Preoperative Treatment of Locally Advanced Rectal Cancer.

BACKGROUND: Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain. METHODS: We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects. RESULTS: From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy. CONCLUSIONS: In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.).

Current Practices in Hepatic Artery Infusion (HAI) Chemotherapy: An International Survey of the HAI Consortium Research Network.

BACKGROUND: An increasing number of hepatic artery infusion (HAI) programs have been established worldwide. Practice patterns for this complex therapy across these programs have not been reported. This survey aimed to identify current practice patterns in HAI therapy with the long-term goal of defining best practices and performing prospective studies. METHODS: Using SurveyMonkeyTM, a 28-question survey assessing current practices in HAI was developed by 12 HAI Consortium Research Network (HCRN) surgical oncologists. Content analysis was used to code textual responses, and the frequency of categories was calculated. Scores for rank-order questions were generated by calculating average ranking for each answer choice. RESULTS: Thirty-six (72%) HCRN members responded to the survey. The most common intended initial indications for HAI at new programs were unresectable colorectal liver metastases (uCRLM; 100%) and unresectable intrahepatic cholangiocarcinoma (uIHC; 56%). Practice patterns evolved such that uCRLM (94%) and adjuvant therapy for CRLM (adjCRLM; 72%) have become the most common current indications for HAI at established centers. Referral patterns for pump placement differed between uCRLM and uIHC, with most patients referred while receiving second- and first-line therapy, respectively, with physicians preferring to evaluate patients for HAI while receiving first-line therapy for CRLM. Concern for extrahepatic disease was ranked as the most important factor when considering a patient for HAI. CONCLUSIONS: Indication and patient selection factors for HAI therapy are relatively uniform across most HCRN centers. The increasing use of adjuvant HAI therapy and overall consistency of practice patterns among HCRN centers provides a robust environment for prospective data collection and randomized clinical trials.

Impact of new cancer therapies on outpatient treatment delivery for colorectal cancer: A population-based study.

We investigated the impact of new systemic therapies approved in Canada for colorectal cancer on the frequency, intensity and duration of oncology clinic and infusion visits over five treatment phases from diagnosis (P1, P3) to treatment (P2, P4) of primary and metastatic disease, respectively, and during the last 6 months of life (P5). In total, 15,157 adult patients with newly diagnosed colorectal cancer and referred between 2000 and 2012 to any cancer clinic in British Columbia, Canada, were included. Frequency, intensity and duration of medical oncology clinic visits (CVs), oncology infusions (OIs) and oncology prescriptions (OPs) were measured by treatment phase. Mean, total and adjusted total duration for CVs increased for P1-5. CVs increased in P1-5, and in P1-4 when adjusted by treatment length. Adjusted and unadjusted OIs decreased in P1 coinciding with the introduction of an oral treatment option, but increased in P2-5. Mean OI duration increased in P1-5, while total and adjusted total decreased in P1 and increased in P2-5. OPs increased in P2-4, but were unchanged in P1 and P5. Multi-fold increases in resources and time required per patient were also observed, which have significant implications for demand projections in cancer care planning and delivery. In conclusion, patients required more visits in almost all treatment phases, visits on average took longer and patients were in treatment for longer periods of time.

The Impact of Chronic Kidney Disease in Patients With Locally Advanced Rectal Cancer Treated With Neoadjuvant Chemoradiation.

