Machine Learning Predicts Oxaliplatin Benefit in Early Colon Cancer.

PURPOSE: A combination of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is the standard for adjuvant therapy of resected early-stage colon cancer (CC). Oxaliplatin leads to lasting and disabling neurotoxicity. Reserving the regimen for patients who benefit from oxaliplatin would maximize efficacy and minimize unnecessary adverse side effects. METHODS: We trained a new machine learning model, referred to as the colon oxaliplatin signature (COLOXIS) model, for predicting response to oxaliplatin-containing regimens. We examined whether COLOXIS was predictive of oxaliplatin benefits in the CC adjuvant setting among 1,065 patients treated with 5-fluorouracil plus leucovorin (FULV; n = 421) or FULV + oxaliplatin (FOLFOX; n = 644) from NSABP C-07 and C-08 phase III trials. The COLOXIS model dichotomizes patients into COLOXIS+ (oxaliplatin responder) and COLOXIS- (nonresponder) groups. Eight-year recurrence-free survival was used to evaluate oxaliplatin benefits within each of the groups, and the predictive value of the COLOXIS model was assessed using the P value associated with the interaction term (int P) between the model prediction and the treatment effect. RESULTS: Among 1,065 patients, 526 were predicted as COLOXIS+ and 539 as COLOXIS-. The COLOXIS+ prediction was associated with prognosis for FULV-treated patients (hazard ratio [HR], 1.52 [95% CI, 1.07 to 2.15]; P = .017). The model was predictive of oxaliplatin benefits: COLOXIS+ patients benefited from oxaliplatin (HR, 0.65 [95% CI, 0.48 to 0.89]; P = .0065; int P = .03), but COLOXIS- patients did not (COLOXIS- HR, 1.08 [95% CI, 0.77 to 1.52]; P = .65). CONCLUSION: The COLOXIS model is predictive of oxaliplatin benefits in the CC adjuvant setting. The results provide evidence supporting a change in CC adjuvant therapy: reserve oxaliplatin only for COLOXIS+ patients, but further investigation is warranted.

Review of Safety Data for Adenovirus 5 as a Delivery Vector for Intratumoral Cancer Gene Therapy.

With efficient transduction across most cell types and larger packaging capacity, Adenovirus 5 (Ad5) makes an attractive choice as a viral vector. However, a reported past mortality and known immunogenicity cast doubt on the safety of its use. An online database search was performed for all clinical trials administering intratumoral injection of gene therapy packaged in Ad5, being conducted in the United States, and using the Common Terminology Criteria for Adverse Events (CTCAE). Studies with unclear adverse events (AE) were excluded. The primary outcome collected was grade ≥3 (AE). Analyses were performed using Fisher's exact test. Thirty-nine prospective clinical trials across a variety of cancers were identified: 14 studies of therapeutic Ad5 alone, 12 with chemotherapy, 16 with radiation, and 11 with surgery. There were 3 mortalities out of 756 patients (0.4%), which were most likely unrelated to Ad5: 1 due to hypoxic encephalopathy, 1 due to splenic vein thrombus, and 1 due to disease progression. In trials that reported total AE (grades 1-5), there were 284 (10.3%) grade ≥3 AE out of 2,745 total AE in 477 patients. The overall life-threatening (grade 4) AE rate was 1.4% (34/2,425 AE in 428 patients). Overall, the most frequent grade ≥3 AE were lymphopenia (20.6% in 14 trials, 209 patients), dyspnea (8.7% in 11 trials, 208 patients), and neutropenia (8.6% in 12 trials, 174 patients). The most frequent grade 4 AE were neutropenia (4.6%), lymphopenia (3.3%), and leukopenia (3.1% in 13 trials, 192 patients). Our analyses demonstrated relative overall safety of Ad5 and warrant re-evaluation for the use of Ad5 as a delivery vector for gene therapy products.

Consensus statement and clinical pathway for the management of colon cancer with peritoneal metastases in the state of Delaware.

