SARS-CoV-2 infection among physicians over time in Ontario, Canada: a population-based retrospective cohort study.

AIM: To assess this risk of SARS-CoV-2 infection among Ontario physicians by specialty and in comparison with non-physician controls during the COVID-19 pandemic. METHODS: In this retrospective cohort study, the primary outcome was incident SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR). Secondary outcomes were hospitalization, use of critical care, and mortality. RESULTS: From March 1, 2020 to December 31, 2022, 6172/30 617 (20%) active Ontario physicians tested positive for SARS-CoV-2. Infection was less likely if physicians were older (OR 0.78 [0.76-0.81] per 10 years), rural residents (OR 0.70 [0.59-0.83]), and lived in more marginalized neighborhoods (OR 0.74 [0.62-0.89]), but more likely if they were female (OR 1.14 [1.07-1.22]), worked in long-term care settings (OR 1.16 [1.02-1.32]), had higher patient volumes (OR 2.05 [1.82-2.30] for highest vs lowest), and were pediatricians (OR 1.25 [1.09-1.44]). Compared with community-matched controls (n=29 763), physicians had a higher risk of infection during the first two waves of the pandemic (OR 1.38 [1.20-1.59]) but by wave 3 the risk was no longer significantly different (OR 0.93 [0.83-1.05]). Physicians were less likely to be hospitalized within 14 days of their first positive PCR test than non-physicians (P<0.0001), but there was no difference in the use of critical care (P=0.48) or mortality (P=0.15). CONCLUSION: Physicians had higher rates of infection than community-matched controls during the first two waves of the pandemic in Ontario, but not from wave 3 onward. Physicians practicing in long-term care facilities and pediatricians were more likely to test positive for SARS-CoV-2 than other physicians.

Quality of End-of-Life Care in Gastrointestinal Cancers: A 13-Year Population-Based Retrospective Analysis in Ontario, Canada.

Population-based quality indicators of either aggressive or supportive care at end of life (EOL), especially when specific to a cancer type, help to inform quality improvement efforts. This is a population-based, retrospective cohort study of gastrointestinal (GI) cancer decedents in Ontario from 1 January 2006-31 December 2018, using administrative data. Quality indices included hospitalizations, emergency department (ED) use, intensive care unit admissions, receipt of chemotherapy, physician house call, and palliative home care in the last 14-30 days of life. Previously defined aggregate measures of both aggressive and supportive care at end of life were also used. In our population of 69,983 patients who died of a GI malignancy during the study period, the odds of experiencing aggressive care at EOL remained stable, while the odds of experiencing supportive care at EOL increased. Most of our population received palliative care in the last year of life (n = 65,076, 93.0%) and a palliative care home care service in the last 30 days of life (n = 45,327, 70.0%). A significant number of patients also experienced death in an acute care hospital bed (n = 28,721, 41.0%) or had a new hospitalisation in the last 30 days of life (n = 33,283, 51.4%). The majority of patients received palliative care in the last year of life, and a majority received a palliative care home service within the last 30 days of life. The odds of receiving supportive care at EOL have increased over time. Differences in care exist according to income, age, and rurality.

Neoadjuvant Chemoradiotherapy and Surgery for Esophageal Squamous Cell Carcinoma Versus Definitive Chemoradiotherapy With Salvage Surgery as Needed: The Study Protocol for the Randomized Controlled NEEDS Trial.

Background: The globally dominant treatment with curative intent for locally advanced esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemoradiotherapy (nCRT) with subsequent esophagectomy. This multimodal treatment leads to around 60% overall 5-year survival, yet with impaired post-surgical quality of life. Observational studies indicate that curatively intended chemoradiotherapy, so-called definitive chemoradiotherapy (dCRT) followed by surveillance of the primary tumor site and regional lymph node stations and surgery only when needed to ensure local tumor control, may lead to similar survival as nCRT with surgery, but with considerably less impairment of quality of life. This trial aims to demonstrate that dCRT, with selectively performed salvage esophagectomy only when needed to achieve locoregional tumor control, is non-inferior regarding overall survival, and superior regarding health-related quality of life (HRQOL), compared to nCRT followed by mandatory surgery, in patients with operable, locally advanced ESCC. Methods: This is a pragmatic open-label, randomized controlled phase III, multicenter trial with non-inferiority design with regard to the primary endpoint overall survival and a superiority hypothesis for the experimental intervention dCRT with regard to the main secondary endpoint global HRQOL one year after randomization. The control intervention is nCRT followed by preplanned surgery and the experimental intervention is dCRT followed by surveillance and salvage esophagectomy only when needed to secure local tumor control. A target sample size of 1200 randomized patients is planned in order to reach 462 events (deaths) during follow-up. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04460352.

