Cancer Medicines: What Is Essential and Affordable in India?

PURPOSE: The WHO essential medicines list (EML) guides selection of drugs for national formularies. Here, we evaluate which medicines are considered highest priority by Indian oncologists and the extent to which they are available in routine practice. METHODS: This is a secondary analysis of an electronic survey developed by the WHO EML Cancer Medicine Working Group. The survey was distributed globally using a hierarchical snowball method to physicians who prescribe systemic anticancer therapy. The survey captured the 10 medicines oncologists considered highest priority for population health and their availability in routine practice. RESULTS: The global study cohort included 948 respondents from 82 countries; 98 were from India and 67 were from other low- and middle-income countries. Compared with other low- and middle-income countries, the Indian cohort was more likely to be medical oncologist (70% v 31%, P < .001) and work exclusively in the private health system (52% v 17%, P < .001). 14/20 most commonly selected medicines were conventional cytotoxic drugs. Universal access to these medicines was reported by a minority of oncologists; risks of significant out-of-pocket expenditures for each medicine were reported by 19%-58% of oncologists. Risk of catastrophic expenditure was reported by 58%-67% of oncologists for rituximab and trastuzumab. Risks of financial toxicity were substantially higher within the private health system compared with the public system. CONCLUSION: Most high-priority cancer medicines identified by Indian oncologists are generic chemotherapy agents that provide substantial improvements in survival and are already included in WHO EML. Access to these treatments remains limited by major financial burdens experienced by patients. This is particularly acute within the private health system. Strategies are urgently needed to ensure that high-quality cancer care is affordable and accessible to all patients in India.

Access to cancer medicines deemed essential by oncologists in 82 countries: an international, cross-sectional survey.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: None.

Assessment of Bone Lesions with 18F-FDG PET Compared with 99mTc Bone Scintigraphy Leads to Clinically Relevant Differences in Metastatic Breast Cancer Management.

It is unknown whether assessment of potential bone lesions in metastatic breast cancer (MBC) by 18F-FDG PET instead of 99mTc bone scintigraphy (BS) supports clinically relevant changes in MBC management. Therefore, we retrospectively compared management recommendations based on bone lesion assessment by 18F-FDG PET plus contrast-enhanced CT (ceCT) or BS plus ceCT, for patients with newly diagnosed MBC. Methods: Baseline ceCT, BS, and 18F-FDG PET for all patients included in the IMPACT-MBC study (NCT01957332) at the University Medical Center Groningen were reviewed for bone lesions. If bone lesions were found by any imaging modality, virtual MBC management recommendations were made by a multidisciplinary expert panel, based on either 18F-FDG PET plus ceCT or BS plus ceCT. The panel had access to standard clinicopathologic information and baseline imaging findings outside the skeleton. Clinically relevant management differences between the 2 recommendations were defined either as different treatment intent (curative, noncurative, or unable to determine) or as different systemic or local treatment. If no bone lesions were found by any imaging modality, the patients were included in the analyses without expert review. Results: In total, 3,473 unequivocal bone lesions were identified in 102 evaluated patients (39% by ceCT, 26% by BS, and 87% by 18F-FDG PET). Additional bone lesions on 18F-FDG PET plus ceCT compared with BS plus ceCT led to change in MBC management recommendations in 16% of patients (95% CI, 10%-24%). BS also changed management compared with 18F-FDG PET in 1 patient (1%; 95% CI, 0%-5%). In 26% (95% CI, 19%-36%) of patients, an additional 18F-FDG PET exam was requested, because BS provided insufficient information. Conclusion: In this exploratory analysis of newly diagnosed MBC patients, 18F-FDG PET versus BS to assess bone lesions resulted in clinically relevant management differences in 16% of patients. BS delivered insufficient information in over one fourth of patients, resulting in an additional request for 18F-FDG PET. On the basis of these data, 18F-FDG PET should be considered a primary imaging modality for assessment of bone lesions in newly diagnosed MBC.

Comparative Assessment of Clinical Benefit Using the ESMO-Magnitude of Clinical Benefit Scale Version 1.1 and the ASCO Value Framework Net Health Benefit Score.

