Development and validation of AI-assisted transcriptomic signatures to personalize adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment. PATIENTS AND METHODS: We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the 'Pancreas-View' tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial. RESULTS: Patients who were predicted to be sensitive to the administered drugs (n = 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months [stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001] and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n = 86; 25.1%) or those resistant to all drugs (n = 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively). CONCLUSIONS: This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.

Shifting practice in definitive chemoradiation for localized esophageal cancer.

BACKGROUND: The efficacy of carboplatin-paclitaxel in the trimodality setting was demonstrated in the cross trial. Because of better tolerance, that regimen has been adopted as an alternative for patients receiving definitive chemoradiation (dcrt). The purpose of our study was to compare outcomes in patients with localized esophageal and gastroesophageal junction (gej) cancer who received dcrt using either platinum-5-fluorouracil (5fu) or carboplatin-paclitaxel. METHODS: Medical records and outcomes for all patients diagnosed with localized carcinoma of the esophagus and gej at our centre between 2008 and 2015 were reviewed. All patients who underwent dcrt using cisplatin-5fu, carboplatin-5fu, or carboplatin-paclitaxel were included. RESULTS: The 73 identified patients (34 cisplatin-5fu, 13 carboplatin-5fu, 26 carboplatin-paclitaxel) were all prescribed concomitant radiotherapy of 50 Gy in 25 daily fractions. The diagnosis was adenocarcinoma in 64% and squamous cell carcinoma in 36%. Median overall survival (os) duration for the cisplatin-5fu group was 28 months [95% confidence interval (ci): 19 to 41 months], with a 3-year os rate of 44%, in contrast to the 15 months (95% ci: 11 to 17 months) and 15% in the carboplatin-paclitaxel group (log-rank p = 0.0047). Median os duration for the carboplatin-5fu group was 17 months (95% ci: 11 to 68 months) with a 3-year os rate of 31%. Adjusting for patient and disease factors, better os durations and rates were associated with cisplatin-5fu (hazard ratio: 0.34; p = 0.0016) and carboplatin-5fu (hazard ratio: 0.55; p = 0.20) than with carboplatin-paclitaxel. CONCLUSIONS: In a dcrt regimen, a better os is associated with cisplatin-5fu than with carboplatin-paclitaxel. Clinical trials to determine optimal chemotherapy regimens are warranted for patients who are not suitable for surgery.

The predictive effect of primary tumour location in the treatment of metastatic colorectal cancer: a Canadian consensus statement.

In recently published data, the predictive value of primary tumour location for the treatment of metastatic colorectal cancer with available biologic therapies has been explored. Recognizing the potential effect of those data on clinical practice, we convened a meeting of Canadian experts who treat metastatic colorectal cancer to develop a set of national, evidence-based treatment guidelines based on primary tumour location. This report summarizes the relevant evidence and presents the consensus recommendations of those experts.

Phase I/II trial of dose-reduced capecitabine in elderly patients with advanced colorectal cancer.

BACKGROUND: Combination chemotherapy is associated with improved outcomes in trials of selected fit patients with advanced colorectal cancer (acrc). For older or less-fit patients, combination chemotherapy is associated with greater toxicity and less benefit. Capecitabine monotherapy is a reasonable option for those patients, but the optimal dose remains controversial. METHODS: A multicentre phase i/ii trial of reduced-dose capecitabine (2000 mg/m2, days 1-14 every 21 days) was conducted in 221 patients representing one or more of the following subsets: age greater than 65 years (n = 167), Eastern Cooperative Oncology Group (ecog) performance status of 1 or greater (n = 139), elevated lactate dehydrogenase (ldh) (n = 105), or prior pelvic radiation (n = 54). Based on phase i results, patients with prior pelvic radiation received capecitabine 750 mg/m2 twice daily. The goal was to ascertain efficacy in a design that was unlikely to cause high levels of toxicity. RESULTS: Median age in the patient cohort was 72 years. A median of 5 and a mean of 8 capecitabine cycles were given (range: 0-50 cycles). Grade 3 or 4 toxicity occurred in 25% of patients during the first 3 cycles (8.1% hand-foot syndrome, 7.7% diarrhea). The response rate was 13.6%, with a 69.7% disease control rate. Median progression-free survival (pfs) was 5.6 months. Post progression, 56 patients received further capecitabine monotherapy (median of 4 additional cycles). Median overall survival duration for the patients was 14.3 months. Median survival was significantly higher for those who, at baseline, had an ecog performance status of 0 (compared with 1 or more) and normal ldh (compared with elevated ldh). CONCLUSIONS: Toxicity is less with dose-reduced capecitabine than with historical full-dose capecitabine, with only a small trade-off in efficacy, seen as a lower objective response rate. The improved tolerability could lead to an increased number of cycles of therapy, and pfs appears to be consistently higher at the lower dose. Those observations should, in the absence of a head-to-head clinical trial, be viewed as compelling evidence that 1000 mg/m2, or even 750 mg/m2, twice daily is an appropriate dose in elderly or frail patients with acrc.