Interventions for the treatment of oral cavity and oropharyngeal cancer: chemotherapy.

BACKGROUND: Oral cavity and oropharyngeal cancers are the most common cancers arising in the head and neck. Treatment of oral cavity cancer is generally surgery followed by radiotherapy, whereas oropharyngeal cancers, which are more likely to be advanced at the time of diagnosis, are managed with radiotherapy or chemoradiation. Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects. The development of new chemotherapy agents, new combinations of agents and changes in the relative timing of surgery, radiotherapy, and chemotherapy treatments may potentially bring about increases in both survival and quality of life for this group of patients. This review updates one last published in 2011. OBJECTIVES: To determine whether chemotherapy, in addition to radiotherapy and/or surgery for oral cavity and oropharyngeal squamous cell carcinoma results in improved overall survival, improved disease-free survival and/or improved locoregional control, when incorporated as either induction therapy given prior to locoregional treatment (i.e. radiotherapy or surgery), concurrent with radiotherapy or in the adjuvant (i.e. after locoregional treatment with radiotherapy or surgery) setting. SEARCH METHODS: An information specialist searched 4 bibliographic databases up to 15 September 2021 and used additional search methods to identify published, unpublished and ongoing studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) where more than 50% of participants had primary tumours in the oral cavity or oropharynx, and that evaluated the addition of chemotherapy to other treatments such as radiotherapy and/or surgery, or compared two or more chemotherapy regimens or modes of administration. DATA COLLECTION AND ANALYSIS: For this update, we assessed the new included trials for their risk of bias and at least two authors extracted data from them. Our primary outcome was overall survival (time to death from any cause). Secondary outcomes were disease-free survival (time to disease recurrence or death from any cause) and locoregional control (response to primary treatment). We contacted trial authors for additional information or clarification when necessary. MAIN RESULTS: We included 100 studies with 18,813 participants. None of the included trials were at low risk of bias.  For induction chemotherapy, we reported the results for contemporary regimens that will be of interest to clinicians and people being treated for oral cavity and oropharyngeal cancers. Overall, there is insufficient evidence to clearly demonstrate a survival benefit from induction chemotherapy with platinum plus 5-fluorouracil prior to radiotherapy (hazard ratio (HR) for death 0.85, 95% confidence interval (CI) 0.70 to 1.04, P = 0.11; 7427 participants, 5 studies; moderate-certainty evidence), prior to surgery (HR for death 1.06, 95% CI 0.71 to 1.60, P = 0.77; 198 participants, 1 study; low-certainty evidence) or prior to concurrent chemoradiation (CRT) with cisplatin (HR for death 0.71, 95% CI 0.37 to 1.35, P = 0.30; 389 participants, 2 studies; low-certainty evidence). There is insufficient evidence to support the use of an induction chemotherapy regimen with cisplatin plus 5-fluorouracil plus docetaxel prior to CRT with cisplatin (HR for death 1.08, 95% CI 0.80 to 1.44, P = 0.63; 760 participants, 3 studies; low-certainty evidence).  There is insufficient evidence to support the use of adjuvant chemotherapy over observation only following surgery (HR for death 0.95, 95% CI 0.73 to 1.22, P = 0.67; 353 participants, 5 studies; moderate-certainty evidence). Among studies that compared post-surgical adjuvant CRT, as compared to post-surgical RT, adjuvant CRT showed a survival benefit (HR 0.84, 95% CI 0.72 to 0.98, P = 0.03; 1097 participants, 4 studies; moderate-certainty evidence). Primary treatment with CRT, as compared to radiotherapy alone,  was associated with a reduction in the risk of death (HR for death 0.74, 95% CI 0.67 to 0.83, P < 0.00001; 2852 participants, 24 studies; moderate-certainty evidence).  AUTHORS' CONCLUSIONS: The results of this review demonstrate that chemotherapy in the curative-intent treatment of oral cavity and oropharyngeal cancers only seems to be of benefit when used in specific circumstances together with locoregional treatment. The  evidence does not show a clear survival benefit from the use of induction chemotherapy prior to radiotherapy, surgery or CRT. Adjuvant CRT reduces the risk of death by 16%, as compared to radiotherapy alone. Concurrent chemoradiation as compared to radiation alone is associated with a greater than 20% improvement in overall survival; however, additional research is required to inform how the specific chemotherapy regimen may influence this benefit.

