last dose of RT. Adjuvant CT with FOLFOX or XELOX was administered according to pathological report. Results: Between 2007 and 2022, a total of 186 patients were enrolled, mean age was 61 years. 19 (10.2%) patients were clinically stage II and 167 (89.8%) were clinically stage III. Any grade most common toxicities during neoadjuvant CT/RT included diarrhea (53.2%), proctitis (51.2%) and neutropenia (14.5%). The most common grade 3/4 toxicity was diarrhea (9.1%). A total of 146 (78.5%) patients achieved a downstaging after CT/RT and 174 (93.5%) patients underwent surgery with R0 resection. Clinical meaningful surgical morbidities included infections (10.7%), anastomotic fistula (10.2%) and anastomotic leakage (7.5%). The pathological complete response (pCR) rate was 25.3%. Adjuvant CT was administered in 122 (65.6%) patients. Local recurrences and distant metastases were confirmed in 6 (3.2%) and 54 (29%) cases respectively. Median observation time, calculated with reverse Kaplan-Meier estimator, was 84 months and median overall survival (OS) was not reached. The estimated probability of OS (Kaplan-Meier method) at 3-5 years were 92.8% and 85.5% respectively. The median disease-free survival (DFS) was not reached and the estimated probability of DFS at 3-5 years were 74.7% and 69% respectively. Conclusions: Considering the low rate of toxicities and the comparable efficacy in terms of downstaging, pCR, probability of DFS and OS to other TNT regimens proposed in recent studies, our schedule of neoadjuvant CT/RT may represent a potential alternative to standard CT/RT in selected patients with LARC.

Perioperative or adjuvant mFOLFIRINOX for resectable pancreatic cancer (PREOPANC-3): study protocol for a multicenter randomized controlled trial

BackgroundSurgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach.MethodsThis multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and ≤ 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2 at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m2). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized.DiscussionThe multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer.Trial registrationClinical Trials: NCT04927780. Registered June 16, 2021.

The association between sociodemographic, clinical, and potentially preventive therapies with oxaliplatin-induced peripheral neuropathy in colorectal cancer patients.

The purpose of this retrospective cohort study was to evaluate whether several potentially preventive therapies reduced the rate of oxaliplatin-induced peripheral neuropathy (OIPN) in colorectal cancer patients and to assess the relationship of sociodemographic/clinical factors with OIPN diagnosis. Data were obtained from the Surveillance, Epidemiology, and End Results database combined with Medicare claims. Eligible patients were diagnosed with colorectal cancer between 2007 and 2015, ≥ 66years of age, and treated with oxaliplatin. Two definitions were used to denote diagnosis of OIPN based on diagnosis codes: OIPN 1 (specific definition, drug-induced polyneuropathy) and OIPN 2 (broader definition, additional codes for peripheral neuropathy). Cox regression was used to obtain hazard ratios (HR) with 95% confidence intervals (CI) for the relative rate of OIPN within 2years of oxaliplatin initiation. There were 4792 subjects available for analysis. At 2years, the unadjusted cumulative incidence of OIPN 1 was 13.1% and 27.1% for OIPN 2. For both outcomes, no therapies reduced the rate of OIPN diagnosis. The anticonvulsants gabapentin and oxcarbazepine/carbamazepine were associated with an increased rate of OIPN (both definitions) as were increasing cycles of oxaliplatin. Compared to younger patients, those 75-84years of age experienced a 15% decreased rate of OIPN. For OIPN 2, prior peripheral neuropathy and moderate/severe liver disease were also associated with an increased hazard rate. For OIPN 1, state buy-in health insurance coverage was associated with a decreased hazard rate. Additional studies are needed to identify preventive therapeutics for OIPN in cancer patients treated with oxaliplatin.

