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1.  Temsirolimus Maintenance Therapy After Docetaxel Induction in Castration-Resistant Prostate Cancer 
The Oncologist  2015;20(12):1351-1352.
Lessons Learned.
Temsirolimus maintenance therapy after docetaxel induction chemotherapy
is safe in patients with castration-resistant prostate cancer, although biochemical or tumor responses are rare;
does not diminish quality of life; and
delays radiological and/or symptomatic progression by approximately 6 months.
No standard therapy is available for men with castration-resistant prostate cancer (CRPC) who have responded to docetaxel and do not yet have disease progression. Hence, we designed a single-arm phase II trial to explore whether the mTOR inhibitor temsirolimus can maintain the response to docetaxel without compromising quality of life.
After successful docetaxel induction (75 mg/m2 every 3 weeks; 6–10 cycles), 21 CRPC patients underwent temsirolimus maintenance treatment (25 mg weekly; 4 weeks per cycle). The primary endpoint was the time to treatment failure (TTTF) (i.e., radiological and/or symptomatic progression). The secondary endpoints included the tumor response rate (RECIST 1.0), safety (National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0), quality of life (Functional Assessment of Cancer Therapy-Prostate [FACT-P]), pain (Present Pain Intensity [PPI] scale), prostate-specific antigen (PSA) parameters, including time to PSA progression (TTPP) according to Prostate Cancer Clinical Trials Working Group criteria, and serial enumeration of circulating endothelial cells (CECs) and endothelial progenitor cells (CEPs).
Patients received a median of 7 cycles of temsirolimus (range, 1–28), resulting in a median TTTF of 24.3 weeks (95% confidence interval [CI], 16.1–33.0), 1 partial tumor response (4.8%), 1 PSA response (4.8%), and a median TTPP of 12.2 weeks (95% CI, 7.8–23.9). Grade 3-4 adverse events were infrequent, and FACT-P and PPI scores remained stable during treatment. CECs did not predict clinical benefit, and CEPs were not consistently detectable.
Temsirolimus maintenance therapy after successful docetaxel induction is feasible, does not adversely affect quality of life, and, in this exploratory single-arm phase II study, resulted in a median TTTF of 24.3 weeks.
PMCID: PMC4679087  PMID: 26542984
2.  Do retroperitoneal extragonadal germ cell tumours exist? 
Extragonadal germ cell tumours (GCTs) have been described arising in midline structures. Although primary retroperitoneal extragonadal GCTs (RPGCTs) comprise 30% to 40% of these, their existence as a genuine disease has been questioned. Our study evaluated clinicopathological findings to examine this question in RPGCT patients at our centre.
Data from 414 men between 1980 and 2014 treated at London Health Sciences Centre with chemotherapy for testicular GCTs were reviewed retrospectively. Primary RPGCT was defined as pathologically diagnosed GCT with no evidence of GCT in the testes by physical exam or ultrasound. Patients thought to have primary RPGCT at the time of initial diagnosis were identified from an electronic database and data were extracted.
In total, 18 men with a diagnosis of metastatic RPGCT were identified. Four were excluded due to ultrasound reports that were incomplete or suggested malignancy. The remaining 14 patients had negative or non-specific ultrasounds, and all received platinum-based combination chemotherapy. Ten patients (71%) underwent post-chemotherapy RP lymph node dissections; of those 8 (57%) who underwent orchiectomy, none had corresponding pathologically normal testicular tissue.
RPGCT patients present with more advanced disease stage. Our study sample size is limited, but the findings are consistent with existing literature suggesting that primary RPGCTs may not exist as a unique disease, but instead may represent metastatic disease from a clinically occult testicular primary. By corollary, viable malignant germ cells may be present in testes of patients with presumed primary RPGCT, and may persist as a site of residual malignant disease after chemotherapy.
PMCID: PMC4707886  PMID: 26788225
3.  A Population-Based Study of 30-day Incidence of Ischemic Stroke Following Surgical Neck Dissection 
Medicine  2015;94(33):e1106.
Supplemental Digital Content is available in the text
The objective of this study was to determine the 30-day incidence of ischemic stroke following neck dissection compared to matched patients undergoing non-head and neck surgeries.
A surgical dissection of the neck is a common procedure performed for many types of cancer. Whether such dissections increase the risk of ischemic stroke is uncertain.
