Scott R. Berry

Randomized Phase II Study of Two Doses of Gefitinib in Hormone-Refractory Prostate Cancer: A Trial of the National Cancer Institute of Canada-Clinical Trials Group

PURPOSE Overexpression of the epidermal growth factor receptor has been demonstrated in advanced prostate cancer and is associated with a poor outcome. A multi-institutional, randomized, phase II study was undertaken by the National Cancer Institute of Canada-Clinical Trials Group to evaluate the efficacy and toxicity of two doses of oral gefitinib in patients with minimally symptomatic, hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS Between July and November 2001, 40 patients with HRPC and increasing prostate-specific antigen (PSA) or progression in measurable disease who had not received prior chemotherapy were randomly assigned to 250 mg (n = 19) or 500 mg (n = 21) oral gefitinib daily continuously. The primary end points were PSA response rate and objective measurable response. Functional Assessment of Cancer Therapy Prostate Cancer Subscale (FACT-P) quality-of-life questionnaires were completed at baseline and during treatment. RESULTS None of the patients demonstrated a PSA or objective measurable response. Five (14.3%) of 35 assessable patients had stable PSA (one patient at 250 mg and four patients at 500 mg), and five patients (14.3%) had a best response of stable disease (duration, 2.5 to 16.8 months). No significant effect on the rate of increase in PSA was seen. The most common drug-related nonhematologic toxicities observed were grade 1 to 2 diarrhea (250 mg, 65%; 500 mg, 56%), fatigue (250 mg, 29%; 500 mg, 33%), and grade 1 to 2 skin rash (250 mg, 24%; 500 mg, 39%). FACT-P scores decreased during treatment, indicating worsening of symptoms compared with baseline. CONCLUSION Gefitinib did not result in any responses in PSA or objective measurable disease at either dose level. Gefitinib has minimal single-agent activity in HRPC.

Randomized Phase II Trial of Custirsen (OGX-011) in Combination with Docetaxel or Mitoxantrone as Second-line Therapy in Patients with Metastatic Castrate-Resistant Prostate Cancer Progressing after First-line Docetaxel: CUOG Trial P-06c

Purpose: Clusterin (CLU) is an antiapoptotic, stress-induced protein conferring treatment resistance when overexpressed. This study tested custirsen, a CLU inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing during or within 6 months of initial docetaxel therapy. Patients and Methods: Men were randomized to receive either docetaxel + prednisone + custirsen (DPC) or mitoxantrone + prednisone + custirsen (MPC). Results: Forty-two patients received study treatment. Toxicity was similar in both arms. Twenty patients treated with DPC received a median of 8 cycles; overall survival (OS) was 15.8 months. Median time to pain progression (TTPP) was 10.0 months; 10 of 13 (77%) evaluable patients had pain responses. Three of 13 (23%) evaluable patients had objective partial responses. Prostate-specific antigen (PSA) declines of 90% or more, 50% or more, and 30% or more occurred in 4 (20%), 8 (40%), and 11 (55%) patients, respectively. Twenty-two patients treated with MPC received a median of 6 cycles; OS was 11.5 months. The median TTPP was 5.2 months; 6 of 13 (46%) evaluable patients had pain responses. No objective responses were observed. PSA declines of 50% or more and 30% or more occurred in 6 (27%) and 7 (32%) patients, respectively. Low serum CLU levels during treatment showed superior survival for patients based on modeling with proportional hazard regression with a time-dependent covariate and different landmarks. Conclusions: Custirsen plus either docetaxel or mitoxantrone was feasible in patients with progressive mCRPC following first-line docetaxel therapy. Pain relief was higher than expected, with interesting correlations between serum CLU and survival. A phase III trial evaluating the pain palliation benefit of custirsen with taxane therapy is ongoing. Clin Cancer Res; 17(17); 5765–73. ©2011 AACR.

Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer a randomized clinical trial

Importance Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. Objective To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. Design, Setting, and Participants Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015. Interventions Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. Main Outcomes and Measures The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. Results Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13). Conclusions and Relevance Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment. Trial Registration clinicaltrials.gov identifier: NCT00265850

Continental Divide? The Attitudes of US and Canadian Oncologists on the Costs, Cost-Effectiveness, and Health Policies Associated With New Cancer Drugs