A case of pathologic complete response after neoadjuvant triplet chemotherapy for locally advanced colon cancer with mismatch repair enzyme proficiency

Patients with potentially resectable colon cancer and expected to have negative margins should undergo resection rather than neoadjuvant chemotherapy. Recent studies have suggested that neoadjuvant immunotherapy may be an option for tumors with mismatch repair enzyme deficiency (dMMR), but standard treatment for locally advanced colon cancer with mismatch repair enzyme proficiency (pMMR) is still unclear. A 37-year-old male patient was diagnosed with clinical stage IIIC (T4b N1a M0) transverse colon cancer. Mismatch repair proteins were proficient. After 3 cycles of oxaliplatin (85 mg/m2, day 1), irinotecan (150 mg/m2, IV, day 1), leucovorin (200 mg/m2, IV, day 1), and 5-fluorouracil (3000 mg/m2, 46 hours of continuous infusion initiating from day 1), there was a remarkable reduction in the tumoral mass on the abdominal computed tomography. A right hemicolectomy was performed. A pathologic complete response was obtained. Although there is no consensus on which patients are suitable for neoadjuvant therapy in pMMR locally advanced colon cancer, triplet chemotherapy may be a reasonable option in selected patients.

The Neo-PLANET phase II trial of neoadjuvant camrelizumab plus concurrent chemoradiotherapy in locally advanced adenocarcinoma of stomach or gastroesophageal junction

The synergistic effect of neoadjuvant immunotherapy and chemoradiotherapy in gastric adenocarcinoma is unclear. This phase II trial (NCT03631615) investigated this neoadjuvant combination in locally advanced adenocarcinoma of stomach or gastroesophageal junction. Thirty-six patients received capecitabine 850 mg/m2 twice daily and simultaneous radiotherapy for 5 weeks, sandwiched by a 21-day cycle of oxaliplatin 130 mg/m2 (day 1) plus capecitabine 1000 mg/m2 twice daily (days 1–14), respectively, followed by surgery. Camrelizumab 200 mg (day 1) was given for 5 cycles since initiating chemotherapy. Primary endpoint was pathological complete response (pCR, ypT0) rate. Secondary endpoints included total pCR (tpCR, ypT0N0) rate, major pathological response (MPR, < 10% residual tumor cells) rate, margin-free (R0) resection rate, downstaging, progression-free survival (PFS), overall survival (OS), and safety. The pCR rate was 33.3% (95% CI, 18.6–51.0), meeting pre-specified endpoint. TpCR, MPR, and R0 resection rates were 33.3%, 44.4%, and 91.7%, respectively. Twenty-eight (77.8%) patients reached ypN0. Two-year PFS and OS rates were 66.9% and 76.1%, respectively. The most common grade 3–4 adverse event was decreased lymphocyte count (27 [75.0%]). Neoadjuvant camrelizumab plus concurrent chemoradiotherapy exhibits promising pathological response in patients with locally advanced gastric adenocarcinoma, with an acceptable safety profile.

Prognostic Impact of Early Treatment and Oxaliplatin Discontinuation in Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 11 Adjuvant Trials.

Oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) for 6 months remains a standard in high-risk stage III patients. Data are lacking as to whether early discontinuation of all treatment (ETD) or early discontinuation of oxaliplatin (EOD) could worsen the prognosis. We studied the prognostic impact of ETD and EOD in patients with stage III CC from the ACCENT/IDEA databases, where patients were planned to receive 6 months of infusional fluorouracil, leucovorin, and oxaliplatin or capecitabine plus oxaliplatin. ETD was defined as discontinuation of treatment and EOD as discontinuation of oxaliplatin only before patients had received a maximum of 75% of planned cycles. Association between ETD/EOD and overall survival and disease-free survival (DFS) were assessed by Cox models adjusted for established prognostic factors. Analysis of ETD and EOD included 10,447 (20.9% with ETD) and 7,243 (18.8% with EOD) patients, respectively. Compared with patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, with Eastern Cooperative Oncology Group performance status ≥ 1, and for ETD, older with a lower body mass index. In multivariable analyses, ETD was associated with a decrease in disease-free survival and overall survival (hazard ratio [HR], 1.61, P < .001 and HR, 1.73, P < .001), which was not the case for EOD (HR, 1.07, P = .3 and HR, 1.13, P = .1). However, patients who received < 50% of the planned cycles of oxaliplatin had poorer outcomes. In patients treated with 6 months of oxaliplatin-based chemotherapy for stage III CC, ETD was associated with poorer oncologic outcomes. However, this was not the case for EOD. These data favor discontinuing oxaliplatin while continuing fluoropyrimidine in individuals with significant neurotoxicity having received > 50% of the planned 6-month chemotherapy.

