Transitioning to Neoadjuvant Therapy for Resectable Non-Small Cell Lung Cancer: Trends and Surgical Outcomes in a Regionalized Pulmonary Oncology Network.

BACKGROUND: Several regulatory agencies have approved the use of the neoadjuvant chemo-immunotherapy for resectable stage II and III of non-small cell lung cancer (NSCLC) and numerous trials investigating novel agents are underway. However, significant concerns exist around the feasibility and safety of offering curative surgery to patients treated within such pathways. The goal in this study was to evaluate the impact of a transition towards a large-scale neoadjuvant therapy program for NSCLC. METHODS: Medical charts of patients with clinical stage II and III NSCLC who underwent resection from January 2015 to December 2020 were reviewed. The primary outcome was perioperative complication rate between neoadjuvant-treated versus upfront surgery patients. Multivariable logistic regression estimated occurrence of postoperative complications and overall survival was assessed as an exploratory secondary outcome by Kaplan-Meier and Cox-regression analyses. RESULTS: Of the 428 patients included, 106 (24.8%) received neoadjuvant therapy and 322 (75.2%) upfront surgery. Frequency of minor and major postoperative complications was similar between groups (P = .22). Occurrence in postoperative complication was similar in both cohort (aOR = 1.31, 95% CI 0.73-2.34). Neoadjuvant therapy administration increased from 10% to 45% with a rise in targeted and immuno-therapies over time, accompanied by a reduced rate of preoperative radiation therapy use. 1-, 2-, and 5-year overall survival was higher in neoadjuvant therapy compared to upfront surgery patients (Log-Rank P = .017). CONCLUSIONS: No significant differences in perioperative outcomes and survival were observed in resectable NSCLC patients treated by neoadjuvant therapy versus upfront surgery. Transition to neoadjuvant therapy among resectable NSCLC patients is safe and feasible from a surgical perspective.

A Phase II Exploratory Study to Identify Biomarkers Predictive of Clinical Response to Regorafenib in Patients with Metastatic Colorectal Cancer Who Have Failed First-Line Therapy.

Single-agent regorafenib is approved in Canada for metastatic colorectal cancer (mCRC) patients who have failed previous lines of therapy. Identifying prognostic biomarkers is key to optimizing therapeutic strategies for these patients. In this clinical study (NCT01949194), we evaluated the safety and efficacy of single-agent regorafenib as a second-line therapy for mCRC patients who received it after failing first-line therapy with an oxaliplatin or irinotecan regimen with or without bevacizumab. Using various omics approaches, we also investigated putative biomarkers of response and resistance to regorafenib in metastatic lesions and blood samples in the same cohort. Overall, the safety profile of regorafenib seemed similar to the CORRECT trial, where regorafenib was administered as ≥ 2 lines of therapy. While the mutational landscape showed typical mutation rates for the top five driver genes (APC, KRAS, BRAF, PIK3CA, and TP53), KRAS mutations were enriched in intrinsically resistant lesions. Additional exploration of genomic-phenotype associations revealed several biomarker candidates linked to unfavorable prognoses in patients with mCRC using various approaches, including pathway analysis, cfDNA profiling, and copy number analysis. However, further research endeavors are necessary to validate the potential utility of these promising genes in understanding patients' responses to regorafenib treatment.

Reasons for delay in timely administration of adjuvant chemotherapy for patients with stage III colon cancer: a multicentre cohort study from the McGill University Department of Oncology.

PURPOSE: Adjuvant chemotherapy within 56 or 84 days following curative resection is globally accepted as the standard of care for stage III colon cancer as it has been associated with improved overall survival. Initiation of adjuvant chemotherapy within this time frame is therefore recommended by clinical practice guidelines, including the European Society for Medical Oncology. The objective of this study was to evaluate adherence to these clinical practice guidelines for patients with stage III colon cancer across the Rossy Cancer Network (RCN); a partnership of McGill University's Faculty of Medicine, McGill University Health Centre, Jewish General Hospital and St Mary's Hospital Center. PATIENTS AND METHODS: 187 patients who had been diagnosed with stage III colon cancer and received adjuvant chemotherapy within the RCN partner hospitals from 2012 to 2015 were included. Patient and treatment information was retrospectively determined by chart review. Χ2 and Wilcoxon rank-sum tests were used to measure associations and a multivariate Cox regression model was used to determine risk factors contributing to delays in administration of adjuvant chemotherapy. RESULTS: The median turnaround time between surgery and adjuvant chemotherapy was 69 days. Importantly, only 27% of patients met the 56-day target, and 71% met the 84-day target. Increasing age, having more than one surgical complication and being diagnosed between 2013-2014 and 2014-2015 reduced the likelihood that patients met these targets. Furthermore, delays were observed at most intervals from surgery to first adjuvant chemotherapy treatment. CONCLUSION: Our study found that within these academic hospital settings, 27% of patients met the 56-day target, and 71% met the 84-day target. Delays were associated with hospital, surgeon and patient-related factors. Initiatives in quality improvement are needed in order to improve adherence to recommended treatment guidelines for prompt administration of adjuvant chemotherapy for stage III colon cancer.

Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study.

PURPOSE: Pembrolizumab monotherapy is standard first-line therapy for metastatic non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50% without actionable driver mutations. It is not known whether adding ipilimumab to pembrolizumab improves efficacy over pembrolizumab alone in this population. METHODS: In the randomized, double-blind, phase III KEYNOTE-598 trial (ClinicalTrials.gov identifier: NCT03302234), eligible patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing EGFR or ALK aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6 weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3 weeks for up to 35 doses. Primary end points were overall survival and progression-free survival. RESULTS: Of the 568 participants, 284 were randomly allocated to each group. Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9 months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; P = .74). Median progression-free survival was 8.2 months for pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard ratio, 1.06; 95% CI, 0.86 to 1.30; P = .72). Grade 3-5 adverse events occurred in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The external data and safety monitoring committee recommended that the study be stopped for futility and that participants discontinue ipilimumab and placebo. CONCLUSION: Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable EGFR or ALK aberrations. These data do not support use of pembrolizumab-ipilimumab in place of pembrolizumab monotherapy in this population.

Phase I/II Trial of Sorafenib in Combination with Vinorelbine as First-Line Chemotherapy for Metastatic Breast Cancer.

BACKGROUND: Preclinical models have reported a synergistic interaction between sorafenib and vinorelbine. We investigated the toxicity, efficacy, and pharmacokinetics interaction of this combination as first-line treatment for patients with metastatic breast cancer. METHODS: Patients were HER2-negative and treated with vinorelbine 30 mg/m2 IV days 1,8 every 21 plus daily oral sorafenib. In the phase I portion (3+3 design) patients received sorafenib 200 mg BID (cohort 1) or 400 mg BID (cohort 2). In the phase II expansion, 21 more evaluable patients were planned to receive the maximum tolerated dose (MTD). Pharmacokinetic analysis was performed in 6 patients: blood concentrations were compared for each drug in the presence or absence of the other drug. RESULTS: In cohort 1, one patient experienced a dose-limiting toxicity (DLT) (grade 3 pancreatitis), requiring the expansion of this cohort to 6 patients, without further documented DLTs. In cohort 2, one patient of six experienced a grade 4 DLT (asymptomatic rise in amylase not requiring drug discontinuation), establishing this dose level as the MTD (sorafenib 400 mg BID). After expansion at the MTD, a total of 27 patients (median age 57) were treated for a median of 8 cycles. One grade 5 febrile neutropenia occurred. With repeated cycles, 52% of patients required at least 1 dose reduction of either drug. One patient experienced a sustained grade 3 fatigue resulting in treatment discontinuation. The response rate was 30%. Median PFS was 5.7 months (95% CI 4.4-7.6), and clinical benefit (absence of disease progression at 6 months) was 48%. PK analysis showed a significant interaction between the two drugs, resulting in a higher Cmax of vinorelbine in the presence of sorafenib. CONCLUSION: The combination of sorafenib and vinorelbine at full doses is feasible but not devoid of toxicity, likely also due to a significant PK interaction. TRIAL REGISTRATION: ClinicalTrials.gov NCT00764972.

Eleven years disease-free: role of chemotherapy in metastatic BRCA2-related breast cancer.

BACKGROUND: Infiltrating ductal carcinoma of the breast, staged as pT1N3, was diagnosed in a 41-year-old premenopausal French-Canadian woman. Rapid nodal recurrence progressed to diffuse bone metastases, despite tamoxifen and megestrol. Following enrollment in an in-house study protocol, she received high-dose anthracycline-based induction chemotherapy followed by tandem autologous bone marrow transplantation with high-dose alkylator and platinum-based conditioning regimens. Upon full remission, protocol-mandated locoregional breast and prophylactic cranial radiation was delivered. Complete clinical and radiologic remission has been maintained in the 11 years since study enrolment, which prompted further investigation. INVESTIGATIONS: Pedigree construction and BRCA1/2 mutation analysis. DIAGNOSIS: A BRCA2 8765delAG mutation was identified, in the context of unusual and sustained complete remission from widely metastatic breast cancer. MANAGEMENT: The patient is now followed at a multidisciplinary high-risk prevention clinic because BRCA2 mutations are associated with increased risk of ovarian and breast cancers. This case supports the possibility of differential treatment response in BRCA2-positive breast cancer, although this remains to be conclusively demonstrated.