Stakeholder engagement in economic evaluation: Protocol for using the nominal group technique to elicit patient, healthcare provider, and health system stakeholder input in the development of an early economic evaluation model of chimeric antigen receptor T-cell therapy.

INTRODUCTION: Chimeric antigen receptor T-cell (CAR-T) therapy is a class of immunotherapy. An economic evaluation conducted at an early stage of development of CAR-T therapy for treatment of adult relapsed or refractory acute lymphoblastic leukaemia could provide insight into factors contributing to the cost of treatment, the potential clinical benefits, and what the health system can afford. Traditionally, stakeholders are engaged in certain parts of health technology assessment processes, such as in the identification and selection of technologies, formulation of recommendations, and implementation of recommendations; however, little is known about processes for stakeholder engagement during the conduct of the assessment. This is especially the case for economic evaluations. Stakeholders, such as clinicians, policy-makers, patients, and their support networks, have insight into factors that can enhance the validity of an economic evaluation model. This research outlines a specific methodology for stakeholder engagement and represents an avenue to enhance health economic evaluations and support the use of these models to inform decision making for resource allocation. This protocol may inform a tailored framework for stakeholder engagement processes in future economic evaluation model development. METHODS AND ANALYSIS: We will involve clinicians, healthcare researchers, payers, and policy-makers, as well as patients and their support networks in the conduct and verification of an early economic evaluation of a novel health technology to incorporate stakeholder-generated knowledge. Three stakeholder-specific focus groups will be conducted using an online adaptation of the nominal group technique to elicit considerations from each. This study will use CAR-T therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia as a basis for investigating broader stakeholder engagement processes. ETHICS AND DISSEMINATION: This study received ethics approval from the Ottawa Hospital Research Institute Research Ethics Board (REB 20200320-01HT) and the results will be shared via conference presentations, peer-reviewed publications, and ongoing stakeholder engagement.

Minimization of resource utilization data collected within cost-effectiveness analyses conducted alongside Canadian Cancer Trials Group phase III trials.

BACKGROUND: Cost-effectiveness analyses embedded within randomized trials allow for evaluation of value alongside conventional efficacy outcomes; however, collection of resource utilization data can require considerable trial resources. METHODS: We re-analyzed the results from four phase III Canadian Cancer Trials Group trials that embedded cost-effectiveness analyses to determine the impact of minimizing potential cost categories on the incremental cost-effectiveness ratios. For each trial, we disaggregated total costs into component incremental cost categories and recalculated incremental cost-effectiveness ratios using (1) only the top 3 cost categories, (2) the top 5 cost categories, and (3) all cost components. Using individual trial-level data, confidence intervals for each incremental cost-effectiveness ratio simulation were generated by bootstrapping and descriptively presented with the original confidence intervals (and incremental cost-effectiveness ratios) from the publications. RESULTS: Drug acquisition costs represented the highest incremental cost category in three trials, while hospitalization costs represented the other consistent cost driver and the top incremental cost category in the fourth trial. Recalculated incremental cost-effectiveness ratios based on fewer cost components (top 3 and top 5) did not differ meaningfully from the original published results. Based on conventional willingness-to-pay thresholds (US$50,000-US$100,000 per quality-adjusted life-year), none of the re-analyses would have changed the original perception of whether the experimental therapies were considered cost-effective. CONCLUSIONS: These results suggest that the collection of resource utilization data within cancer trials could be narrowed. Omission of certain cost categories that have minimal impact on incremental cost-effectiveness ratio, such as routine laboratory investigations, could reduce the costs and undue burden associated with the collection of data required for cancer trial cost-effectiveness analyses.

