Systemic Therapy for Melanoma: ASCO Guideline Update.

PURPOSE: To provide guidance to clinicians regarding the use of systemic therapy for melanoma. METHODS: American Society of Clinical Oncology convened an Expert Panel and conducted an updated systematic review of the literature. RESULTS: The updated review identified 21 additional randomized trials. UPDATED RECOMMENDATIONS: Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease. For patients with unresectable or metastatic cutaneous melanoma, nivolumab plus relatlimab was added as a potential option regardless of BRAF mutation status and nivolumab plus ipilimumab followed by nivolumab was preferred over BRAF/MEK inhibitor therapy. Talimogene laherparepvec is no longer recommended as an option for patients with BRAF wild-type disease who have progressed on anti-PD-1 therapy. Ipilimumab- and ipilimumab-containing regimens are no longer recommended for patients with BRAF-mutated disease after progression on other therapies.This full update incorporates the new recommendations for uveal melanoma published in the 2022 Rapid Recommendation Update.Additional information is available at www.asco.org/melanoma-guidelines.

Systemic therapy for melanoma: ASCO guideline update

To provide guidance to clinicians regarding the use of systemic therapy for melanoma. American Society of Clinical Oncology convened an Expert Panel and conducted an updated systematic review of the literature. The updated review identified 21 additional randomized trials. Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease. For patients with unresectable or metastatic cutaneous melanoma, nivolumab plus relatlimab was added as a potential option regardless of BRAF mutation status and nivolumab plus ipilimumab followed by nivolumab was preferred over BRAF/MEK inhibitor therapy. Talimogene laherparepvec is no longer recommended as an option for patients with BRAF wild-type disease who have progressed on anti­PD-1 therapy. Ipilimumab- and ipilimumab-containing regimens are no longer recommended for patients with BRAF-mutated disease after progression on other therapies. This full update incorporates the new recommendations for uveal melanoma published in the 2022 Rapid Recommendation Update. Additional information is available at www.asco.org/melanoma-guidelines

Impact of acceptance and commitment therapy on physical and psychological symptoms in advanced gastrointestinal cancer patients and caregivers: Secondary results of a pilot randomized trial.

Patients with advanced gastrointestinal cancer often experience high symptom burden, which is associated with heightened distress in both patients and their family caregivers. Few interventions have been tested to jointly address patient and caregiver symptoms in advanced gastrointestinal cancer. In a randomized pilot trial, telephone-based, dyadic acceptance and commitment therapy (ACT) was found to be feasible in this population. The present secondary analyses examined the impact of this intervention on patient and caregiver physical and psychological symptoms. Patients and caregivers (N = 40 dyads) were recruited from clinics in Indianapolis, Indiana and randomized to either six weeks of telephone-based ACT or education/support, an attention control condition. Outcomes were assessed at baseline and at 2 weeks and 3 months post-intervention. Study group differences in outcomes were not statistically significant. However, when examining within-group change, only ACT patients experienced moderate reductions in pain severity and interference at 2 weeks post-intervention (effect size [ES]=-0.47; -0.51) as well as moderate reductions in depressive symptoms at 2 weeks (ES=-0.42) and 3 months (ES=-0.41) post-intervention. ACT caregivers experienced moderate reductions in sleep disturbance (ES=-0.56; -0.49) and cognitive concerns (ES=-0.61; -0.85) across follow-ups. Additionally, caregivers in both conditions experienced moderate reductions in fatigue (ES=-0.38 to -0.70) and anxiety (ES=-0.40 to -0.49) across follow-ups. Findings suggest that ACT may improve certain symptoms in dyads coping with advanced gastrointestinal cancer and warrant replication in a larger trial.

Acceptance and commitment therapy for patient fatigue interference and caregiver burden in advanced gastrointestinal cancer: Results of a pilot randomized trial.