A retrospective cohort study using data from linked administrative and registry databases (1995–2012) in the province of Ontario, Canada was performed. Patients were matched 1-to-1 on age, sex, date of surgery, and comorbidities to patients undergoing non-head and neck surgeries. The primary outcome was ischemic stroke assessed in hospitalized patients using validated database codes.
A total of 14,837 patients underwent surgical neck dissection. The 30-day incidence of ischemic stroke following the dissection was 0.7%. This incidence decreased in recent years (1.1% in 1995 to 2000; 0.8% in 2001 to 2006; 0.3% in 2007 to 2012; P for trend <0.0001). The 30-day incidence of ischemic stroke in patients undergoing neck dissection is similar to matched patients undergoing thoracic surgery (0.5%, P = 0.26) and colectomy (0.5%, P = 0.1). Factors independently associated with a higher risk of stroke in 30 days following neck dissection surgery were of age ≥75 years (odds ratio (OR) 1.63, 95% confidence interval (CI) 1.05–2.53), and a history of diabetes (OR 1.60, 95% CI 1.02–2.49), hypertension (OR 2.64, 95% CI 1.64–4.25), or prior stroke (OR 4.06, 95% CI 2.29–7.18).
Less than 1% of patients undergoing surgical neck dissection will experience an ischemic stroke in the following 30 days. This incidence of stroke is similar to thoracic surgery and colectomy.
PMCID: PMC4616442  PMID: 26287406
4.  Application of a Policy Framework for the Public Funding of Drugs for Rare Diseases 
Journal of General Internal Medicine  2014;29(Suppl 3):774-779.
In many countries, decisions about the public funding of drugs are preferentially based on the results of randomized trials. For truly rare diseases, such trials are not typically available, and approaches by public payers are highly variable. In view of this, a policy framework intended to fairly evaluate these drugs was developed by the Drugs for Rare Diseases Working Group (DRDWG) at the request of the Ontario Public Drug Programs.
To report the initial experience of applying a novel evaluation framework to funding applications for drugs for rare diseases.
Retrospective observational cohort study.
Clinical effectiveness, costs, funding recommendations, funding approval.
Between March 2008 and February 2013, eight drugs were evaluated using the DRDWG framework. The estimated average annual drug cost per patient ranged from 28,000 to 1,200,000 Canadian dollars (CAD). For five drugs, full evaluations were completed, specific funding recommendations were made by the DRDWG, and funding was approved after risk-sharing agreements with the manufacturers were negotiated. For two drugs, the disease indications were determined to be ineligible for consideration. For one drug, there was insufficient natural history data for the disease to provide a basis for recommendation. For the five drugs fully evaluated, 32 patients met the predefined eligibility criteria for funding, and five were denied based on predefined exclusion criteria.
The framework improved transparency and consistency for evaluation and public funding of drugs for rare diseases in Ontario. The evaluation process will continue to be iteratively refined as feedback on actual versus expected clinical and economic outcomes is incorporated.
PMCID: PMC4124122  PMID: 25029973
rare diseases; cost effectiveness; drug reimbursement
5.  Testing personalized medicine: patient and physician expectations of next-generation genomic sequencing in late-stage cancer care 
Developments in genomics, including next-generation sequencing technologies, are expected to enable a more personalized approach to clinical care, with improved risk stratification and treatment selection. In oncology, personalized medicine is particularly advanced and increasingly used to identify oncogenic variants in tumor tissue that predict responsiveness to specific drugs. Yet, the translational research needed to validate these technologies will be conducted in patients with late-stage cancer and is expected to produce results of variable clinical significance and incidentally identify genetic risks. To explore the experiential context in which much of personalized cancer care will be developed and evaluated, we conducted a qualitative interview study alongside a pilot feasibility study of targeted DNA sequencing of metastatic tumor biopsies in adult patients with advanced solid malignancies. We recruited 29/73 patients and 14/17 physicians; transcripts from semi-structured interviews were analyzed for thematic patterns using an interpretive descriptive approach. Patient hopes of benefit from research participation were enhanced by the promise of novel and targeted treatment but challenged by non-findings or by limited access to relevant trials. Family obligations informed a willingness to receive genetic information, which was perceived as burdensome given disease stage or as inconsequential given faced challenges. Physicians were optimistic about long-term potential but conservative about immediate benefits and mindful of elevated patient expectations; consent and counseling processes were expected to mitigate challenges from incidental findings. These findings suggest the need for information and decision tools to support physicians in communicating realistic prospects of benefit, and for cautious approaches to the generation of incidental genetic information.