Research output and the public health burden of cancer: is there any relationship?

PURPOSE: The relative distribution of research output across cancer sites is not well described. Here, we evaluate whether the volume of published research is proportional to the public health burden of individual cancers. We also explore whether research output is proportional to research funding. METHODS: Statistics from the Canadian and American cancer societies were used to identify the top ten causes of cancer death in 2013. All journal articles and clinical trials published in 2013 by Canadian or U.S. authors for those cancers were identified. Total research funding in Canada by cancer site was obtained from the Canadian Cancer Research Alliance. Descriptive statistics and Pearson correlation coefficients were used to describe the relationship between research output, cancer mortality, and research funding. RESULTS: We identified 19,361 publications and 2661 clinical trials. The proportion of publications and clinical trials was substantially lower than the proportion of deaths for lung (41% deaths, 15% publications, 16% clinical trials), colorectal (14%, 7%, 6%), pancreatic (10%, 7%, 5%), and gastroesophageal (7%, 5%, 3%) cancers. Conversely, research output was substantially greater than the proportion of deaths for breast cancer (10% deaths, 29% publications, 30% clinical trials) and prostate cancer (8%, 15%, 17%). We observed a stronger correlation between research output and funding (publications r = 0.894, p < 0.001; clinical trials r = 0.923, p < 0.001) than between research output and cancer mortality (r = 0.363, p = 0.303; r = 0.340, p = 0.337). CONCLUSIONS: Research output is not well correlated with the public health burden of individual cancers, but is correlated with the relative level of research funding.

Corrigendum: Eastern Canadian Gastrointestinal Cancer Consensus Conference 2014.

[This corrects the article DOI: 10.3747/co.22.2603.].

Eastern Canadian Colorectal Cancer Consensus Conference 2013: emerging therapies in the treatment of pancreatic, rectal, and colorectal cancers.

The annual Eastern Canadian Colorectal Cancer Consensus Conference held in Montreal, Quebec, 17-19 October 2013, marked the 10-year anniversary of this meeting that is attended by leaders in medical, radiation, and surgical oncology. The goal of the attendees is to improve the care of patients affected by gastrointestinal malignancies. Topics discussed during the conference included pancreatic cancer, rectal cancer, and metastatic colorectal cancer.

Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016 was held in Montreal, Quebec, 5-7 February. Experts in radiation oncology, medical oncology, surgical oncology, and infectious diseases involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics: ■ Follow-up and survivorship of patients with resected colorectal cancer■ Indications for liver metastasectomy■ Treatment of oligometastases by stereotactic body radiation therapy■ Treatment of borderline resectable and unresectable pancreatic cancer■ Transarterial chemoembolization in hepatocellular carcinoma■ Infectious complications of antineoplastic agents.

A phase 2 study of cediranib in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: a trial of the Princess Margaret, Chicago and California Phase II Consortia.

