Systemic therapy in the curative treatment of head-and-neck squamous cell cancer: Cancer Care Ontario clinical practice guideline.

OBJECTIVE: The aim of the present work was to make recommendations about the use of systemically administered drugs in combination or in sequence with radiation (rt) or surgery, or both, for cure or organ preservation, or both, in patients with locally advanced nonmetastatic (stages iii-ivb) squamous cell carcinoma of the head and neck (lascchn). METHODS: The Meta-analysis of Chemotherapy in Head and Neck Cancer (mach-nc) reports have, de facto, guided practice since 2000, and so we searched the literature for systematic reviews published from January 2000 to February 2015 in reference to five research questions. A search was also conducted up to February 2015 for randomized trials (rcts) not included in the meta-analyses. Recommendations were constructed using the Cancer Care Ontario Program in Evidence-Based Care practice guidelines development cycle. RESULTS: In addition to updated mach-nc reports, five additional meta-analyses and thirty rcts were identified. Five recommendations for lascchn treatment were generated based on those data. Concurrent chemoradiation (ccrt) is recommended to maximize the chance of cure in patients less than 71 years of age when rt is used as definitive treatment. The same recommendation also applies to patients with resected lascchn considered to be at high risk for locoregional recurrence. For lascchn patients who are candidates for organ preservation strategies and would otherwise require total laryngectomy, either ccrt or induction chemotherapy, followed by rt or surgery based on tumour response is recommended. The addition of cetuximab to intensified rt (concomitant boost or hyperfractionated schedule) is an alternative to ccrt. Routine use of induction chemotherapy to improve overall survival is not recommended. CONCLUSIONS: We were able to use high-level evidence from patients receiving rt as definitive or postoperative treatment to generate recommendations for the use of systemic therapy in the treatment of lascchn. A limitation is a lack of stratification for human papillomavirus-related cancers of the oropharynx. One rct provided evidence for the use of cetuximab as an alternative to chemotherapy in the definitive rt setting. Concurrent chemoradiation provides one strategy for larynx preservation, but the best strategy is unclear. Use of induction chemotherapy does not improve overall survival, and its use should be limited to patients requiring immediate tumour downsizing before local therapy.

Adjuvant systemic chemotherapy for stages II and III colon cancer after complete resection: a clinical practice guideline.

BACKGROUND: Updated practice guidelines on adjuvant chemotherapy for completely resected colon cancer are lacking. In 2008, Cancer Care Ontario's Program in Evidence-Based Care developed a guideline on adjuvant therapy for stages ii and iii colon cancer. With newer regimens being assessed in this patient population and older agents being either abandoned because of non-effectiveness or replaced by agents that are more efficacious, a full update of the original guideline was undertaken. METHODS: Literature searches (January 1987 to August 2015) of medline, embase, and the Cochrane Library were conducted; in addition, abstracts from the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress were reviewed (the latter for January 2007 to August 2015). A practice guideline was drafted that was then scrutinized by internal and external reviewers whose comments were incorporated into the final guideline. RESULTS: Twenty-six unique reports of eighteen randomized controlled trials and thirteen unique reports of twelve meta-analyses or pooled analyses were included in the evidence base. The 5 recommendations developed included 3 for stage ii colon cancer and 2 for stage iii colon cancer. CONCLUSIONS: Patients with completely resected stage iii colon cancer should be offered adjuvant 5-fluorouracil (5fu)-based chemotherapy with or without oxaliplatin (based on definitive data for improvements in survival and disease-free survival). Patients with resected stage ii colon cancer without "high-risk" features should not receive adjuvant chemotherapy. For patients with "high-risk" features, 5fu-based chemotherapy with or without oxaliplatin should be offered, although no clinical trials have been conducted to conclusively demonstrate the same benefits seen in stage iii colon cancer.

Nonsurgical management of advanced hepatocellular carcinoma: a clinical practice guideline.

Background: Practice guidelines based on a systematic review of the literature regarding the nonsurgical management of hepatocellular carcinoma (hcc) in North America are lacking. Resection and transplantation are the foundations for cure of hcc; however, most patients are diagnosed at an advanced stage, precluding those curative treatments. A number of local or regional therapies are used and are followed by systemic therapy for advanced or progressive disease. Other treatments are available, but their efficacy, compared with those standards, is not well known. Methods: First, systematic review questions were developed. Literature searches of the medline, embase, and Cochrane library databases (January 2000 to July 2018 or January 2005 to July 2018 depending on the question) were conducted; in addition, abstracts from the 2018 annual meeting of the American Society of Clinical Oncology were reviewed. A practice guideline was drafted that was then scrutinized by internal and external reviewers. Results: Seventy-seven studies were included in the guideline: no guidelines, two systematic reviews, and seventy-five primary studies published in full (including one pooled analysis). Five recommendations were developed. Conclusions: There is no evidence for or against the use of local or regional interventions other than transarterial chemoembolization for the treatment of intermediate- or advanced-stage hcc. Furthermore, there is no evidence to support the addition of sorafenib to any local or regional therapy. Sorafenib or lenvatinib are recommended for first-line systemic treatment of intermediate-stage hcc. Regorafenib or cabozantinib provide survival benefits when given as second-line treatment. Antiviral treatment is recommended in individuals with advanced hcc who are positive for the hepatitis B surface antigen.

Adjuvant Chemotherapy for Stage II and III Colon Cancer Following Complete Resection: A Cancer Care Ontario Systematic Review.