BACKGROUND: Patients with chronic kidney disease are commonly excluded from clinical trials. The impact of chronic kidney disease on outcomes in patients with locally advanced rectal cancer has not been previously studied. OBJECTIVE: This study aimed to investigate the impact of chronic kidney disease on outcomes in patients with locally advanced rectal cancer. DESIGN: This is a multi-institutional, retrospective cohort study. SETTINGS: This study was conducted at academic and community cancer centers participating in the Canadian Health Outcomes Research Database Consortium Rectal Cancer Database. PATIENTS: Consecutive patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation before curative-intent surgery from 2005 to 2013 were selected. MAIN OUTCOME MEASURES: Disease-free survival, overall survival, pathologic complete response, and neoadjuvant chemotherapy/radiotherapy completion rate were the primary outcomes measured. RESULTS: A total of 1254 patients were included. Median age was 62, and 29%/69% had clinical stage II and III disease. Median estimated creatinine clearance was 93 mL/min, with 11% <60 mL/min (n = 136). There was no significant difference in the completion rate of neoadjuvant chemotherapy (82% vs 85%, p = 0.36) or radiotherapy (93% vs 95%, p = 0.45) between patients with and without chronic kidney disease. Patients with chronic kidney disease were less likely to receive adjuvant chemotherapy (63% vs 77%, p < 0.01). On multivariate analysis, patients with chronic kidney disease had decreased disease-free survival (HR, 1.37; 95% CI, 1.03-1.82; p = 0.03) but not overall survival (HR, 1.23; 95% CI, 0.88-1.75; p = 0.23) or pathologic complete response (OR, 0.83; 95% CI, 0.50-1.39; p = 0.71). LIMITATIONS: This study was limited by its retrospective design and by limited events for overall survival analysis. CONCLUSIONS: In patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation, baseline chronic kidney disease was associated with less use of adjuvant chemotherapy and decreased disease-free survival. Chronic kidney disease was not independently associated with neoadjuvant chemotherapy/radiotherapy completion rate, pathologic complete response, or overall survival. These data suggest that patients with locally advanced rectal cancer with chronic kidney disease may have distinct outcomes and, accordingly, the results of landmark clinical trials may not be generalizable to this population. See Video Abstract at http://links.lww.com/DCR/B694. LA REPERCUSIN DE LA ENFERMEDAD RENAL CRNICA EN PACIENTES CON CNCER DE RECTO LOCALMENTE AVANZADO TRATADOS CON QUIMIORRADIOTERAPIA NEOADYUVANTE: ANTECEDENTES:Los pacientes con enfermedad renal crónica generalmente se excluyen de los ensayos clínicos. La repercusión de la enfermedad renal crónica en el desenlace en pacientes con cáncer de recto localmente avanzado no se ha estudiado previamente.OBJETIVO:Investigar la repercusión de la enfermedad renal crónica en los desenlaces en pacientes con cáncer de recto localmente avanzado.DISEÑO:Estudio de cohorte retrospectivo multiinstitucional.ESCENARIO:Centros oncológicos académicos y comunitarios que participan en la base de datos de cáncer rectal del consorcio CHORD.PACIENTES:Pacientes consecutivos con cáncer de recto localmente avanzado, tratados con quimiorradioterapia neoadyuvante, previa a la cirugía con intención curativa del 2005 al 2013.PRINCIPALES VARIABLES EVALUADAS:Sobrevida libre de enfermedad, sobrevida global, respuesta patológica completa, tasa de conclusión de quimioterapia / radioterapia neoadyuvante.RESULTADOS:Se incluyeron 1254 pacientes. El promedio de edad fue de 62, y el 29% / 69% tenían enfermedad en estadio clínico II y III, respectivamente. El promedio de la depuración de creatinina estimada fue de 93 mililitros / minuto, con un 11% <60 mililitros / minuto (n = 136). No hubo diferencias significativas en la tasa de conclusión de la quimioterapia neoadyuvante (82% vs 85%, p = 0,36) o radioterapia (93% vs 95%, p = 0,45) entre pacientes con y sin enfermedad renal crónica. Los pacientes con enfermedad renal crónica tenían menos probabilidades de recibir quimioterapia adyuvante (63% contra el 77%, p <0,01). En el análisis multivariado, los pacientes con enfermedad renal crónica tenían una sobrevida libre de enfermedad menor (HR 1,37, IC 95% 1,03-1,82, p = 0,03) pero no en la sobrevida global (HR 1,23, IC 95% 0,88-1,75, p = 0,23) o respuesta patológica completa (OR 0,83, IC 95% 0,50-1,39, p = 0,71).LIMITACIONES:Diseño retrospectivo y acontecimientos limitados para el análisis de sobrevida global.CONCLUSIONES:En pacientes con cáncer de recto localmente avanzado tratados con quimiorradioterapia neoadyuvante, la enfermedad renal crónica de base se asoció con un menor uso de quimioterapia adyuvante y una menor sobrevida libre de enfermedad. La enfermedad renal crónica no se asoció de forma independiente con la tasa de conclusión de la quimioterapia / radioterapia neoadyuvante, la respuesta patológica completa o la sobrevida global. Estos datos sugieren que los pacientes con cáncer de recto localmente avanzado con enfermedad renal crónica pueden tener resultados distintos y, en consecuencia, los resultados de los ensayos clínicos de referencia pueden no ser generalizables a esta población. Consulte Video Resumen en http://links.lww.com/DCR/B694.