Non-surgical management of advanced hepatocellular carcinoma: A systematic review by Cancer Care Ontario.

Background: Hepatocellular carcinoma (HCC) is a global health problem, accounting for 4.7% of all new cancer cases and 8.2% of all cancer deaths worldwide in 2018. Resection and transplantation are the only modalities that offer a cure for HCC; however, most patients are diagnosed at an advanced stage, precluding these curative treatments. A number of local (ie, ablative therapies) and/or local-regional therapies (ie, chemo-embolization) are used and followed by systemic therapy for advanced or progressive disease. Other treatments are available, but their efficacy compared with these standards is not well known. Methods: Literature searches (1/2000 to 1/2020 or 1/2005 to 1/2020, depending on the specific systematic review question) were conducted, including MEDLINE, Embase and the Cochrane Database of Systematic Reviews. Results: Over 30,000 articles were identified. In total, 49 studies were included in the systematic review. Conclusions: There is no evidence to support the addition of sorafenib to any local or regional therapy. First-line systemic therapy options for unresectable or metastatic HCC include sorafenib, lenvatinib, and atezolizumab + bevacizumab. Regorafenib or cabozantinib provide survival benefits when given as second-line treatment.

Patterns of Care and Costs for Older Patients With Colorectal Cancer at the End of Life: Descriptive Study of the United States and Canada.

PURPOSE: End-of-life (EOL) cancer care is costly, with challenges regarding intensity and place of care. We described EOL care and costs for patients with colorectal cancer (CRC) in the United States and the province of Ontario, Canada, to inform better care delivery. METHODS: Patients diagnosed with CRC from 2007 to 2013, who died of any cancer from 2007 to 2013 at age ≥ 66 years, were selected from the US SEER cancer registries linked to Medicare claims (n = 16,565) and the Ontario Cancer Registry linked to administrative health data (n = 6,587). We estimated total and resource-specific costs (2015 US dollars) from public payer perspectives over the last 360 days of life by 30-day periods, by stage at diagnosis (0-II, III, IV). RESULTS: In all months, especially 30 days before death, higher percentages of SEER-Medicare than Ontario patients received chemotherapy (15.7% v 8.0%), and imaging tests (39.4% v 31.1%). A higher percentage of Ontario patients were hospitalized (62.5% v 51.0%), but 43.2% of hospitalized SEER-Medicare patients had intensive care unit (ICU) admissions versus 17.9% of hospitalized Ontario patients. Cost differences between cohorts were greater for patients with stage IV disease. In the last 30 days, mean total costs for patients with stage IV disease were $15,881 (SEER-Medicare) and $12,034 (Ontario) versus $19,354 and $17,312 for stage 0-II. Hospitalization costs were higher for SEER-Medicare patients ($11,180 v $9,434), with lower daily hospital costs in Ontario ($1,067 v $2,004). CONCLUSION: These findings suggest opportunities for reducing chemotherapy and ICU use in the United States and hospitalizations in Ontario.

Impact of smoking on health system costs among cancer patients in a retrospective cohort study in Ontario, Canada.