PMCID: PMC3925281  PMID: 23860039
personalized medicine; cancer care; qualitative research; clinical trials; genetic testing; clinical sequencing
6.  ECF chemotherapy for liver metastases due to castration-resistant prostate cancer 
Most men with metastatic castration-resistant prostate cancer (CRPC) have biochemical response to docetaxel, but the objective response rate is low. Liver metastases are uncommon with CRPC and associated with shorter survival. More active treatment might benefit these patients. Epirubicin, cisplatin and flurouracil (ECF) is a standard regimen for gastric cancer and response in CRPC liver metastases has been reported. We reviewed our experience with ECF in CRPC with the primary objective of determining its anti-tumour activity in patients with liver metastatic CRPC.
Men with CRPC treated with ECF were identified from electronic databases and data were extracted from medical records. Men with tumours showing neuroendocrine features were excluded.
In total, we identified 14 CRPC patients treated with ECF were identified, of which 8 had liver metastases. The median age was 56 (range: 42–76) and all had multiple poor prognostic features. A median of 6 cycles of ECF were administered (range: 1–10) and toxicities were similar to previous reports. Of the 8 patients with liver metastases, 5 had partial remission.
ECF was highly active in this small selected group of younger men with liver metastases from CRPC and multiple poor prognostic features. Despite important limitations, this is the third report of high objective response rates with ECF in CRPC. Objective response rates are low with current monotherapies. A higher probability of ORR is preferred for critical organ disease, therefore the anti-tumour activity should encourage testing of ECF in comparison to the most active current therapies.
PMCID: PMC4216294  PMID: 25408803
7.  Randomized Phase 3 Trial of Abiraterone Acetate in Men with Metastatic Castration-Resistant Prostate Cancer and No Prior Chemotherapy 
The New England journal of medicine  2012;368(2):138-148.
Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) post-chemotherapy. Many mCRPC patients never receive chemotherapy and thus cannot benefit from abiraterone acetate; we evaluated this agent in mCRPC patients who had not received chemotherapy.
In this double-blind study, 1088 patients were randomized 1:1 to abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. Co-primary end points were radiographic progression-free survival (rPFS) and OS. Secondary end points measured clinically relevant landmarks of mCRPC progression. Patient-reported outcomes included pain progression and quality of life.
The study was unblinded after a planned interim analysis (IA) at 43% of OS events. Treatment with abiraterone acetate-prednisone resulted in a 57% reduction in the risk of radiographic progression or death (hazard ratio [HR], 0.43; 95% confidence interval [CI]: 0.35 to 0.52; P<0.001; 13% OS events IA) and an estimated 25% decrease in the risk of death (HR, 0.75; 95% CI: 0.61 to 0.93; P=0.009; 43% OS events IA). Secondary end points supported superiority of abiraterone acetate-prednisone: time to cytotoxic chemotherapy initiation, opiate use for cancer-related pain, prostate-specific antigen progression (all P<0.001) and performance status deterioration (P=0.005). Self-reported time to pain progression and patient functional status degradation favored abiraterone acetate-prednisone (P=0.05 and P=0.003). Grade 3/4 mineralocorticoid-related adverse events and liver function test abnormalities were more common with abiraterone acetate-prednisone.
Abiraterone acetate produces OS and rPFS benefits, as well as significant delays in clinical deterioration and initiation of chemotherapy, in mCRPC.
PMCID: PMC3683570  PMID: 23228172
Abiraterone acetate; prednisone; metastatic castration-resistant prostate cancer; androgen; CYP17
8.  Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) 
Secondary analyses of two randomized controlled trials (RCTs) and supportive epidemiologic and preclinical indicated the potential of selenium and vitamin E for preventing prostate cancer.
To determine whether selenium or vitamin E or both could prevent prostate cancer with little or no toxicity in relatively healthy men.
Design, Setting, and Participants
Randomization of a planned 32,400 men to selenium, vitamin E, selenium plus vitamin E, and placebo in a double-blinded fashion. Participants were recruited and followed in community practices, local hospitals and HMOs, and tertiary cancer centers in the United States, Canada and Puerto Rico. Baseline eligibility included 50 years or older (African American) or 55 years or older (all others), a serum prostate-specific antigen (PSA) ≤ 4 ng/mL, and a digital rectal examination (DRE) not suspicious for prostate cancer. Between 2001 and 2004, 35,533 men (10% more than planned because of a faster-than-expected accrual rate) were randomly assigned to the four study arms, which were well balanced with respect to all potentially important risk factors.