A phase Ib study of a PI3Kinase inhibitor BKM120 in combination with panitumumab in patients with KRAS wild-type advanced colorectal cancer.

Background Resistance to Epidermal Growth Factor inhibition (EGFRi) in patients with KRAS wild-type (wt) Colorectal Cancer (CRC) may occur as a result of PI3K/AKT/mTOR signaling. We conducted a study to establish the recommended phase II dose (RP2D) and response rate of panitumumab, an EGFRi, plus BKM120, a PI3K inhibitor, in advanced CRC. Methods Patients with chemotherapy refractory KRAS wt CRC, who were EGFRi naive were enrolled. A 3 + 3 dose escalation design was utilized. The starting dose of panitumumab was 6 mg/kg iv every 2 weeks with BKM120 at 60 mg oral daily. Results Nineteen patients were treated and 17 were evaluable for response. The starting dose was not tolerable (mucositis, fatigue). At dose level (DL) 1, three of six patients discontinued treatment due to toxicity, DL - 1 had no significant toxicity. Panitumumab 6 mg/kg iv q 2 weeks with BKM120 60 mg given 5 out of 7 days per week was declared the RP2D. One patient (5.9%) who was PTEN and PIK3CA negative by IHC had a partial response, seven had stable disease, and nine had disease progression. Conclusion Panitumumab (6 mg/kg iv q 2 weeks) with BKM120 60 mg given 5 out of 7 days per week was declared the RP2D. Toxicities including fatigue, rash and mucositis. There was little evidence of activity in this biomarker unselected cohort.

Impact of initial imaging with gallium-68 dotatate PET/CT on diagnosis and management of patients with neuroendocrine tumors.

BACKGROUND: Somatostatin analog functional imaging with gallium-68 (Ga-68) dotatate positron emission tomography/computed tomography (PET/CT) has demonstrated superiority in lesion detection in patients with neuroendocrine tumors (NETs). The clinical impact of this imaging modality on US surgical and medical oncology practices has not been established. METHODS: Consecutive patients with NET at our institution who received an initial Ga-68 dotatate PET/CT between July 2017 and September 2018 were included. Ga-68 dotatate PET/CT was compared with prior imaging. RESULTS: Among 101 eligible patients, 51 of 50 were female/male, site of origin was gastroenteropancreatic (75%), unknown primary (13%), lung (8%), thymus (2%), and other (2%). All NETs were histologically well/moderately differentiated. Ga-68 dotatate imaging findings altered management in 36 (35.6%) patients: documentation of progression led to the initiation of systemic therapy in 14 patients, obviated the need for biopsy in four patients, and altered surgical plans in 7 of 14 (50%) patients referred for surgery. In 11 patients, decisions regarding peptide receptor radionucleotide therapy and somatostatin analogs were altered. CONCLUSIONS: In this series, Ga-68 dotatate PET/CT altered diagnosis and management in one-third of patients and changed operative plans in half of the patients who were referred for surgical evaluation. These results support the routine use of this imaging in the care of patients with early-stage and advanced NETs.

Outcomes of Surgical and Chemotherapeutic Treatments of Goblet Cell Carcinoid Tumors of the Appendix.

BACKGROUND: Goblet cell carcinoids (GCCs) of the appendix are rare mucinous neoplasms, for which optimal therapy is poorly described. We examined prognostic clinical and treatment factors in a population-based cohort. METHODS: Patients diagnosed with GCC from 1984 to 2014 were identified from the British Columbia Cancer Agency and the Vancouver Lower Mainland Pathology Archive. RESULTS: Of 88 cases with confirmed appendiceal GCCs, clinical data were available in 86 cases (annual population incidence: 0.66/1,000,000). Median age was 54 years (range 25-91) and 42 patients (49%) were male. Metastasis at presentation was the strongest predictor of overall survival (OS), with median OS not reached for stage I-III patients, and measuring 16.2 months [95% confidence interval (CI) 9.1-29] for stage IV patients. In 67 stage I-III patients, 51 (76%) underwent completion hemicolectomy and 9 (17%) received adjuvant 5-fluorouracil-based chemotherapy. No appendicitis at initial presentation and Tang B histology were the only prognostic factors, with inferior 5-year recurrence-free survival (53 vs. 83% with appendicitis, p = 0.02; 45% Tang B vs. 89% Tang A, p < 0.01). Of 19 stage IV patients, 10 (62.5%) received 5-fluorouracil-based chemotherapy and 11 (61%) underwent multiorgan resection (MOR) ± hyperthermic intraperitoneal chemotherapy (HIPEC). Low mitotic rate and MOR ± HIPEC were associated with improved 2-year OS, but only MOR ± HIPEC remained significant on multivariate analysis (hazard ratio 5.4, 95% CI 1.4-20.9; p = 0.015). CONCLUSIONS: In this population-based cohort, we demonstrate excellent survival outcomes in stage I-III appendiceal GCCs and clinical appendicitis. Hemicolectomy remains the standard treatment. In metastatic disease, outcomes remain poor, although MOR ± HIPEC may improve survival.