PURPOSE: Cediranib is a potent multitargeted inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2 and 3. The study was initiated to evaluate the activity of cediranib in patients (pts) with recurrent ovarian, peritoneal or fallopian tube cancer (OC). METHODS: Eligible pts had persistent/recurrent OC following one prior platinum-based chemotherapy with measurable disease or progression based on Gynecologic Cancer Inter Group CA-125 criteria. Because of toxicities observed in the first 23 pts, the initial starting dose of oral daily (od) cediranib was reduced from 45mg to 30mg. The primary endpoint was objective response rate at 16weeks. This study was stratified into two arms: platinum-sensitive (PL-S) and platinum-resistant (PL-R). RESULTS: 74 pts were enrolled; 39 were PL-S and 35 PL-R, with a median age of 58years [31-87]. In PL-S group, 10 (26%) partial responses (PR) and 20 (51%) stable disease (SD) were confirmed while in the PL-R arm there were no confirmed PR and 23 pts (66%) had SD. The main grade 3/4 toxicities observed at the 30 mg starting dose were hypertension (27%), fatigue (20%) and diarrhea (14%). The median progression-free survival for all patients was 4.9months [3.9-7.0], 7.2months [4.3-9] for PL-S and 3.7months [2.6-4.5] for PL-R groups. The median overall survival was 18.9months (95% CI: 13.5-31.5); 27.7months [17.8-43.3] for PL-S and 11.9months [8.1-18.9] for PL-R groups. CONCLUSION: Cediranib shows significant activity in recurrent platinum sensitive OC. The toxicities were expected and manageable at the dose of 30mg od.

Management and outcomes of localized esophageal and gastroesophageal junction cancer in older patients.

BACKGROUND: Older patients are commonly excluded from clinical trials in esophageal and gastroesophageal junction (gej) cancer. High-level evidence to guide management in this group is lacking. In the present study, we compared outcomes and described tolerance for curative- and noncurative-intent treatments among patients 70 years of age and older. METHODS: We retrospectively reviewed all patients 70 years of age and older diagnosed with localized esophageal and gej cancer at our centre between 2005 and 2012. RESULTS: The 74 patients identified had a median age of 77 years. Of those patients, 62% received curative-intent treatment, consisting mostly of concomitant chemoradiation therapy (n = 43, 93%). Median overall survival for patients receiving curative-intent treatment was 18.6 months [95% confidence interval (ci): 13.0 to 28.0 months], with 23% being long-term survivors (95% ci: 11.3% to 36.7%). In contrast, patients receiving noncurative-intent treatment had a median overall survival of 8.8 months (95% ci: 6.7 to 11.9 months), with none being long-term survivors (p < 0.0001). Improvement of dysphagia was seen after curative (81%) or palliative radiotherapy (78%) in symptomatic patients, and toxicities were manageable. The odds of not receiving curative treatment was higher by a factor of 8.5 among patients 80 years of age or older compared with those 70-79 years of age (95% ci: 2.5 to 28.7). CONCLUSIONS: In managing older patients with esophageal and gej cancer, curative-intent treatment (compared with noncurative-intent treatment) leads to a significant survival benefit with a reasonable toxicity profile. Informed counselling of patients and their families about a curative treatment approach and efforts to increase awareness among oncology care providers are suggested.

The optimal organization of gynecologic oncology services: a systematic review.

BACKGROUND: A system-level organizational guideline for gynecologic oncology was identified by a provincial cancer agency as a key priority based on input from stakeholders, data showing more limited availability of multidisciplinary or specialist care in lower-volume than in higher-volume hospitals in the relevant jurisdiction, and variable rates of staging for ovarian and endometrial cancer patients. METHODS: A systematic review assessed the relationship of the organization of gynecologic oncology services with patient survival and surgical outcomes. The electronic databases medline and embase (ovid: 1996 through 9 January 2015) were searched using terms related to gynecologic malignancies combined with organization of services, patterns of care, and various facility and physician characteristics. Outcomes of interest included overall or disease-specific survival, short-term survival, adequate staging, and degree of cytoreduction or optimal cytoreduction (or both) for ovarian cancer patients by hospital or physician type, and rate of discrepancy in initial diagnoses and intraoperative consultation between non-specialist pathologists and gyne-oncology-specialist pathologists. RESULTS: One systematic review and sixteen additional primary studies met the inclusion criteria. The evidence base as a whole was judged to be of lower quality; however, a trend toward improved outcomes with centralization of gynecologic oncology was found, particularly with respect to the gynecologic oncology care of patients with advanced-stage ovarian cancer. CONCLUSIONS: Improvements in outcomes with centralization of gynecologic oncology services can be attributed to a number of factors, including access to specialist care and multidisciplinary team management. Findings of this systematic review should be used with caution because of the limitations of the evidence base; however, an expert consensus process made it possible to create recommendations for implementation.