OBJECTIVE: Smoking is the main modifiable cancer risk factor. The objective of this study was to examine the impact of smoking on health system costs among newly diagnosed adult patients with cancer. Specifically, costs of patients with cancer who were current smokers were compared with those of non-smokers from a publicly funded health system perspective. METHODS: This population-based cohort study of patients with cancer used administrative databases to identify smokers and non-smokers (1 April 2014-31 March 2016) and their healthcare costs in the 12-24 months following a cancer diagnosis. The health services included were hospitalisations, emergency room visits, drugs, home care services and physician services (from the time of diagnosis onwards). The difference in cost (ie, incremental cost) between patients with cancer who were smokers and those who were non-smokers was estimated using a generalised linear model (with log link and gamma distribution), and adjusted for age, sex, neighbourhood income, rurality, cancer site, cancer stage, geographical region and comorbidities. RESULTS: This study identified 3606 smokers and 14 911 non-smokers. Smokers were significantly younger (61 vs 65 years), more likely to be male (53%), lived in poorer neighbourhoods, had more advanced cancer stage,and were more likely to die within 1 year of diagnosis, compared with non-smokers. The regression model revealed that, on average, smokers had significantly higher monthly healthcare costs ($5091) than non-smokers ($4847), p<0.05. CONCLUSIONS: Smoking status has a significant impact on healthcare costs among patients with cancer. On average, smokers incurred higher healthcare costs than non-smokers. These findings provide a further rationale for efforts to introduce evidence-based smoking cessation programmes as a standard of care for patients with cancer as they have the potential not only to improve patients' outcomes but also to reduce the economic burden of smoking on the healthcare system.

Economic analysis of osimertinib in previously untreated EGFR-mutant advanced non-small cell lung cancer in Canada.

INTRODUCTION: Osimertinib improves progression-free survival in previously untreated EGFR-positive advanced non-small cell lung cancer (NSCLC) patients, with marked intracranial response rates. However, its cost-effectiveness in a publically funded health care system has not been established. We assessed the cost-effectiveness of first-line osimertinib from the public payer perspective in the Canadian health care system. METHODS: A Markov model was developed to project the outcomes and direct medical costs of initial treatment with osimertinib or current standard-of-care (SoC) EGFR TKIs, gefinitib or afatinib, in patients with previously untreated EGFR-mutant advanced NSCLC. Clinical and cost input estimates were informed from the available literature. Model outcomes included costs (in 2018 Canadian dollars), life years (LYs), quality-adjusted life-years (QALYs), and the cost utility of osimertinib compared to SoC EGFR TKI, or incremental cost per QALY gained. RESULTS: Initial treatment with osimertinib was associated with a gain of 0.79 QALY [95% confidence interval (CI), 0.74 to 0.83] at an incremental cost of $176,394 CAD (95% CI, 176,383 to 176,405) vs. SoC EGFR TKI (incremental cost-effectiveness ratio [ICER]: $223,133/QALY gained; 95%CI, 198,144 to 252,805). Osimertinib had a 0% probability of being cost-effective at a willingness-to-pay threshold of $100,000 per QALY. Deterministic sensitivity analysis showed that the cost of osimertinib had the largest impact on ICER results. CONCLUSION: At the current marketed price, first-line osimertinib therapy in patients with advanced EGFR-mutant lung adenocarcinoma is not cost-effective in Canada. Reduction of osimertinib cost, for example by 25%, can significantly improve the cost-effectiveness profile.

Do patients with reduced or excellent performance status derive the same clinical benefit from novel systemic cancer therapies? A systematic review and meta-analysis.

BACKGROUND: Whether patients with excellent and reduced performance status (PS) derive different net clinical benefit from novel anticancer systemic therapies on clinical trials is unclear. MATERIALS AND METHODS: A systematic review was conducted of randomised controlled trials (RCTs) cited for drug approvals between 2006 and August 2015 by the Food and Drug Administration, the European Medicines Agency and Health Canada. Included studies had overall survival (OS) and/or progression-free survival (PFS) primary endpoints. Meta-analyses of OS/PFS based on PS dichotomised into excellent and reduced subgroups were performed using random effects. RESULTS: The systematic review identified 110 RCTs, with none reporting PS subgroup analyses for toxicity and 66 (60%) for efficacy. For these 66 RCTs involving 44 511 patients, pooled HRs for excellent and reduced groups were 0.65 (95% CI 0.61 to 0.70) and 0.67 (95% CI 0.62 to 0.72), respectively, with no difference between the two groups (p=0.68). Sensitivity analyses based on drug or cancer type and type of endpoints (OS or PFS) demonstrated similar results. CONCLUSIONS: No decrease in relative efficacy from novel systemic therapy was found for patients with reduced PS when compared with patients with excellent PS for the range which were included in modern RCTs. Reporting of PS subgroup analyses of toxicities and more inclusion of patients with borderline low PS in RCTs should be considered for a more comprehensive understanding of the net clinical benefits of contemporary systemic therapies in patients across the spectrum of different PS.