S3168 Sinusoidal Obstruction Syndrome: A Known and Often Missed Complication of Oxaliplatin Therapy

Introduction: Sinusoidal obstruction syndrome (SOS) is caused by sinusoidal endothelial injury due to hematopoietic cell transplantation, liver irradiation or exposure to chemotherapy such as oxaliplatin and may occur days to weeks following exposure. SOS can be a life-threatening complication and its presentation may include jaundice, volume overload or hepatic failure. We present the case of a 32-year-old male with gastroesophageal adenocarcinoma who underwent oxaliplatin-based chemotherapy and developed SOS. Case Description/Methods: A 32-year-old male with no significant medical history presented with dysphagia and weight loss. Esophagogastroduodenoscopy showed a mass at the gastroesophageal junction. He underwent diagnostic laparoscopy which showed peritoneal metastasis. Tissue biopsy was consistent with stage 4 gastroesophageal junction adenocarcinoma. He was started on 5-fluorouracil (5-FU), oxaliplatin and nivolumab. The patient developed thrombocytopenia and moderate aminotransferase elevation after 6 cycles of chemotherapy. An abdominal ultrasound obtained after 10 of 12 cycles of chemotherapy showed portal hypertension. Subsequent abdominal imaging showed worsening ascites (serum ascites to albumin gradient > 1.1), anasarca and splenomegaly. Transjugular liver biopsy showed elevated portal hepatic venous pressure gradient, focal sinusoidal dilatation and centrizonal ischemic changes suggesting drug induced hepatopathy, and a diagnosis of oxaliplatin induced SOS was made. The patient was not a candidate for defibrotide and was treated conservatively. He continued to have worsening ascites with severe direct hyperbilirubinemia and moderately elevated aminotransferases without biliary obstruction (Figure). Discussion: Oxaliplatin-based chemotherapies are known to cause the potentially life-threatening complication of SOS which is oftentimes missed. Our patient developed signs and symptoms suggestive of SOS by cycle 10 of oxaliplatin therapy. These changes included thrombocytopenia, elevated liver associated enzymes, volume overload and portal hypertension. He went on to complete 12 cycles of oxaliplatin with eventual worsening of his portal hypertension related symptoms and worsening of his hepatic function. This case highlights the importance of having a high index of suspicion for the development of SOS with plans to pursue patient-centered discussions regarding alternative chemotherapeutic regimens, instituting prophylactic therapies and timely SOS screening protocols.Figure 1.: Timeline of events leading up to SOS diagnosis.

Adjuvant oxaliplatin and fall-related injury in patients with colorectal cancer.

78 Background: Adjuvant oxaliplatin improves colorectal cancer (CRC) survival but causes dose-dependent peripheral neuropathy, possibly increasing the risk of fall-related injuries (FRI) such as fractures. In this retrospective cohort study, we examined the impact of adjuvant oxaliplatin cycles on FRIs. Methods: All data were ascertained from linked health administrative and population databases. We included Ontarians aged 18-85 years at CRC diagnosis between January 1 2007 to December 31 2018 who underwent curative resection and received adjuvant oxaliplatin. We excluded those with a prior cancer diagnosis within 5 years, prior CRC diagnosis ever, non-adenocarcinoma histology, prior oxaliplatin, and &lt;2 years of Ontario health insurance prior to CRC diagnosis. Oxaliplatin dose was determined in the 382 days after resection and dichotomized (1-6 vs. 7-12 cycles). The outcome was FRI, defined by ICD10 codes W00-W19 for any injury caused by a fall requiring emergency or inpatient care. Follow-up began at the end of the treatment window and terminated at the first of FRI, death, loss of Ontario health insurance, or March 31 2020. To account for differences between groups, clinical and demographic characteristics at diagnosis (Table) were used to estimate propensity scores for treatment and calculate inverse probability of treatment weights. These weights were applied to a Fine &amp; Gray regression model to determine the subdistribution hazard ratio (sHR) estimating the association between FRI and 1-6 versus 7-12 cycles of oxaliplatin, with death as a competing risk. Standardized differences &lt;0.1 indicated negligible imbalance. An interaction term tested for effect modification by age at diagnosis. Results: 9,324 patients were included in the study; 1,870 received 1-6 cycles and 7,454 received 7-12 cycles of oxaliplatin. Those exposed to 1-6 cycles were older (61.0 vs. 59.1 years), had higher comorbidity scores (13.5 vs 12.3), and more often had rectal cancer (27.5 vs. 22.2%). Negligible imbalance remained after weighting. Median follow-up was 50.2 months. Total follow-up was 44,472 person-years. There were 1,223 FRIs and 1,913 deaths. The sHR for FRIs comparing 7-12 cycles against 1-6 cycles of oxaliplatin was 0.98 (95% CI 0.85-1.14). The interaction p-value for age and oxaliplatin dose was 0.24. Conclusions: In this population-based retrospective cohort study of 9,324 patients with CRC, the risk of FRIs was similar for 7-12 cycles compared with 1-6 cycles of adjuvant oxaliplatin. This finding was consistent across age at diagnosis. Future research should examine the relationship between oxaliplatin dose and falls not resulting in injury. [Table: see text]