BACKGROUND: Fatigue often interferes with functioning in patients with advanced cancer, resulting in increased family caregiver burden. Acceptance and commitment therapy, a promising intervention for cancer-related suffering, has rarely been applied to dyads coping with advanced cancer. AIM: To examine the feasibility, acceptability, and preliminary efficacy of acceptance and commitment therapy for patient-caregiver dyads coping with advanced gastrointestinal cancer. Primary outcomes were patient fatigue interference and caregiver burden. DESIGN: In this pilot trial, dyads were randomized to six weekly sessions of telephone-delivered acceptance and commitment therapy or education/support, an attention control. Outcomes were assessed at baseline and at 2 weeks and 3 months post-intervention. SETTING/PARTICIPANTS: Forty patients with stage III-IV gastrointestinal cancer and fatigue interference and family caregivers with burden or distress were recruited from two oncology clinics and randomized. RESULTS: The eligibility screening rate (54%) and retention rate (81% at 2 weeks post-intervention) demonstrated feasibility. At 2 weeks post-intervention, acceptance and commitment therapy participants reported high intervention helpfulness (mean = 4.25/5.00). Group differences in outcomes were not statistically significant. However, when examining within-group change, acceptance and commitment therapy patients showed moderate decline in fatigue interference at both follow-ups, whereas education/support patients did not show improvement at either follow-up. Acceptance and commitment therapy caregivers showed medium decline in burden at 2 weeks that was not sustained at 3 months, whereas education/support caregivers showed little change in burden. CONCLUSIONS: Acceptance and commitment therapy showed strong feasibility, acceptability, and promise and warrants further testing. TRIAL REGISTRATION: ClinicalTrials.gov NCT04010227. Registered 8 July 2019, https://clinicaltrials.gov/ct2/show/NCT04010227?term=catherine+mosher&draw=2&rank=1.

Acceptance and commitment therapy for fatigue interference in advanced gastrointestinal cancer and caregiver burden: protocol of a pilot randomized controlled trial.

BACKGROUND: Fatigue interference with activities, mood, and cognition is one of the most prevalent and bothersome concerns of advanced gastrointestinal (GI) cancer patients. As fatigue interferes with patient functioning, family caregivers often report feeling burdened by increasing responsibilities. Evidence-based interventions jointly addressing cancer patient fatigue interference and caregiver burden are lacking. In pilot studies, acceptance and commitment therapy (ACT) has shown promise for addressing symptom-related suffering in cancer patients. The current pilot trial seeks to test a novel, dyadic ACT intervention for both advanced GI cancer patients with moderate-to-severe fatigue interference and their family caregivers with significant caregiving burden or distress. METHODS: A minimum of 40 patient-caregiver dyads will be randomly assigned to either the ACT intervention or an education/support control condition. Dyads in both conditions attend six weekly 50-min telephone sessions. Outcomes are assessed at baseline as well as 2 weeks and 3 months post-intervention. We will evaluate the feasibility, acceptability, and preliminary efficacy of ACT for improving patient fatigue interference and caregiver burden. Secondary outcomes include patient sleep interference and patient and caregiver engagement in daily activities, psychological flexibility, and quality of life. We will also explore the effects of ACT on patient and caregiver physical and mental health service use. DISCUSSION: Findings will inform a large-scale trial of intervention efficacy. Results will also lay the groundwork for further novel applications of ACT to symptom interference with functioning and caregiver burden in advanced cancer. TRIAL REGISTRATION: ClinicalTrials.gov , NCT04010227 . Registered 8 July 2019.

Systemic Therapy for Melanoma: ASCO Guideline.

PURPOSE: To provide guidance to clinicians regarding the use of systemic therapy for melanoma. METHODS: ASCO convened an Expert Panel and conducted a systematic review of the literature. RESULTS: A systematic review, one meta-analysis, and 34 additional randomized trials were identified. The published studies included a wide range of systemic therapies in cutaneous and noncutaneous melanoma. RECOMMENDATIONS: In the adjuvant setting, nivolumab or pembrolizumab should be offered to patients with resected stage IIIA/B/C/D BRAF wild-type cutaneous melanoma, while either of those two agents or the combination of dabrafenib and trametinib should be offered in BRAF-mutant disease. No recommendation could be made for or against the use of neoadjuvant therapy in cutaneous melanoma. In the unresectable/metastatic setting, ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone should be offered to patients with BRAF wild-type cutaneous melanoma, while those three regimens or combination BRAF/MEK inhibitor therapy with dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib should be offered in BRAF-mutant disease. Patients with mucosal melanoma may be offered the same therapies recommended for cutaneous melanoma. No recommendation could be made for or against specific therapy for uveal melanoma. Additional information is available at www.asco.org/melanoma-guidelines.

