Drug costs and benefits of medical treatments in high-unmet need solid tumours in the Nordic countries

Abstract Regional and hospital decision-makers increasingly require analyses assessing the cost-benefit profile of new cancer drugs. This analysis evaluates the cost-benefit profile of nano albumin-bound paclitaxel (nab-paclitaxel) in pancreatic cancer, versus other drugs indicated in high-unmet need solid tumour indications in Nordic countries (Sweden, Denmark, Finland, Norway and Sweden). For a selected number of cancer dugs, approved for metastatic cancer or non-curable treatment intention patients by the European Medicine Agency (EMA) after 2000, and indicated in high-unmet need solid tumours (defined as OS in first line for trial comparator ≤12 months), a regression analysis was conducted. Overall treatment costs of cancer drugs, divided by OS and PFS months, were related to the clinical improvement offered versus trial comparator. Eleven of 42 drugs (26.2%) with at least one indication in solid tumours met inclusion criteria. On average, a good (R2=0.5359) fit between costs per OS month and OS relative benefit versus trial comparator was observed. Nab-paclitaxel offered an OS improvement of +27% versus trial comparator (average improvement: +31%), at a cost per OS month of €1,684 (average cost: €2,247). Correlation between costs per PFS month and relative PFS benefit versus trial comparator was still observed, but the goodness of fit was lower (R2=0.1853) than for the OS analysis. Treatment costs of new cancer therapies should reflect their clinical value, consistently among different indications with comparable characteristics. Nab-paclitaxel, recently approved in pancreatic cancer, showed a similar cost per OS or PFS month ratio compared to other drugs for high-unmet need solid tumours.Peer reviewe

Cetuximab every 2 weeks versus standard weekly dosing administration schedule

Dosing schedule; Efficacy; PharmacokineticsPrograma de dosificació; Eficàcia; FarmacocinèticaPrograma de dosificación; Eficacia; FarmacocinéticaCetuximab every 2 weeks (Q2W) dosing schedule is approved by the US FDA and by the Japanese Pharmaceuticals and Medical Devices Agency in patients with metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Phase II trials have found comparable efficacy and safety for the weekly (Q1W) and Q2W schedules, and real-world studies have shown noninferiority of the Q2W compared with the Q1W schedule. Several guidelines recommend cetuximab Q2W administration as an alternative to the Q1W dosing schedule. Cetuximab Q2W can be administered with a Q2W dose of chemotherapy, making it a more convenient option to the Q1W schedule, potentially resulting in reduced costs for administration, increased flexibility for clinical staff and improved patient adherence

A phase II study of daily encorafenib in combination with biweekly cetuximab in patients with BRAF V600E mutated metastatic colorectal cancer:the NEW BEACON study

Abstract Background Patients with BRAF V600E mutated metastatic colorectal cancer (mCRC) have a poor prognosis. The introduction of BRAF targeted therapy with encorafenib and weekly administered cetuximab have shown improved survival with a median progression free survival (PFS) of 4.3 months. However, a regimen with cetuximab given every second week may have comparable efficacy and is more convenient for patients. While BRAF targeted therapy is a new standard therapy in pre-treated patients with BRAF V600E mutated mCRC, resistance invariably occurs and is an emerging challenge. The aim of this study is to investigate the efficacy and tolerability of cetuximab given every second week in combination with daily encorafenib and to explore the correlation between markers of resistance and outcome. Methods The study is an open label, single arm, phase II study, investigating the efficacy and tolerability of cetuximab given every second week in combination with encorafenib in patients with BRAF V600E mutated mCRC. Furthermore, we will be investigating mechanisms of response and resistance against BRAF targeted therapy though comprehensive genomic profiling on tumor tissue and blood for circulating tumor DNA analysis. A total of 53 patients (19 + 34 in two steps) will be included according to Simon’s optimal two stage design. The primary end point of the study is 2 months PFS rate. Discussion By combining BRAF inhibitor with cetuximab given every second week we can halve the number of visits in the hospital compared to the currently approved regimen with weekly cetuximab. This seems particularly relevant in a group of patients with a median overall survival of 9.3 months. Resistance after initial response to targeted therapy can be either adaptive (e.g., epigenetic, or transcriptomic alterations) or acquired (selective genetic alterations - e.g., activating de novo mutations) resistance. It is of great importance to untangle these complex mechanisms of resistance in patients with BRAF V600E mutated mCRC to improve treatment strategies in the future potentially even further. Trial registration EU Clinical Trial Register, Eudract no. 2020-003283-10 . Registered on 11 November 2020