A multicentre, open-label phase II study of Irinotecan, capecitabine (Xeloda®), and Oxaliplatin (IXO) as first-line treatment in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Purpose Chemotherapy remains the primary treatment for metastatic gastric/GEJ cancer but optimal agents and schedule remain controversial. This study examined the safety and efficacy of first-line Irinotecan, capecitabine (Xeloda®), and Oxaliplatin (IXO). Patients and Methods Eligible patients with HER2-unamplified/unknown, metastatic gastric/GEJ adenocarcinoma were treated with 21-day cycle IXO at dose level 1 (DL1: Day 1 O-100 mg/m2 & I-160 mg/m2 IV, Day 2-15 X-1900 mg/m2/day PO divided doses) or modified IXO (mIXO): Day 1 O-85 mg/m2 & I-120 mg/m2 IV, Day 2-15 X-1425 mg/m2/day PO divided doses). This Bryant and Day two-stage designed study had dual primary endpoints of objective response rate (ORR) and toxicity. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results Fifty patients were enrolled and received a median of 7 cycles. After accrual of 9 patients at DL1, evaluable RR was 88% however dose limiting toxicity (DLT) rate was 56% thus doses were adjusted to mIXO. Fifteen patients accrued at mIXO had a RR of 60% and DLT rate of 13% allowing continuation to stage 2. Overall, 48 and 49 patients were evaluable for efficacy and safety, respectively, with ORR of 54% and DLTs in 24% of patients (DL1 = 56%; mIXO = 18%). Disease control rate was 85%. The most frequent grade 3/4 adverse events were diarrhea, neutropenia, fatigue, hypokalemia, and nausea. Median PFS and OS were 7.5 and 13.0 months, respectively, with a median follow-up of 9.7 months. Conclusion mIXO demonstrates promising ORR, PFS, OS, and acceptable toxicity compared to standard triplet regimens. IXO should be evaluated in phase III trials.

Prognostic Factors for Locoregional Recurrence in Neuroendocrine Tumors of the Rectum.

BACKGROUND: Optimal management of rectal neuroendocrine tumors is not yet well defined. Various pathologic factors, particularly tumor size, have been proposed as prognostic markers. OBJECTIVE: We characterized sequential patients diagnosed with rectal neuroendocrine tumors in a population-based setting to determine whether tumor size and other pathologic markers could be useful in guiding locoregional management. DESIGN: This study is a retrospective analysis of data from the British Columbia provincial cancer registry. SETTINGS: The study was conducted at a tertiary care center. PATIENTS: Sequential patients diagnosed with rectal neuroendocrine tumors between 1999 and 2011 were identified. Neuroendocrine tumors were classified as G1 and G2 tumors with a Ki-67 ≤20% and/or mitotic count ≤20 per high-power field. MAIN OUTCOME MEASURES: Baseline clinicopathologic data including TNM staging, depth of invasion, tumor size, treatment modalities, and outcomes including survival data were measured. RESULTS: Of 91 rectal neuroendocrine tumors, the median patient age was 58 years, and 35 were men. Median tumor size was 6 mm. Median length of follow-up was 58.1 months, with 3 patients presenting with stage IV disease. Treatment included local ablation (n = 5), local excision (n = 79), surgical resection (n = 4), and pelvic radiation (n = 1; T3N1 tumor). Final margin status was positive in 17 cases. Local relapse occurred in 8 cases and 1 relapse to bone 13 months after T3N1 tumor resection. Univariate analysis demonstrated an association between local relapse and Ki-67, mitotic count, grade, and lymphovascular invasion (p < 0.01). Larger tumor size was associated with decreased disease-free survival. LIMITATIONS: Sample size was 91 patients in the whole provincial population over a 13-year time period because of the low incidence of rectal neuroendocrine tumors. CONCLUSIONS: In this population-based cohort, rectal neuroendocrine tumors generally presented with small, early tumors and were treated with local excision or surgical resection without pelvic radiation. Pathologic markers play a role in risk stratification and prognostication. See Video Abstract at http://links.lww.com/DCR/A514.

