Circumferential Resection Margin as Predictor of Nonclinical Complete Response in Nonoperative Management of Rectal Cancer.

BACKGROUND: Short-course radiation therapy and consolidation chemotherapy with nonoperative intent has emerged as a novel treatment paradigm for patients with rectal cancer, but there are no data on the predictors of clinical complete response. OBJECTIVE: Evaluate the predictors of clinical complete response and survival. DESIGN: Retrospective cohort. SETTINGS: National Cancer Institute-designated cancer center. PATIENTS: Patients with stage I to III rectal adenocarcinoma treated between January 2018 and May 2019 (n = 86). INTERVENTIONS: Short-course radiation therapy followed by consolidation chemotherapy. MAIN OUTCOME MEASURES: Logistic regression was performed to assess for predictors of clinical complete response. The end points included local regrowth-free survival, regional control, distant metastasis-free survival, and overall survival. RESULTS: A positive (+) circumferential resection margin by MRI at diagnosis was a significant predictor of nonclinical complete response (OR: 4.1, p = 0.009) when adjusting for CEA level and primary tumor size. Compared to patients with a negative (-) pathologic circumferential resection margin, patients with a positive (+) pathologic circumferential resection margin had inferior local regrowth-free survival (29% vs 87%, p < 0.001), regional control (57% vs 94%, p < 0.001), distant metastasis-free survival (43% vs 95%, p < 0.001), and overall survival (86% vs 95%, p < 0.001) at 2 years. However, the (+) and (-) circumferential resection margin by MRI subgroups in patients who had a clinical complete response both had similar regional control, distant metastasis-free survival, and overall survival of more than 90% at 2 years. LIMITATIONS: Retrospective design, modest sample size, short follow-up, and the heterogeneity of treatments. CONCLUSIONS: Circumferential resection margin involvement by MRI at diagnosis is a strong predictor of nonclinical complete response. However, patients who achieve a clinical complete response after short-course radiation therapy and consolidation chemotherapy with nonoperative intent have excellent clinical outcomes regardless of the initial circumferential resection margin status. See Video Abstract at http://links.lww.com/DCR/C190 . EL MARGEN DE RESECCIN CIRCUNFERENCIAL COMO PREDICTOR NO CLNICO DE RESPUESTA COMPLETA EN EL MANEJO CONSERVADOR DEL CNCER DE RECTO: ANTECEDENTES:La radioterapia de corta duración y la quimioterapia de consolidación en el manejo conservador, han surgido como un nuevo paradigma de tratamiento, para los pacientes con cáncer de recto, lastimosamente no hay datos definitivos sobre los predictores de una respuesta clínica completa.OBJETIVO:Evaluar los predictores de respuesta clínica completa y de la sobrevida.DISEÑO:Estudio retrospectivo de cohortes.AJUSTES:Centro oncológico designado por el NCI.PACIENTES:Adenocarcinomas de recto estadio I-III tratados entre 01/2018 y 05/2019 (n = 86).INTERVENCIONES:Radioterapia de corta duración seguida de quimioterapia de consolidación.PRINCIPALES MEDIDAS DE RESULTADO:Se realizó una regresión logística para evaluar los predictores de respuesta clínica completa. Los criterios de valoración incluyeron la sobrevida libre de recidiva local, el control regional, la sobrevida libre de metástasis a distancia y la sobrevida general.RESULTADOS:Un margen de resección circunferencial positivo (+) evaluado por imagenes de resonancia magnética nuclear en el momento del diagnóstico fue un predictor no clínico muy significativo de respuesta completa (razón de probabilidades/ OR: 4,1, p = 0,009) al ajustar el nivel de antígeno carcinoembrionario y el tamaño del tumor primario. Comparando con los pacientes que presetaban un margen de resección circunferencial patológico negativo (-), los pacientes con un margen de resección circunferencial patológico positivo (+) tuvieron una sobrevida libre de recidiva local (29% frente a 87%, p < 0,001), un control regional (57% frente a 94%, p < 0,001), una sobrevida libre de metástasis a distancia (43% frente a 95%, p < 0,001) y una sobrevida global (86% frente a 95%, p < 0,001) inferior en 2 años de seguimiento. Sin embargo, los subgrupos de margen de resección circunferencial (+) y (-) evaluados por imágenes de resonancia magnética nuclear en pacientes que tuvieron una respuesta clínica completa tuvieron un control regional similar, una sobrevida libre de metástasis a distancia y una sobrevida general >90% en 2 años de seguimiento.LIMITACIONES:Diseño retrospectivo, tamaño modesto de la muestra, seguimiento corto y heterogeneidad de tratamientos.CONCLUSIONES:La afectación del margen de resección circunferencial evaluado por resonancia magnética nuclear al momento del diagnóstico es un fuerte factor predictivo no clínico de respuesta completa. Sin embargo, los pacientes que logran una respuesta clínica completa después de un curso corto de radioterapia y quimioterapia de consolidación como manejo conservador tienen excelentes resultados clínicos independientemente del estado del margen de resección circunferencial inicial. Consulte Video Resumen en http://links.lww.com/DCR/C190 . (Traducción-Dr. Xavier Delgadillo ).