SONCAR study: A prospective randomized controlled study on optimized neoadjuvant chemotherapy-oxaliplatin plus CRT in patients with locally advanced rectal cancer.

117 Background: The benefit of adding Oxaliplatin to neoadjuvant chemoradiotherapy in Locally Advanced Rectal Cancer (LARC) patients remains controversial. The present study investigated whether induction chemotherapy (CapOX), 2 cycles of CapOX combined with standard radiation (Oxa-CRT) concurrently and consolidation chemotherapy (CapOX) could improve OS compared with standard treatment (nCRT) for locally advanced rectal cancer. Methods: We conducted this randomized, single center, open-label, phase III trial in China. Eligible patients were pathologically confirmed rectal adenocarcinoma, clinical T3-4 with or without regional N + and no sign of distance metastasis determined by pelvic MRI, chest and abdominal CT scan. All patients were randomly allocated to the experimental group: pelvic radiation of 50Gy/25 fractions with 4 cycles of oxaliplatin and capecitabine (1 cycle of CapOX (oxaliplatin: 130mg/m2, cape: 1000mg/m2, bid, Day 1 to Day 14) administrated before radiotherapy as induction chemotherapy, 2 cycles of CapOX (oxaliplatin: 100mg/m2, cape: 1000mg/m2, bid, Day 1 to Day 14) administrated concurrent with RT, and 1 cycle of CapOX (oxaliplatin: 130mg/m2, cape: 1000mg/m2, bid, Day 1 to Day 14) conducted as consolidation chemotherapy); or control group: radiation with capecitabine. The primary end point was OS. This trial was registered with ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT02031939). Results: From January 2014 to June 2020, 556 patients enrolled in this study (n=278 in both groups), and 536 patients were evaluable (269 in experimental group and 267 patients in control group). Surgery was performed in 235 patients (84.5%) in experimental group and 242 patients (87.1%) in control group. The pCR rates were 27.8% (75 in 269) and 19.4% in control group (52 in 267) (p = 0.025). 16 and 5 patients achieved clinical complete response (cCR) in experimental and control group, respectively. Grade 3-4 toxicities were recorded in 42 (21.8%) and 6 (5.1%) patients in experimental and control group. The most common grade 3-4 toxicities were leukopenia, thrombocytopenia and neutropenia. The overall surgical complication rate was not significantly different between two groups (12.1% vs. 11.9%). Conclusions: Four cycles of CapOX combined with RT in LARC significantly increased complete tumor response in Chinese patients with acceptable toxicities. Clinical trial information: NCT02031939.

Preventives for oxaliplatin-induced peripheral neuropathy in colorectal cancer patients.

83 Background: For colorectal cancer patients treated with the chemotherapy drug oxaliplatin, oxaliplatin-induced peripheral neuropathy (OIPN) is a serious side effect. We conducted an observational comparative effectiveness study to evaluate whether several potential preventives reduced the rate of OIPN diagnosis in the two years following chemotherapy initiation. Methods: This was a retrospective cohort study that utilized the Surveillance, Epidemiology, and End Results database combined with Medicare claims (SEER-Medicare). Eligible patients were diagnosed with colorectal cancer between 2007-2015, 66 years of age or older, and received at least two cycles of oxaliplatin. We used two definitions to denote diagnosis of OIPN: OIPN 1 (diagnosis codes specific to CIPN) and OIPN 2 (additional codes for peripheral neuropathy). Multinomial propensity score weighting was used to balance potential confounders. The Fine-Gray subdistribution hazards model was used to perform a competing risk, time to event analysis for diagnosis of OIPN. Results: There were 4,482 subjects analyzed for the outcome of OIPN 1 (n = 477, 10.1%), and 4,561 for OIPN 2 (n = 1,191, 26.1%). Duloxetine, venlafaxine (marginally significant for OIPN 1), opioids, and minocycline were associated with a decreased rate of OIPN according to both definitions. In addition, memantine and neuromuscular therapy were associated with a decreased rate of OIPN 1 but not OIPN 2. Gabapentin and pregabalin exposure was associated with an increased rate of OIPN diagnosis according to both definitions. Mixed results were obtained for nortriptyline and cannabinoids. Conclusions: This study revealed several potentially effective preventive options for OIPN in colorectal cancer patients receiving oxaliplatin. A limitation of this study is the observational design which cannot directly inform treatment guidelines. However, evidence from this study may serve as preliminary data to support a future randomized clinical trial.[Table: see text]