PURPOSE Oncologists in the United States and Canada work in different health care systems, but physicians in both countries face challenges posed by the rising costs of cancer drugs. We compared their attitudes regarding the costs and cost-effectiveness of medications and related health policy. METHODS Survey responses of a random sample of 1,355 United States and 238 Canadian medical oncologists (all outside of Québec) were compared. RESULTS Response rate was 59%. More US oncologists (67% v 52%; P < .001) favor access to effective treatments regardless of cost, while more Canadians favor access to effective treatments only if they are cost-effective (75% v 58%; P < .001). Most (84% US, 80% Canadian) oncologists state that patient out-of-pocket costs influence their treatment recommendations, but less than half the respondents always or frequently discuss the costs of treatments with their patients. The majority of oncologists favor more use of cost-effectiveness data in coverage decisions (80% US, 69% Canadian; P = .004), but fewer than half the oncologists in both countries feel well equipped to use cost-effectiveness information. Majorities of oncologists favor government price controls (57% US, 68% Canadian; P = .01), but less than half favor more cost-sharing by patients (29% US, 41% Canadian; P = .004). Oncologists in both countries prefer to have physicians and nonprofit agencies determine whether drugs provide good value. CONCLUSION Oncologists in the United States and Canada generally have similar attitudes regarding cancer drug costs, cost-effectiveness, and associated policies, despite practicing in different health care systems. The results support providing education to help oncologists in both countries use cost-effectiveness information and discuss drug costs with their patients.

Clinically important aspects of lymph node assessment in colon cancer.

There has been considerable discussion in the literature regarding the importance and validity of lymph node retrieval and lymph node count for patients with colon cancer. In this article we summarize the importance of lymph node resection and assessment in contemporary colon cancer care, key clinical determinants of lymph node assessment, and discuss the role of lymph node assessment as a quality marker in colon cancer care. J. Surg. Oncol. 2009;99:248–255.

Non-hormonal systemic therapy in men with hormone-refractory prostate cancer and metastases: a systematic review from the Cancer Care Ontario Program in Evidence-based Care's Genitourinary Cancer Disease Site Group

BackgroundProstate cancer that has recurred after local therapy or disseminated distantly is usually treated with androgen deprivation therapy; however, most men will eventually experience disease progression within 12 to 20 months. New data emerging from randomized controlled trials (RCTs) of chemotherapy provided the impetus for a systematic review addressing the following question: which non-hormonal systemic therapies are most beneficial for the treatment of men with hormone-refractory prostate cancer (HRPC) and clinical evidence of metastases?MethodsA systematic review was performed to identify RCTs or meta-analyses examining first-line non-hormonal systemic (cytotoxic and non-cytotoxic) therapy in patients with HRPC and metastases that reported at least one of the following endpoints: overall survival, disease control, palliative response, quality of life, and toxicity. Excluded were RCTs of second-line hormonal therapies, bisphosphonates or radiopharmaceuticals, or randomized fewer than 50 patients per trial arm. MEDLINE, EMBASE, the Cochrane Library, and the conference proceedings of the American Society of Clinical Oncology were searched for relevant trials. Citations were screened for eligibility by four reviewers and discrepancies were handled by consensus.ResultsOf the 80 RCTs identified, 27 met the eligibility criteria. Two recent, large trials reported improved overall survival with docetaxel-based chemotherapy compared to mitoxantrone-prednisone. Improved progression-free survival and rates of palliative and objective response were also observed. Compared with mitoxantrone, docetaxel treatment was associated with more frequent mild toxicities, similar rates of serious toxicities, and better quality of life. More frequent serious toxicities were observed when docetaxel was combined with estramustine. Three trials reported improved time-to-disease progression, palliative response, and/or quality of life with mitoxatrone plus corticosteroid compared with corticosteroid alone. Single trials reported improved disease control with estramustine-vinblastine, vinorelbine-hydrocortisone, and suramin-hydrocortisone compared to controls. Trials of non-cytotoxic agents have reported equivocal results.ConclusionDocetaxel-based chemotherapy modestly improves survival and provides palliation for men with HRPC and metastases. Other than androgen deprivation therapy, this is the only other therapy to have demonstrated improved overall survival in prostate cancer in RCTs. Further investigations to identify more effective therapies for HRPC including the use of systemic therapies earlier in the natural history of prostate cancer are warranted.