The utility of abbreviated patient-reported outcomes for predicting survival in early stage colorectal cancer.

BACKGROUND: Patient-reported outcomes (PROs) are increasingly used in clinical settings. Prior research suggests that PROs collected at baseline may be associated with cancer survival, but most of those studies were conducted in patients with breast or lung cancer. The objective of this study was to determine the correlation between prospectively collected PROs and cancer-specific outcomes in patients with early stage colorectal cancer. METHODS: Patients who had newly diagnosed stage II or III colorectal cancer from 2009 to 2010 and had a consultation at the British Columbia Cancer Agency completed the brief Psychosocial Screen for Cancer (PSSCAN) questionnaire, which collects data on patients' perceived social supports, quality of life (QOL), anxiety and depression, and general health. PROs from the PSSCAN were linked with the Gastrointestinal Cancers Outcomes Database, which contains information on patient and tumor characteristics, treatment details, and cancer outcomes. Cox regression models were constructed for overall survival (OS), and Fine and Gray regression models were developed for disease-specific survival (DSS). RESULTS: In total, 692 patients were included. The median patient age was 67 years (range, 26-95 years), and the majority had colon cancer (61%), were diagnosed with stage III disease (54%), and received chemotherapy (58%). In general, patients felt well supported and reported good overall health and QOL. On multivariate analysis, increased fatigue was associated with worse OS (hazard ratio [HR], 1.99; P = .00007) and DSS (HR, 1.63; P = .03), as was lack of emotional support (OS: HR, 4.36; P = .0003; DSS: HR, 1.92; P = .02). CONCLUSIONS: Although most patients described good overall health and QOL and indicated that they were generally well supported, patients who experienced more pronounced fatigue or lacked emotional support had a higher likelihood of worse OS and DSS. These findings suggest that abbreviated PROs can inform and assist clinicians to identify patients who have a worse prognosis and may need more vigilant follow-up. Cancer 2017;123:1839-1847. © 2017 American Cancer Society.

Prophylactic versus reactive treatment of acneiform skin rashes from epidermal growth factor receptor inhibitors in metastatic colorectal cancer.

PURPOSE: There are concerns regarding potential negative effects of prophylactic treatment of epidermal growth factor receptor (EGFR)-inhibitor-related rashes on metastatic colorectal cancer (mCRC) outcomes. We aimed to characterize treatment patterns of EGFR-inhibitor-induced rashes and evaluate prophylactic versus reactive approaches to rash management in relation to overall survival (OS). METHODS: Patients diagnosed with KRAS wild-type mCRC from July 2010 to June 2012 in British Columbia and prescribed cetuximab or panitumumab were reviewed to describe patterns of use of oral antibiotics and steroid creams. Using Cox regression, the relationship between prophylactic versus reactive rash management and OS was characterized. RESULTS: A total 119 patients were analyzed: median age was 63 years, 61 % were male, 34 % received cetuximab, 66 % received panitumumab, and median number of EGFR inhibitor treatment was nine cycles. Rash occurred in >90 % of patients, and reactive was favored over prophylactic treatment (66 vs. 34 %). Older patients and those with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 were more likely to receive prophylactic creams (44 vs. 20 % for age <60, p = 0.01) and oral antibiotics (62 vs. 12 % for ECOG ≥2, p = 0.01), respectively. Median OS was 7.0 months. The number of treatment cycles and OS were similar in both prophylactic and reactive groups (both p > 0.05). In Cox regression, ECOG >2 correlated with worse survival (hazard ratio (HR) 22.01, 95 % confidence interval (CI) 5.25-92.30, p < 0.01). However, survival outcomes were similar between patients prescribed antibiotics prophylactically versus reactively (HR = 1.10, 95 % CI 0.43-2.80, p = 0.85), and steroid creams prophylactically versus reactively (HR = 2.00, 95 % CI 0.58-6.92, p = 0.27). CONCLUSION: Prophylactic treatment of EGFR-inhibitor-related rashes is associated with similar outcomes compared to reactive rash treatment in mCRC.