Prognostic impact of early treatment discontinuation and early oxaliplatin discontinuation in patients treated with 6 months of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer: an ACCENT/IDEA pooled analysis of 11 trials.

11 Background: Six months of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) remains a standard in high-risk stage III patients. Early treatment discontinuation (ETD) could worsen the prognosis. In addition, there is current lack of data on the prognostic impact of early oxaliplatin only discontinuation (EOD). Methods: We studied the prognostic impact of ETD and EOD in patients with stage III CC who participated in 11 relevant clinical trials of the ACCENT and IDEA databases, where patients were planned to receive 6 months of adjuvant fluoropyrimidine plus oxaliplatin (FOLFOX or CAPOX). ETD was defined as discontinuation of treatment before 75% of cycles of chemotherapy. EOD was defined as discontinuation of oxaliplatin only, while continuing the fluoropyrimidine, before 75% of cycles of oxaliplatin. Association between ETD/EOD and overall survival (OS) and disease-free survival (DFS) was assessed by Cox model adjusted for prognostic factors. Results: ETD analysis included 10,444 patients (FOLFOX n = 7,033; CAPOX n = 3,411), with 20.9% of patients with ETD (17.8% with FOLFOX and 27.2% with CAPOX, p &lt; 0.001). Out of 7,243 patients, 18.8% experienced EOD (17.4% FOLFOX versus 21.4% with CAPOX, p &lt; 0.001). Compared to patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, older, with higher ECOG-PS ≥ 1, and in addition for ETD, a Body Mass Index (BMI) &lt; 18.5 kg/m2. In multivariate analyses, ETD was associated with a decrease in DFS and OS in the overall population (HR: 1.40 95%CI 1.23-1.58, p &lt; 0.001 and HR: 1.51 95%CI 1.31-1.74, p &lt; 0.001, respectively). The same pattern was present with FOLFOX and CAPOX regimen, and also in low-risk and high-risk groups for each regimen with the exception of the CAPOX regimen in the low-risk group for DFS and OS. By contrast, EOD was not associated with reduced DFS or OS in the overall population (HR: 1.10 95%CI 0.77-1.58, p = 0.6 and HR: 0.97 95%CI 0.62-1.52, p = 0.9, respectively), in the low-risk group (HR: 0.97 95%CI 0.56-1.66, p = 0.9 and HR: 0.97 95%CI 0.51-1.82, p = 0.9, respectively) and high-risk group (HR: 1.22 95%CI 0.74-2.02, p = 0.4 and HR: 1.05 95%CI 0.53-2.08, p = 0.9, respectively) and for all subgroups of regimen. Conclusions: In patients treated with 6 months of oxaliplatin-based adjuvant chemotherapy for stage III CC, ETD was associated with a decrease in DFS and OS. By contrast, EOD was not significantly associated with poorer outcomes. In case of relevant neurotoxicity during a 6 months schedule, these data are not in favor of continuing oxaliplatin beyond 75% of planned cycles of adjuvant chemotherapy, and demonstrate that fluoropyrimidines remain the cornerstone of adjuvant chemotherapy in localized CC.