Prophylactic cranial irradiation in advanced breast cancer: a case for caution.

PURPOSE: Prophylactic cranial irradiation (PCI) has a well-recognized role in the treatment of leukemia and small-cell lung cancer. Clinical utility has yet to be determined for breast cancer, where an emerging group at high risk of brain metastasis has fuelled consideration of PCI. METHODS AND MATERIALS: In reviewing our experience with PCI as part of a complex protocol for advanced breast cancer, we present descriptive data on late central nervous system outcomes in those receiving PCI. After high-dose anthracycline-based induction chemotherapy, Stage IIIB/IV breast cancer responders underwent tandem autologous marrow transplantation. Those in continued remission were referred for PCI. Whole-brain radiotherapy was delivered by usual means, at 36 Gy in 20 fractions. RESULTS: Twenty-four women, with median age 45 (28-61), were enrolled between 1995 and 1998. Disease was largely metastatic (79%), and 75% were previously exposed to chemotherapy or hormonotherapy. Ten patients received PCI, at a median of 13.4 (11.8-16.5) months from study entry. Six patients developed brain metastases, 2 despite PCI. Striking functional decline was documented in 3 patients (at 9 months, 4 years, and 5 years post-PCI), including one previously high-functioning woman requiring full care for posttreatment dementia. CONCLUSIONS: We present a series of advanced breast cancer patients treated prophylactically with whole-brain radiotherapy following an aggressive chemotherapy regimen. Although the therapeutic benefit of PCI is not ascertainable here, we describe brain metastases occurring despite PCI and serious long-term neurobehavioral sequelae in PCI-treated patients. Any further investigation of PCI in high-risk breast cancer will need to be approached with caution.

Long-term use of antihypertensive drugs and risk of cancer.

PURPOSE: Determine the relative risk of cancer users of commonly prescribed antihypertensive drugs with a focus on documenting risk in long-term users (>7.5 years). METHODS: We conducted a nested case-control study using the Saskatchewan Health databases. Cancer risks in users of beta-blockers, calcium channel blockers (CCBs), and rennin-angiotensin system inhibitors (RASIs), respectively, were compared to risks in users of thiazide diuretics. RESULTS: A total of 11,697 first cases of cancer and the subset of 6918 subjects who died from cancer were each matched to 10 controls. The mean total duration of use of the four classes of antihypertensive drugs (estimated by dispensation of prescriptions) ranged from 3.6 to 5.7 years. A subgroup of cases was exposed long term (mean total duration of use: 9.7-11.4 years, range: 7.5-23.1 years). Modest differences in risk between users of the four classes were detected for colon, head & neck, lung, and hematological cancers but none of these associations demonstrated a clear dose response relationship for both first cancer and fatal cancer. Otherwise, for cancer at all sites combined and for the four most common cancers, we were able to rule out, with reasonable confidence, small to modest differences in the risk of cancer among users of any duration (upper 95% confidence intervals (CIs): 1.45) and modest to large differences in risk among long-term users (upper 95%CI: 3.06). CONCLUSIONS: The long-term use of commonly prescribed classes of antihypertensive drugs does not appear to promote or initiate cancer.

Prospective serial proton MR spectroscopic assessment of response to tamoxifen for recurrent malignant glioma.

OBJECTIVE: Early prediction of imminent failure during chemotherapy for malignant glioma has the potential to guide proactive alterations in treatment before frank tumor progression. We prospectively followed patients with recurrent malignant glioma receiving tamoxifen chemotherapy using proton magnetic resonance spectroscopic imaging ((1)H-MRSI) to identify intratumoral metabolic changes preceding clinical and radiological failure. METHODS: We performed serial (1)H-MRSI examinations to assess intratumoral metabolite intensities in 16 patients receiving high-dose oral tamoxifen monotherapy for recurrent malignant glioma (WHO grade III or IV) as part of a phase II clinical trial. Patients were followed until treatment failure, death, or trial termination. RESULTS: Patients were officially classified as responders (7 patients) or non-responders (9 patients) 8 weeks into treatment. At 8 weeks, responders and non-responders had different intratumoral intensities across all measured metabolites except choline. Beyond 8 weeks, metabolite intensities remained stable in all responders, but changed again with approaching disease progression. Choline, lipid, choline/NAA, and lactate/NAA were significantly elevated (P < 0.02), while creatine (P < 0.04) was significantly reduced, compared to stabilized levels on average 4 weeks prior to failure. Lactate was significantly elevated (P = 0.036) fully 8 weeks prior to failure. In one patient who was still responding to tamoxifen at the conclusion of the trial, metabolite intensities never deviated from 8-week levels for the duration of follow-up. CONCLUSIONS: Characteristic global intratumoral metabolic changes, detectable on serial (1)H-MRSI studies, occur in response to chemotherapy for malignant glioma and may predict imminent treatment failure before actual clinical and radiological disease progression.