Targeted metabolomics in colorectal cancer: a strategic approach using standardized laboratory tests of the blood and urine.

BACKGROUND: Glycolytic markers have been detected in colorectal cancer (CRC) using advanced analytical methods. METHODS: Using commercially available assays, by-products of anaerobic metabolism were prospectively measured in the blood and urine of 20 patients with metastatic colorectal cancer (mCRC) and 20 patients with local disease. Twenty-four-hour urine citrate, plasma lactate, ketones, venous blood gas, anion gap, and osmolar gap were investigated. Results of patients with metastatic and local CRC were compared using two-sample t-tests or equivalent nonparametric tests. In addition, plasma total CO2 concentrations in our local hospital (5,931 inpatients and 1,783 outpatients) were compared retrospectively with those in our dedicated cancer center (1,825 outpatients) over 1 year. RESULTS: The average venous pCO2 was higher in patients with mCRC (50.2 mmHg; standard deviation [SD]=9.36) compared with those with local disease (42.8 mmHg; SD=8.98), p=0.045. Calculated serum osmolarity was higher in mCRC and attributed to concomitant sodium and urea elevations. In our retrospective analysis, plasma total CO2 concentrations (median=27 mmol/L) were higher in cancer patients compared to both hospital inpatients (median=23 mmol/L) and outpatients (median=24 mmol/L), p<0.0001. CONCLUSION: Patients with mCRC had higher venous pCO2 levels than those with local disease. Although causation cannot be established, we hypothesize that pCO2 elevation may stem from a perturbed metabolism in mCRC.

The combined use of surgery and radiotherapy to treat patients with epidural cord compression due to metastatic disease: a cost-utility analysis.

Neoplastic metastatic epidural spinal cord compression is a common complication of cancer that causes pain and progressive neurologic impairment. The previous standard treatment for this condition involved corticosteroids and radiotherapy (RT). Direct decompressive surgery with postoperative radiotherapy (S + RT) is now increasingly being chosen by clinicians to significantly improve patients' ability to walk and reduce their need for opioid analgesics and corticosteroids. A cost-utility analysis was conducted to compare S + RT with RT alone based on the landmark randomized clinical trial by Patchell et al. (2005). It was performed from the perspective of the Ontario Ministry of Health and Long-Term Care. Ontario-based costs were adjusted to 2010 US dollars. S + RT is more costly but also more effective than corticosteroids and RT alone, with an incremental cost-effectiveness ratio of US$250 307 per quality-adjusted life year (QALY) gained. First order probabilistic sensitivity analysis revealed that the probability of S + RT being cost-effective is 18.11%. The cost-effectiveness acceptability curve showed that there is a 91.11% probability of S + RT being cost-effective over RT alone at a willingness-to-pay of US$1 683 000 per QALY. In practice, the results of our study indicate that, by adopting the S + RT strategy, there would still be a chance of 18.11% of not paying extra at a willingness-to-pay of US$50 000 per QALY. Those results are sensitive to the costs of hospice palliative care. Our results suggest that adopting a standard S + RT approach for patients with MSCC is likely to increase health care costs but would result in improved outcomes.

Interventions for the treatment of oral cavity and oropharyngeal cancer: chemotherapy.