Simplified Graded Infusion Strategy for Mitigation of Oxaliplatin Hypersensitivity

BackgroundHypersensitivity reactions (HSRs) to oxaliplatin present a therapeutic challenge. The standard desensitization protocol consists of 12 infusion steps with 3 drug dilutions, often in an inpatient setting. Several years ago we implemented a simplified outpatient graded infusion protocol for oxaliplatin with 2 drug dilutions and 3 infusion steps. Materials and MethodsWe performed a retrospective analysis of our experience to define the safety and outcomes associated with this simplified, ambulatory, graded infusion strategy. ResultsBetween January 1, 2011 and December 1, 2020, 374 patients who had experienced an oxaliplatin-related HSR were treated via a 3-step graded infusion in the outpatient setting. Of these 374 patients, 283 (76%) did not experience a subsequent HSR, while 91 (24%) did experience a breakthrough HSR. Of the 374 patients, 19 (5%) experienced a grade 3 or 4 HSR. Three patients (0.8%) were hospitalized. There was no grade 5 (fatal) HSRs. Overall, the 374 patients received a median additional 3 cycles of oxaliplatin (range 1-41). The most common reasons for treatment discontinuation were disease progression (35%), breakthrough HSRs (24%), completion of treatment (21%), and toxicity other than HSR (20%). Fifteen patients who experienced breakthrough HSRs during a graded infusion were subsequently treated with the standard 12-step desensitization. Five of these 15 patients had an HSR during their initial desensitization and 5 developed an HSR on subsequent 12-step desensitizations. Thus, treatment was discontinued in 67% of these 15 patients due to persistent HSRs. ConclusionOur data indicate that the simplified 3-step graded infusion protocol is a safe outpatient strategy for patients with a history of HSR to oxaliplatin.

Synchronous concomitant pancreatic acinar cell carcin and gastric adenocarcinoma: A case report and review of literature

BACKGROUNDMultiple primary malignant tumors are two or more malignancies in an individual without any relationship between the neoplasms. In recent years, an increasing number of cases have been reported. However, concomitant primary gastric and pancreatic cancer reported a relatively small incidence, involving no pancreatic acinar cell carcinoma reports. Here, we present the first case of concomitant pancreatic acinar cell carcinoma and gastric adenocarcinoma.CASE SUMMARYA 69-year-old male presented to our department with a history of vomiting, epigastric pain, and weight loss. Imaging revealed space-occupying lesions in the stomach and the tail of the pancreas, respectively. The patient underwent laparoscopic radical gastrectomy and pancreatectomy simultaneously. The pathologies of surgical specimens were completely different: The resected gastric specimen was moderate to poorly differentiated adenocarcinoma, whereas the pancreatic tumor was consistent with acinar cell carcinoma. The patient was treated with six cycles of oxaliplatin and S-1 chemotherapy. As of March 2021, the patient was healthy without any recurrence or metastasis. After thoroughly reviewing the literature on simultaneous pancreatic and gastric cancers at home and abroad, we discussed the clinical characteristics of these rare synchronous double cancers. Most of the cases had undergone surgery and adjuvant chemotherapy, and all of the cases were pathologically confirmed by the postoperative specimen.CONCLUSIONSynchronous pancreatic acinar cells and gastric adenocarcinoma can occur and should be considered when tumors are found in these organs.

A phase II study of FOLFIRINOX with primary prophylactic pegfilgrastim for chemotherapy-na\xefve Japanese patients with metastatic pancreatic cancer

BackgroundAlthough FOLFIRINOX is currently one of the standard therapies for chemotherapy-naïve patients with metastatic pancreatic cancer (MPC), the high rate of febrile neutropenia (FN) presents a clinical problem. This study aimed to evaluate the safety and efficacy of primary prophylactic pegfilgrastim with FOLFIRINOX in Japanese MPC patients.MethodsFOLFIRINOX (intravenous oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, levofolinate 200 mg/m2, 5-fluorouracil (5-FU) bolus 400 mg/m2 and 5-FU 46 h infusion 2400 mg/m2) and pegfilgrastim 3.6 mg on day 4 or 5, every 2 weeks was administered to previously untreated MPC patients. The primary endpoint was the incidence of FN during the first 3 cycles. The planned sample size was 35 patients, but the trial was predefined to discontinue enrollment for safety if 4 patients developed FN.ResultsAt the enrollment of 22 patients, 4 patients developed FN in the first cycle, resulting in an incidence of FN of 18% {95% confidence interval [CI], 0.5–40.3%}, and enrollment was discontinued early. The incidence of grade 3 or higher neutropenia was 36.4%. Median relative dose intensities during the initial 3 cycles of oxaliplatin, irinotecan, bolus 5-FU, infusional 5-FU, and levofolinate maintained high (100%, 89.0%, 100%, 66.0%, and 100%, respectively). Response rate and median overall survival were 54.5% (95% CI 32.7–74.9) and 15.7 months (95% CI 7.9–18.8), respectively.ConclusionsThis phase II study could not demonstrate any reduction in the incidence of FN, nevertheless some patients experience benefits for efficacy by maintaining dose intensity using prophylactic pegfilgrastim.Trial registrationhttp://www.umin.ac.jp/ctr/index-j.htm, UMIN000017538. Date of registration: May/13/2015