Eastern Canadian Gastrointestinal Cancer Consensus Conference 2014.

The annual Eastern Canadian Colorectal Cancer Consensus Conference was held in Montreal, Quebec, 23-25 October 2014. Expert radiation, medical, and surgical oncologists and pathologists involved in the management of patients with gastrointestinal malignancies participated in presentations and discussions resulting in consensus statements on such hot topics as management of neuroendocrine tumours, advanced and metastatic pancreatic cancer, and metastatic colorectal cancer.

Liver resection for colorectal cancer metastases.

QUESTIONS: Should surgery be considered for colorectal cancer (crc) patients who have liver metastases plus (a) pulmonary metastases, (b) portal nodal disease, or (c) other extrahepatic metastases (ehms)?What is the role of chemotherapy in the surgical management of crc with liver metastases in (a) patients with resectable disease in the liver, or (b) patients with initially unresectable disease in the liver that is downsized with chemotherapy ("conversion")?What is the role of liver resection when one or more crc liver metastases have radiographic complete response (rcr) after chemotherapy? PERSPECTIVES: Advances in chemotherapy have improved survival in crc patients with liver metastases. The 5-year survival with chemotherapy alone is typically less than 1%, although two recent studies with folfox or folfoxiri (or both) reported rates of 5%-10%. However, liver resection is the treatment that is most effective in achieving long-term survival and offering the possibility of a cure in stage iv crc patients with liver metastases. This guideline deals with the role of chemotherapy with surgery, and the role of surgery when there are liver metastases plus ehms. Because only a proportion of patients with crc metastatic disease are considered for liver resection, and because management of this patient population is complex, multidisciplinary management is required. METHODOLOGY: Recommendations in the present guideline were formulated based on a prepublication version of a recent systematic review on this topic. The draft methodology experts, and external review by clinical practitioners. Feedback was incorporated into the final version of the guideline. PRACTICE GUIDELINE: These recommendations apply to patients with liver metastases from crc who have had or will have a complete (R0) resection of the primary cancer and who are being considered for resection of the liver, or liver plus specific and limited ehms, with curative intent. 1(a). Patients with liver and lung metastases should be seen in consultation with a thoracic surgeon. Combined or staged metastasectomy is recommended when, taking into account anatomic and physiologic considerations, the assessment is that all pulmonary metastases can also be completely removed. Furthermore, liver resection may be indicated in patients who have had a prior lung resection, and vice versa.1(b). Routine liver resection is not recommended in patients with portal nodal disease. This group includes patients with radiologically suspicious portal nodes or malignant portal nodes found preoperatively or intraoperatively. Liver plus nodal resection, together with perioperative systemic therapy, may be an option-after a full discussion with the patient-in cases with limited nodal involvement and with metastases that can be completely resected.1(c). Routine liver resection is not recommended in patients with nonpulmonary ehms. Liver plus extrahepatic resection, together with perioperative systemic therapy, may be an option-after a full discussion with the patient-for metastases that can be completely resected.2(a). Perioperative chemotherapy, either before and after resection, or after resection, is recommended in patients with resectable liver metastatic disease. This recommendation extends to patients with ehms that can be completely resected (R0). Risks and potential benefits of perioperative chemotherapy should be discussed for patients with resectable liver metastases. The data on whether patients with previous oxaliplatin-based chemotherapy or a short interval from completion of adjuvant therapy for primary crc might benefit from perioperative chemotherapy are limited.2(b). Liver resection is recommended in patients with initially unresectable metastatic liver disease who have a sufficient downstaging response to conversion chemotherapy. If complete resection has been achieved, postoperative chemotherapy should be considered.3. Surgical resection of all lesions, including lesions with rcr, is recommended when technically feasible and when adequate functional liver can be left as a remnant. When a lesion with rcr is present in a portion of the liver that cannot be resected, surgery may still be a reasonable therapeutic strategy if all other visible disease can be resected. Postoperative chemotherapy might be considered in those patients. Close follow-up of the lesion with rcr is warranted to allow localized treatment or further resection for an in situ recurrence.