BACKGROUND: Increasing data suggests that the combination of modern systemic therapies and Cytoreductive surgery with or without Hyperthermic Intraperitoneal Chemotherapy (HIPEC) may improve the outcome of patients with colon cancer with peritoneal metastases. Patient selection and sequence of treatments remains ill-defined. MATERIALS AND METHODS: A working group, the State of Delaware Peritoneal Surface Malignancies Task Force (DE-PSM-TF), was created including representatives from medical and surgical oncology from the acute care hospitals in Delaware. An extensive review of all available literature was carried out. Virtual meetings were held, and interpretation and discussion of the data was conducted. RESULTS: A clinical pathway that includes a multidisciplinary evaluation at the time of diagnosis of colon cancer with peritoneal metastases and reflects a consensus from the Task Force on 7 key points that suggest the management of these patients based on the severity of their peritoneal metastases and incorporates all currently available therapies was created. The sequence of therapies of this multimodality treatment was determined by the Peritoneal Surface Disease Severity Score (PSDSS) (Fig. 1). CONCLUSION: The current pathway represents a comprehensive, team effort that should improve the outcome of patients with Colon Cancer with peritoneal metastases in the state of Delaware by having multidisciplinary discussions at the time of diagnosis, selecting the best order of sequence of currently available therapies in order to maximize benefits and minimize morbidity.

A cost analysis of sorafenib for desmoid tumors.

INTRODUCTION: A recent randomized trial demonstrated that sorafenib improved progression free survival (PFS) in patients with desmoid tumors despite many patients experiencing stable disease or spontaneous regression without treatment. Utilizing these trial data, we performed a cost analysis of sorafenib efficacy through two years of treatment. METHODS: Current Medicare Part D rates for sorafenib were utilized (dose 400 mg/day, cost $309/day). Annual costs per progression and objective response were calculated. Radiologic progression and response were defined using RECIST criteria. Patients with disease progression were separately analyzed in two groups: both clinical and radiologic (CAR), and radiologic alone. RESULTS: 84 previously randomized patients were analyzed (placebo: 35, sorafenib: 49). At one year, sorafenib was associated with a 43% absolute risk reduction (ARR) of CAR progression and number-needed-to-treat (NNT) of 2.3 patients/year, costing $259,406. At two years, ARR was 48% and NNT of 2.1 patients/year, costing $473,697. When evaluating only patients with RECIST defined radiologic progression, sorafenib patients experienced ARR of 13.9% with NNT 7.2 and estimated costs of $812,052 at one year. Two-year ARR was 17.5% with NNT 5.7 and estimated costs $1,285,052. Sorafenib patients experienced improved RECIST partial response rates at 1 and 2 years of 14.7% and 14.3%, with NNT 6.8 and 6.9, and costs of $766,938 and $1,556,433; respectively. CONCLUSION: For the treatment of desmoid tumors, Sorafenib led to improved PFS, but at a significant cost per patient. Favorable RECIST outcomes were less likely and costlier. Patients should be informed of possible benefits of treatment versus potential financial burden.

NSABP FC-6: Surgical conversion rate in colorectal cancer patients with unresectable, KRAS wild-type liver metastases receiving mFOLFOX7 plus cetuximab.

PURPOSE: This study sought to determine the R0 resection rate in KRAS wild-type (WT), liver-only metastatic colorectal cancer (CRC) patients initially identified as having unresectable disease who were treated with FOLFOX7 plus cetuximab. Exploratory molecular analyses were undertaken before and after treatment. METHODS: Twenty patients were enrolled. None had prior adjuvant chemotherapy. Cetuximab was added to a FOLFOX7 backbone and administered at 500 mg/m2 every 14 days with dose reductions to 400 and 300 mg/m2 in the event of toxicity. In the absence of toxicity, dose-escalations to 600, 700, and 800 mg/m2 were allowed. The mean dose of cetuximab (mg/m2 /week) throughout the study was 289 mg/m2 . Paired samples were collected for correlative studies, where feasible. RESULTS: We assessed the conversion rates from unresectable to resectable in hepatic-only, KRAS exon 2 WT mCRC. Seventeen of 20 patients undergoing chemotherapy were considered resectable by imaging criteria; R0 resection was achieved in 15/20 patients. Molecular profiling revealed heterogeneity between patients at the gene-expression, pathway signaling, and immune-profile levels. CONCLUSIONS: Although 15/20 (75%) converted to R0 resection, by 2 years, 10/15 R0 resections had recurred. Therefore, chemotherapy plus cetuximab is of limited long-term benefit in this setting. ctDNA analysis may guide additional therapy including immunotherapy.

