Objective To quantify the association of cancer treatment delay and mortality for each four week increase in delay to inform cancer treatment pathways. Design Systematic review and meta-analysis. Data sources Published studies in Medline from 1 January 2000 to 10 April 2020. Eligibility criteria for selecting studies Curative, neoadjuvant, and adjuvant indications for surgery, systemic treatment, or radiotherapy for cancers of the bladder, breast, colon, rectum, lung, cervix, and head and neck were included. The main outcome measure was the hazard ratio for overall survival for each four week delay for each indication. Delay was measured from diagnosis to first treatment, or from the completion of one treatment to the start of the next. The primary analysis only included high validity studies controlling for major prognostic factors. Hazard ratios were assumed to be log linear in relation to overall survival and were converted to an effect for each four week delay. Pooled effects were estimated using DerSimonian and Laird random effect models. Results The review included 34 studies for 17 indications (n=1 272 681 patients). No high validity data were found for five of the radiotherapy indications or for cervical cancer surgery. The association between delay and increased mortality was significant (P<0.05) for 13 of 17 indications. Surgery findings were consistent, with a mortality risk for each four week delay of 1.06-1.08 (eg, colectomy 1.06, 95% confidence interval 1.01 to 1.12; breast surgery 1.08, 1.03 to 1.13). Estimates for systemic treatment varied (hazard ratio range 1.01-1.28). Radiotherapy estimates were for radical radiotherapy for head and neck cancer (hazard ratio 1.09, 95% confidence interval 1.05 to 1.14), adjuvant radiotherapy after breast conserving surgery (0.98, 0.88 to 1.09), and cervix cancer adjuvant radiotherapy (1.23, 1.00 to 1.50). A sensitivity analysis of studies that had been excluded because of lack of information on comorbidities or functional status did not change the findings. Conclusions Cancer treatment delay is a problem in health systems worldwide. The impact of delay on mortality can now be quantified for prioritisation and modelling. Even a four week delay of cancer treatment is associated with increased mortality across surgical, systemic treatment, and radiotherapy indications for seven cancers. Policies focused on minimising system level delays to cancer treatment initiation could improve population level survival outcomes.

Oncology has lagged in realizing the time burdens of cancer care. Trials should report time toxicity

For the past 5 decades, the randomized clinical trial (RCT) has been the standard to establish efficacy of new cancer therapies. However, there have been important changes in RCT design and end points since its widespread adoption in the 1970s. In 2008, our group described characteristics of RCTs published in major journals during the era of cytotoxic chemotherapy (1975-2004) for breast, colorectal, and non–small cell lung cancers.¹ During this period, the size of RCTs increased substantially; primary end points shifted from response rate to overall survival (OS); the proportion of trials with a statistically significant difference in favor of the experimental arm doubled (23% to 42%); and, although the magnitude of benefit did not change over time, authors of modern recent RCTs were more likely to strongly endorse the experimental arm as a new standard of care. We also reported a major shift in funding: while government grants supported most RCTs (60%) in the 1970s and 1980s, by the late 1990s and early 2000s, 57% of trials were funded by industry. Finally, our original overview demonstrated sponsorship bias (ie, independent of effect size and statistical significance, industry-funded trials are more likely to be “positive”—defined in the present study as RCTs in which the primary end point has a statistically significant difference in favor of the experimental arm).

The WHO Essential Medicines List (EML) identifies priority medicines that are most important to public health. Over time, the EML has included an increasing number of cancer medicines. We aimed to investigate whether the cancer medicines in the EML are aligned with the priority medicines of frontline oncologists worldwide, and the extent to which these medicines are accessible in routine clinical practice. This international, cross-sectional survey was developed by investigators from a range of clinical practice settings across low-income to high-income countries, including members of the WHO Essential Medicines Cancer Working Group. A 28-question electronic survey was developed and disseminated to a global network of oncologists in 89 countries and regions by use of a hierarchical snowball method; each primary contact distributed the survey through their national and regional oncology associations or personal networks. The survey was open from Oct 15 to Dec 7, 2020. Fully qualified physicians who prescribe systemic anticancer therapy to adults were eligible to participate in the survey. The primary question asked respondents to select the ten cancer medicines that would provide the greatest public health benefit to their country; subsequent questions explored availability and cost of cancer medicines. Descriptive statistics were used to compare access to medicines between low-income and lower-middle-income countries, upper-middle-income countries, and high-income countries. 87 country-level contacts and two regional networks were invited to participate in the survey; 46 (52%) accepted the invitation and distributed the survey. 1697 respondents opened the survey link; 423 were excluded as they did not answer the primary study question and 326 were excluded because of ineligibility. 948 eligible oncologists from 82 countries completed the survey (165 [17%] in low-income and lower-middle-income countries, 165 [17%] in upper-middle-income countries, and 618 [65%] in high-income countries). The most commonly selected medicines were doxorubicin (by 499 [53%] of 948 respondents), cisplatin (by 470 [50%]), paclitaxel (by 423 [45%]), pembrolizumab (by 414 [44%]), trastuzumab (by 402 [42%]), carboplatin (by 390 [41%]), and 5-fluorouracil (by 386 [41%]). Of the 20 most frequently selected high-priority cancer medicines, 19 (95%) are currently on the WHO EML; 12 (60%) were cytotoxic agents and 13 (65%) were granted US Food and Drug Administration regulatory approval before 2000. The proportion of respondents indicating universal availability of each top 20 medication was 9–54% in low-income and lower-middle-income countries, 13–90% in upper-middle-income countries, and 68–94% in high-income countries. The risk of catastrophic expenditure (spending >40% of total consumption net of spending on food) was more common in low-income and lower-middle-income countries, with 13–68% of respondents indicating a substantial risk of catastrophic expenditures for each of the top 20 medications in lower-middle-income countries versus 2–41% of respondents in upper-middle-income countries and 0–9% in high-income countries. These data demonstrate major barriers in access to core cancer medicines worldwide. These findings challenge the feasibility of adding additional expensive cancer medicines to the EML. There is an urgent need for global and country-level policy action to ensure patients with cancer globally have access to high priority medicines. None.

Low- and middle-income countries will account for 75% of global cancer deaths by 2030.¹ In this context, there is an urgent need for building collaboration and capacity in these regions. Randomized clinical trials (RCTs) remain the most powerful tool to change clinical practice and improve outcomes. Randomized clinical trials are increasingly multinational, funded by industry, and more likely to use putative surrogate end points and identify modest effect size.^2-5 Despite these aspects, only a minority of new cancer drugs offer substantial clinical benefit for patients.^6-9 This body of work supports the assertion that research priorities are shaped by the pharmaceutical industry in high-income countries (HICs) rather than by population-specific and context-specific needs.