Eastern Canadian Colorectal Cancer Consensus Conference: standards of care for the treatment of patients with rectal, pancreatic, and gastrointestinal stromal tumours and pancreatic neuroendocrine tumours.

The annual Eastern Canadian Colorectal Cancer Consensus Conference was held in Halifax, Nova Scotia, October 20-22, 2011. Health care professionals involved in the care of patients with colorectal cancer participated in presentation and discussion sessions for the purposes of developing the recommendations presented here. This consensus statement addresses current issues in the management of rectal cancer, including pathology reporting, neoadjuvant systemic and radiation therapy, surgical techniques, and palliative care of rectal cancer patients. Other topics discussed include multidisciplinary cancer conferences, treatment of gastrointestinal stromal tumours and pancreatic neuroendocrine tumours, the use of folfirinox in pancreatic cancer, and treatment of stage ii colon cancer.

Outcomes Following Treatment with FOLFOX for Patients with Resectable or Potentially Resectable Metastatic Colorectal Cancer: A Population-based Cohort Study.

AIMS: To evaluate the safety and effectiveness of oxaliplatin-based combination chemotherapy for patients with metastatic colorectal cancer (mCRC) to extrahepatic sites. MATERIALS AND METHODS: We conducted a population-based retrospective study examining the safety and effectiveness of perioperative oxaliplatin for resectable or potentially resectable colorectal metastases in Ontario, Canada. Outcomes were also compared with patients with liver-only metastases. Patients received oxaliplatin for mCRC between 1 January 2013 and 30 June 2020. RESULTS: In total, 192 patients had extrahepatic metastases. Seventy per cent had R0 metastasectomy. The 3-year disease-free survival and overall survival were 62% and 79%, respectively; <4% of patients died within 60 days of metastasectomy and 74-90% of patients received treatment according to recommendations from a multidisciplinary setting. Compared with liver-only controls (n = 1306), patients had mCRC to the lung only (n = 115), lung and liver (n = 55) and liver with non-pulmonary site (n = 22). Extrahepatic metastases were more likely to be found for patients whose primary colorectal resection had positive margins (14% versus 7%, P = 0.005) and primary tumours located in the rectum [odds ratio 4.01 (2.31-6.97)]. After adjustment, there was no difference in overall survival between liver-only controls and patients with lung-only [hazard ratio 0.82 (0.59-1.15)] or liver and lung metastases [hazard ratio 1.26 (0.85-1.87)] (P = 0.24). In total, 79/115 (69%) of patients with lung-only metastases had a metastasectomy compared with 645/1306 (49%) and 15/55 (27%) of patients with liver-only and liver and lung metastases, respectively. Hospital visits were similar between patients with liver-only and extrahepatic metastases. CONCLUSION: Oxaliplatin-based chemotherapy for patients with resectable or potentially resectable mCRC with extrahepatic metastases was safe and resulted in similar outcomes in appropriately selected patients when compared with patients with liver-only metastases.

Comparative Effectiveness of FOLFIRINOX Versus Gemcitabine and Nab-paclitaxel in Initially Unresectable Locally Advanced Pancreatic Cancer: A Population-based Study to Assess Subsequent Surgical Resection and Overall Survival.