Adjuvant chemotherapy use and outcomes of patients with high-risk versus low-risk stage II colon cancer.

BACKGROUND: Adjuvant chemotherapy (AC) is frequently considered in patients with stage II colon cancer who are considered to be at high risk. However, to the authors' knowledge, the survival benefits associated with AC in these patients remain largely unproven. In the current study, the authors sought to examine the use of AC in patients with AJCC stage II colon cancer and to compare the impact of AC on outcomes in patients with high-risk versus low-risk disease in a population-based setting. METHODS: Patients with stage II colon cancer who were evaluated at 1 of 5 regional cancer centers in British Columbia from 1999 to 2008 were analyzed. Kaplan-Meier and Cox regression methods were used to correlate high-risk versus low-risk status and receipt of AC with recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). RESULTS: A total of 1697 patients were identified: 1286 (76%) with high-risk and 411 (24%) with low-risk disease, among whom 373 (29%) and 51 (12%),respectively, received AC. Individuals with high-risk disease treated with AC were younger (median age, 62 years vs 72 years; P<.001) and had better Eastern Cooperative Oncology Group performance status (0/1: 47% vs 33%; P = .001). For high-risk patients, AC was associated with improved OS (hazard ratio [HR], 0.65; 95% confidence interval [95% CI], 0.50-0.83 [P = .001]). However, no significant benefits with regard to RFS or DSS were observed. Subgroup analyses revealed that AC in patients with T4 disease was associated with significantly improved RFS (HR, 0.63; 95% CI, 0.42-0.95 [P = .03]), DSS (HR, 0.59; 95% CI, 0.37-0.93 [P = .02]), and OS (HR, 0.50; 95% CI, 0.33-0.77 [P = .002]). For patients with low-risk disease, AC was associated with inferior RFS (HR, 2.18; 95% CI, 1.00-4.79 [P = .05]) and DSS (HR, 3.01; 95% CI, 1.10-8.23 [P = .03]). CONCLUSIONS: In this population-based analysis, AC was associated with an OS advantage in high-risk patients, most likely due to patient selection. RFS, DSS, and OS benefits were mainly observed in patients with T4 disease, suggesting a limited role for AC in patients deemed to be high risk by non-T4 features.

Phase 2 study of MK-2206, an allosteric inhibitor of AKT, as second-line therapy for advanced gastric and gastroesophageal junction cancer: A SWOG cooperative group trial (S1005).

BACKGROUND: The AKT inhibitor MK-2206 at a dose of 60 mg every other day was evaluated in gastric/gastroesophageal junction cancers. METHODS: Patients who had progressed after first-line treatment were eligible. Pertinent eligibility criteria included adequate organ function, a fasting serum glucose level ≤ 150 mg/dL, and less than grade 2 malabsorption or chronic diarrhea. MK-2206 was given orally (60 evaluable patients required). The primary endpoint was overall survival, and a median survival of 6.5 months (power, 89%; significance level, 0.07) was considered encouraging for further investigation. RESULTS: Seventy patients were included in the final analyses. The median age was 59.8 years (range, 30.4-86.7 years); 70% were male, 89% were white, and 7% were Asian. There were 2 deaths possibly related to the study drug (cardiac arrest and respiratory failure). Grade 4 adverse events included hyperglycemia, anemia, and lung infection (1 each). Grade 3 adverse events occurred in < 5% of patients except for fatigue (6%). Other adverse events (all grades) included anemia (17%), anorexia (30%), diarrhea (26%), fatigue (50%), hyperglycemia (30%), nausea (40%), vomiting (22%), dry skin (19%), maculopapular rash (30%), and acneiform rash (13%). The response rate was 1%, the median progression-free survival was 1.8 months (95% confidence interval, 1.7-1.8 months), and the median overall survival was 5.1 months (95% confidence interval, 3.7-9.4 months) CONCLUSIONS: MK-2206 as second-line therapy was well tolerated by an unselected group of patients with gastric/gastroesophageal junction cancers, but it did not have sufficient activity (response rate, 1%; overall survival, 5.1 months) to warrant further testing in this population.

Consensus Recommendations for the Diagnosis and Management of Pancreatic Neuroendocrine Tumors: Guidelines from a Canadian National Expert Group.