Oral selenium (200 µg/day from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/day of all rac-α-tocopheryl acetate) and matched selenium placebo, or the two combined or placebo plus placebo for a planned minimum of 7 and maximum of 12 years.
Main Outcome Measures
Prostate cancer (as determined by routine community diagnostic standards) and prespecified secondary outcomes including lung, colorectal and overall cancer.
Study supplements were discontinued at the recommendation of the Data and Safety Monitoring Committee at a planned 7-year interim analysis because the evidence convincingly demonstrated no benefit from either study agent (p < 0.0001) and no possibility of a benefit to the planned degree with additional follow-up. As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17 and 7.33). Hazard ratios (number of prostate cancers, 99% confidence intervals [CIs]) for prostate cancer were 1.13 for vitamin E (n=473; CI, 0.91–1.41), 1.04 for selenium (n=432; CI, 0.83–1.30), and 1.05 for the combination (n=437; CI, 0.83–1.31) compared with placebo (n=416). There were no significant differences (all p-values > 0.15) in any prespecified cancer endpoints. There were nonsignificant increased risks of prostate cancer in the vitamin E arm (p=0.06; relative risk [RR]=1.13; 99% CI, 0l95–1.35) and of Type 2 diabetes mellitus in the selenium arm (p=0.16; RR=1.07; 99% CI, 0.94–1.22), but they were not observed in the combination arm.
Selenium or vitamin E, alone or in combination, did not prevent prostate cancer in this population at the doses and formulations used.
PMCID: PMC3682779  PMID: 19066370
9.  A Case Report and Genetic Characterization of a Massive Acinic Cell Carcinoma of the Parotid with Delayed Distant Metastases 
We describe the presentation, management, and clinical outcome of a massive acinic cell carcinoma of the parotid gland. The primary tumor and blood underwent exome sequencing which revealed deletions in CDKN2A as well as PPP1R13B, which induces p53. A damaging nonsynonymous mutation was noted in EP300, a histone acetylase which plays a role in cellular proliferation. This study provides the first insights into the genetic underpinnings of this cancer. Future large-scale efforts will be necessary to define the mutational landscape of salivary gland malignancies to identify therapeutic targets and biomarkers of treatment failure.
PMCID: PMC3638544  PMID: 23653877
10.  Randomized Phase III Study Comparing Paclitaxel/Cisplatin/ Gemcitabine and Gemcitabine/Cisplatin in Patients With Locally Advanced or Metastatic Urothelial Cancer Without Prior Systemic Therapy: EORTC Intergroup Study 30987 
Journal of Clinical Oncology  2012;30(10):1107-1113.
The combination of gemcitabine plus cisplatin (GC) is a standard regimen in patients with locally advanced or metastatic urothelial cancer. A phase I/II study suggested that a three-drug regimen that included paclitaxel had greater antitumor activity and might improve survival.
Patients and Methods
We conducted a randomized phase III study to compare paclitaxel/cisplatin/gemcitabine (PCG) with GC in patients with locally advanced or metastatic urothelial carcinoma. Primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), overall response rate, and toxicity.
From 2001 to 2004, 626 patients were randomly assigned; 312 patients were assigned to PCG, and 314 patients were assigned to GC. After a median follow-up of 4.6 years, the median OS was 15.8 months on PCG versus 12.7 months on GC (hazard ratio [HR], 0.85; P = .075). OS in the subgroup of all eligible patients was significantly longer on PCG (3.2 months; HR, 0.82; P = .03), as was the case in patients with bladder primary tumors. PFS was not significantly longer on PCG (HR, 0.87; P = .11). Overall response rate was 55.5% on PCG and 43.6% on GC (P = .0031). Both treatments were well tolerated, with more thrombocytopenia and bleeding on GC than PCG (11.4% v 6.8%, respectively; P = .05) and more febrile neutropenia on PCG than GC (13.2% v 4.3%, respectively; P < .001).
The addition of paclitaxel to GC provides a higher response rate and a 3.1-month survival benefit that did not reach statistical significance. Novel approaches will be required to obtain major improvements in survival of incurable urothelial cancer.
PMCID: PMC3341152  PMID: 22370319
11.  Early-stage squamous cell carcinoma of the oropharynx: Radiotherapy vs. Trans-Oral Robotic Surgery (ORATOR) – study protocol for a randomized phase II trial 
BMC Cancer  2013;13:133.