A Population Health Assessment in a Community Cancer Center Catchment Area: Triple-Negative Breast Cancer, Alcohol Use, and Obesity in New Castle County, Delaware.

BACKGROUND: The NCI requires designated cancer centers to conduct catchment area assessments to guide cancer control and prevention efforts designed to reduce the local cancer burden. We extended and adapted this approach to a community cancer center catchment area with elevated rates of triple-negative breast cancer (TNBC). METHODS: Cancer registry data for 462 TNBC and 2,987 "Not-TNBC" cases diagnosed between 2012 and 2020 at the Helen F. Graham Cancer Center & Research Institute (HFGCCRI), located in New Castle County, Delaware, were geocoded to detect areas of elevated risk (hot spots) and decreased risk (cold spots). Next, electronic health record (EHR) data on obesity and alcohol use disorder (AUD) and catchment area measures of fast-food and alcohol retailers were used to assess for spatial relationships between TNBC hot spots and potentially modifiable risk factors. RESULTS: Two hot and two cold spots were identified for TNBC within the catchment area. The hot spots accounted for 11% of the catchment area but nearly a third of all TNBC cases. Higher rates of unhealthy alcohol use and obesity were observed within the hot spots. CONCLUSIONS: The use of spatial methods to analyze cancer registry and other secondary data sources can inform cancer control and prevention efforts within community cancer center catchment areas, where limited resources can preclude the collection of new primary data. IMPACT: Targeting community outreach and engagement activities to TNBC hot spots offers the potential to reduce the population-level burden of cancer efficiently and equitably.

Pancreatic resections: 30 and 90-day outcomes in octogenarians.

BACKGROUND: Pancreatic tumors are frequently found in a geriatric population. Given that the median age of patients with pancreatic cancer is 70 years at diagnosis and the ubiquity of CT and MRI imaging has increased the detection of pancreas masses, pancreatic surgeons often find themselves operating on patients of advanced age. This study sought to evaluate the outcomes of pancreatic resection in an octogenarian population at a single institution with a dedicated surgical oncology team. STUDY DESIGN: A retrospective chart review was performed for all patients undergoing pancreatic resection over a 13-year period at an academic community cancer center. Patient characteristics and operative outcomes were compared between patients aged 80 and older, and those younger than 80. Student t-tests, Fisher's exact test, and Kruskal-Wallis tests were used for univariate analyses. RESULTS: Over the 13-year period, a total of 48 patients of 403 undergoing pancreatic resections were aged 80 or older. Of these 48 patients, 35 underwent pancreaticoduodenectomy (Whipple) and 13 underwent distal pancreatectomy. Patient characteristics including ASA classification were similar among the two age groups. The procedures themselves were equally complicated with similar operative times, transfusion requirements, estimated blood losses, and portal vein resections. The number and severity of complications such as delayed gastric emptying and pancreatic leak were not statistically different between the two groups. Additionally, the 30-day reoperation, readmission, and mortality rates were not statistically different. Outcomes at 90-days revealed an increased rate of readmission amongst octogenarians who underwent Whipple without an increase in rates of major complications. The total number of deaths in the octogenarian group was 3 (6.2%) vs. 6 (1.7%) in the non-octogenarian group (p = 0.080). The median length of stay was similar amongst the two age groups. CONCLUSIONS: At a large-volume academic community cancer center with a dedicated surgical oncology team, highly selected octogenarians can undergo pancreatic resection safely with outcomes that do not differ significantly from their younger counterparts.

Characteristics of Gastrointestinal Stromal Tumors incidentally discovered during abdominal surgery.