PURPOSE: To better understand the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) and the ASCO Value Framework Net Health Benefit score version 2 (ASCO-NHB v2), ESMO and ASCO collaborated to evaluate the concordance between the frameworks when used to assess clinical benefit attributable to new therapies. METHODS: The 102 randomized controlled trials in the noncurative setting already evaluated in the field testing of ESMO-MCBS v1.1 were scored using ASCO-NHB v2 by its developers. Measures of agreement between the frameworks were calculated and receiver operating characteristic curves used to define thresholds for the ASCO-NHB v2 corresponding to ESMO-MCBS v1.1 categories. Studies with discordant scoring were identified and evaluated to understand the reasons for discordance. RESULTS: The correlation of the 102 pairs of scores for studies in the noncurative setting is estimated to be 0.68 (Spearman's rank correlation coefficient; overall survival, 0.71; progression-free survival, 0.67). Receiver operating characteristic curves identified thresholds for ASCO-NHB v2 for facilitating comparisons with ESMO-MCBS v1.1 categories. After applying pragmatic threshold scores of 40 or less (ASCO-NHB v2) and 2 or less (ESMO-MCBS v1.1) for low benefit and 45 or greater (ASCO-NHB v2) and 4 to 5 (ESMO-MCBS v1.1) for substantial benefit, 37 discordant studies were identified. Major factors that contributed to discordance were different approaches to evaluation of relative and absolute gain for overall survival and progression-free survival, crediting tail of the curve gains, and assessing toxicity. CONCLUSION: The agreement between the frameworks was higher than observed in other studies that sought to compare them. The factors that contributed to discordant scores suggest potential approaches to improve convergence between the scales.

Integrating molecular nuclear imaging in clinical research to improve anticancer therapy.

Effective patient selection before or early during treatment is important to increasing the therapeutic benefits of anticancer treatments. This selection process is often predicated on biomarkers, predominantly biospecimen biomarkers derived from blood or tumour tissue; however, such biomarkers provide limited information about the true extent of disease or about the characteristics of different, potentially heterogeneous tumours present in an individual patient. Molecular imaging can also produce quantitative outputs; such imaging biomarkers can help to fill these knowledge gaps by providing complementary information on tumour characteristics, including heterogeneity and the microenvironment, as well as on pharmacokinetic parameters, drug-target engagement and responses to treatment. This integrative approach could therefore streamline biomarker and drug development, although a range of issues need to be overcome in order to enable a broader use of molecular imaging in clinical trials. In this Perspective article, we outline the multistage process of developing novel molecular imaging biomarkers. We discuss the challenges that have restricted the use of molecular imaging in clinical oncology research to date and outline future opportunities in this area.

Micro-computed tomography (micro-CT) for intraoperative surgical margin assessment of breast cancer: A feasibility study in breast conserving surgery.

PURPOSE: Around 15%-30% of patients receiving breast-conserving surgery (BCS) for invasive breast carcinoma or ductal carcinoma in situ (DCIS) need a reoperation due to tumor-positive margins at final histopathology. Currently available intraoperative surgical margin assessment modalities all have specific limitations. Therefore, we aimed to assess the feasibility and accuracy of micro-computed tomography (micro-CT) as a novel method for intraoperative margin assessment in BCS. METHODS: Lumpectomy specimens from 30 consecutive patients diagnosed with invasive breast cancer or DCIS were imaged using a micro-CT. Margin status was assessed on micro-CT images by two investigators who were blinded to the final histopathological margin status. The micro-CT margin status was compared with the histopathological margin status. RESULTS: The margin status could be assessed by micro-CT in 29 out of 30 patients. Of these, nine patients had a positive tumor margin and 20 a negative tumor margin at final histopathology. Margin status evaluation by micro-CT took always less than 15 min. The margin status in 25 patients was correctly predicted by micro-CT. There were four false-negative predictions. The accuracy, sensitivity, specificity, positive predictive value and negative predictive value of micro-CT in margin status prediction were 86%, 56%, 100%, 100% and 83%, respectively. With micro-CT, the positive margin rate could potentially have been reduced from 31% to 14%. CONCLUSIONS: Whole lumpectomy specimen micro-CT scanning is a promising technique for intraoperative margin assessment in BCS. Intraoperative quick feedback on the margin status could potentially lead to a reduction in the number of reoperations.

Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group.

Patients with active CNS disease are often excluded from clinical trials, and data regarding the CNS efficacy of systemic agents are usually obtained late in the drug development process or not at all. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we provide detailed recommendations on when patients with brain metastases from solid tumours should be included or excluded in clinical trials of systemic agents. We also discuss the limitations of retrospective studies in determining the CNS efficacy of systemic drugs. Inclusion of patients with brain metastases early on in the clinical development of a drug or a regimen is needed to generate appropriate CNS efficacy or non-efficacy signals. We consider how to optimally incorporate or exclude such patients in systemic therapy trials depending on the likelihood of CNS activity of the agent by considering three scenarios: drugs that are considered very unlikely to have CNS antitumour activity or efficacy; drugs that are considered very likely to have CNS activity or efficacy; and drugs with minimal baseline information on CNS activity or efficacy. We also address trial design issues unique to patients with brain metastases, including the selection of appropriate CNS endpoints in systemic therapy trials.