Trajectories of participation in daily life among individuals newly diagnosed with cancer: A 5-month longitudinal study.

PURPOSE: To determine how participation in daily life is impacted during the first six months following a new cancer diagnosis and to identify risk factors for participation restrictions. Patient-reported outcomes (PROs) were used to suggest referrals to rehabilitation services. METHODS: Participants (n = 123) were adults (> 18 years) with the newly diagnosed primary brain, breast, colorectal, or lung cancer. PROs were collected at baseline (within 30 days of diagnosis/treatment initiation), two and five months post baseline. Daily life participation was assessed through the community participation indicators (CPI) (score range: 0-1) and patient-reported outcome measurement information system (PROMIS) ability to participate, (score range: 20-80; mean: 50, SD: 10). PROMIS-43 profile was also completed. Linear mixed-effect models with random intercept evaluated change in participation over time. RESULTS: The baseline total sample mean CPI score was 0.56; patients reported mildly impaired participation based on PROMIS scores (baseline: 46.19, 2-month follow-up: 44.81, 5 months: 44.84). However, no statistically significant changes in participation were observed over the study period. Risk factors for lower participation included receiving chemotherapy, lower physical function, higher anxiety and fatigue, and reduction in employment, p < 0.05. PROs indicated that roughly half of the participants may benefit from physical or occupational therapy or mental health support, but only 20-36% were referred by their medical team. CONCLUSION: People newly diagnosed with cancer experience impaired participation, but they are infrequently referred to supportive services such as rehabilitation. The use of PROs to assess participation, physical function, and mental health can promote access to supportive care services by identifying patients who may benefit from rehabilitation beyond those identified through routine clinical care.

Effect of metastatic site on survival in patients with neuroendocrine neoplasms (NENs). An analysis of SEER data from 2010 to 2014.

BACKGROUND: Neuroendocrine neoplasms (NENs) display variable behaviors based on origin and grade. We assumed that both tumor origin and the location of metastasis may play a role in survival. METHODS: We queried the SEER database (2010-2014) for patients with an established diagnosis of NENs and documented site of metastasis and identified 2005 patients. Overall survival (OS) at the time points were estimated by the Kaplan-Meier method Cox proportional-hazards models were used to evaluate the relationship of the interested variables and OS. RESULTS: Lung, liver, bone and brain metastases were observed in 9, 77, 7 and 6% of metastatic patients respectively. In the multivariate model, metastasis locations were significantly associated with worse survival (liver HR: 1.677 (1.226-2.294); (bone metastasis HR: 1.412 (0.965-2.065); brain HR: 1.666 (1.177-2.357)). We produced a scoring system based on site of origin, metastasis location, age, gender, histology and tumor size that can stratify metastatic NEN patients in low, intermediate and high-risk categories to help physicians with decision making. CONCLUSION: Site of metastasis plays an important role in survival of metastatic NEN patients independent of commonly described prognostic factors and should be considered in survival estimates.

Phase II Randomized Trial of Sequential or Concurrent FOLFOXIRI-Bevacizumab Versus FOLFOX-Bevacizumab for Metastatic Colorectal Cancer (STEAM).