BACKGROUND: Gastrointestinal Stromal Tumors (GISTs) are rare sarcomas with 5000 new cases arising in the United States each year. Despite their low incidence, general surgeons should be familiar with GISTs since a quarter of these neoplasms are encountered incidentally. METHODS: A retrospective medical records review was conducted to create a database of all GISTs resected from January 2005 to May 2019. We isolated patients who had incidental discovery of GISTs intraoperatively or within final pathology. Characteristics of patient (Age, gender), index procedure (malignant vs. benign, elective vs. emergent) and tumor (location, size and mitotic rate) were analyzed. RESULTS: A total 48 patients were incidentally discovered to have a GIST excised during index operation. The mean age of these patients was 62 years, with 27 females and 21 males. The primary location of tumors in descending frequency was stomach (30), small bowel (15), colon/rectum (2) and esophagus (1). The average size of all tumors was 1.2 cm, with the average size of the stomach, small bowel, colon/rectum and esophagus at 0.9 cm, 1.7 cm, 0.9 cm and 0.3 cm respectively. Mitotic rate was less than 5 mitosis per 50 HPF in 96% of patients. Incidental tumors were identified during both bariatric (13) and non-bariatric stomach surgery (8), colorectal surgery (14), hernia repair (4), ampullary/pancreatic surgery (5), esophageal surgery (2) liver surgery (1) and uterine surgery (1). Most incidental-GISTs were identified during elective surgery (81%, 39). Finally, 15 of the tumors were identified during surgery for other malignancies. CONCLUSIONS: One quarter (25%) of the GISTs encountered at our academic community cancer center over a 15-year period were discovered incidentally. These tumors had less malignant characteristics overall and were likely cured with surgical resection.

The disclosure slide-Informative or obligatory, 5 years of SSO Cancer Symposium oral presentations.

BACKGROUND: Financial disclosure (FD) highlights potential conflicts of interest but is often overlooked at academic conferences. METHODS: Retrospective review of 2015-2019 Society of Surgical Oncology Cancer Symposium oral presentation slide and/or verbal FD frequency, duration, and content. RESULTS: Of 963 presentations, 331 (34%) omitted disclosure slide/verbalization. 575 (60%) included a slide, 551 (57%) gave verbal disclosure and 133 (14%) stated relevance. 164 presentations (17%) cited 1 + FD. 2019 had greater median FDs/talk than 2015-2018 (3.50 vs. 2.00; p = .010). Compared to 2015-2018, 2019 yielded shorter median slide display of all disclosures (2.00 s vs. 2.47 s; p = .006), median 1 + FD display (3.37 s vs. 4.81 s; p = .04) and median 1 + FD verbalization (2.81 s vs. 3.66 s; p = .54). 2019 all disclosure verbalization increased (1.97 s vs. 1.14 s; p < .001). Multivariable modeling showed longer display with 2015-2018 (+1.3 s, 95% confidence interval [CI] -0.06 to 2.5 s, p = .04), <4 authors (+3.2 s, 95% CI: 2.1-4.3 s; p < .001) and longer verbalization with 2019 (+0.8 s, 95% CI: 0.2-1.4 s; p = .01), relevance (+1.0 s, 95% CI: 0.4-1.6 s; p = .002), ≤ 4 authors (+0.8 s, 95% CI: 0.3-1.3 s, p < .001) and noncommercial FD (+3.8 s, 95% CI: 2.0-5.0 s; p < .001). The five most cited commercial entities were in 39% of talks. CONCLUSION: Presenters' FDs were brief or omitted. Despite FD increase, disclosure time decreased. Improved FD attention will highlight potential COIs.

Microbiome and colorectal cancer: A review of the past, present, and future.

The gastrointestinal tract is home to diverse and abundant microorganisms, collectively referred to as the microbiome. This ecosystem typically contains trillions of microbial cells that play an important role in regulation of human health. The microbiome has been implicated in host immunity, nutrient absorption, digestion, and metabolism. In recent years, researchers have shown that alteration of the microbiome is associated with disease development, such as obesity, inflammatory bowel disease, and cancer. This review discusses the five decades of research into the human microbiome and the development of colorectal cancer - the historical context including experiments that sparked interest, the explosion of research that has occurred in the last decade, and finally the future of testing and treatment.

A Comparison of Colectomy Outcomes Utilizing Open, Laparoscopic, and Robotic Techniques.