Clinical Assessment of 5-Fluorouracil/Leucovorin, Nab-Paclitaxel, and Irinotecan (FOLFIRABRAX) in Untreated Patients with Gastrointestinal Cancer Using UGT1A1 Genotype-Guided Dosing.

PURPOSE: 5-Fluorouracil (5-FU)/leucovorin, irinotecan, and nab-paclitaxel are all active agents in gastrointestinal cancers; the combination, FOLFIRABRAX, has not been previously evaluated. UDP Glucuronosyltransferase 1A1 (UGT1A1) clears SN-38, the active metabolite of irinotecan. UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity and predisposes to toxicity. We performed a trial to assess the safety and tolerability of FOLFIRABRAX with UGT1A1 genotype-guided dosing of irinotecan. PATIENTS AND METHODS: Patients with previously untreated, advanced gastrointestinal cancers received FOLFIRABRAX with prophylactic pegfilgrastim every 14 days. UGT1A1 *1/*1, *1/*28, and *28/*28 patients received initial irinotecan doses of 180, 135, and 90 mg/m2, respectively. 5-FU 2,400 mg/m2 over 46 hours, leucovorin 400 mg/m2, and nab-paclitaxel 125 mg/m2 were administered. Doses were deemed tolerable if the dose-limiting toxicity (DLT) rate during cycle 1 was ≤35% in each genotype group. DLTs were monitored using a sequential procedure. RESULTS: Fifty patients enrolled, 30 pancreatic, 9 biliary tract, 6 gastroesophageal, and 5 others. DLTs occurred in 5 of 23 (22%) *1/*1 patients, 1 of 19 (5%) *1/*28 patients, and 0 of 7 *28/*28 patients. DLTs were all grade 3: diarrhea (3 patients), nausea (2 patients), and febrile neutropenia (1 patient). The overall response rate was 31%. Response rates in pancreatic, gastroesophageal, and biliary tract cancers were 34%, 50%, and 11%, respectively. Eighteen patients (36%) received therapy for at least 24 weeks. CONCLUSIONS: FOLFIRABRAX with genotype-guided dosing of irinotecan is tolerable in patients with advanced gastrointestinal cancer and UGT1A1*1*1 or UGT1A1*1*28 genotypes. Too few *28/*28 patients were enrolled to provide conclusive results. Responses occurred across multiple tumor types.

Overall survival of patients with recurrent pancreatic cancer treated with systemic therapy: a retrospective study.

BACKGROUND: Only a few patients with pancreatic ductal adenocarcinoma (PDAC) recurring after curative resection and peri-operative (neoadjuvant and adjuvant) therapy are included in clinical trials of metastatic PDAC. As such, there is a paucity of data to guide treatment after relapse, and patients are treated similarly to those with de novo metastatic PDAC (mPDAC). We evaluated the patterns of chemotherapy use and over-all survival (OS) in patients with recurrent PDAC (rPDAC) following curative therapy. METHODS: In this retrospective study, the Indiana University pancreatic cancer database was used to identify patients with PDAC who underwent curative resection and subsequently developed recurrence. Demographics, tumor and treatment characteristics were collected. Patients were broadly divided into those who received chemotherapy for rPDAC and those who did not. Patients in the former category were further subdivided into those who received single agent therapy, any standard combination therapy (5-fluorouracil/irinotecan/oxaliplatin combination or gemcitabine/nab-paclitaxel) and those who received non-standard combinations. Survival analysis was performed by the Kaplan-Meier method. Log rank tests were used to determine differences in survival between treated rPDAC patients and those not treated. Cox regression analysis was employed to evaluate factors associated with OS. RESULTS: We identified 435 patients with resected PDAC treated between 2008 and 2014. Two hundred and twenty-three patients (51.2%) were diagnosed with rPDAC. Of these, 140 patients (63%) received chemotherapy whereas 71 patients (32%) did not receive chemotherapy. The 74 patients (53%) who received any standard, approved multiagent combination regimen had a median OS of 14 months compared to 8 months for the 47 patents (34%) who received other non-standard combinations and the 19 (13%) who received single agent therapy (P = 0.029). Multivariate cox regression analysis showed that margin negative resection, peri-operative therapy, radiotherapy and the use of any chemotherapy for rPDAC were associated with improved OS. CONCLUSION: Our findings support the use of standard approved multi-agent therapy in rPDAC. Patients derive significant benefit from these standard combination therapies with median OS that is comparable to what is observed with treatment for de novo mPDAC.