The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has markedly increased over the last three decades due to newly found associations with human papillomavirus (HPV) infection. Primary radiotherapy (RT) is the treatment of choice for OPSCC at most centers, and over the last decade, the addition of concurrent chemotherapy has led to a significant improvement in survival, but at the cost of increased acute and late toxicity. Transoral robotic surgery (TORS) has emerged as a promising alternative treatment, with preliminary case series demonstrating encouraging oncologic, functional, and quality of life (QOL) outcomes. However, comparisons of TORS and RT in a non-randomized fashion are susceptible to bias. The goal of this randomized phase II study is to compare QOL, functional outcomes, toxicity profiles, and survival following primary RT (± chemotherapy) vs. TORS (± adjuvant [chemo] RT) in patients with OPSCC.
The target patient population comprises OPSCC patients who would be unlikely to require chemotherapy post-resection: Tumor stage T1-T2 with likely negative margins at surgery; Nodal stage N0-2, ≤3 cm in size, with no evidence of extranodal extension on imaging. Participants will be randomized in a 1:1 ratio between Arm 1 (RT ± chemotherapy) and Arm 2 (TORS ± adjuvant [chemo] RT). In Arm 1, patients with N0 disease will receive RT alone, whereas N1-2 patients will receive concurrent chemoradiation. In Arm 2, patients will undergo TORS along with selective neck dissections, which may be staged. Pathologic high-risk features will be used to determine the requirement for adjuvant radiotherapy +/- chemotherapy. The primary endpoint is QOL score using the M.D. Anderson Dysphagia Inventory (MDADI), with secondary endpoints including survival, toxicity, other QOL outcomes, and swallowing function. A sample of 68 patients is required.
This study, if successful, will provide a much-needed randomized comparison of the conventional strategy of primary RT vs. the novel strategy of primary TORS. The trial is designed to provide a definitive QOL comparison between the two arms, and to inform the design of an eventual phase III trial for survival outcomes.
Trial registration
PMCID: PMC3621077  PMID: 23514246
Head and neck cancer; Oropharynx; Human papillomavirus; Radiotherapy; Transoral robotic surgery; Quality of life; Survival; Randomized controlled trial
12.  Does HPV type affect outcome in oropharyngeal cancer? 
An epidemic of human papillomavirus (HPV)-related oropharyngeal squamous cell cancer (OPSCC) has been reported worldwide largely due to oral infection with HPV type-16, which is responsible for approximately 90% of HPV-positive cases. The purpose of this study was to determine the rate of HPV-positive oropharyngeal cancer in Southwestern Ontario, Canada.
A retrospective search identified ninety-five patients diagnosed with OPSCC. Pre-treatment biopsy specimens were tested for p16 expression using immunohistochemistry and for HPV-16, HPV-18 and other high-risk subtypes, including 31,33,35,39,45,51,52,56,58,59,67,68, by real-time qPCR.
Fifty-nine tumours (62%) were positive for p16 expression and fifty (53%) were positive for known high-risk HPV types. Of the latter, 45 tumors (90%) were identified as HPV-16 positive, and five tumors (10%) were positive for other high-risk HPV types (HPV-18 (2), HPV-67 (2), HPV-33 (1)). HPV status by qPCR and p16 expression were extremely tightly correlated (p < 0.001, Fishers exact test). Patients with HPV-positive tumors had improved 3-year overall (OS) and disease-free survival (DFS) compared to patients with HPV-negative tumors (90% vs 65%, p = 0.001; and 85% vs 49%, p = 0.005; respectively). HPV-16 related OPSCC presented with cervical metastases more frequently than other high-risk HPV types (p = 0.005) and poorer disease-free survival was observed, although this was not statistically significant.
HPV-16 infection is responsible for a significant proportion of OPSCC in Southwestern Ontario. Other high-risk subtypes are responsible for a smaller subset of OPSCC that present less frequently with cervical metastases and may have a different prognosis.
PMCID: PMC3650940  PMID: 23663293
Human papillomavirus; Oropharyngeal cancer; Epidemiology
14.  Effects of Funding Policy Changes and Health Warnings on the Use of Erythropoiesis-Stimulating Agents 
Journal of Oncology Practice  2012;8(3):179-183.
Formulary access and safety warnings had significant impacts on the new use of ESAs in patients with cancer, suggesting that both are effective means of influencing the use of these drugs.
