A David and Goliath set-up: a qualitative study of the challenges of ensuring the introduction of cost-effective new cancer medicines in Finland.

BACKGROUND: To combat the global challenge of cancer, priority has been placed on the research and development of new cancer medicines (NCMs). NCMs are often approved for marketing in accelerated processes. Despite significant advances in treating cancer, the overall added value and high prices of NCMs has been questioned. While market authorisations for NCMs are granted at the EU level, the assessment of added value, price negotiations and purchase or reimbursement decisions are made by member states. This article explores the practices in Finland for assessing and deciding on purchasing or reimbursing NCMs. METHODS: Semi-structured interviews were conducted with 26 civil servants, hospital employees, scientists, and representatives of cancer NGOs and of the pharmaceutical industry in 2019 and 2020. The transcribed interviews were coded inductively using Atlas.ti software and analysed thematically under 3 major themes and 11 sub-themes. RESULTS: The clinical value of NCMs is considered to be high, especially regarding NCMs for certain types of cancer. Proper patient selection is important but difficult and not all NCMs can be considered as adding value. The prices are considered to often be very high, leading to concerns about the sustainability and equity of health systems. Equity concerns among cancer patients are raised concerning differences in the availability of NCMs between hospital districts and cost differences for patients between those receiving outpatient and inpatient treatment. The systems and processes in Finland for deciding on the introduction of NCMs are fragmentary, involving separate approaches for outpatient care and hospital medicines by under-resourced evaluation bodies. The scientific evidence available is often limited for evidence-based decisions on introduction. Individual hospital districts sometimes introduce NCMs without assessment by national bodies. This can hamper the proper assessment of some NCMs before their uptake and lead to unequal access to NCMs by hospitals. There is an increasing lack of transparency about pricing, due to the rapid increase of market entry agreements. Lack of transparency on information on prices poses a challenge for authorities responsible for equitable access to cost-effective care within the available resources. CONCLUSIONS: Robust reform of the national introductory systems is needed. Internationally, efforts are needed to increase price transparency, to revise incentives within the system of market approval and to accumulate and assess evidence of comparable value and cost-effectiveness after the market approval of NCMs.

Effect of Adjuvant Trastuzumab for a Duration of 9 Weeks vs 1 Year With Concomitant Chemotherapy for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: The SOLD Randomized Clinical Trial.

Importance: Trastuzumab plus chemotherapy is the standard adjuvant treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. While the standard duration of trastuzumab treatment is 12 months, the benefits and harms of trastuzumab continued beyond the chemotherapy are unclear. Objective: To evaluate the efficacy and safety of adjuvant trastuzumab continued beyond chemotherapy in women treated with up-front chemotherapy containing a taxane and trastuzumab. Design, Setting, and Participants: Open-label, randomized (1:1) clinical trial including women with HER2-positive breast cancer. Chemotherapy was identical in the 2 groups, consisting of 3 cycles of 3-weekly docetaxel (either 80 or 100 mg/m2) plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide. Thereafter, no trastuzumab was administered in the 9-week group, whereas controls received trastuzumab to complete 1 year of administration. Disease-free survival (DFS) was compared between the groups using a Cox model and the noninferiority approach. The estimated sample size was 2168 patients (1-sided testing, with a relative noninferiority margin of 1.3). From January 3, 2008, to December 16, 2014, 2176 patients were accrued from 7 countries. Intervention: Docetaxel plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide in both groups. Controls continued trastuzumab to 1 year. Main Outcomes and Measures: The primary objective was DFS; secondary objectives included distant disease-free survival, overall survival, cardiac DFS, and safety. Results: In the 2174 women analyzed, median age was 56 (interquartile range [IQR], 48-64) years. The median follow-up was 5.2 (IQR, 3.8-6.7) years. Noninferiority of the 9-week treatment could not be demonstrated for DFS (hazard ratio, 1.39; 2-sided 90% CI, 1.12-1.72). Distant disease-free survival and overall survival did not differ substantially between the groups. Thirty-six (3%) and 21 (2%) patients in the 1-year and the 9-week groups, respectively, had cardiac failure; the left ventricle ejection fraction was better maintained in the 9-week group. An interaction was detected between the docetaxel dose and DFS; patients in the 9-week group treated with 80 mg/m2 had inferior and those treated with 100 mg/m2 had similar DFS as patients in the 1-year group. Conclusions and Relevance: Nine weeks of trastuzumab was not noninferior to 1 year of trastuzumab when given with similar chemotherapy. Cardiac safety was better in the 9-week group. The docetaxel dosing with trastuzumab requires further study. Trial Registration: ClinicalTrials.gov Identifier: NCT00593697.