An oncology perspective on the benefits and cost of combined androgen blockade in advanced prostate cancer.

OBJECTIVES: To provide context in oncology for the significance of the benefits and cost of combined androgen blockade (CAB) in the treatment of advanced prostate cancer. METHODS: Canadian drug costs for the survival benefit with CAB in advanced prostate cancer were compared with the costs of benefit with new treatments in advanced non-small-cell lung cancer (NSCLC), metastatic colorectal cancer, and metastatic breast cancer. Clinical toxicities were also compared. RESULTS: The survival benefit with CAB in advanced prostate cancer appears to be approximately 3 months. The survival benefit with the addition of vinorelbine to cisplatin for the treatment of advanced NSCLC is approximately 2 months, and the survival benefit with the addition of irinotecan to fluorouracil (and leucovorin) for the treatment of metastatic colorectal cancer is approximately 2 to 3 months. The survival benefit with anastrozole or exemestane in advanced breast cancer, or with the addition of trastuzumab to standard chemotherapy in metastatic breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2), is approximately 4 to 5 months. The calculated cost per month of survival benefit with bicalutamide in CAB for prostate cancer is 437 US dollars to 1107 US dollars. The cost per month of survival benefit with vinorelbine for NSCLC is 1241 US dollars and with irinotecan for colorectal cancer is 6812 to 11,214 US dollars. The calculated cost per month of survival benefit with anastrozole for breast cancer is 170 US dollars, for exemestane is 185 US dollars, and the cost per month with the addition of trastuzumab is 5230 US dollars. Vinorelbine and irinotecan are associated with severe grade 3 or 4 clinical toxicities, and an increased frequency of heart failure has been observed when trastuzumab is added to anthracyclines. Anastrozole, exemestane and nonsteroidal antiandrogens are associated with mild to moderate side effects. CONCLUSIONS: The advantages offered by CAB (including the cost per month of survival benefit and minimal associated clinical toxicities) are comparable to the reported advantages of new treatments for other common cancers such as NSCLC, colorectal cancer, and breast cancer.

Weekly paclitaxel and gemcitabine chemotherapy for metastatic non-small cell lung carcinoma (NSCLC): a dose-optimizing phase II trial.

BACKGROUND: The current dose-optimizing Phase II study evaluated the effect of weekly paclitaxel and gemcitabine on the response rate and survival of patients with non-small cell lung carcinoma (NSCLC) using dose modifications that permitted optimal treatment intensity. METHODS: Forty-five patients (40 with TNM Stage IV and 5 with TNM Stage IIIB NSCLC) were treated with gemcitabine at 1000 mg/m(2) via a 30-minute intravenous (i.v.) infusion and with paclitaxel at 100 mg/m(2) via a 60-minute i.v. infusion. The first 3 patients received chemotherapy on Days 1, 8, and 15 every 4 weeks; the next 42 patients, participating in the Phase II trial, received chemotherapy on Days 1 and 8 every 3 weeks. RESULTS: The 3 patients who received paclitaxel and gemcitabine on Days 1, 8, and 15 every 4 weeks tolerated the treatment poorly. One patient died suddenly after Day 15 treatment during the first cycle, and the other 2 patients discontinued the treatment because of unacceptable toxicity before the third cycle of chemotherapy. The next 42 patients, 40 of whom were evaluable, entered this trial between May 2000 and April 2001. They received paclitaxel at 100 mg/m(2) i.v. followed by gemcitabine at 1000 mg/m(2) i.v. on Days 1 and 8 every 3 weeks. Two patients (5%) achieved complete response, 20 (50%) achieved partial response, and 8 (20%) had stable disease. Median survival (MS) was 9.8 months; and 1-year survival was 35%. The 32 patients with performance status (PS) 0 or 1 had an MS of 11 months; the 8 patients with PS 2 had an MS of 3 months. Toxicity (especially hematologic toxicity, neuropathy, and alopecia) was minimal. CONCLUSION: A weekly paclitaxel and gemcitabine regimen that incorporated the authors' dose modifications resulted in good efficacy with minimal toxicity.