BACKGROUND: First-line treatment for metastatic colorectal cancer (mCRC) typically entails a biologic such as bevacizumab (BEV) with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) or 5-fluorouracil/leucovorin/irinotecan (FOLFIRI). STEAM (NCT01765582) assessed the efficacy of BEV plus FOLFOX/FOLFIRI (FOLFOXIRI), administered concurrently (cFOLFOXIRI-BEV) or sequentially (sFOLFOXIRI-BEV, FOLFOX-BEV alternating with FOLFIRI-BEV), versus FOLFOX-BEV for mCRC. PATIENTS AND METHODS: Patients with previously untreated mCRC (n = 280) were randomized 1:1:1 to cFOLFOXIRI-BEV, sFOLFOXIRI-BEV, or FOLFOX-BEV and treated with 4-6-month induction followed by maintenance. Coprimary objectives were overall response rate (ORR; first-line cFOLFOXIRI-BEV vs. FOLFOX-BEV) and progression-free survival (PFS; pooled first-line cFOLFOXIRI-BEV and sFOLFOXIRI-BEV vs. FOLFOX-BEV). Secondary/exploratory objectives included overall survival (OS), liver resection rates, biomarker analyses, and safety. RESULTS: ORR was 72.0%, 72.8%, and 62.1% and median PFS was 11.9, 11.4, and 9.5 months with cFOLFOXIRI-BEV, sFOLFOXIRI-BEV, and FOLFOX-BEV, respectively. OS was similar between arms. ORR between cFOLFOXIRI-BEV and FOLFOX-BEV did not significantly differ (p = .132); thus, the primary ORR endpoint was not met. cFOLFOXIRI-BEV and sFOLFOXIRI-BEV numerically improved ORR and PFS, regardless of RAS status. Median PFS was higher with pooled concurrent and sequential FOLFOXIRI-BEV versus FOLFOX-BEV (11.7 vs. 9.5 months; hazard ratio, 0.7; 90% confidence interval, 0.5-0.9; p < .01). Liver resection rates were 17.2% (cFOLFOXIRI-BEV), 9.8% (sFOLFOXIRI-BEV), and 8.4% (FOLFOX-BEV). Grade ≥ 3 treatment-emergent adverse events (TEAEs) were observed in 91.2% (cFOLFOXIRI-BEV), 86.7% (sFOLFOXIRI-BEV), and 85.6% (FOLFOX-BEV) of patients, with no increase in serious chemotherapy-associated TEAEs. CONCLUSION: cFOLFOXIRI-BEV and sFOLFOXIRI-BEV were well tolerated with numerically improved ORR, PFS, and liver resection rates versus FOLFOX-BEV, supporting triplet chemotherapy plus BEV as a first-line treatment option for mCRC. IMPLICATIONS FOR PRACTICE: The combination of first-line FOLFIRI with FOLFOX and bevacizumab (concurrent FOLFOXIRI-BEV) improves clinical outcomes in patients with metastatic colorectal cancer (mCRC) relative to FOLFIRI-BEV or FOLFOX-BEV, but it is thought to be associated with increased toxicity. Alternating treatment of FOLFOX and FOLFIRI (sequential FOLFOXIRI-BEV) could improve tolerability. In the phase II STEAM trial, which is the largest study of FOLFOXIRI-BEV in patients in the U.S., it was found that both concurrent and sequential FOLFOXIRI-BEV are active and well tolerated in patients with previously untreated mCRC, supporting the use of these regimens as potential first-line treatment options for this population.

Systemic Therapy for Combined Hepatocellular-Cholangiocarcinoma: A Single-Institution Experience.

Background: Combined hepatocellular-cholangiocarcinoma tumors (cHCC-CCA) are a heterogeneous group of rare malignancies that have no established optimal treatment. Patients and Methods: We identified patients with cHCC-CCA treated at a tertiary center and retrospectively examined their histology, interventions, and outcomes. We calculated disease control rate (DCR), disease progression, overall survival, and progression-free survival (PFS) between treatment subgroups. Results: A total of 123 patients were evaluable. Interventions included resection, locoregional therapy, transplant, chemotherapy, and targeted agents. Ultimately, 68 patients received systemic treatment-57 with gemcitabine plus either 5-fluoropyrimidine (5-FU) or a platinum combination. Disease progression was more common in the gemcitabine/5-FU group versus gemcitabine/platinum (P=.028), whereas DCR favored gemcitabine/platinum (78.4% vs 38.5%; P=.0143). Median PFS from time of initial diagnosis favored the gemcitabine/platinum group, but the difference did not reach statistical significance. Targeted agents had minimal to no effect on survival metrics. Conclusions: Gemcitabine/platinum seems to be a superior regimen for patients with cHCC-CCA who require systemic treatment. Further studies are needed to clarify the regimen's efficacy and applicability in patient subgroups.

Optimal extent of surgical and pathologic lymph node evaluation for resected intrahepatic cholangiocarcinoma.

BACKGROUND: Lymph node (LN) status is an important predictor of overall survival for resected IHCC, yet guidelines for the extent of LN dissection are not evidence-based. We evaluated whether the number of LNs resected at the time of surgery is associated with overall survival for IHCC. METHODS: Patients undergoing curative-intent (R0 or R1) resection for IHCC between 2004 and 2012 were identified within the US National Cancer Database. LN thresholds were evaluated using maximal chi-square testing and five-year overall survival was modeled using Kaplan-Meier and Cox regressions. RESULTS: 57% (n = 1,132) of 2,000 patients had one or more LNs resected and pathologically examined. In the 631 patients undergoing R0 resection with pN0 disease, maximal chi-square testing identified ≥3 LNs as the threshold most closely associated with overall survival. Only 39% of resections reached this threshold. On multivariable survival analysis, no threshold of LNs was associated with overall survival, including ≥3 LNs (p = 0.186) and the current American Joint Committee on Cancer recommendation of ≥6 LNs (p = 0.318). CONCLUSION: In determining the extent of lymphadenectomy at the time of curative-intent resection for IHCC, surgeons should carefully consider the prognostic yield in the absence of overall survival benefit.

A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor.

BACKGROUND: Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS- or BRAF-mutant colorectal cancer. METHODS: Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS, RAF, and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples. RESULTS: Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial). CONCLUSIONS: Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population.

Interferon-based chemoradiation followed by gemcitabine for resected pancreatic adenocarcinoma: long-term follow-up.