AIMS: First-line FOLFIRINOX (FOLinic acid, Fluorouracil, IRINotecan, and OXaliplatin) and gemcitabine plus nab-paclitaxel (GnP) have been publicly funded for patients with unresectable locally advanced pancreatic cancer (uLAPC) in Ontario, Canada. We examined the overall survival and surgical resection rate after first-line FOLFIRINOX or GnP and determined the association between resection and overall survival in patients with uLAPC. MATERIALS AND METHODS: We conducted a retrospective population-based study including patients with uLAPC who received first-line treatment FOLFIRINOX or GnP from April 2015 to March 2019. The cohort was linked to administrative databases to ascertain demographic and clinical characteristics. Propensity score methods were used to balance differences between FOLFIRINOX and GnP. The Kaplan-Meier method was used to calculate overall survival. Cox regression was used to determine the association between receipt of treatment and overall survival, adjusting for time-dependent surgical resections. RESULTS: We identified 723 patients with uLAPC (mean age = 65.8, 43.5% female) who received FOLFIRINOX (55.2%) or GnP (44.8%). The median overall survival and 1-year overall survival probability were higher for FOLFIRINOX (13.7 months, 54.6%) than for GnP (8.7 months, 34.0%). Post-chemotherapy surgical resection occurred in 89 (12.3%) patients (FOLFIRINOX: 74 [18.5%] versus GnP: 15 [4.6%]), with no difference in survival since surgery between FOLFIRINOX and GnP (P = 0.29). After adjusting time-dependent post-treatment surgical resection, FOLFIRINOX (inverse probability treatment weighting hazard ratio 0.72, 95% confidence interval 0.61, 0.84) was independently associated with improved overall survival. CONCLUSIONS: In this real-world population-based study of patients with uLAPC, FOLFIRINOX was associated with improved survival and higher resection rates. FOLFIRINOX was associated with improved survival in patients with uLAPC after accounting for the effect of post-chemotherapy surgical resection, suggesting the benefit of FOLFIRINOX was not solely due to improving resectability.

A phase II study single agent of aflibercept (VEGF Trap) in patients with recurrent or metastatic gynecologic carcinosarcomas and uterine leiomyosarcoma. A trial of the Princess Margaret Hospital, Chicago and California Cancer Phase II Consortia.

OBJECTIVE: The aim of this multi-institutional non randomized phase II trial was to determine the efficacy and safety of single agent aflibercept (VEGF Trap), a recombinant fusion protein that blocks multiple vascular endothelial growth factor isoforms, in women with gynecologic soft tissue sarcoma. METHODS: Patients were enrolled in two cohorts each with Simon two stage designs: uterine leiomyosarcoma and carcinosarcoma of endometrial, ovarian or fallopian tube origin. Eligibility criteria included ≤2 prior lines of chemotherapy for metastatic disease and ECOG performance status of ≤2. Aflibercept 4mg/kg was administered intravenously on day 1 of a 14 day cycle. Primary endpoints were objective response and disease stabilization (Progression Free Survival (PFS) at 6 months). RESULTS: 41 patients with uterine leiomyosarcoma and 22 patients with carcinosarcoma (19 uterine, 3 ovarian) were enrolled on study. In the leiomyosarcoma cohort, eleven (27%) patients had stable disease (SD), 4 with SD lasting at least 24 weeks. The 6 month PFS was 17%, with median time to progression (TTP) of 1.8 (95% CI:1.6-2.1) months. In the carcinosarcoma cohort, two (9%) patients had SD, one lasting >24 weeks, median TTP was 1.6 months (95%CI: 1.1-1.7) No partial responses were observed in patients from either cohort. Grade 3 or more aflibercept related toxicity was uncommon and included hypertension, fatigue, headache and abdominal pain. CONCLUSIONS: Single agent aflibercept has modest activity in patients with uterine leiomyosarcoma and minimal activity in women with carcinosarcoma.

A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study.

PURPOSE: Sunitinib is a multitargeted receptor tyrosine kinase inhibitor. We conducted a two-stage phase II study to evaluate the objective response rate of oral sunitinib in recurrent epithelial ovarian cancer. PATIENTS AND METHODS: Eligibility required measurable disease and one or two prior chemotherapies, at least one platinum based. Platinum-sensitive or -resistant disease was allowed. Initial dose schedule was sunitinib 50 mg daily, 4 of 6 weeks. Observation of fluid accumulations during off-treatment periods resulted in adoption of continuous 37.5 mg daily dosing in the second stage of accrual. RESULTS: Of 30 eligible patients, most had serous histology (67%), were platinum sensitive (73%) and had two prior chemotherapies (60%). One partial response (3.3%) and three CA125 responses (10%) were observed, all in platinum-sensitive patients using intermittent dosing. Sixteen (53%) had stable disease. Five had >30% decrease in measurable disease. Overall median progression-free survival was 4.1 months. Common adverse events included fatigue, gastrointestinal symptoms, hand-foot syndrome and hypertension. No gastrointestinal perforation occurred. CONCLUSIONS: Single-agent sunitinib has modest activity in recurrent platinum-sensitive ovarian cancer, but only at the 50 mg intermittent dose schedule, suggesting that dose and schedule may be vital considerations in further evaluation of sunitinib in this cancer setting.