BACKGROUND: Oral cavity and oropharyngeal cancers are frequently described as part of a group of oral cancers or head and neck cancer. Treatment of oral cavity cancer is generally surgery followed by radiotherapy, whereas oropharyngeal cancers, which are more likely to be advanced at the time of diagnosis, are managed with radiotherapy or chemoradiation. Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects, notably impaired ability to eat, drink and talk. The development of new chemotherapy agents, new combinations of agents and changes in the relative timing of surgery, radiotherapy, and chemotherapy treatments may potentially bring about increases in both survival and quality of life for this group of patients. OBJECTIVES: To determine whether chemotherapy, in addition to radiotherapy and/or surgery for oral cavity and oropharyngeal cancer results in improved survival, disease free survival, progression free survival, locoregional control and reduced recurrence of disease. To determine which regimen and time of administration (induction, concomitant or adjuvant) is associated with better outcomes. SEARCH STRATEGY: Electronic searches of the Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE, EMBASE, AMED were undertaken on 1st December 2010. Reference lists of recent reviews and included studies were also searched to identify further trials. SELECTION CRITERIA: Randomised controlled trials where more than 50% of participants had primary tumours in the oral cavity or oropharynx, and which compared the addition of chemotherapy to other treatments such as radiotherapy and/or surgery, or compared two or more chemotherapy regimens or modes of administration, were included. DATA COLLECTION AND ANALYSIS: Eighty-nine trials which met the inclusion criteria were assessed for risk of bias and data were extracted by two or more review authors. The primary outcome was total mortality. Trial authors were contacted for additional information or for clarification. MAIN RESULTS: There is evidence of a small increase in overall survival associated with induction chemotherapy compared to locoregional treatment alone (25 trials), hazard ratio (HR) of mortality 0.92 (95% confidence interval (CI) 0.84 to 1.00, P = 0.06). Post-surgery adjuvant chemotherapy is associated with improved overall survival compared to surgery ± radiotherapy alone (10 trials), HR of mortality 0.88 (95% CI 0.79 to 0.99, P = 0.03), and there is some evidence that this improvement may be greater with concomitant adjuvant chemoradiotherapy (4 trials), HR of mortality 0.84 (95% CI 0.72 to 0.98, P = 0.03). In patients with unresectable tumours, there is evidence that concomitant or alternating chemoradiotherapy is associated with improved survival compared to radiotherapy alone (26 trials), HR of mortality 0.78 (95% CI 0.73 to 0.83, P < 0.00001). These findings are confirmed by sensitivity analyses based on studies assessed at low risk of bias. There is insufficient evidence to identify which agent(s) and/or regimen(s) are the most effective. The additional toxicity attributable to chemotherapy in the combined regimens remains unquantified. AUTHORS' CONCLUSIONS: Chemotherapy, in addition to radiotherapy and surgery, is associated with improved overall survival in patients with oral cavity and oropharyngeal cancers. Induction chemotherapy may prolong survival by 8 to 20% and adjuvant concomitant chemoradiotherapy may prolong survival by up to 16%. In patients with unresectable tumours, concomitant or alternating chemoradiotherapy may prolong survival by 10 to 22%. There is insufficient evidence as to which agent or regimen is most effective and the additional toxicity associated with chemotherapy given in addition to radiotherapy and/or surgery cannot be quantified.

Interventions for the treatment of oral cavity and oropharyngeal cancer: radiotherapy.

BACKGROUND: The management of advanced oral cavity and oropharyngeal cancers is problematic and has traditionally relied on surgery and radiotherapy, both of which are associated with substantial adverse effects. Radiotherapy has been in use since the 1950s and has traditionally been given as single daily doses. This method of dividing up the total dose, or fractionation, has been modified over the years and a variety of approaches have been developed with the aim of improving survival whilst maintaining acceptable toxicity. OBJECTIVES: To determine which radiotherapy regimens for oral cavity and oropharyngeal cancers result in increased overall survival, disease free survival, progression free survival and locoregional control. SEARCH STRATEGY: The following electronic databases were searched: the Cochrane Oral Health Group's Trials Register (to 28 July 2010), CENTRAL (The Cochrane Library 2010, Issue 3), MEDLINE via OVID (1950 to 28 July 2010) and EMBASE via OVID (1980 to 28 July 2010). There were no restrictions regarding language or date of publication. SELECTION CRITERIA: Randomised controlled trials where more than 50% of participants had primary tumours of the oral cavity or oropharynx, and which compared two or more radiotherapy regimens, radiotherapy versus other treatment modality, or the addition of radiotherapy to other treatment modalities. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of risk of bias was undertaken independently by two or more authors. Study authors were contacted for additional information as required. Adverse events data were collected from published trials. MAIN RESULTS: 30 trials involving 6535 participants were included. Seventeen trials compared some form of altered fractionation (hyperfractionation/accelerated) radiotherapy with conventional radiotherapy; three trials compared different altered fractionation regimens; one trial compared timing of radiotherapy, five trials evaluated neutron therapy and four trials evaluated the addition of pre-operative radiotherapy. Pooling trials of any altered fractionation radiotherapy compared to a conventional schedule showed a statistically significant reduction in total mortality (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76 to 0.98). In addition, a statistically significant difference in favour of the altered fractionation was shown for the outcome of locoregional control (HR 0.79, 95% CI 0.70 to 0.89). No statistically significant difference was shown for disease free survival.No statistically significant difference was shown for any other comparison. AUTHORS' CONCLUSIONS: Altered fractionation radiotherapy is associated with an improvement in overall survival and locoregional control in patients with oral cavity and oropharyngeal cancers. More accurate methods of reporting adverse events are needed in order to truly assess the clinical performance of different radiotherapy regimens.