To characterize the effects of formulary changes and governmental safety warnings on use of erythropoiesis-stimulating agents (ESAs) in patients with cancer.
Patients and Methods:
We conducted a cross-sectional time-series analysis using health administrative data from Ontario, Canada. From January 1997 to December 2009 we identified all ESA initiations among patients diagnosed with cancer. We explored the effects of two formulary changes that progressively liberalized coverage for ESAs, first by rescinding the requirement for blood transfusion in 2003 and then by removing all restrictions in 2007. We also explored the effect of US Food and Drug Administration and Health Canada warnings issued in the second quarter of 2007. To assess regional variability in ESA use, we determined prescription rates for each of Ontario's 14 regional cancer centers.
After the first formulary change, the ESA initiation rate increased to 1.66 new users per 1,000 patients with cancer, 374% more than predicted (P < .001). After the second formulary change, the initiation rate increased to 3.97 new users per 1,000 patients with cancer, 73% more than predicted (P < .001). After the safety warnings, this rate declined 81% by study end (P < .001). We found significant regional variation in ESA use.
Formulary access and safety warnings had significant impacts on the new use of ESA drugs in patients with cancer. This suggests that both are effective means of influencing the use of these drugs. Variable ESA prescription rates across our region may reflect a lack of consensus regarding their utility.
PMCID: PMC3396807  PMID: 22942813
15.  Cost-Effectiveness of Adding Cetuximab to Platinum-Based Chemotherapy for First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer 
PLoS ONE  2012;7(6):e38557.
To assess the cost effectiveness of adding cetuximab to platinum-based chemotherapy in first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) from the perspective of the Canadian public healthcare system.
We developed a Markov state transition model to project the lifetime clinical and economic consequences of recurrent or metastatic HNSCC. Transition probabilities were derived from a phase III trial of cetuximab in patients with recurrent or metastatic HNSCC. Cost estimates were obtained from London Health Sciences Centre and the Ontario Case Costing Initiative, and expressed in 2011 CAD. A three year time horizon was used. Future costs and health benefits were discounted at 5%.
In the base case, cetuximab plus platinum-based chemotherapy compared to platinum-based chemotherapy alone led to an increase of 0.093 QALY and an increase in cost of $36,000 per person, resulting in an incremental cost effectiveness ratio (ICER) of $386,000 per QALY gained. The cost effectiveness ratio was most sensitive to the cost per mg of cetuximab and the absolute risk of progression among patients receiving cetuximab.
The addition of cetuximab to standard platinum-based chemotherapy in first-line treatment of patients with recurrent or metastatic HNSCC has an ICER that exceeds $100,000 per QALY gained. Cetuximab can only be economically attractive in this patient population if the cost of cetuximab is substantially reduced or if future research can identify predictive markers to select patients most likely to benefit from the addition of cetuximab to chemotherapy.
PMCID: PMC3379991  PMID: 22745668
16.  Consolidative high-dose chemotherapy after conventional-dose chemotherapy as first salvage treatment for male patients with metastatic germ cell tumours 
Some men with metastatic germ cell tumours that have progressed after response to initial cisplatin-based combination chemotherapy are cured with conventional dose first salvage chemotherapy (CDCT) – however, many are not. High-dose chemotherapy with autologous stem cell rescue (HDCT) may be of value in these patients. Prognosis has recently been better defined by International Prognostic Factor Study Group (IPFSG) prognostic factors. HDCT after response to CDCT has been offered at our institution over the past two decades. We retrospectively assessed the validity of the IPFSG prognostic factors in our patients and evaluated the value of HDCT.
We identified eligible men with metastatic germ cell tumour progressed after at least 3 cycles of cisplatin-based chemotherapy and treated with cisplatin-based CDCT alone or with carboplatin-based HDCT. We also collected their clinical data. Patients were classified into risk groups using IPFSG factors, and progression-free and overall survival factors were analyzed and compared in patients treated with CDCT alone and with HDCT.
We identified 38 eligible first salvage patients who had received a median of 4 cycles (range, 1 to 7 cycles) of CDCT. Twenty patients received CDCT alone and 18 patients received CDCT plus HDCT. The overall median progression- free survival was 24.6 months (95%CI, 7.3 to 28.7 months) and overall median overall survival was 34.6 months (95%CI, 17.2 to 51.3 months). Distribution by IPFSG category and 2-year progression- free survival and 3-year overall survival rates within each risk category were very similar to the IPFSG results. There were two toxic deaths with CDCT and none with HDCT. Overall, patients treated with CDCT plus HDCT had improved progression- free survival and overall survival.