To report long-term follow up of a phase II, single-arm trial of resectable pancreatic ductal adenocarcinoma (PDAC) treated with adjuvant interferon-based chemoradiation followed by gemcitabine to determine survival, recurrence, and complications. METHODS: From 2002 to 2005, 53 patients with PDAC underwent pancreaticoduodenectomy and received adjuvant interferon-based chemoradiation consisting of external-beam irradiation and simultaneous 3-drug chemotherapy of continuous daily 5-fluorouracil infusion, weekly intravenous bolus cisplatin, and subcutaneous interferon-α, followed by two months of weekly intravenous gemcitabine. RESULTS: Actual overall survival for the 5- and 10-year periods were 26% and 10%, respectively, with a median overall survival of 25 months (95% CI: 16.4-38.5). Adverse prognostic factors on multivariate analysis were positive tumor margin (p < 0.035), lymphovascular invasion (p < 0.015), and perineural invasion (p < 0.026). Median time to recurrence was 11 months. Positive tumor margin was associated with lymph node involvement (p < 0.005), portal vein resection (p < 0.038), and metastases (p < 0.018). Late complications were frequent and predominated by gastrointestinal and infectious complications. CONCLUSIONS: Adjuvant interferon-based chemoradiation for PDAC improves long-term survival compared to standard therapy. However, recurrence rates and long-term complications remain high, thus further studies are indicated to assess patient characteristics that indicate a favorable treatment profile.

Utility of a multidisciplinary tumor board in the management of pancreatic and upper gastrointestinal diseases: an observational study.

BACKGROUND & OBJECTIVES: Multidisciplinary tumor boards (MDTBs) are frequently employed in cancer centers but their value has been debated. We reviewed the decision-making process and resource utilization of our MDTB to assess its utility in the management of pancreatic and upper gastrointestinal tract conditions. METHODS: A prospectively-collected database was reviewed over a 12-month period. The primary outcome was change in management plan as a result of case discussion. Secondary outcomes included resources required to hold MDTB, survival, and adherence to treatment guidelines. RESULTS: Four hundred seventy cases were reviewed. MDTB resulted in a change in the proposed plan of management in 101 of 402 evaluable cases (25.1%). New plans favored obtaining additional diagnostic workup. No recorded variables were associated with a change in plan. For newly-diagnosed cases of pancreatic ductal adenocarcinoma (n = 33), survival time was not impacted by MDTB (p = .154) and adherence to National Comprehensive Cancer Network guidelines was 100%. The estimated cost of physician time per case reviewed was $190. CONCLUSIONS: Our MDTB influences treatment decisions in a sizeable number of cases with excellent adherence to national guidelines. However, this requires significant time expenditure and may not impact outcomes. Regular assessments of the effectiveness of MDTBs should be undertaken.

Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial.

BACKGROUND: In pancreatic ductal adenocarcinoma, the CCL2-CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. This pathway has prognostic implications in pancreatic cancer, and blockade of CCR2 restores anti-tumour immunity in preclinical models. We aimed to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil). METHODS: We did this open-label, dose-finding, non-randomised, phase 1b study at one centre in the USA. We enrolled treatment-naive patients aged 18 years or older with borderline resectable or locally advanced biopsy-proven pancreatic ductal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1, and normal end-organ function. Patients were allocated to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), and bolus fluorouracil 400 mg/m(2), followed by 2400 mg/m(2) 46-h continuous infusion), administered every 2 weeks for a total of six treatment cycles, or in combination with oral PF-04136309, administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 12 weeks. The primary endpoints were the safety, tolerability, and recommended phase 2 dose of PF-04136309 plus FOLFIRINOX, with an expansion phase planned at the recommended dose. We analysed the primary outcome by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01413022. RESULTS: Between April 19, 2012, and Nov 12, 2014, we treated 47 patients with FOLFIRINOX alone (n=8) or with FOLFIRINOX plus PF-04136309 (n=39). One patient had a dose-limiting toxic effect in the dose de-escalation group receiving FOLFIRINOX plus PF-04136309 at 500 mg twice daily (n=6); this dose was established as the recommended phase 2 dose. We pooled patients in the expansion-phase group (n=33) with those in the dose de-escalation group that received PF-04136309 at the recommended phase 2 dose for assessment of treatment-related toxicity. Six (75%) of the eight patients receiving FOLFIRINOX alone were assessed for treatment toxicity, after exclusion of two (25%) patients due to insurance coverage issues. The median duration of follow-up for treatment toxicity was 72·0 days (IQR 49·5-89·0) in the FOLFIRINOX alone group and 77·0 days (70·0-90·5) in the FOLFIRINOX plus PF-04136309 group. No treatment-related deaths occurred. Two (5%) patients in the FOLFIRINOX plus PF-04136309 group stopped treatment earlier than planned due to treatment-related toxic effects. Grade 3 or higher adverse events reported in at least 10% of the patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Grade 3 or higher adverse events reported in at least 10% of patients receiving FOLFIRINOX alone were neutropenia (n=6), febrile neutropenia (n=1), anaemia (n=2), lymphopenia (n=1), diarrhoea (n=2), hypoalbuminaemia (n=1), and hypokalaemia (n=3). Therapy was terminated because of treatment-related toxicity in one (17%) of the six patients receiving FOLFIRINOX alone. 16 (49%) of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients. In the FOLFIRINOX alone group, none of the five patients with repeat imaging achieved an objective response, although four (80%) of those patients achieved stable disease. INTERPRETATION: CCR2-targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable. FUNDING: Washington University-Pfizer Biomedical Collaborative.