Molecular characterization of a large unselected cohort of metastatic colorectal cancers in relation to primary tumor location, rare metastatic sites and prognosis

Background: We have reported that BRAF V600E mutations and microsatellite instability-high (MSI-H) are more prevalent in a population-based cohort of metastatic colorectal cancer (mCRC) patients than has been reported from clinical trials or hospital-based patient groups. The aim was to explore if other mutations in mCRC differ in prevalence between these cohorts in relation to mismatch repair status and primary tumor location and if presence of bone or brain metastases is associated with any mutations. Material and methods: A population-based cohort of 798 mCRC patients from three regions in Scandinavia was used. Forty-four cancer related genes were investigated in a custom designed Ampliseq hotspot panel. Differences in survival were analyzed using the Kaplan–Meier estimator and the Cox regression analysis. Results: Determination of mutations was possible in 449/501 patients for 40/44 genes. Besides BRAF V600E, seen in 19% of the tumors, none of the other mutations appeared more prevalent than in trial cohorts. BRAF V600E and MSI-H, seen in 8%, were associated with poor prognosis as was right-sided primary tumor location (39%) when compared to left-sided and rectum together; however, in a multivariable regression, only the BRAF mutation retained its statistical significance. No other mutations were associated with poor prognosis. ERBB2 alterations were more common if bone metastases were present at diagnosis (17% vs. 4%, p = .011). No association was found for brain metastases. Fifty-two percent had an alteration that is treatable with an FDA-approved targeted therapy, chiefly by EGFR-inhibitor for RAS wild-type and a check-point inhibitor for MSI-H tumors. Conclusions: Right-sided tumor location, BRAF V600E mutations, but no other investigated mutation, and MSI-H are more commonly seen in an unselected cohort than is reported from clinical patient cohorts, likely because they indicate poor prognosis. Half of the patients have a tumor that is treatable with an already FDA-approved targeted drug for mCRC.publishedVersio

Randomized study comparing full dose monotherapy (S-1 followed by irinotecan) and reduced dose combination therapy (S-1/oxaliplatin followed by S-1/irinotecan) as initial therapy for older patients with metastatic colorectal cancer : NORDIC 9

Background: Metastatic colorectal cancer (mCRC) is a disease of older age, but there is a relative lack of knowledge about effects of chemotherapy in older patients as they are under-represented in clinical trials. Little data can guide whether the strategy in older mCRC patients should be a sequential full-dose monotherapy chemotherapy approach or a dose-reduced combination chemotherapy approach. The oral 5FU prodrug S-1 seems to have less side effects than capecitabine and should be an optimal drug for older patients, but few data are available. Improved geriatric assessments are needed to select which older patients should receive therapy. Methods: The NORDIC 9 trial is a Nordic multicenter randomized phase II study comparing full dose monotherapy (S-1 30 mg/m(2) twice daily days 1-14 every 3 weeks, followed by second line irinotecan 250-350 mg/m(2) iv day 1 every 3 weeks or 180-250 mg/m(2) iv day 1 every 2 weeks) with reduced dose combination therapy (S-1 20 mg/m(2) days 1-14 + oxaliplatin 100 mg/m(2) iv day 1 every 3 weeks, followed by second line S-1 20 mg/m(2) days 1-14 + irinotecan 180 mg/m(2) day 1 every 3 week) for older patients (>= 70 years) with mCRC who are not candidates for full-dose standard combination therapy. Additional bevacizumab (7.5 mg/kg) is optional in first-line. Blood samples and tumor tissue will be collected to investigate predictive markers. Geriatric screening tools (G-8, VES-13, Timed-Up-and- Go and Handgrip strength), Charlson Comorbidty Index and quality of life (EORTC QLQ-C30) will be evaluated as predictors of efficacy and toxicity. The target sample size is 150 patients. The primary endpoint is progression-free survival and secondary endpoints are time-to-failure of strategy, overall survival, response rate, toxicity, and correlations between biomarkers, pre-treatment characteristics and geriatric assessments. Discussion: The study will add knowledge on how to treat older mCRC patients who are not candidates for standard combination therapy. Furthermore it may provide understanding of efficacy and tolerability of chemotherapy in older cancer patients and thus offer a better chance for tailored treatment strategies in these patients.Peer reviewe