Dose-Dependent Increases in Circulating TGF-α and Other EGFR Ligands Act As Pharmacodynamic Markers for Optimal Biological Dosing of Cetuximab and Are Tumor Independent

Purpose: The objective of this study was to characterize treatment-induced circulating ligand changes during therapy with epidermal growth factor receptor (EGFR) inhibitors and evaluate their potential as surrogate indicators of the optimal biological dose. Experimental Design: Conditioned medium from human tumor cell lines, ascites fluid from tumor xenografts, and plasma samples from normal mice, as well as colorectal cancer patients, were assessed for ligand elevations using ELISA, following treatment with cetuximab (Erbitux), an anti–mouse EGFR neutralizing antibody, or a small-molecule EGFR tyrosine kinase inhibitor. Results: A rapid elevation in human transforming growth factor α (TGF-α) was observed in all cell lines after treatment with cetuximab, but not with small-molecule inhibitors. The elevation showed a dose-response effect and plateau that corresponded to the maximal decrease in A431 proliferation in vitro and HT29 tumor growth in vivo. The TGF-α increase was exacerbated by ongoing ligand production and cleavage from the plasma membrane but did not involve transcriptional up-regulation of TGF-α or the matrix metalloproteinase tumor necrosis factor-α–converting enzyme/ADAM17. Elevations in plasma TGF-α, amphiregulin, and epiregulin were also detected in normal mice treated with an anti–mouse EGFR monoclonal antibody, illustrating a host tissue–dependent component of this effect in vivo. Finally, circulating TGF-α increased in the plasma of six patients with EGFR-negative colorectal tumors during cetuximab treatment. Conclusions: Treatment-induced increases in circulating ligands, particularly TGF-α, should be serially assessed in clinical trials of anti-EGFR therapeutic antibodies as potential biomarkers to aid in determination of the optimal biological dose.

Just Say Die

As a medical oncologist, I spend most of my time treating people with incurable cancers. Depending on the person and the specific illness that person has, that question may come on the first visit with me or on the tenth: “How long have I got?” It may come out of the blue or as part of a larger discussion about the progress of their disease. I will say, “It may be only a few months until the end ” or “until you pass away, ” but I rarely say exactly what I mean: “It’s only going to be a few months until you die.” Die is a short, simple word. The problem is that I rarely use it when I speak to my dying patients, and I don’t think I’m alone. Quality end-of-life care is an ethical imperative, and improving conversations about the end-oflife is an important part of improving that care. Although it’s acknowledged that discussions about dying are important, little has been written about the words we use during these discussions. I would like to examine why it is so difficult for physicians to use the word “die,” and why it may be so important that we use it more often.

Clinical bioethics integration, sustainability, and accountability: the Hub and Spokes Strategy

The “lone” clinical bioethicist working in a large, multisite hospital faces considerable challenges. While attempting to build ethics capacity and sustain a demanding range of responsibilities, he or she must also achieve an acceptable level of integration, sustainability, and accountability within a complex organisational structure. In an effort to address such inherent demands and to create a platform towards better evaluation and effectiveness, the Clinical Ethics Group at the Joint Centre for Bioethics at the University of Toronto is implementing the Hub and Spokes Strategy at seven hospitals. The goal of the Hub and Spokes Strategy is to foster an ethical climate and strengthen ethics capacity broadly throughout healthcare settings as well as create models in clinical bioethics that are excellent and effective.

External influences and priority-setting for anti-cancer agents: a case study of media coverage in adjuvant trastuzumab for breast cancer

BackgroundSetting priorities for the funding of new anti-cancer agents is becoming increasingly complex. The funding of adjuvant trastuzumab for breast cancer has brought this dilemma to the fore. In this paper we review external factors that may influence decision-making bodies and present a case study of media response in Ontario, Canada to adjuvant trastuzumab for breast cancer.MethodsA comprehensive search of the databases of Canadian national and local newspapers and television was performed. Articles pertaining to trastuzumab in adjuvant breast cancer as well as 17 other anti-cancer drugs and indications were retrieved. The search period was from the date when individual trial results were announced to the date funding was made available in Ontario.ResultsDuring the 2.6 months between the release of the trastuzumab results to funding approval in Ontario, we identified 51 episodes of media coverage. For the 17 other drugs/indications (7 breast and 10 non-breast), the median time to funding approval was 31 months (range 14–46). Other recent major advances in oncology such as adjuvant vinorelbine/cisplatin for resected NSCLC and docetaxel for advanced prostate cancer received considerably less media attention (17 media reports for each) than trastuzumab. The median number of media reports for breast cancer drugs was 4.5 compared to 2.5 for non-breast cancer drugs (p = 0.56).ConclusionPriority-setting for novel anti-cancer agents is a complex process that tries to ensure fair use of constrained resources to fund therapies with the best evidence of clinical benefit. However, this process is subject to external factors including the influence of media, patient advocates, politicians, and industry. The data in this case study serve to illustrate the significant involvement one (or all) of these external factors may play in the debate over priority-setting.