The IPFSG prognostic risk factors appeared valid in our patient population. The safety of HDCT with etoposide and carboplatin was confirmed. HDCT was associated with improved progression- free survival and overall survival outcomes, consistent with observations of the IPFSG group. Ideally, the value of optimal HDCT should be determined in comparison to optimal CDCT as first salvage therapy in men with metastatic germ cell tumour with a randomized trial.
PMCID: PMC3328550  PMID: 22511417
17.  Fluorescence in situ hybridization gene amplification analysis of EGFR and HER2 in patients with malignant salivary gland tumors treated with lapatinib 
Head & neck  2009;31(8):1006-1012.
Gene amplification status of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2) were analyzed and correlated with clinical outcome in patients with progressive malignant salivary glands tumors (MSGT) treated with the dual EGFR/Her2 tyrosine kinase inhibitor lapatinib
Fluorescence in situ hybridization (FISH) analysis for both EGFR and HER2 gene amplification was performed successfully in the archival tumor specimens of 20 patients with adenoid cystic carcinomas (ACC) and 17 patients with non-ACC, all treated with lapatinib.
For ACC, no EGFR or HER2 amplifications were detected. For non-ACC, no EGFR gene amplifications were detected but 3 patients (18%) were HER2 amplified and all had stained 3+ for both EGFR and HER2 by immunohistochemistry (IHC) in their archival specimens. Two of these patients had time-to-progression (TTP) durations of 8.3 months and 18.4 months respectively. Interestingly, patients with low and high HER2/chromosome-specific centromeric enumeration probe (CEP) 17 ratio had a prolonged TTP than those with moderate ratios for both ACC and non-ACC subtypes.
HER2 to CEP17 FISH ratio may predict which patients with MSGT have an increased likelihood to benefit from lapatinib. The finding of HER2:CEP17 ratio as a predictive marker of efficacy to lapatinib warrants further investigation.
PMCID: PMC2711990  PMID: 19309723
MSGT; lapatinib; EGFR and HER2 gene amplification; FISH
18.  High-intensity focused ultrasound for prostate cancer: a practice guideline 
The aim of this practice guideline was to develop evidence-based recommendations for clinicians on the use of high-intensity focused ultrasound (HIFU) in patients with localized prostate cancer.
The guideline was developed using the methods of Cancer Care Ontario’s Program in Evidence-Based Care (PEBC). The core methodology of the PEBC’s guideline development process is systematic review. A comprehensive literature search was undertaken to identify high-quality studies, reviews and other practice guidelines on the use of HIFU in prostate cancer. The evidence formed the basis of the recommendations, which were reviewed and amended where necessary, by clinical experts in medical and radiation oncology and urology.
The literature review yielded limited evidence. No randomized controlled trials or meta-analyses comparing HIFU with currently accepted management approaches were identified. The body of evidence is primarily based on data from case series. Internal feedback was provided by the PEBC Genitourinary Disease Site Group membership and the Report Approval Panel. External peer review included targeted review by clinical experts specifically requested to comment on the guideline, and professional consultation through an online survey of health care professionals.
HIFU is currently not recommended as an alternative to accepted curative treatment approaches for localized prostate cancer.
PMCID: PMC2910764  PMID: 20694096
19.  Interferon-alfa in the treatment of patients with inoperable locally advanced or metastatic renal cell carcinoma: a systematic review 
A systematic review was undertaken to determine whether interferon-alfa (IFN-α) is an effective treatment for patients with inoperable locally advanced or metastatic renal cell carcinoma (mRCC). MEDLINE, EMBASE, the Cochrane Library, guideline databases and relevant meeting proceedings were searched. Randomized clinical trials (RCTs) or meta-analyses comparing IFN-α-containing regimens to placebo or non-immunotherapy controls, and that reported response rate, survival, toxicity or quality of life data were eligible. Two systematic reviews and eight RCTs met the selection criteria. A Cochrane review updated in 2005 reported higher response rates and reduced one-year mortality based on 4 RCTs in patients who received IFN-α. Of the eight RCTs, three reporting objective response rate showed significant differences favouring IFN-α. Two of five trials reporting survival data showed longer median survival in the IFN-α group. Adverse effects of IFN-α were consistent across the trials with increased intensity and frequency concordant with increased IFN-α dose. Meta-analyses of seven RCTs for objective response and six RCTs for mortality favoured IFN-α: odds ratio 6.87 (95% Confidence Interval [CI], 3.29 to 14.35) and hazard ratio 0.79 (95% CI, 0.69 to 0.91), respectively. The effectiveness of IFN-α in mRCC has been subject to skepticism. As IFN-α has been used as a control arm in RCTs of new targeted therapies, therapies which not all patients may have access to, information about its effectiveness remains relevant. These data confirm genuine, if modest, effectiveness of IFN-α in mRCC.