Hypofractionated stereotactic body radiotherapy for localized prostate cancer - first Nordic clinical experience.

BACKGROUND: The use of hypofractionated stereotactic body radiotherapy (SBRT) as primary treatment modality in clinically localized prostate cancer (PCa) is emerging, because the low α/ß-ratio favors the use of high dose per fraction in PCa. There is a need for more data about SBRT, especially in high-risk PCa patients. The purpose of this retrospective study was to evaluate the safety and the short-term efficacy of robotic SBRT in a clinical patient cohort with localized PCa including also high-risk patients (D'Amico risk stratification). MATERIALS AND METHODS: A total of 240 consecutive patients with clinically localized PCa were treated primarily with SBRT to total doses of 35 Gy or 36.25 Gy in 5 fractions using a robotic SBRT device (CyberKnife®). All risk groups (D'Amico risk stratification) were represented as follows: 48 (22%), 59 (27%) and 111 (51%) of the patients representing low-, intermediate- and high-risk group, respectively. Data on acute and intermediate-term toxicities and early PSA responses were analyzed. RESULTS: Neither acute grade 3 or higher GU nor rectal toxicity was observed. Regardless of the fact that 29 (13.3%) patients experienced intermediate-term toxicity requiring diagnostic interventions, the rates of intermediate-term grade 3 GU, rectal and infectious toxicity were low, 1.8%, 0.9% and 1.4%, respectively. A biochemical relapse was observed in ten (4.6%) patients. With the median follow-up time of 23 months the biochemical relapse-free survival (bRFS) rate was 100%, 96.6% and 92.8% in low-, intermediate- and high-risk group, respectively. CONCLUSIONS: The toxicity of robotic SBRT in a large clinical cohort of PCa patients was tolerable and the early PSA response was good in all risk groups. The hypofractionated SBRT offers a possibility to high dose per fraction and to provide the whole radiotherapy treatment within two to three weeks.

Dosimetric Comparison and Evaluation of 4 Stereotactic Body Radiotherapy Techniques for the Treatment of Prostate Cancer.

PURPOSE: The aim of this study was to compare dosimetric characteristics, monitor unit, and delivery efficiency of 4 different stereotactic body radiotherapy techniques for the treatment of prostate cancer. METHODS: This study included 8 patients with localized prostate cancer. Dosimetric assets of 4 delivery techniques for stereotactic body radiotherapy were evaluated: robotic CyberKnife, noncoplanar intensity-modulated radiotherapy, and 2 intensity-modulated arc therapy techniques (RapidArc and Elekta volumetric-modulated arc therapy). All the plans had equal treatment margins and a prescription dose of 35 Gy in 5 fractions. RESULTS: Statistically significant differences were observed in homogeneity index and mean doses of bladder wall and penile bulb, all of which were highest with CyberKnife. No significant differences were observed in the mean doses of rectum, with values of 15.2 ± 2.6, 13.3 ± 2.6, 13.1 ± 2.8, and 13.8 ± 1.6 Gy with CyberKnife, RapidArc, volumetric-modulated arc therapy, and noncoplanar intensity-modulated radiotherapy, respectively. The highest dose conformity was realized with RapidArc. The dose coverage of the planning target volume was lowest with noncoplanar intensity-modulated radiotherapy. Treatment times and number of monitor units were largest with CyberKnife (on average 34.0 ± 5.0 minutes and 8704 ± 1449 monitor units) and least with intensity-modulated arc therapy techniques (on average 5.1 ± 1.1 minutes and 2270 ± 497 monitor units). CONCLUSION: Compared to CyberKnife, the RapidArc, volumetric-modulated arc therapy, and noncoplanar intensity-modulated radiotherapy produced treatment plans with similar dosimetric quality, with RapidArc achieving the highest dose conformity. Overall, the dosimetric differences between the studied techniques were marginal, and thus, the choice of the technique should rather focus on the delivery accuracies and dose delivery times.