Imaging Features of Biphenotypic Primary Liver Carcinoma (Hepatocholangiocarcinoma) and the Potential to Mimic Hepatocellular Carcinoma: LI-RADS Analysis of CT and MRI Features in 61 Cases.

OBJECTIVE: The purpose of this study was to determine the frequency with which biphenotypic primary liver carcinoma (also called hepatocholangiocarcinoma) may be misclassified as hepatocellular carcinoma (HCC) when only Liver Imaging Reporting and Data System (LI-RADS) major features are used and after consideration of ancillary features. MATERIALS AND METHODS: A review of all pathologically proven biphenotypic primary liver carcinomas diagnosed at one institution from 2006 to 2014 was performed. Two subspecialized abdominal imagers independently reviewed cases using LI-RADS version 2014 and assigned major features, ancillary features, and additional findings. The number of lesions meeting imaging criteria for HCC was determined after assessment of major features alone and after the addition of ancillary features. RESULTS: Sixty-one patients (30 men, 31 women; mean age, 62 years; range, 22-89 years) with biphenotypic primary liver carcinomas who underwent pretreatment multiphasic contrast-enhanced MRI (48 patients) or CT (13 patients) were included. According to LI-RADS major features alone, 33 (54.1%) lesions met criteria for HCC and therefore might have been misclassified. Thirteen had arterial phase hyperenhancement, washout, and a capsule. Twenty had arterial phase hyperenhancement with either washout (15 lesions) or a capsule (five lesions). After evaluation of ancillary features, 29 of these potential mimics exhibited at least one ancillary feature favoring non-HCC malignancy, possibly leading to appropriate reclassification. Of the four carcinomas that met criteria for HCC by major features and did not have ancillary features favoring non-HCC malignancy, two (3.3% of all tumors) fell within the Milan criteria. CONCLUSION: Most biphenotypic primary liver carcinomas have features of non-HCC malignancy and can be correctly categorized as such. Addition of ancillary features to major features may improve diagnostic accuracy over systems in which only major features are used.

A phase II study of adjuvant gemcitabine plus docetaxel followed by concurrent chemoradation in resected pancreaticobiliary carcinoma.

OBJECTIVES: Adjuvant gemcitabine with or without chemoradiation is a standard therapeutic option for patients with resected pancreatic cancer. The feasibility and toxicity of gemcitabine with docetaxel before and after 5-fluorouracil (5FU)-based chemoradiation in the adjuvant pancreatic and biliary cancer setting were investigated. METHODS: After a curative-intent resection, eligible patients with pancreaticobiliary cancers were treated with two cycles of gemcitabine and docetaxel followed by 5FU-based chemoradiation. Four weeks after completing chemoradiation, two cycles of gemcitabine and docetaxel were administered. The primary endpoint was the incidence of severe toxicities. Secondary endpoints included disease-free survival (DFS) and overall survival (OS). RESULTS: Fifty patients with pancreaticobiliary cancers were enrolled. Twenty-nine patients had pancreatic cancer whereas 21 patients had biliary tract or ampullary cancers. There was one death as a result of pneumonia, and 15% of patients experienced grade 3 or greater non-haematological toxicities. The median DFS and OS for patients with pancreatic cancer were 9.6 and 17 months, respectively, and for those with resected biliary tract cancer were 12 and 23 months, respectively. CONCLUSIONS: This combination of gemcitabine and docetaxel with chemoradiation is feasible and tolerable in the adjuvant setting. Future studies utilizing a different gemcitabine/taxane combination and schedule may be appropriate in the adjuvant treatment of both pancreatic cancer and biliary tumours.

A multidisciplinary approach to the diagnosis and treatment of gastrointestinal stromal tumor.

Management of patients with gastrointestinal stromal tumor (GIST) typically involves a combination of surgical, pathologic, and pharmacologic interventions. Gastroenterologists are often the first specialists to encounter patients presenting with GIST and are therefore responsible for facilitating early intervention strategies. Although patients with gastric or small-bowel GISTs typically present with symptoms, a diagnosis of GIST should be considered whenever a submucosal lesion is seen endoscopically. Visualization by standard endoscopy often can determine tumor location and size, although endoscopic ultrasound (EUS) is the most accurate imaging technique for submucosal lesions. Biopsy techniques that yield sufficient tumor samples for diagnostic studies, such as EUS-guided fine needle aspiration, are essential, although other approaches such as EUS-guided core needle biopsy may increase diagnostic yield for subepithelial lesions. Pathology assessment should include immunohistochemical staining for KIT and possibly DOG1 expression, and mutational analysis can have prognostic and predictive value for certain patients. R0 resection is the goal for patients with localized or potentially resectable tumors, which often can be accomplished by laparoscopic resection, even for larger tumors. Medical oncologists play a key role in assessing risk of recurrence after resection and optimizing tyrosine kinase inhibitor therapy in the adjuvant or metastatic setting. Cytoreductive surgery may have value for patients with recurrent or metastatic GIST who exhibit stable disease or respond to tyrosine kinase inhibitor therapy. A coordinated multidisciplinary approach over the course of the disease will serve to enhance communication among GIST team members, reduce risk of progression, and optimize outcomes.