Indications for hyperthermic intraperitoneal chemotherapy with cytoreductive surgery: a clinical practice guideline.

Objective: The purpose of the present review was to provide evidence-based guidance about the provision of cytoreductive surgery (crs) with hyperthermic intraperitoneal chemotherapy (hipec) in the treatment of peritoneal cancers. Methods: The guideline was developed by the Program in Evidence-Based Care together with the Surgical Oncology Program at Ontario Health (Cancer Care Ontario) through a systematic review of relevant literature, patient- and caregiver-specific consultation, and internal and external reviews. Results: Recommendation 1a: For patients with newly diagnosed stage iii primary epithelial ovarian or fallopian tube carcinoma, or primary peritoneal carcinoma, hipec should be considered for those with at least stable disease after neoadjuvant chemotherapy at the time that interval crs (if complete) or optimal cytoreduction is achieved. Recommendation 1b: There is insufficient evidence to recommend the addition of hipec when primary crs is performed for patients with newly diagnosed advanced primary epithelial ovarian or fallopian tube carcinoma, or primary peritoneal carcinoma, outside of a clinical trial. Recommendation 2: There is insufficient evidence to recommend hipec with crs in patients with recurrent ovarian cancer outside the context of a clinical trial. Recommendation 3: There is insufficient evidence to recommend hipec with crs in patients with peritoneal colorectal carcinomatosis outside the context of a clinical trial. Recommendation 4: There is insufficient evidence to recommend hipec with crs for the prevention of peritoneal carcinomatosis in colorectal cancer outside the context of a clinical trial; however, hipec using oxaliplatin is not recommended. Recommendation 5: There is insufficient evidence to recommend hipec with crs for the treatment of gastric peritoneal carcinomatosis outside the context of a clinical trial. Recommendation 6: There is insufficient evidence to recommend hipec with crs for the prevention of gastric peritoneal carcinomatosis outside the context of a clinical trial. Recommendation 7: There is insufficient evidence to recommend hipec with crs as a standard of care in patients with malignant peritoneal mesothelioma; however, patients should be referred to hipec specialty centres for assessment for treatment as part of an ongoing research protocol. Recommendation 8: There is insufficient evidence to recommend hipec with crs as a standard of care in patients with disseminated mucinous neoplasm in the appendix; however, patients should be referred to hipec specialty centres for assessment for treatment as part of an ongoing research protocol.

Decreased dose density of standard chemotherapy does not compromise survival for ovarian cancer patients.

For women diagnosed with ovarian cancer, the standard practice of surgery followed by adjuvant platinum-taxane combination chemotherapy, with cycles administered every 3 weeks, is based on randomized control trials. However, a substantial number of patients require delays or reductions on this schedule. The Cancer Centre of Southeastern Ontario (CCSEO) has historically administered chemotherapy every 4 weeks. We analyzed survival outcomes of our cohort. All ovarian cancer patients treated with chemotherapy at the CCSEO from 1995 to end-2002 were included in this study. Overall survival and progression-free survival were calculated from initiation of chemotherapy using the Kaplan-Meier technique and log-rank tests. Cox regression analysis was used to adjust for age and disease stage. A total of 171 patients were treated with chemotherapy (cisplatin-paclitaxel or carboplatin-paclitaxel), of which 144 received chemotherapy every 4 weeks and 27 every 3 weeks. Median progression-free survival was 19.2 months for the group treated every 4 weeks vs 13.2 months for the 3-weekly group. Median overall survival was 36.5 months compared to 27.1 months, respectively. Trends favored treatment every 4 weeks. In early-stage disease, 5-year overall survival was 74% and 5-year progression-free survival was 68%. Administration of platinum-paclitaxel chemotherapy every 4 weeks did not reduce survival of ovarian cancer patients. Importantly, median survival is favorable compared to results from landmark trials where patients were treated every 3 weeks. These results suggest that decreasing the frequency of chemotherapy cycles does not decrease survival. Prospective trials would be required to compare quality of life and cost-effectiveness.