[Stereotactic radiotherapy is established treatment in localized non-small cell lung cancer]. / Stereotaktinen sädehoito paikallisen ei-pienisoluisen keuhkosyövän hoidossa.

Surgery has been the standard treatment in localized non-small cell lung cancer. Some of the early stage lung cancer patients are not suitable for surgery owing to associated diseases or refusing surgery. Ninety percent of untreated patients die within five years. Stereotactic ablative radiotherapy is a technique in which highly focused radiation treatment is given at a couple of high single doses to the tumor region. The treatment results in an average of 90% local control of the cancer, and the adverse effects are minor. Treatment outcome is equivalent to those of surgical therapy and is better than obtained with conventional external radiation therapy.

Breast cancer biological subtypes and protein expression predict for the preferential distant metastasis sites: a nationwide cohort study.

INTRODUCTION: Some molecular subtypes of breast cancer have preferential sites of distant relapse. The protein expression pattern of the primary tumor may influence the first distant metastasis site. METHODS: We identified from the files of the Finnish Cancer Registry patients diagnosed with breast cancer in five geographical regions Finland in 1991-1992, reviewed the hospital case records, and collected primary tumor tissue. Out of the 2,032 cases identified, 234 developed distant metastases after a median follow-up time of 2.7 years and had the first metastatic site documented (a total of 321 sites). Primary tumor microarray (TMA) cores were analyzed for 17 proteins using immunohistochemistry and for erbB2 using chromogenic in situ hybridization, and their associations with the first metastasis site were examined. The cancers were classified into luminal A, luminal B, HER2+ enriched, basal-like or non-expressor subtypes. RESULTS: A total of 3,886 TMA cores were analyzed. Luminal A cancers had a propensity to give rise first to bone metastases, HER2-enriched cancers to liver and lung metastases, and basal type cancers to liver and brain metastases. Primary tumors that gave first rise to bone metastases expressed frequently estrogen receptor (ER) and SNAI1 (SNAIL) and rarely COX2 and HER2, tumors with first metastases in the liver expressed infrequently SNAI1, those with lung metastases expressed frequently the epidermal growth factor receptor (EGFR), cytokeratin-5 (CK5) and HER2, and infrequently progesterone receptor (PgR), tumors with early skin metastases expressed infrequently E-cadherin, and breast tumors with first metastases in the brain expressed nestin, prominin-1 and CK5 and infrequently ER and PgR. CONCLUSIONS: Breast tumor biological subtypes have a tendency to give rise to first distant metastases at certain body sites. Several primary tumor proteins were associated with homing of breast cancer cells.

Development and evaluation of a virtual microscopy application for automated assessment of Ki-67 expression in breast cancer.

BACKGROUND: The aim of the study was to develop a virtual microscopy enabled method for assessment of Ki-67 expression and to study the prognostic value of the automated analysis in a comprehensive series of patients with breast cancer. METHODS: Using a previously reported virtual microscopy platform and an open source image processing tool, ImageJ, a method for assessment of immunohistochemically (IHC) stained area and intensity was created. A tissue microarray (TMA) series of breast cancer specimens from 1931 patients was immunostained for Ki-67, digitized with a whole slide scanner and uploaded to an image web server. The extent of Ki-67 staining in the tumour specimens was assessed both visually and with the image analysis algorithm. The prognostic value of the computer vision assessment of Ki-67 was evaluated by comparison of distant disease-free survival in patients with low, moderate or high expression of the protein. RESULTS: 1648 evaluable image files from 1334 patients were analysed in less than two hours. Visual and automated Ki-67 extent of staining assessments showed a percentage agreement of 87% and weighted kappa value of 0.57. The hazard ratio for distant recurrence for patients with a computer determined moderate Ki-67 extent of staining was 1.77 (95% CI 1.31-2.37) and for high extent 2.34 (95% CI 1.76-3.10), compared to patients with a low extent. In multivariate survival analyses, automated assessment of Ki-67 extent of staining was retained as a significant prognostic factor. CONCLUSIONS: Running high-throughput automated IHC algorithms on a virtual microscopy platform is feasible. Comparison of visual and automated assessments of Ki-67 expression shows moderate agreement. In multivariate survival analysis, the automated assessment of Ki-67 extent of staining is a significant and independent predictor of outcome in breast cancer.