Multi-institutional experience with FOLFIRINOX in pancreatic adenocarcinoma.

CONTEXT: Combination chemotherapy with FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) was shown to be effective in a large phase III trial. OBJECTIVE: The purpose of this study was to examine the tolerance and effectiveness of FOLFIRINOX as practiced outside of the confines of a clinical trial and to document any dose modifications used by practicing oncologists. METHODS: Data on patients with all stages of pancreatic adenocarcinoma treated with FOLFIRINOX at three institutions was analyzed for efficacy, tolerance, and use of any dose modifications. RESULTS: Total of 61 patients was included in this review. Median age was 58 years (range: 37 to 72 years), 33 were male (54.1%) and majority had ECOG performance of 0 or 1 (86.9%, 53 patients). Thirty-eight (62.3%) had metastatic disease, while 23 (37.7%) were treated for locally advanced or borderline resectable disease. Patients were treated with a median number of four cycles of FOLFIRINOX, with dose modifications in 58.3% (176/302) of all cycles. Ten patients had stable disease (16.4%), four had a partial response (6.6%) while eight had progressive disease (13.1%) on best imaging following therapy. Median progression-free survival and overall survival were 7.5 months and 13.5 months, respectively. The most common grade 3-4 adverse event was neutropenia at 19.7% (12 cases), with 4.9% (3 cases) rate of febrile neutropenia. Twenty-one patients (34.4%) were hospitalized as a result of therapy but there were no therapy-related deaths. Twenty-three (37.7%) had therapy eventually discontinued as a result of adverse events. CONCLUSION: Despite substantial rates of adverse events and use of dose modifications, FOLFIRINOX was found to be clinically effective in both metastatic and non-metastatic patients. Regimen toxicity did not detract from overall response and survival.

A Phase I Study of Apolizumab, an Anti-HLA-DR ß-chain Monoclonal Antibody, in Patients With Solid Tumor Malignancies.

BACKGROUND: Human leukocyte antigen (HLA)-DR, a member of the major histocompatibility complex class II antigen family, is a target for antibody-based therapeutics. Apolizumab (Hu1D10, Remitogen), a humanized IgG1 monoclonal anti-HLA-DR ß-chain antibody targets the antigen, 1D10, expressed on a wide variety of hematologic and solid tumor malignancies. In this Phase 1 trial, the maximum tolerated dose and dose-limiting toxicity of weekly apolizumab in patients with advanced solid tumor malignancies were determined. PATIENTS AND METHODS: Eligible patients with refractory solid tumors were initially screened for ID10 Ag on their tumor. Patients whose tumors expressed 1D10 were administered apolizumab 0.5, 1.0, 1.5, or 3.0 mg/kg intravenously over 90 minutes weekly for 4 consecutive weeks, followed by a 4-week break, and assessment of response. Patients whose disease had not progressed were offered additional treatment. RESULTS: Tumors from 75 patients were screened for 1D10 Ag of which 17 patients were positive and underwent treatment. The first 3 dose levels were well-tolerated. Dose-limiting toxicities of grade 3 infusion-related hypersensitivity reactions and grade 3 headache and hypertension occurred in 2 patients, respectively, at apolizumab 3.0 mg/kg. Four patients, 1 each with breast carcinoma, melanoma, renal cell carcinoma, and sarcoma had stable disease for a median of 15 weeks (range: 12 to 19 wk). CONCLUSION: Apolizumab can be administered safely at a maximum tolerated dose of 1.5 mg/kg for 4 consecutive weeks. Adverse events and limited clinical data in both hematologic and solid tumor malignancies resulted in discontinuation of clinical development of apolizumab. HLA-DR remains an interesting immunotherapeutic target.

Cost-effectiveness of Total Neoadjuvant Therapy With Short-Course Radiotherapy for Resectable Locally Advanced Rectal Cancer.