Detailed statistical assessment of the characteristics of the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) threshold rules.

BACKGROUND: The European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS), a tool to assess the magnitude of clinical benefit from new cancer therapies. Grading is guided by a dual rule comparing the relative benefit (RB) and the absolute benefit (AB) achieved by the therapy to prespecified threshold values. The ESMO-MCBS v1.0 dual rule evaluates the RB of an experimental treatment based on the lower limit of the 95%CI (LL95%CI) for the hazard ratio (HR) along with an AB threshold. This dual rule addresses two goals: inclusiveness: not unfairly penalising experimental treatments from trials designed with adequate power targeting clinically meaningful relative benefit; and discernment: penalising trials designed to detect a small inconsequential benefit. METHODS: Based on 50 000 simulations of plausible trial scenarios, the sensitivity and specificity of the LL95%CI rule and the ESMO-MCBS dual rule, the robustness of their characteristics for reasonable power and range of targeted and true HRs, are examined. The per cent acceptance of maximal preliminary grade is compared with other dual rules based on point estimate (PE) thresholds for RB. RESULTS: For particularly small or particularly large studies, the observed benefit needs to be relatively big for the ESMO-MCBS dual rule to be satisfied and the maximal grade awarded. Compared with approaches that evaluate RB using the PE thresholds, simulations demonstrate that the MCBS approach better exhibits the desired behaviour achieving the goals of both inclusiveness and discernment. CONCLUSIONS: RB assessment using the LL95%CI for HR rather than a PE threshold has two advantages: it diminishes the probability of excluding big benefit positive studies from achieving due credit and, when combined with the AB assessment, it increases the probability of downgrading a trial with a statistically significant but clinically insignificant observed benefit.

89Zr-mAb3481 PET for HER3 tumor status assessment during lapatinib treatment.

Treatment of human epidermal growth factor receptor 2 (HER2)-driven breast cancer with tyrosine kinase inhibitor lapatinib can induce a compensatory HER3 increase, which may attenuate antitumor efficacy. Therefore, we explored in vivo HER3 tumor status assessment after lapatinib treatment with zirconium-89 (89Zr)-labeled anti-HER3 antibody mAb3481 positron emission tomography (PET). Lapatinib effects on HER3 cell surface expression and mAb3481 internalization were evaluated in human breast (BT474, SKBR3) and gastric (N87) cancer cell lines using flow cytometry. Next, in vivo effects of daily lapatinib treatment on89Zr-mAb3481 BT474 and N87 xenograft tumor uptake were studied. PET-scans (BT474 only) were made after daily lapatinib treatment for 9 days, starting 3 days prior to 89Zr-mAb3481 administration. Subsequently, ex vivo 89Zr-mAb3481 organ distribution analysis was performed and HER3 tumor levels were measured with Western blot and immunohistochemistry. In vitro, lapatinib increased membranous HER3 in BT474, SKBR3 and N87 cells, and consequently mAb3481 internalization 1.7-fold (BT474), 1.4-fold (SKBR3) and 1.4-fold (N87). 89Zr-mAb3481 BT474 tumor uptake was remarkably high at SUVmean 5.6±0.6 (51.8±7.7%ID/g) using a 10 µg 89Zr-mAb3481 protein dose in vehicle-treated mice. However, compared to vehicle, lapatinib did not affect 89Zr-mAb3481 ex vivo uptake in BT474 and N87 tumors, while HER3 tumor expression remained unchanged. In conclusion, lapatinib increased in vitro HER3 tumor cell expression, but not when these cells were xenografted. 89Zr-mAb3481 PET accurately reflected HER3 tumor status. 89Zr-mAb3481 PET showed high, HER3-specific tumor uptake, and such an approach might sensitively assess HER3 tumor heterogeneity and treatment response in patients.

Response assessment criteria for brain metastases: proposal from the RANO group.

CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials.

Assessment of estrogen receptor expression in epithelial ovarian cancer patients using 16α-18F-fluoro-17ß-estradiol PET/CT.