The efficacy and safety of different radiotherapy doses in neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

This study aimed to evaluate efficacy and adverse effects of different radiotherapy (RT) doses in neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Fifty-nine patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy in hospital between January 2015 and May 2017 were enrolled in retrospective analysis. The patients were divided into the 56-Gy group and the 50-Gy group. The concurrent chemotherapy regimen was based on capecitabine. All patients received one cycle of oxaliplatin combined with capecitabine induction chemotherapy. All patients completed neoadjuvant chemoradiotherapy and received radical surgery. Of the patients in this study, 29 patients and 30 patients received a radiation dose of 56- and 50-Gy, respectively. All clinical characteristics were matched between the two groups. All patients received surgery 6 to 8 weeks after completing RT. The therapeutical effective rate in the 56-Gy group was 93.10% (27/29), compared with 66.67% in the 50-Gy group (20/30); the difference between the two groups was statistically significant (χ2=6.36, P=0.01). The pathological complete remission (pCR) rate in the 56-Gy group (37.93%, 11/29) was statistically significantly higher than that in the 50-Gy group (13.33%, 4/30) (χ2=4.71, P=0.030). The anal preservation rate in the 56-Gy group (65.5%, 19/29) was statistically significantly higher than that in the 50-Gy group (33.33%, 10/30) (χ2=6.11, P=0.01). The 56-Gy group had a local recurrence rate of 0% (0/29) and a distant metastasis rate of 10.34% (3/29), while the 50-Gy group had a local recurrence rate of 6.67% (2/30) and a distant metastasis rate of 16.67% (5/30); no significant difference existed between the two groups (χ2=2.00, 0.50, P=0.16, 0.48). The incidence of adverse reactions (gastrointestinal reactions, bone marrow suppression, and perianal skin reactions) in the 56-Gy group was not significantly different from that in the 50-Gy group (P>0.05). Increasing the radiation dose can significantly improve the anal preservation and pCR rates of patients with locally advanced rectal cancer, thus improving their life quality. Moreover, it does not increase the rates of recurrence or adverse reactions. Our findings have certain clinical significance, but further prospective study is needed.

Long-term outcome of a phase III trial on neoadjuvant chemoradiation with capecitabine and irinotecan in patients with locally advanced rectal cancer: Updated results of the CinClare trial.

3603 Background: Adding UGT1A1-guided irinotecan to capecitabine-based neoadjuvant chemoradiotherapy (CRT) significantly increased the pathological complete response (pCR) rate nearly doubling [J Clin Oncol. 2020 Dec 20;38(36):4231-4239]. Here, results of long-term outcome are reported. Methods: Eligible patients with clinical stage II/III rectal adenocarcinoma, UGT1A1 genotype *1*1 or *1*28 were randomized to the control group: pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine, followed by a cycle of oxaliplatin and capecitabine; or the experimental group: radiation with capecitabine combined with weekly irinotecan 80 mg/m2 for patients with *1*1 or 65 mg/m2 for patients with *1*28, followed by a cycle of irinotecan and capecitabine. Surgery was scheduled for 8 weeks after completion of CRT. Five cycles of adjuvant XELOX chemotherapy were administered regardless of the pathologic result. Patients were stratified by UGT1A1 genotype (*1*1 vs. *1*28) clinical T stage (cT3 vs. cT4) and tumor distance from the anal verge (≤5 cm vs. &gt; 5 cm). The primary end point of pCR was reached. Survival time was calculated from the date of randomization to the date of event or the last follow-up. Secondary endpoints were defined as local failure for local control (LC), tumor recurrence or death from any cause for disease-free survival (DFS), and death from any cause for overall survival (OS). Results: Of the 360 patients initially enrolled, 356 were evaluated as the modified intention-to-treat population (n = 178 in both groups). A total of 311 patients underwent surgery and pCR was achieved in 80 patients, another 10 patients undergo a watch-and-wait approach after achieving cCR. With a median follow-up time of 48 months (Q25-Q75, 41-55 months), 57 deaths (33 and 24), 17 local failures (11 and 6) and 69 distant metastases (37 and 32) were observed, respectively. Overall, the 4y LC rate were 93% and 96% in control and experimental groups, with estimated LC HR of 0.53 (95% confidence interval [CI], 0.20-1.43), the 4y DFS rates were 69% and 74% (HR = 0.74, 95% CI 0.49-1.10), and the 4y OS were 80% and 85%, (HR = 0.70, 95% CI 0.42-1.19), respectively. In the subgroup analysis, irinotecan showed a significant improvement in DFS (HR = 0.77, 95% CI 0.61-0.98) and OS (HR = 0.71, 95% CI 0.51-0.98) in UGT1A1 *1*1 patients. Conclusions: The addition of irinotecan to standard capecitabine-based CRT had a tendency towards improving LC, DFS, and OS, but without reaching statistical significance. UGT1A1 *1*1 patients seem to benefit the most from irinotecan. Molecular studies and subsequent therapies should be considered. Clinical trial information: NCT02605265.

