Low-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallel-group, non-inferiority, randomised, phase 3 trial.

BACKGROUND: Regimens for palliation in patients with head and neck cancer recommended by the US National Comprehensive Cancer Network (NCCN) have low applicability (less than 1-3%) in low-income and middle-income countries (LMICs) because of their cost. In a previous phase 2 study, patients with head and neck cancer who received metronomic chemotherapy had better outcomes when compared with those who received intravenous cisplatin, which is commonly used as the standard of care in LMICs. We aimed to do a phase 3 study to substantiate these findings. METHODS: We did an open-label, parallel-group, non-inferiority, randomised, phase 3 trial at the Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India. We enrolled adult patients (aged 18-70 years) who planned to receive palliative systemic treatment for relapsed, recurrent, or newly diagnosed squamous cell carcinoma of the head and neck, and who had an Eastern Cooperative Oncology Group performance status score of 0-1 and measurable disease, as defined by the Response Evaluation Criteria In Solid Tumors. We randomly assigned (1:1) participants to receive either oral metronomic chemotherapy, consisting of 15 mg/m2 methotrexate once per week plus 200 mg celecoxib twice per day until disease progression or until the development of intolerable side-effects, or 75 mg/m2 intravenous cisplatin once every 3 weeks for six cycles. Randomisation was done by use of a computer-generated randomisation sequence, with a block size of four, and patients were stratified by primary tumour site and previous cancer-directed treatment. The primary endpoint was median overall survival. Assuming that 6-month overall survival in the intravenous cisplatin group would be 40%, a non-inferiority margin of 13% was defined. Both intention-to-treat and per-protocol analyses were done. All patients who completed at least one cycle of the assigned treatment were included in the safety analysis. This trial is registered with the Clinical Trials Registry-India, CTRI/2015/11/006388, and is completed. FINDINGS: Between May 16, 2016, and Jan 17, 2020, 422 patients were randomly assigned: 213 to the oral metronomic chemotherapy group and 209 to the intravenous cisplatin group. All 422 patients were included in the intention-to-treat analysis, and 418 patients (211 in the oral metronomic chemotherapy group and 207 in the intravenous cisplatin group) were included in the per-protocol analysis. At a median follow-up of 15·73 months, median overall survival in the intention-to-treat analysis population was 7·5 months (IQR 4·6-12·6) in the oral metronomic chemotherapy group compared with 6·1 months (3·2-9·6) in the intravenous cisplatin group (unadjusted HR for death 0·773 [95% CI 0·615-0·97, p=0·026]). In the per-protocol analysis population, median overall survival was 7·5 months (4·7-12·8) in the oral metronomic chemotherapy group and 6·1 months (3·4-9·6) in the intravenous cisplatin group (unadjusted HR for death 0·775 [95% CI 0·616-0·974, p=0·029]). Grade 3 or higher adverse events were observed in 37 (19%) of 196 patients in the oral metronomic chemotherapy group versus 61 (30%) of 202 patients in the intravenous cisplatin group (p=0·01). INTERPRETATION: Oral metronomic chemotherapy is non-inferior to intravenous cisplatin with respect to overall survival in head and neck cancer in the palliative setting, and is associated with fewer adverse events. It therefore represents a new alternative standard of care if current NCCN-approved options for palliative therapy are not feasible. FUNDING: Tata Memorial Center Research Administration Council. TRANSLATIONS: For the Hindi, Marathi, Gujarati, Kannada, Malayalam, Telugu, Oriya, Bengali, and Punjabi translations of the abstract see Supplementary Materials section.

Citius, Altius, Fortius: The New Paradigm in the Treatment of Chronic Hepatitis C Disease.

With the advent of the direct-acting antiviral agents (DAAs) for chronic hepatitis C infection, the treatment paradigm has dramatically changed, especially the duration, tolerability, and response to therapy. The DAAs fall into several classes and are variously indicated in the treatment of one or more genotypes of infection. All these agents are orally administered and, as they are largely renally eliminated (with exceptions), do not require adjustment in mild to moderate renal insufficiency. Most of these agents demonstrate a high barrier to resistance and are extremely well-tolerated by patients. Overall efficacy rates are ≥90%.

Health and Public Policy to Facilitate Effective Prevention and Treatment of Substance Use Disorders Involving Illicit and Prescription Drugs: An American College of Physicians Position Paper.

Substance use disorders involving illicit and prescription drugs are a serious public health issue. In the United States, millions of individuals need treatment for substance use disorders but few receive it. The rising number of drug overdose deaths and the changing legal status of marijuana pose new challenges. In this position paper, the American College of Physicians maintains that substance use disorder is a treatable chronic medical condition and offers recommendations on expanding treatment options, the legal status of marijuana, addressing the opioid epidemic, insurance coverage of substance use disorders treatment, education and workforce, and public health interventions.

Public awareness of warning symptoms, risk factors, and treatment of stroke in northwest India.

BACKGROUND AND PURPOSE: This study assessed public awareness of warning symptoms, risk factors, and treatment of stroke in Ludhiana, Punjab, North West India. METHODS: A hospital-based survey was conducted between February 2002 and September 2002 by the Stroke section of Christian Medical College. The study subjects were relatives of patients without history of stroke, attending the outpatient department of the hospital. Trained medical students, interns, and a nurse interviewed subjects using a structured, pretested, open-ended questionnaire. RESULTS: Nine hundred forty-two individuals were interviewed during the study period (56.4% men, mean age 40.1 years, age range 15 to 80 years). Forty-five percent of the subjects did not recognize the brain as the affected organ in stroke. In the multivariate analysis, higher education (P<0.001; odds ratio 2.6; 95%, CI 1.8 to 3.8) and upper socioeconomic status (P<0.005; odds ratio 1.6; CI, 1.1 to 2.2) correlated with a better knowledge of which organ was affected in stroke. Twenty-three percent of the participants did not know a single warning symptom of stroke. Twenty-one percent of the subjects could not identify even a single risk factor for stroke. Seven percent of the study population believed that oil massage would improve stroke victims. A small proportion of subjects believed in witchcraft, faith healing, homeopathic, and ayurvedic treatment (3%). CONCLUSIONS: This hospital-based survey reveals a better awareness of stroke warning signs and risk factors. However, knowledge regarding the organ involved, etiology, and treatment of stroke is lacking. Considerable education is needed to increase public awareness in modern concepts of stroke treatment.

Potential risk factors for prolonged recovery following whiplash injury.

A retrospective analysis of insurance data was made of 600 individuals claiming compensation for whiplash following motor vehicle accidents. Three hundred randomly selected claimants who had settled their injury claims within 9 months of the accident were compared with 300 who had settled more than 24 months after the accident. We compared the two groups to identify possible risk factors for prolonged recovery, for which settlement time greater than 24 months was a marker. Variables considered included demographic factors, type of collision, degree of vehicle damage, workers compensation, prior claim or neck disability, treatment and time to settlement. Consulting a solicitor was associated with a highly significant, four-fold increase of late settlement of the claim. A concurrent workers' compensation claim, prior neck disability and undergoing physiotherapy or chiropractic treatment were weakly associated with late settlement. The degree of damage to the vehicle (as indicated by cost of repairs) was not a significant predictor of late settlement. Late settlement may be the direct effect of legal intervention, independent of the severity of the injury. Whilst the financial benefit to the claimant of consulting a solicitor is apparent, the benefit of prolonged disability is not. It may be to the advantage of both insurers and claimants if those likely to proceed to late settlement could be recognised early and their claims settled expeditiously.