Chronic inflammatory demyelinating polyradiculoneuropathy secondary to immune checkpoint inhibitors in melanoma patients.

IMPORTANCE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune neurological disorder that is characterized by symmetrical progressive worsening or relapsing weakness and numbness of the limbs. There are no reliable diagnostic tests or definitive diagnostic criteria, and the diagnosis remains one of excluding other cases of polyneuropathy. Typical treatment for CIDP includes corticosteroids, intravenous immunoglobulin (IVIG), and plasma exchange. Little is known about CIDP as a treatment complication of immune checkpoint inhibitors (ipilimumab and nivolumab). This report will be helpful in increasing awareness and knowledge about this unique entity. OBSERVATIONS: We describe two cases of CIDP secondary to treatment with combined ipilimumab and nivolumab in patients with metastatic melanoma that were successfully treated with prednisone and IVIG. Conclusion and Relevance: This report illustrates that treatment with immune checkpoint inhibitors can lead to CIDP that can be successfully treated with complete resolution of symptoms. CIDP secondary to checkpoint inhibitors may have unique features such as low-grade lymphocytic pleocytosis on CSF evaluation as well as severe neuropathic pain as an early presenting symptom. Additionally, it is interesting to note that both patients presented in this report remained melanoma-free on follow-up more than 16 months later.

Phase 1 study of EUS-guided photodynamic therapy for locally advanced pancreatic cancer.

BACKGROUND AND AIMS: Locally advanced pancreatic cancer (LAPC) has a poor prognosis. There are limited data describing the use of photodynamic therapy (PDT) for pancreatic cancer in humans. We hypothesized that EUS-guided PDT for LAPC is safe, technically feasible, and produces a dose- and time-dependent increasing degree of image-defined tumor necrosis. METHODS: In a single-center, prospective, dose-escalation phase 1 study, patients with treatment-naïve LAPC received intravenous porfimer sodium (Concordia Laboratories Inc, St Michael, Barbados) followed 2 days later by EUS-PDT. EUS-PDT was performed by puncture with a 19-gauge needle and insertion of a 1.0-cm light diffuser (Pioneer Optics, Bloomfield, Conn) and illumination with a 630-nm light (Diomed Inc, Andover, Mass). A CT scan 18 days after PDT was done to assess for change in pancreatic necrosis. Nab-paclitaxel (125 mg/ m2 intravenously) and gemcitabine (1000 mg /m2 intravenously) were initiated 7 days after CT and given weekly for 3 of 4 weeks (1 cycle) until disease progression or unacceptable toxicity. RESULTS: Twelve patients (mean age, 67 ± 6 years; 8 male) with tumors (mean diameter, 45.2 ± 12.9 mm) in the head and/or neck (8) or body and/or tail (4) underwent EUS-PDT. Compared with baseline imaging, increased volume and percentage of tumor necrosis were observed in 6 of 12 patients (50%) after EUS-PDT. The mean overall increases in volume and percentage necrosis were 10 ± 26 cm3 (P = .20) and 18% ± 22% (P = .016), respectively. After a median follow-up of 10.5 months (range, 1.0-37.4 months), median progression-free (PFS) and overall survival (OS) were 2.6 months (95% confidence interval, 0.7, not estimable) and 11.5 months (95% confidence interval, 1.1, 16.9), respectively. Surgical resection was attempted in 2 patients, and pathology showed a complete response (n = 1) and residual 2-mm tumor (n = 1). There were 8 serious adverse events and none related to EUS or EUS-PDT. CONCLUSION: EUS-PDT for LAPC appears to be safe and produces measurable imaged-defined tumor necrosis. Phase 2 studies are warranted. (Clinical trial registration number: NCT01770132.).