UNLABELLED: The estrogen receptor α (ERα) is expressed in approximately 70% of ovarian cancer tumors. PET of tumor ERα expression with the tracer 16α-(18)F-fluoro-17ß-estradiol ((18)F-FES) may be valuable to select ovarian cancer patients for endocrine therapy. The aim of this study was to evaluate the feasibility of (18)F-FES PET to determine tumor ERα expression noninvasively in epithelial ovarian cancer patients. METHODS: (18)F-FES PET/CT was performed shortly before cytoreductive surgery. Tumor (18)F-FES uptake was quantified for all lesions 10 mm or greater on CT and expressed as maximum standardized uptake value. (18)F-FES PET/CT findings were compared with histology and immunohistochemistry for ERα, ERß, and progesterone receptor. Receptor expression was scored semiquantitatively using H-scores (percentage of positive tumor cells × staining intensity). The optimum threshold to discriminate ER-positive and -negative lesions was determined by receiver-operating-characteristic analysis. RESULTS: In the 15 included patients with suspected ovarian cancer, 32 measurable lesions greater than 10 mm were present on CT. Tumor (18)F-FES uptake could be quantified for 28 lesions (88%), and 4 lesions were visible but nonquantifiable because of high uptake in adjacent tissue. During surgery, histology was obtained of 23 of 28 quantified lesions (82%). Quantitative (18)F-FES uptake correlated with the semiquantitative immunoscore for ERα (ρ = 0.65, P < 0.01) and weakly with progesterone receptor expression (ρ = 0.46, P = 0.03) and was not associated with ERß expression (ρ = 0.21, P = 0.33). The optimum threshold to discriminate ERα-positive and ERα-negative lesions was a maximum standardized uptake value greater than 1.8, which provided a 79% sensitivity, 100% specificity, and area under the curve of 0.86 (95% confidence interval, 0.70-1.00). In 2 of 7 patients with cytology/histology available at primary diagnosis and at debulking surgery, immunohistochemical ERα expression had changed over time. (18)F-FES PET was in accordance with histology at debulking surgery but not at primary diagnosis, indicating that (18)F-FES PET could provide reliable information about current tumor ERα status. CONCLUSION: (18)F-FES PET/CT can reliably assess ERα status in epithelial ovarian cancer tumors and metastases noninvasively. Evaluation of the predictive value of (18)F-FES PET/CT for endocrine therapy in epithelial ovarian cancer patients is warranted.

Toward molecular imaging-driven drug development in oncology.

With current testing strategies, the number of novel targeted anticancer agents will exceed our drug selection capacity. Molecular imaging is a powerful additional tool that can assist us in selecting effective drugs and help patients benefit from targeted agents. Moreover, measurement of the functional effects of such targeted agents could permit dynamic tuning of treatment selection at the earliest time point at which loss of functional effects is observed.

Translating pharmacogenomics: challenges on the road to the clinic.

Pharmacogenomics is one of the first clinical applications of the postgenomic era. It promises personalized medicine rather than the established "one size fits all" approach to drugs and dosages. The expected reduction in trial and error should ultimately lead to more efficient and safer drug therapy. In recent years, commercially available pharmacogenomic tests have been approved by the Food and Drug Administration (FDA), but their application in patient care remains very limited. More generally, the implementation of pharmacogenomics in routine clinical practice presents significant challenges. This article presents specific clinical examples of such challenges and discusses how obstacles to implementation of pharmacogenomic testing can be addressed.

Quantitative assessment of P-glycoprotein function in the rat blood-brain barrier by distribution volume of [11C]verapamil measured with PET.

The blood-brain barrier (BBB) is a functional barrier that hampers the delivery of various drugs to the brain by its physicoanatomical properties and by the presence of ATP-driven drug efflux pumps, such as P-glycoprotein (P-gp). The aims of this study were (1) to study whether the distribution volume (DV) is useful for quantification of (labeled) P-gp substrate kinetics over the BBB and (2) to study how brain DV is affected by P-gp modulation. We measured the kinetics of the P-gp substrate [11C]verapamil (0.1 mg/kg) in rat brains using positron emission tomography (PET) and arterial blood sampling. Cyclosporin A (CsA) at 0, 10, 15, 25, 35, and 50 mg/kg of body weight was used as a P-gp modulator. The [11C]verapamil kinetics were very well described by DV, computed by noncompartmental Logan analysis. Logan analysis resulted in excellent fits of dynamic PET data, revealing the reversible behavior of [11C]verapamil and its associated DV. The DV in unmodulated rats was 0.65 ml/ml +/- 0.23 (mean +/- SD). After modulation with 10, 15, 25, 35, and 50 mg/kg of CsA, DV values increased to 0.82 +/- 0.06, 1.04 +/- 0.20, 2.85 +/- 0.51, 2.91 +/- 0.64, and 3.77 +/- 1.23, respectively. The [11C]Verapamil kinetics were saturable at modulation levels above 25 mg/kg of CsA. The data fitted well by a four-parameter Hill plot (R2 = 0.79). In conclusion, the DV of [11C]verapamil is a valid and potent tool to measure the kinetics of (labeled) P-gp substrates in vivo at the BBB. The brain DV of [11C]verapamil increases dose dependently by P-gp modulation. Quantitative insight into in vivo P-gp modulation may be a promising step toward assessment of P-gp substrate delivery to human brains.