Incidence of hypersensitivity reactions in patients on H1-receptor antagonists receiving oxaliplatin-based chemotherapy.

This study determined the incidence of hypersensitivity reactions in patients receiving oxaliplatin-based chemotherapy while on H1-receptor antagonists (H1RAs). Prophylaxis for patients receiving oxaliplatin is not currently recommended. H1RAs are used for the treatment of reactions; however, prophylactic H1RAs have not been well-studied. This retrospective chart review included patients with solid tumor malignancies who received H1RAs while on oxaliplatin-based chemotherapy between August 1, 2016 and October 31, 2019. Of fifty-one patients, there were four hypersensitivity reactions (8%), most of which were mild, occurred within 60 minutes of the start of the infusion, and did not result in an interruption in treatment. One severe reaction occurred, which required discontinuation of therapy. Forty-two patients (82%) were able to receive at least 9 cycles of oxaliplatin without a reported reaction. In this observational study, the incidence rate of hypersensitivity reactions in patients receiving oxaliplatin while on H1RAs was lower than reported in previous literature. Most reactions were mild, and patients were able to continue oxaliplatin-based therapy. With future, randomized controlled trials, H1RAs may prove to be effective in preventing or delaying the onset of hypersensitivity reactions related to oxaliplatin.

The protocol of a prospective, multicenter, randomized, controlled phase III study evaluating different cycles of oxaliplatin combined with S-1 (SOX) as neoadjuvant chemotherapy for patients with locally advanced gastric cancer: RESONANCE-II trial

BackgroundCuring locally advanced gastric cancer through surgery alone is difficult. Adjuvant and neoadjuvant chemotherapy bring potential benefits to more patients with gastric cancer based on several clinical trials. According to phase II studies and guidelines, SOX regimen as neoadjuvant chemotherapy is efficient. However, the optimal duration of neoadjuvant chemotherapy has not been established. In this study, we will evaluate the efficacy and safety of different cycles of SOX as neoadjuvant chemotherapy for patients with locally advanced gastric cancer.MethodsRESONANCE-II trial is a prospective, multicenter, randomized, controlled phase III study which will enroll 524 patients in total. Eligible patients will be registered, pre-enrolled and receive three cycles of SOX, after which tumor response evaluations will be carried out. Those who show stable disease or progressive disease will be excluded. Patients showing complete response or partial response will be enrolled and assigned into either group A for another three cycles of SOX (six cycles in total) followed by D2 surgery; or group B for D2 surgery (three cycles in total). The primary endpoint is the rate of pathological complete response and the secondary endpoints are R0 resection rate, three-year disease-free survival, five-year overall survival, and safety.DiscussionThis study is the first phase III randomized trial to compare the cycles of neoadjuvant chemotherapy using SOX for resectable locally advanced cancer. Based on a total of six to eight cycles of perioperative chemotherapy usually applied in locally advanced gastric cancer, patients in group A can be considered to have completed all perioperative chemotherapy, the results of which may suggest the feasibility of using chemotherapy only before surgery in gastric cancer.Trial registrationRegistered prospectively in the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) with registration number ChiCTR1900023293 on May 21st, 2019.