Germline and Somatic DNA Damage Repair Gene Mutations and Overall Survival in Metastatic Pancreatic Adenocarcinoma Patients Treated with FOLFIRINOX.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with lack of predictive biomarkers. We conducted a study to assess DNA damage repair (DDR) gene mutations as a predictive biomarker in PDAC patients treated with FOLFIRINOX. EXPERIMENTAL DESIGN: Indiana University Simon Cancer Center pancreatic cancer database was used to identify patients with metastatic PDAC, treated with FOLFIRINOX and had tissue available for DNA sequencing. Baseline demographic, clinical, and pathologic information was gathered. DNA isolation and targeted sequencing was performed using the Ion AmpliSeq protocol. Overall survival (OS) analysis was conducted using Kaplan-Meier, logistic regression and Cox proportional hazard methods. Multivariate models were adjusted for age, gender, margin status, CA 19-9, adjuvant chemotherapy, tumor and nodal stage. RESULTS: Overall, 36 patients were sequenced. DDR gene mutations were found in 12 patients. Mutations were seen in BRCA1 (N = 7), BRCA2 (N = 5), PALB2 (N = 3), MSH2 (N = 1), and FANCF (N = 1) of all the DDR genes sequenced. Median age was 65.5 years, 58% were male, 97.2% were Caucasian and 51.4% had any family history of cancer. The median OS was near significantly superior in those with DDR gene mutations present vs. absent [14 vs. 5 months; HR, 0.58; 95% confidence interval (CI), 0.29-1.14; log-rank P = 0.08]. Multivariate logistic (OR, 1.47; 95% CI, 1.04-2.06; P = 0.04) and Cox regression (HR, 0.37; 95% CI, 0.15-0.94; P = 0.04) showed presence of DDR gene mutations was associated with improved OS. CONCLUSIONS: In a single institution, retrospective study, we found that the presence of DDR gene mutations are associated with improved OS in PDAC patients treated with FOLFIRINOX.

A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors.

BACKGROUND: Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis. METHODS: Patients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample t test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin). RESULTS: 24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (- 0.12 vs. - 0.16; P = 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities. CONCLUSIONS: Adding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers. IMPACT: Combining metformin with sirolimus did not improve mTOR inhibition.

Integrating therapies for surgical adult soft tissue sarcoma patients.

Sarcomas are an uncommon group of over 50 different individual histological malignancies arising from mesenchymal (non-epithelial or connective) tissues. Overall, they constitute 1% of human malignancies with an annual incidence rate of fewer than 5 patients per million. Sarcoma may arise from any mesenchymal cell lineages including fat, muscle, or other connective tissues. Due to the rarity of these groups of malignancies, many subtypes were, and still today, are managed as a single entity. This review focused on soft tissue sarcomas with an emphasis on how to integrate therapies for patients with this rare disorder. The role for surgical resection in cure and palliation as well as the relative benefits of adjuvant therapies such as chemotherapy and radiation therapy are discussed.

Impact of Nab-Paclitaxel-based Second-line Chemotherapy in Metastatic Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with median survival of 20% at 1 year. We conducted a retrospective study to assess the efficacy and tolerability of nab-paclitaxel (NP)-based second-line chemotherapy in metastatic PDAC. PATIENTS AND METHODS: The Indiana University Simon Cancer Center pancreatic cancer program was used to identify patients with metastatic PDAC who received any second-line chemotherapy. Demographic, clinical and outcomes data were collected by manual chart abstraction. Patients were divided into two groups: a NP-based treatment group and a non- NP-based treatment group. Overall (OS) and progression-free (PFS) survival were estimated using Kaplan-Meier method. Cox proportional hazards regression was used for multivariate analyses. RESULTS: A total of 120 patients received second-line chemotherapy. There were 47 (39%) patients in the NP group and 73 (61%) in the non-NP group. As compared to the non-NP group, the NP group showed improved median PFS [2.8 vs. 2.1 months; hazard ratio (HR)=0.62, 95% confidence interval (CI)=0.38-1.02; p=0.06] and median OS (7.5 vs. 4.7 months; HR=0.67, 95% CI=0.45-1.00; p=0.05). Multivariate analyses adjusted for age showed a significantly improved PFS (adjusted HR=0.60, 95% CI=0.36-0.98; p=0.04) and a suggestion of improved OS (adjusted HR=0.67, 95% CI=0.44-1.01, p=0.05) in the NP group as compared to non-NP group. Serious adverse events were seen in 13.3% of patients in the non-NP group and 17.1% patients in the NP group. CONCLUSION: In a single-institution retrospective cohort study, we report a significant improvement in the PFS and suggestion of improvement in the OS with NP-based second-line chemotherapy with an acceptable toxicity rate.

Excellent response to Anti-PD-1 therapy in a patient with hepatocellular carcinoma: case report and review of literature.