NCT01110291: induction of CYP3A activity and lowered exposure to docetaxel in patients with primary breast cancer.

PURPOSE: To study the CYP3A activity before and after docetaxel administration. Furthermore, it was investigated whether peroral midazolam could predict docetaxel exposure and adverse events. METHODS: Twenty patients with primary high risk breast cancer were given docetaxel as a 1-h infusion 80 mg/m(2) in a 21-day cycle in 3 cycles followed by 3 cycles of cyclophosphamide, epirubicin and fluorouracil. CYP3A activity was assessed a day before and a day after docetaxel by 7.5 mg oral midazolam. All patients were given peroral dexamethasone a total dose of 45 mg, of which 15 mg was given before docetaxel infusion and 30 mg before the latter assessment of CYP3A activity. All except one patient were given 11-19 mg of intravenous dexamethasone before docetaxel infusion. RESULTS: CYP3A activity was clearly induced when assessed a day after docetaxel administration as shown by lower midazolam AUC (P < 0.0001) and higher AUC ratio (1-OH-midazolam/midazolam, P = 0.018). The mean docetaxel AUC was about a half of that previously reported in the literature. Incidence of febrile neutropenia was smaller (15%) than reported in literature with comparable docetaxel doses and seemed to associate with slower metabolism. No correlation between pharmacokinetics of midazolam and docetaxel was found at baseline. CONCLUSIONS: We show here a markedly reduced docetaxel exposure followed by CYP3A induction by, most likely, dexamethasone. Peroral midazolam seemed not to predict docetaxel exposure. Slow CYP3A-mediated metabolism might predispose patients to adverse events of docetaxel.

Molecular subtypes of breast cancers detected in mammography screening and outside of screening.

PURPOSE: The frequency and significance of gene expression profile-derived molecular subtypes of breast cancers found in mammography screening are unknown. EXPERIMENTAL DESIGN: We identified breast cancers diagnosed in women of any age living in defined geographic regions in Finland in 1991 to 1992 and collected clinical and pathologic data. Surrogates for the molecular subtypes were determined for 247 cancers found in organized mammography screening and 989 cancers detected outside of screening using immunohistochemistry or in situ hybridization. Molecular subtypes were defined as luminal A [estrogen receptor (ER) positive and/or progesterone receptor (PR) positive, HER2-], luminal B (ER+ and/or PR+, HER2+), basal-like (ER-, PR-, HER2-, cytokeratin 5+, and/or HER1+), HER2+/ER- (ER-, PR-, and HER2+), and unclassified. The median follow-up time was 9.4 years. RESULTS: The luminal type A was common (73.7%) and the HER2+/ER- type is rare (5.7%) in screen-detected cancer, and only 16% were HER2 positive. Women with cancer diagnosed in screening at ages 50 to 69 years had similar molecular subtype distribution as women whose cancer was found outside of screening at age >69 years. In a multivariate model, cancer detection at screening independently predicted favorable distant disease-free survival when the molecular subtype was included as a covariate in addition to age, histologic grade, and cancer size. Women with small (pT(1)N(0)M(0)) HER2-positive cancer had similar outcome regardless of the method of detection. CONCLUSIONS: Molecular subtype distribution of screen-detected breast cancer differs from that of cancers found outside of screening and accounts in part for the better outcome of screen-detected cancer.