Pancreatic neuroendocrine tumors (pNETs) are rare heterogeneous tumors that have been steadily increasing in both incidence and prevalence during the past few decades. Pancreatic NETs are categorized as functional (F) or nonfunctional (NF) based on their ability to secrete hormones that elicit clinically relevant symptoms. Specialized diagnostic tests are required for diagnosis. Treatment options are diverse and include surgical resection, intraarterial hepatic therapy, and peptide receptor radionuclide therapy (PRRT). Systemic therapy options include targeted agents as well as chemotherapy when indicated. Diagnosis and management should occur through a collaborative team of health care practitioners well-experienced in managing pNETs. Recent advances in pNET treatment options have led to the development of the Canadian consensus document described in this report. The discussion includes the epidemiology, classification, pathology, clinical presentation and prognosis, imaging and laboratory testing, medical and surgical management, and recommended treatment algorithms for pancreatic neuroendocrine cancers.

Effect of M1a and M1b category in metastatic colorectal cancer.

BACKGROUND: In 2009, the American Joint Committee on Cancer version 7 staging system introduced the M1 subclassifications M1a (single metastatic site) and M1b (peritoneal or multiple metastatic sites). The study objectives were to evaluate the prognostic effect of site of metastasis and M1a/b category among patients with newly diagnosed colorectal cancer and synchronous metastasis. PATIENTS AND METHODS: Patients with newly diagnosed pathologic or clinical category M1 colorectal cancer referred to the British Columbia Cancer Agency between 1999 and 2007 were included. Demographic, tumor, treatment, and outcome data were prospectively collected, and prognostic factors were identified. Univariate Cox models were used to assess the prognostic impact of individual sites of metastasis and to determine the effect of M1a/b category on overall survival (OS). RESULTS: Among 2,049 eligible patients, 70% had M1a and 30% M1b category disease. The most common sites of common single sites of metastasis included liver (56%), lung (5.3%), and peritoneum (3.6%). Metastasis to a single organ or site, including peritoneum, was associated with improved OS compared with multiple sites of metastasis. In multivariate analysis, M1b category conferred inferior survival and hazard ratio (HR) 1.38 (95% confidence interval [CI]: 1.22, 1.55), along with age >70 and Eastern Cooperative Oncology Group performance status of 3-4. Resection of primary tumor was associated with improved survival, HR 0.46 (95% CI: 0.41, 0.52). Results were similar in subgroup analysis of patients undergoing resection of their primary tumor when histology, tumor, and node category were included. CONCLUSION: The results lend support to the introduction of M1a/b colorectal cancer categories. Consideration may be given to classifying patients with solitary peritoneal metastasis only as M1a rather than M1b category. Further refinement of category M1a to reflect resectability of metastasis at initial diagnosis may improve prognostication.

Association between palliative resection of the primary tumor and overall survival in a population-based cohort of metastatic colorectal cancer patients.

BACKGROUND: The impact of palliative resection of the primary tumor on outcomes in patients with metastatic colorectal cancer (mCRC) remains unclear. The primary objective of this study was to evaluate the association between palliative resection and overall survival (OS) in a population-based cohort of mCRC. METHODS: Patients diagnosed with mCRC between 2006 and 2008 and treated at the BC Cancer Agency were reviewed. Survival analysis was conducted using Kaplan-Meier methods. Cox proportional hazards regression models were fitted to evaluate the relationship between palliative resection and OS while controlling for potential confounders, such as age, gender, Eastern Cooperative Oncology Group status, carcinoembryonic antigen level, primary tumor location, metastatic site and number, and receipt of systemic therapy. To adjust for the heterogeneity and selection bias between the group that underwent palliative resection and the group that did not, a propensity score-matched analysis was also performed. RESULTS: A total of 517 patients were included. Among these cases, 378 (73 %) patients underwent palliative resection of their primary tumor, and 139 (27 %) patients did not. A total of 327 patients (63 %) were treated with palliative chemotherapy. Palliative resection was associated with a longer median OS (17.9 vs. 7.9 months) and more favorable unadjusted and adjusted hazard ratios (HRs) for death (HR 0.46, 95 % CI 0.37-0.56, p < 0.0001 and HR 0.56, 95 % CI 0.40-0.78, p = 0.0007, respectively) when compared with no resection. In a propensity score-matched analysis, prognosis was also more favorable in the resected group (p = 0.0017). CONCLUSIONS: In this cohort of mCRC patients, palliative resection of the primary tumor was associated with improved OS.

Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial.