INTRODUCTION: Robotic colectomy could reduce morbidity and postoperative recovery over laparoscopic and open procedures. This comparative review evaluates colectomy outcomes based on surgical approach at a single community institution. METHODS: A retrospective review of all patients who underwent colectomy by a fellowship-trained colon and rectal surgeon at a single institution from 2015 through 2019 was performed, and a cohort developed for each approach (open, laparoscopic, and robotic). 30-day outcomes were evaluated. For dichotomous outcomes, univariate logistic regression models were used to quantify the individual effect of each predictor of interest on the odds of each outcome. Continuous outcomes received a similar approach; however, linear and Poisson regression modeling were used, as appropriate. RESULTS: 115 patients were evaluated: 14% (n = 16) open, 44% (n = 51) laparoscopic, and 42% (n = 48) robotic. Among the cohorts, there was no statistically significant difference in operative time, rate of reoperation, readmission, or major complications. Robotic colectomies resulted in the shortest length of stay (LOS) (Kruskal-Wallis P < .0001) and decreased estimated blood loss (EBL) (Kruskal-Wallis P = .0012). Median age was 63 years (interquartile range [IQR] 53-72). 54% (n = 62) were female. Median American Society of Anesthesiologists physical status classification was 3 (IQR 2-3). Median body mass index was 28.67 (IQR 25.03-33.47). A malignant diagnosis was noted on final pathology in 44% (n = 51). CONCLUSION: Among the 3 approaches, there was no statistically significant difference in 30-day morbidity or mortality. There was a statistically significant decreased LOS and EBL for robotic colectomies.

Meta-Analysis on the Effect of Pasireotide for Prevention of Postoperative Pancreatic Fistula.

BACKGROUND: A randomized controlled trial of routine administration of pasireotide demonstrated decreased incidence of clinically significant postoperative pancreatic fistula (POPF). Recent studies have not replicated these results. A meta-analysis was performed to evaluate its efficacy in this setting. METHODS: Prospective trials utilizing pasireotide prophylactically after pancreatectomy were reviewed. The primary outcome was clinically significant POPF. Secondary outcomes included length of stay (LOS), readmission rates, and mortality. Study heterogeneity was assessed. RESULTS: Five studies totaling 1571 patients were identified. There was no difference in age, sex, or cancer rates. Pasireotide patients had smaller pancreatic ducts (P < .001) and softer glands (P = .04). For all pancreatectomies, there was no difference in POPF rates (odds ratio [OR] 0.84; 95% CI 0.60-1.16, P = .29). Patients undergoing distal pancreatectomy (OR 0.70; 95% CI 0.30-1.63, P = .41) had similar rates of POPF versus pancreaticoduodenectomy (PD) patients who experienced a lower incidence of POPF (OR 0.60; 95% CI 0.42-0.86, P = .006).Mortality rates and LOS were similar. Readmission rates were decreased with pasireotide (OR 0.61; 95% CI 0.44-0.85). CONCLUSIONS: Routine administration of pasireotide did not decrease POPF rates for all pancreatectomies, but was associated with lower rates for PD, and decreased readmission rates. Further prospective, randomized studies are warranted.

Meta-analysis on the Effect of Pasireotide for Prevention of Postoperative Pancreatic Fistula.

BACKGROUND: A randomized controlled trial (RCT) of routine administration of pasireotide demonstrated decreased incidence of clinically significant postoperative pancreatic fistula (POPF). Recent studies have not replicated these results. A meta-analysis was performed to evaluate its efficacy in this setting. METHODS: Prospective trials utilizing pasireotide prophylactically after pancreatectomy were reviewed. The primary outcome was clinically significant POPF. Secondary outcomes included length of stay (LOS), readmission rates, and mortality. Study heterogeneity was assessed. RESULTS: Five studies totaling 1571 patients were identified. There was no difference in age, sex, or cancer rates. Pasireotide patients had smaller pancreatic ducts (P ≤.001) and softer glands (P = .04). For all pancreatectomies, there was no difference in POPF rates (OR 0.84; 95% CI 0.60-1.16, P = .29). Patients undergoing distal pancreatectomy (OR 0.70; 95% CI 0.30-1.63, P = .41) had similar rates of POPF versus pancreaticoduodenectomy (PD) patients that experienced a lower incidence of POPF (OR 0.60; 95% CI 0.42-0.86, P = .006). Mortality rates and LOS were similar. Readmission rates were decreased with pasireotide (OR 0.61; 95% CI 0.44-0.85). CONCLUSIONS: Routine administration of pasireotide did not decrease POPF rates for all pancreatectomies, but was associated with lower rates for PD and decreased readmission rates. Further prospective, randomized studies are warranted.