Hepatocellular carcinoma (HCC) is an aggressive cancer associated with high mortality worldwide. HCC develops in the setting of underlying cirrhosis due to chronic liver disease. Surgery is usually considered the treatment of choice for early disease; however, most patients have locally advanced or metastatic HCC at diagnosis in which case treatments are limited. Immune checkpoint blockade of programmed death receptor-1 (PD-1) pathway offers a potential treatment strategy based on the encouraging results of the phase I/II trial of nivolumab (Checkmate 040 trial). This has led to the off-label use of nivolumab after failure of treatment with sorafenib either due to intolerance or progression of disease. Although rare (<5%), clinical response to anti-PD-1 antibody may be preceded by "pseudoprogression" -- increase in the size and number of tumor lesions before actual tumor shrinkage. We report a case of pseudoprogression followed by an excellent response in an HCC patient treated with nivolumab and review the literature for ongoing trials of immune checkpoint blockade in HCC. The pseudoprogression in our case is supported by increase in both tumor size and alpha-fetoprotein after four treatments with nivolumab; however, regression of tumor size and normalization of alpha-fetoprotein occurred after subsequent treatments. To our knowledge, there are no reports of pseudoprogression in HCC although pseudoprogression has been well described in melanoma.

Patterns of computed tomography surveillance in survivors of colorectal cancer at Veterans Health Administration facilities.

BACKGROUND: Annual computed tomography (CT) scans are a component of the current standard of care for the posttreatment surveillance of survivors of colorectal cancer (CRC) after curative-intent resection. The authors conducted a retrospective study with the primary aim of assessing patient, physician, and organizational characteristics associated with the receipt of CT surveillance among veterans. METHODS: The Department of Veterans Affairs Central Cancer Registry was used to identify patients diagnosed with AJCC collaborative stage I to III CRC between 2001 and 2009. Patient sociodemographic and clinical (ie, CRC stage and comorbidity) characteristics, provider specialty, and organizational characteristics were measured. Hierarchical multivariable logistic regression models were used to assess the association between patient, provider, and organizational characteristics on receipt of 1) consistently guideline-concordant care (at least 1 CT every 12 months for both of the first 2 years of CRC surveillance) versus no CT receipt and 2) potential overuse (>1 CT every 12 months during the first 2 years of CRC surveillance) of CRC surveillance using CT. The authors also analyzed the impact of the 2005 American Society of Clinical Oncology update in CRC surveillance guidelines on care received over time. RESULTS: For 2263 survivors of stage II/III CRC who were diagnosed after 2005, 19.4% of patients received no surveillance CT, whereas potential overuse occurred in both surveillance years for 14.9% of patients. Guideline-concordant care was associated with younger age, higher stage of disease (stage III vs stage II), and geographic region. In adjusted analyses, younger age and higher stage of disease (stage III vs stage II) were found to be associated with overuse. There was no significant difference in the annual rate of CT scanning noted across time periods (year ≤ 2005 vs year > 2005). CONCLUSIONS: Among a minority of veteran survivors of CRC, both underuse and potential overuse of CT surveillance were present. Patient factors, but no provider or organizational characteristics, were found to be significantly associated with patterns of care. The 2005 change in American Society of Clinical Oncology guidelines did not appear to have an impact on rates of surveillance CT. Cancer 2017;123:2338-2351. © 2017 American Cancer Society.

Pathological complete response with anti-PD-1 therapy in a patient with microsatellite instable high, BRAF mutant metastatic colon cancer: a case report and review of literature.

IMPORTANCE: Mismatch repair (MMR) and BRAF mutation status are established independent prognostic factors for colorectal cancer (CRC). MMR deficient tumors are considered to have better prognosis whereas BRAF mutation is associated with poor prognosis. Studies evaluating the combined effect of BRAF and MMR status suggest MSI-high and BRAF mutant patients have a poorer prognosis as compared to MSI-high and BRAF wild type patients. Emerging evidence suggests MMR status predicts the immune response to anti-PD-1 therapy in CRC patients; however little is known about combined MMR and BRAF mutation status in this context. Therefore, it is important to identify whether there is a differential response to anti-PD-1 therapy based on BRAF status in the subset of MSI-high CRC patients. OBSERVATIONS: We report the first case of MSI-high, BRAF mutant metastatic CRC that had an excellent response (pathologic complete response) to anti-PD-1 therapy. We take this opportunity to review the similar cases in literature and discuss combined MMR and BRAF status as a potential biomarker for anti-PD-1 therapy. CONCLUSION AND RELEVANCE: The case presented illustrates that anti-PD-1 therapy can be effectively used to treat CRC patients with MSI-high and BRAF mutant status which is usually considered a poor prognostic category as opposed to MSI-high and BRAF wild type tumors. Future studies with anti-PD-1 therapy distinguishing these molecular subgroups will improve our knowledge of whether BRAF status can add to MMR status as a predictive biomarker for anti-PD-1 therapy in patients with metastatic CRC.