AAPM medical physics practice guideline 3.b.: Levels of supervision for medical physicists in clinical training

The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education and professional practice of medical physics. The AAPM has more than 8,000 members and is the principal organization of medical physicists in the United States. The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the United States. Existing medical physics practice guidelines will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth anniversary or sooner. Each medical physics practice guideline represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiology requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guidelines and technical standards by those entities not providing these services is not authorized. The following terms are used in the AAPM practice guidelines: (1) Must and Must Not: Used to indicate that adherence to the recommendation is considered necessary to conform to this practice guideline. (2) Should and Should Not: Used to indicate a prudent practice to which exceptions may occasionally be made in appropriate circumstances

The role of immunotherapy in the treatment of colorectal cancer

In Denmark, around 4,500 people are diagnosed with colorectal cancer (CRC) annually. This review investigates that while the efficacy of immunotherapy in CRC is still being studied, immunotherapy is currently only indicated in the treatment of mismatch-repair deficient (dMMR) metastatic CRC, which accounts for 10-15% of patients. Recent studies indicate high rates of pathologic response in dMMR CRC treated with pre-operative immunotherapy while large-scale studies on novel immunotherapy combinations are ongoing

A phase II study of Epirubicin in oxaliplatin-resistant patients with metastatic colorectal cancer and <i>TOP2A</i> gene amplification

ᅟ: The overall purpose of this study is to provide proof of concept for introducing the anthracycline epirubicin as an effective, biomarker-guided treatment for metastatic colorectal cancer (mCRC) patients who are refractory to treatment with oxaliplatin-based chemotherapy and have TOP2A gene amplification in their tumor cells. BACKGROUND: Epirubicin is an anthracycline that targets DNA topoisomerase 2-α enzyme encoded by the TOP2A gene. It is used for treatment of several malignancies, but currently not in CRC. TOP2A gene amplifications predict improved efficacy of epirubicin in patients with breast cancer and thus could be an alternative option for patients with CRC and amplified TOP2A gene. We have previously analysed the frequency of TOP2A gene aberrations in CRC and found that 46.6 % of these tumors had TOP2A copy gain and 2.0 % had loss of TOP2A when compared to adjacent normal tissue. The TOP2A gene is located on chromosome 17 and when the TOP2A/CEN-17 ratio was applied to identify tumors with gene loss or amplifications, 10.5 % had a ratio ≥ 1.5 consistent with gene amplification and 2.6 % had a ratio ≤ 0.8 suggesting gene deletions. Based on these observations and the knowledge gained from treatment of breast cancer patients, we have initiated a prospective clinical, phase II protocol using epirubicin (90 mg/m2 iv q 3 weeks) in mCRC patients, who are refractory to treatment with oxaliplatin. METHODS/DESIGN: The study is an open label, single arm, phase II study, investigating the efficacy of epirubicin in patients with oxaliplatin refractory mCRC and with a cancer cell TOP2A/CEN-17 ratio ≥ 1.5. TOP2A gene amplification measured by fluorescence in situ hybridization. A total of 25 evaluable patients (15 + 10 in two steps) will be included (Simon’s two-stage minimax design). Every nine weeks, response is measured by computed tomography imaging and evaluated according to RECIST 1.1. The primary end-point of the study is progression-free survival. TRIAL REGISTRATION: Eudract no. 2013-001648-79