Importance: Short-course radiotherapy and total neoadjuvant therapy (SCRT-TNT) followed by total mesorectal excision (TME) has emerged as a new treatment paradigm for patients with locally advanced rectal adenocarcinoma. However, the economic implication of this treatment strategy has not been compared with that of conventional long-course chemoradiotherapy (LCCRT) followed by TME with adjuvant chemotherapy. Objective: To perform a cost-effectiveness analysis of SCRT-TNT vs LCCRT in conjunction with TME for patients with locally advanced rectal cancer. Design, Setting, and Participants: A decision analytical model with a 5-year time horizon was constructed for patients with biopsy-proven, newly diagnosed, primary locally advanced rectal adenocarcinoma treated with SCRT-TNT or LCCRT. Markov modeling was used to model disease progression and patient survival after treatment in 3-month cycles. Data on probabilities and utilities were extracted from the literature. Costs were evaluated from the Medicare payer's perspective in 2020 US dollars. Sensitivity analyses were performed for key variables. Data were collected from October 3, 2020, to January 20, 2021, and analyzed from November 15, 2020, to April 25, 2021. Exposures: Two treatment strategies, SCRT-TNT vs LCCRT with adjuvant chemotherapy, were compared. Main Outcomes and Measures: Cost-effectiveness was evaluated using the incremental cost-effectiveness ratio and net monetary benefits. Effectiveness was defined as quality-adjusted life-years (QALYs). Both costs and QALYs were discounted at 3% annually. Willingness-to-pay threshold was set at $50 000/QALY. Results: During the 5-year horizon, the total cost was $41 355 and QALYs were 2.21 for SCRT-TNT; for LCCRT, the total cost was $54 827 and QALYs were 2.12, resulting in a negative incremental cost-effectiveness ratio (-$141 256.77). The net monetary benefit was $69 300 for SCRT-TNT and $51 060 for LCCRT. Sensitivity analyses using willingness to pay at $100 000/QALY and $150 000/QALY demonstrated the same conclusion. Conclusions and Relevance: These findings suggest that SCRT-TNT followed by TME incurs lower cost and improved QALYs compared with conventional LCCRT followed by TME and adjuvant chemotherapy. These data offer further rationale to support SCRT-TNT as a novel cost-saving treatment paradigm in the management of locally advanced rectal cancer.

Clinical Complete Response in Patients With Rectal Adenocarcinoma Treated With Short-Course Radiation Therapy and Nonoperative Management.

PURPOSE: This study aimed to determine the clinical efficacy and safety of nonoperative management (NOM) for patients with rectal cancer with a clinical complete response (cCR) after short-course radiation therapy and consolidation chemotherapy. METHODS AND MATERIALS: Patients with stage I-III rectal adenocarcinoma underwent short-course radiation therapy followed by consolidation chemotherapy between January 2018 and May 2019 (n = 90). Clinical response was assessed by digital rectal examination, pelvic magnetic resonance imaging, and endoscopy. Of the patients with an evaluable initial response, those with a cCR (n = 43) underwent NOM, and those with a non-cCR (n = 43) underwent surgery. The clinical endpoints included local regrowth-free survival, regional control, distant metastasis-free survival, disease-free survival, and overall survival. RESULTS: Compared with patients with an initial cCR, patients with initial non-cCR had more advanced T and N stage (P = .05), larger primary tumors (P = .002), and more circumferential resection margin involvement on diagnostic magnetic resonance imaging (P < .001). With a median follow-up of 30.1 months, the persistent cCR rate was 79% (30 of 38 patients) in the NOM cohort. The 2-year local regrowth-free survival was 81% (95% confidence interval [CI], 70%-94%) in the initial cCR group, and all patients with local regrowth were successfully salvaged. Compared with those with a non-cCR, patients with a cCR had improved 2-year regional control (98% [95% CI, 93%-100%] vs 85% [95% CI, 74%-97%], P = .02), distant metastasis-free survival (100% [95% CI, 100%-100%] vs 80% [95% CI, 69%-94%], P < .01), disease-free survival (98% [95% CI, 93%-100%] vs 71% [95% CI, 59%-87%], P < .01), and overall survival (100% [95% CI, 100%-100%] vs 88% [95% CI, 79%-98%], P = .02). No late grade 3+ gastrointestinal or genitourinary toxicities were observed in the patients who underwent continued NOM. CONCLUSIONS: Short-course radiation therapy followed by consolidation chemotherapy may be a feasible organ preservation strategy in rectal cancer. Additional prospective studies are necessary to evaluate the safety and efficacy of this approach.

A phase 2 trial of gemcitabine, 5-fluorouracil, and radiation therapy in locally advanced nonmetastatic pancreatic adenocarcinoma : cancer and Leukemia Group B (CALGB) 80003.