The objective of this systematic review was to provide current evidence regarding the use of adjuvant systemic chemotherapy for stage II and III colon cancer following curative intent surgery. MEDLINE and EMBASE databases and proceedings of American Society for Clinical Oncology and European Society of Medical Oncology/European Cancer Congress were searched through to August 2015. Systematic reviews (with or without meta-analyses) and randomised controlled trials were included. Patients with completely resected stage III colon cancer have an overall survival benefit from adjuvant chemotherapy. Combination chemotherapy (5-fluorouracil/leucovorin/oxaliplatin or capecitabine/oxaliplatin) provides a larger benefit than monotherapy but with additional toxicity. For stage II colon cancer, a clear overall survival benefit has not been shown. However, based on the subgroup analysis available, patients with high-risk stage II disease may benefit from adjuvant chemotherapy. Patients younger than 70 years of age may derive greater disease-free survival and overall survival benefit from adjuvant chemotherapy (in combination with oxaliplatin) compared with those older than 70 years. Stage II patients with microsatellite instability may have an overall survival detriment if given adjuvant chemotherapy.

Caffeine increases time to fatigue by maintaining force and not by altering firing rates during submaximal isometric contractions.

Caffeine increases time to fatigue [limit of endurance (T(lim))] during submaximal isometric contractions without altering whole muscle activation or neuromuscular junction transmission. We used 10 male volunteers in a randomized, double-blind, repeated-measures experiment to examine single motor unit firing rates during intermittent submaximal contractions and to determine whether administering caffeine increased T(lim) by maintaining higher firing rates. On 2 separate days, subjects performed intermittent 50% maximal voluntary contractions of the quadriceps to T(lim), 1 h after ingesting a caffeine (6 mg/kg) or placebo capsule. Average motor unit firing rates recorded with tungsten microelectrodes were constant for the duration of contractions. Caffeine increased average T(lim) by 20.5 +/- 8.1% (P < 0.05) compared with placebo conditions. This increase was due to seven subjects, termed responders, who increased T(lim) significantly. Two other subjects showed no response, and a third had a shorter T(lim). Neither the increased T(lim) nor the responders' performance could be explained by alterations in firing rates or other neuromuscular variables. However, the amplitude of the evoked twitch and its maximal instantaneous rate of relaxation did not decline to the same degree in the caffeine trial of the responders; this resulted in values 20 and 30% higher at the time point matching the end of the placebo trial (P < 0.05). The amplitude of the evoked twitch and the maximal instantaneous rate of relaxation were linearly correlated (caffeine r = 0.72, placebo r = 0.80, both P < 0.001), suggesting that the increase in T(lim) may be partially explained by caffeine's effects on calcium reuptake and twitch force.

Coronary artery bypass graft surgery and primary percutaneous coronary intervention choices in patients with similar coronary anatomy: A computer-based simulation examines the sex gap.

BACKGROUND: Sex differences (or a 'sex gap') exist in the rates of cardiac revascularization. It was evaluated whether physician preference contributes to this difference. OBJECTIVES: To obtain information on how cardiac specialists manage male and female patients being evaluated for coronary artery disease. METHODS: A computer-based patient simulation program was developed. Six sex-matched clinical vignettes (three pairs) with uninterpreted coronary angiograms were shown to specialists, who were blinded to the purpose of the study. The sex-matched scenarios were balanced with respect to symptoms, comorbidities and coronary anatomy. Physicians were surveyed on management and rationale. RESULTS: Fifty physicians were surveyed, consisting mainly of cardiologists from tertiary cardiac centres in Ontario. Among the three sexmatched pairs, the frequencies at which percutaneous coronary intervention (including drug-eluting stents), bypass surgery and medical therapy were chosen did not differ across sexes. The means for men and women, respectively, were 47% and 50% for percutaneous coronary intervention, 32% and 26% for bypass surgery, and 21% and 24% for medical treatment. CONCLUSIONS: In the present pilot study, cardiac specialists chose similar rates of medical, interventional and surgical procedures independent of a patient's sex. Although large registry trials show that sex differences in management exist, the present data suggest that cardiac specialist preference is less likely to be a factor if coronary angiography was performed. Further research is required to explore the causes of sex discrepancies in cardiac care.

Obtaining force-frequency curves with a single 3-second train of stimuli.

We devised a method to assess the force-frequency relationship (FFR) in human skeletal muscle that involved delivery of a single 2.8-s train of shocks directly to the femoral nerve. This increasing-frequency train (IFT) was based on a power function, with a range of stimulation frequencies beginning at 5 Hz and rising to 100 Hz. We compared the IFT to a standard series of constant-frequency trains (CFT) under two conditions. Force-frequency curves were examined, first in response to altered muscle length and second, following fatigue. There was no leftward shift in the curve when the knee extensors were shortened, although maximal force increased. In contrast, we observed a rightward shift in the curve after fatigue with both protocols; the frequency required to develop 50% of maximal force increased by 48% (P <.01) with CFT and 58% (P <.001) with an IFT. The CFT produced an irregular pattern of low-frequency fatigue recovery. In the IFT, low-frequency fatigue was greatest at the onset of recovery and decreased linearly until 120 s. These experiments show that the IFT protocol reveals alterations in muscle performance similar to the more traditional CFT. However, it requires only 2.8 s to administer and was judged more tolerable by 70% of our subjects. This suggests that the IFT may be an effective alternative for determining the FFR in human muscle for clinical and experimental purposes.