Health-Care Workers' Perception of Reimbursement for Complex Surgical Oncology Procedures.

Perception of physician reimbursement for surgical procedures is not well studied. The few existing studies illustrate that patients believe compensation to be higher than in reality. These studies focus on patient perceptions and have not assessed health-care workers' views. Our study examined health-care workers' perception of reimbursement for complex surgical oncology procedures. An anonymous online survey was distributed to employees at our cancer center with descriptions and illustrations of three oncology procedures-hepatectomy, gastrectomy, and pancreaticoduodenectomy. Participants estimated the Medicare fee and gave their perceived value of each procedure. Participants recorded their perception of surgeon compensation overall, both before and after revealing the Medicare fee schedule. Most of the 113 participants were physicians (33.6%) and nurses (28.3%). When blinded to the Medicare fee schedules, most felt that reimbursements were too low for all procedures (60-64%) and that surgeons were overall undercompensated (57%). Value predictions for each procedure were discordant from actual Medicare fee schedules, with overestimates up to 374 per cent. After revealing the Medicare fee schedules, 55 per cent of respondents felt that surgeons were undercompensated. Even among health-care workers, a large discrepancy exists between perceived and actual reimbursement. Revealing actual reimbursements did not alter perception on overall surgeon compensation.

Intergroup Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil, and Leucovorin Versus Oxaliplatin, 5-Fluorouracil, Leucovorin, and Bevacizumab for Patients with Stage II or III Rectal Cancer Receiving Preoperative Chemoradiation: A Trial of the ECOG-ACRIN Research Group (E5204).

BACKGROUND: The addition of bevacizumab to chemotherapy improved outcomes for patients with metastatic colon cancer. E5204 was designed to test whether the addition of bevacizumab to mFOLFOX6, following neoadjuvant chemoradiation and definitive surgery, could improve overall survival (OS) in patients with stage II/III adenocarcinoma of the rectum. SUBJECTS, MATERIALS, AND METHODS: Patients with stage II/III rectal cancer who had completed neoadjuvant 5-fluorouracil-based chemoradiation and had undergone complete resection were enrolled. Patients were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 with bevacizumab (Arm B) administered every 2 weeks for 12 cycles. RESULTS: E5204 registered only 355 patients (17% of planned accrual goal) as it was terminated prematurely owing to poor accrual. At a median follow-up of 72 months, there was no difference in 5-year overall survival (88.3% vs. 83.7%) or 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. The rate of treatment-related grade ≥ 3 adverse events (AEs) was 68.8% on Arm A and 70.7% on Arm B. Arm B had a higher proportion of patients who discontinued therapy early as a result of AEs and patient withdrawal than did Arm A (32.4% vs. 21.5%, p = .029).The most common grade 3-4 treatment-related AEs were neutropenia, leukopenia, neuropathy, diarrhea (without prior colostomy), and fatigue. CONCLUSION: At 17% of its planned accrual, E5204 did not meet its primary endpoint. The addition of bevacizumab to FOLFOX6 in the adjuvant setting did not significantly improve OS in patients with stage II/III rectal cancer. IMPLICATIONS FOR PRACTICE: At 17% of its planned accrual, E5204 was terminated early owing to poor accrual. At a median follow-up of 72 months, there was no significant difference in 5-year overall survival (88.3% vs. 83.7%) or in 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. Despite significant advances in the treatment of rectal cancer, especially in improving local control rates, the risk of distant metastases and the need to further improve quality of life remain a challenge. Strategies combining novel agents with chemoradiation to improve both distant and local control are needed.