BACKGROUND: The purpose of this study was to assess the efficacy and safety of 5-fluorouracil (5FU) and gemcitabine administered concurrently with radiation in patients with locally advanced, nonmetastatic pancreatic cancer. METHODS: Eligible patients had histologically confirmed pancreatic adenocarcinoma deemed locally unresectable without evidence of metastatic disease. In addition, all patients underwent laparoscopy or laparotomy before study entry to rule out peritoneal carcinomatosis. Patients received radiation therapy (50.4 Gy) with concurrent infusional 5FU (200 mg/m(2) 5 days/week) and weekly gemcitabine (200 mg/m(2) ). After a 3-week break, patients received weekly gemcitabine at 1000 mg/m(2) for 3 of 4 weeks, for 4 cycles. The primary endpoint of the trial was the proportion of patients surviving 9 months from study entry. Secondary endpoints included objective tumor response, CA19-9 response, overall survival (OS) time to progression (TTP), and toxicity. RESULTS: Between November 2001 and October 2004, 81 patients were enrolled, 78 of whom were eligible for analysis. With a median follow-up of 55.2 months, the median OS was 12.2 months (95% confidence interval [CI], 10.9-14.9) and the median TTP was 10 months (95% CI, 6.4-12.0). An objective tumor response was seen in 19 patients (25%), and among 56 patients with an elevated CA19-9 at baseline, 29 (52%) had a sustained CA19-9 response. Overall, 41% of patients had grade 3 or greater treatment-related gastrointestinal adverse events. CONCLUSIONS: The combination of 5FU, gemcitabine, and radiation is well tolerated. Survival is comparable with the best results of other recent studies of 5FU and radiation or gemcitabine and radiation.

Phase 1 study combining alisertib with nab-paclitaxel in patients with advanced solid malignancies.

AIM: Aurora kinase A (AURKA) is a pleiotropic serine/threonine kinase that orchestrates mitotic progression. Paclitaxel stabilises microtubules and disrupts mitotic spindle assembly. The combination of AURKA inhibitor (alisertib) plus paclitaxel may be synergistic in rapidly proliferative cancers. We evaluated the safety and maximum tolerated dose (MTD) of alisertib in combination with nab-paclitaxel and its preliminary efficacy in patients with refractory high-grade neuroendocrine tumours (NETs). METHOD: This is a two-part, Phase 1 study. In Part A (dose escalation), a standard 3 + 3 design was used to determine MTD. In Part B (dose expansion), patients with predominantly refractory high-grade NETs were enrolled. RESULTS: In total, 31 patients were enrolled and treated (16 in Part A and 15 in Part B). The MTD of alisertib was 40 mg BID on D1-3 per week and nab-paclitaxel 100mg/m2 weekly: 3 weeks, 1 week off. Dose-limiting toxicity was neutropenia, and other common side-effects included fatigue, mucositis, and diarrhoea. In Part A, a patient with small-cell lung cancer with partial response (PR) was treated for more than 2 years, whereas four other patients with pancreatic ductal adenocarcinoma (one patient), small cell lung cancer (SCLC) (two patients), or high-grade NET (one patient) achieved stable disease (SD). In Part B, 13 of 15 enrolled patients had high-grade NETs. Of these, one had PR, and four had SD for more than 10 months. CONCLUSIONS: The combination of alisertib and nab-paclitaxel has manageable side-effect profile and showed promising preliminary efficacy in high-grade NETs, warranting further testing. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01677559.

ctDNA MRD Detection and Personalized Oncogenomic Analysis in Oligometastatic Colorectal Cancer From Plasma and Urine.

We hypothesized that circulating tumor DNA (ctDNA) molecular residual disease (MRD) analysis without prior mutational knowledge could be performed after neoadjuvant chemotherapy to assess oligometastatic colorectal cancer (CRC) treated surgically with curative intent. We also investigated urine as an alternative analyte for ctDNA MRD detection in this nongenitourinary setting. PATIENTS AND METHODS: We applied AVENIO targeted next-generation sequencing to plasma, tumor, and urine samples acquired on the day of curative-intent surgery from 24 prospectively enrolled patients with oligometastatic CRC. Age-related clonal hematopoiesis was accounted for by removing variants also present in white blood cells. Plasma and urine ctDNA MRD were correlated with tumor cells detected in the surgical specimen, and adjuvant treatment strategies were proposed based on ctDNA-inferred tumor mutational burden (iTMB) and targetable alterations. RESULTS: Seventy-one percent of patients were treated with neoadjuvant chemotherapy. Tumor-naive plasma ctDNA analysis detected MRD at a median level of 0.62% with 95% sensitivity and 100% specificity, and 94% and 77% sensitivity when only considering patients treated with neoadjuvant chemotherapy and putative driver mutations, respectively. In urine, ctDNA MRD detection specificity remained high at 100%, but sensitivity decreased to 64% with median levels being 11-fold lower than in plasma (P < .0001). Personalized ctDNA MRD oncogenomic analysis revealed 81% of patients might have been candidates for adjuvant immunotherapy based on high iTMB or targeted therapy based on actionable PIK3CA mutations. CONCLUSION: Tumor-naive plasma ctDNA analysis can sensitively and specifically detect MRD in patients with oligometastatic CRC after neoadjuvant chemotherapy. Urine-based ctDNA MRD detection is also feasible; however, it is less sensitive than plasma because of significantly lower levels. Oligometastatic patients with detectable MRD may benefit from additional personalized treatment based on ctDNA-derived oncogenomic profiling.