Interventions for the treatment of oral cavity and oropharyngeal cancer: chemotherapy.

BACKGROUND: Oral cavity and oropharyngeal cancers are frequently described as part of a group of oral cancers or head and neck cancer. Treatment of oral cavity cancer is generally surgery followed by radiotherapy, whereas oropharyngeal cancers, which are more likely to be advanced at the time of diagnosis, are managed with radiotherapy or chemoradiation. Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects, notably impaired ability to eat, drink and talk. The development of new chemotherapy agents, new combinations of agents and changes in the relative timing of surgery, radiotherapy, and chemotherapy treatments may potentially bring about increases in both survival and quality of life for this group of patients. OBJECTIVES: To determine whether chemotherapy, in addition to radiotherapy and/or surgery for oral cavity and oropharyngeal cancer results in improved survival, disease free survival, progression free survival, locoregional control and reduced recurrence of disease. To determine which regimen and time of administration (induction, concomitant or adjuvant) is associated with better outcomes. SEARCH STRATEGY: Electronic searches of the Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE, EMBASE, AMED were undertaken on 28th July 2010. Reference lists of recent reviews and included studies were also searched to identify further trials. SELECTION CRITERIA: Randomised controlled trials where more than 50% of participants had primary tumours in the oral cavity or oropharynx, and which compared the addition of chemotherapy to other treatments such as radiotherapy and/or surgery, or compared two or more chemotherapy regimens or modes of administration, were included. DATA COLLECTION AND ANALYSIS: Trials which met the inclusion criteria were assessed for risk of bias using six domains: sequence generation, allocation concealment, blinding, completeness of outcome data, selective reporting and other possible sources of bias. Data were extracted using a specially designed form and entered into the characteristics of included studies table and the analysis sections of the review. The proportion of participants in each trial with oral cavity and oropharyngeal cancers are recorded in Additional Table 1. MAIN RESULTS: There was no statistically significant improvement in overall survival associated with induction chemotherapy compared to locoregional treatment alone in 25 trials (hazard ratio (HR) of mortality 0.92, 95% confidence interval (CI) 0.84 to 1.00). Post-surgery adjuvant chemotherapy was associated with improved overall survival compared to surgery +/- radiotherapy alone in 10 trials (HR of mortality 0.88, 95% CI 0.79 to 0.99), and there was an additional benefit of adjuvant concomitant chemoradiotherapy compared to radiotherapy in 4 of these trials (HR of mortality 0.84, 95% CI 0.72 to 0.98). Concomitant chemoradiotherapy resulted in improved survival compared to radiotherapy alone in patients whose tumours were considered unresectable in 25 trials (HR of mortality 0.79, 95% CI 0.74 to 0.84). However, the additional toxicity attributable to chemotherapy in the combined regimens remains unquantified. AUTHORS' CONCLUSIONS: Chemotherapy, in addition to radiotherapy and surgery, is associated with improved overall survival in patients with oral cavity and oropharyngeal cancers. Induction chemotherapy is associated with a 9% increase in survival and adjuvant concomitant chemoradiotherapy is associated with a 16% increase in overall survival following surgery. In patients with unresectable tumours, concomitant chemoradiotherapy showed a 22% benefit in overall survival compared with radiotherapy alone.