Current management of gastrointestinal stromal tumors: Surgery, current biomarkers, mutations, and therapy.

In the past decade, the addition of molecular diagnosis of mutations and use of tyrosine kinase inhibitors (TKIs), either as neoadjuvant/adjuvant therapy with surgery or as primary therapy in nonresectable gastrointestinal stromal tumors (GIST), has improved patient outcomes markedly. Additional therapeutics also are on the horizon. The goal of this review is to identify the current incidence, diagnostic modalities, and trends in personalizing the medical and operative management for patients with GIST. Medline, PubMed, and Google scholar were queried for recently published literature regarding new molecular mechanisms, targeted therapies, and clinical trials investigating the treatment of GIST. The objective of this review is to highlight the biomarkers under development, newly discovered mutations, and newer therapies targeting specific mutational phenotypes which are continually improving the outlook for patients with this disease.

The Role of Aspirin, Vitamin D, Exercise, Diet, Statins, and Metformin in the Prevention and Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is a worldwide health problem leading to significant morbidity and mortality. Several strategies based on either lifestyle modifications or pharmacological interventions have been developed in an attempt to reduce the risk of CRC. In this review article, we discuss these interventions including aspirin (and other non-steroidal anti-inflammatory drugs), vitamin D, exercise, diet, statins, and metformin. Depending upon the risk of developing CRC, the current evidence supports the beneficial role of aspirin, vitamin D, diet, and exercise especially in high-risk individuals (advanced adenoma or CRC). However, even with these established interventions, there are significant knowledge gaps such as doses of aspirin and 25-hydroxy vitamin D are not well established. Similarly, there is no convincing data from randomized controlled trials that a high fiber diet or a low animal fat diet reduces the risk of CRC. Some potential interventions, such as statins and metformin, do not have convincing data for clinical use even in high-risk individuals. However, these may have emerging roles in the prevention and treatment of CRC. Greater understanding of molecular mechanisms and the application of genomic tools to risk stratify an individual and tailor the interventions based on that individual's risk will help further advance the field. Some of this work is already underway and is a focus of this article.

Metformin for primary colorectal cancer prevention in patients with diabetes: a case-control study in a US population.

BACKGROUND: Emerging evidence from observational studies has suggested that metformin may be beneficial in the primary prevention of colorectal cancer (CRC). However, to the authors' knowledge, none of these studies was conducted in a US population. Because environmental factors such as Western diet and obesity are implicated in the causation of CRC, a large case-control study was performed to assess the effects of metformin on the incidence of CRC in a US population. METHODS: MarketScan databases were used to identify diabetic patients with CRC. A case was defined as having an incident diagnosis of CRC. Up to 2 controls matched for age, sex, and geographical region were selected for each case. Metformin exposure was assessed by prescription tracking within the 12-month period before the index date. Conditional logistic regression was used to adjust for multiple potential confounders and to calculate adjusted odds ratios (AORs). RESULTS: The mean age of the study participants was 55 years and 57 years, respectively, in the control and case groups (P = 1.0). Approximately 60% of the study participants were male and 40% were female in each group. In the multivariable model, any metformin use was associated with a 15% reduction in the odds of CRC (AOR, 0.85; 95% confidence interval, 0.76-0.95 [P = .007]). After adjusting for health care use, the beneficial effect of metformin was reduced to 12% (AOR, 0.88; 95% confidence interval, 0.77-1.00 [P = .05]). The dose-response analyses demonstrated no significant association with metformin dose, duration, or total exposure. CONCLUSIONS: Metformin use appears to be associated with a reduced risk of developing CRC among diabetic patients in the United States.