PMCID: PMC2874597  PMID: 20514286
21.  Interleukin-2 in the treatment of unresectable or metastatic renal cell cancer: a systematic review and practice guideline 
We performed a systematic review of randomized controlled trials (RCTs) to assess the efficacy of interleukin-2 (IL-2) for the treatment of patients with unresectable or metastatic renal cell carcinoma (RCC).
We searched the literature to identify RCTs or meta-analyses of RCTs comparing treatment regimens with IL-2 to those without. Outcomes of interest included overall or progression-free survival, response rate, toxicity and quality of life.
We identified 36 RCTs, and 6 met the eligibility criteria (1098 patients). We studied IL-2 alone and in combination with other agents, including interferon-alpha (IFN-a), 5-fluorouracil (5-FU), and 13-cis-retinoic acid or tamoxifen. No trials comparing high-dose IL-2 to non-IL-2 regimens were identified. A meta-analysis of 1-year mortality data from the 6 trials did not show a difference between IL-2-based regimens and non-IL-2 controls. Two of the 6 trials detected statistically significant longer survival with IL-2 combined with IFN-a and 5-FU. Of the 4 trials that assessed progression-free survival, 3 reported significantly longer progression-free intervals with IL-2-based regimens. Five trials reported response rates; pooling the rates from these trials gave an overall weighted response rate of 13.3% (range 9%–39%) and 5.3% (range 0%–20%) for IL-2-containing regimens and non-IL-2 regimens, respectively. IL-2-based regimens were more toxic than were non-IL-2 controls; the most frequently reported grade 3–4 toxicities were hypotension (range 6%–68%), fever (2%–56%), nausea or vomiting or both (6%–34%), diarrhea (1%–28%) and cardiac toxicity (11%–25%). None of the trials reported health-related quality-of-life data.
Non-high-dose IL-2 containing regimens do not provide superior treatment efficacy over non-IL-2-based regimens, with added toxicity, and therefore should not be used as standard treatment for patients with unresectable or metastatic RCC. High-dose IL-2 should only be used by experienced physicians in the context of a clinical trial or investigative setting.
PMCID: PMC2422922  PMID: 18542758
22.  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 
BMC Cancer  2006;6:112.
Prostate 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?
A 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.
Of 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.
Docetaxel-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.
PMCID: PMC1550253  PMID: 16670021
23.  Prognostic variables in adult Wilms tumour 
Canadian Journal of Surgery  2008;51(4):252-256.
To identify outcomes and prognostic variables that predict survival outcomes in adult Wilms tumour patients.
We collected data on 128 patients with adult Wilms tumour treated between 1973 and 2006. Six cases from our 2 Canadian centres have not been previously reported. We collected data on the remaining 122 patients from published case reports or case series. Analyzed factors included age, sex, favourable or unfavourable histopathology, clinical stage (I, II, III or IV) and chemotherapy and radiotherapy received. The outcomes studied included overall survival (OS) and disease-specific survival (DSS). Univariate analysis with Kaplan–Meier actuarial methodology and multivariate analyses with Cox regression were used to determine outcomes and predictive clinical factors.
The patients' mean age was 26 (range 15–73) years. After a mean follow-up of 54 (range 2–240) months, the OS and DSS of the entire cohort were both 68%. Favourable histopathology predicted superior OS and DSS (both p < 0.001). Higher clinical stage predicted inferior OS and DSS (both p < 0.001).
Adult Wilms tumour has a poorer prognosis than pediatric Wilms tumour. In adults with Wilms tumour, more aggressive patient-and tumour-specific surveillance and adjunctive therapies than those advocated by pediatric National Wilms Tumor Study guidelines may be warranted, especially in patients with an unfavourable histopathology and higher clinical stage.
PMCID: PMC2552940  PMID: 18815646

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