BACKGROUND: Insulin-like growth factors (IGF-1 and IGF-2) bind to the IGF-1 receptor (IGF-1R), increasing cell proliferation and survival. Ganitumab is a monoclonal IgG1 antibody that blocks IGF-1R. We tested the efficacy and safety of adding ganitumab to endocrine treatment for patients with hormone-receptor-positive breast cancer. METHODS: We did this phase 2 trial in outpatient clinics and hospitals. We enrolled postmenopausal women with hormone-receptor-positive, locally advanced or metastatic breast cancer previously treated with endocrine treatment. They were randomly assigned (2:1) with a central randomisation schedule to receive intravenous ganitumab 12 mg per kg bodyweight or placebo in combination with open-label intramuscular fulvestrant (500 mg on day 1, then 250 mg on days 15, 29, and every 28 days) or oral exemestane (25 mg once daily) on a 28-day cycle. Patients, investigators, study monitors, and the sponsor staff were masked to treatment allocation. Response was assessed every 8 weeks. The primary endpoint was median progression-free survival in the intention-to-treat population. We analysed overall survival as one of our secondary endpoints. The study is registered at ClinicalTrials.gov, number NCT00626106. FINDINGS: We screened 189 patients and enrolled 156 (106 in the ganitumab group and 50 in the placebo group). Median progression-free survival did not differ significantly between the ganitumab and placebo groups (3·9 months, 80% CI 3·6-5·3 vs 5·7 months, 4·4-7·4; hazard ratio [HR] 1·17, 80% CI 0·91-1·50; p=0·44). However, overall survival was worse in the the ganitumab group than in the placebo group (HR 1·78, 80% CI 1·27-2·50; p=0·025). With the exception of hyperglycaemia, adverse events were generally similar between groups. The most common grade 3 or higher adverse event was neutropenia-reported by six of 106 (6%) patients in the ganitumab group and one of 49 (2%) in the placebo group. Hyperglycaemia was reported by 12 of 106 (11%) patients in the ganitumab group (with six patients having grade 3 or 4 hyperglycaemia) and none of 49 in the placebo group. Serious adverse events were reported by 27 of 106 (25%) patients in the ganitumab group and nine of 49 (18%) patients in the placebo group. INTERPRETATION: Addition of ganitumab to endocrine treatment in women with previously treated hormone-receptor-positive locally advanced or metastatic breast cancer did not improve outcomes. Our results do not support further study of ganitumab in this subgroup of patients. FUNDING: Amgen.

Establishing a robust radioligand therapy program: A practical approach for North American centers.

Radioligand therapy (RLT) is a targeted approach to treating cancer that has been shown to be safe and effective in a variety of disease states, including gastroenteropancreatic neuroendocrine tumors, lymphoma, and most recently, advanced prostate cancer. In the United States, patient access to this therapy is currently variable. Implementation of new RLT programs and expansion of existing programs are needed to broaden patient access to and standardize the delivery of RLT, especially as new therapies are introduced into clinical practice. Drawing from experience in establishing RLT programs in different settings, we have developed practical recommendations for building and implementing a robust RLT program. In this review, we present our recommendations for minimal requirements and optimal requirements, as well as system considerations, and special issues associated with implementing an RLT program in North American centers.

Kinetic Profiling of RAS Mutations With Circulating Tumor DNA in the Canadian Cancer Trials Group CO.26 Trial Suggests the Loss of RAS Mutations in Neo-RAS-Wildtype Metastatic Colorectal Cancer Is Transient.

PURPOSE: In metastatic colorectal cancer (mCRC), RAS mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether RAS mutations ever become clonally undetectable. METHODS: CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. RAS mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression. RESULTS: Among the 95 patients with KRAS/NRAS mutations in their archival tumor tissue, 6.3% (6/95) had undetectable RAS mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to RAS-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-RAS-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent RAS mutations (75%), P = .046. The likelihood of synchronous metastases at cancer diagnosis (33% v 63%; P = .15) or liver metastases at trial baseline (50% v 68.5%; P = .17) was not significantly different between patients with disappearing versus persistent RAS mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; P = .52) was not significantly different between those with disappearing versus persistent RAS mutations. The disappearance of RAS mutations was not associated with primary tumor sidedness (P = .41), archival BRAF/MEK/ERK-mutant status (P = .16/1.00/.09), nor baseline ctDNA HER2 amplifications (P = 1.00). CONCLUSION: We identified a 3.2%-6.3% prevalence of the neo-RAS-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.