Current practice in proton therapy delivery in adult cancer patients across Europe.

BACKGROUND AND PURPOSE: Major differences exist among proton therapy (PT) centres regarding PT delivery in adult cancer patient. To obtain insight into current practice in Europe, we performed a survey among European PT centres. MATERIALS AND METHODS: We designed electronic questionnaires for eight tumour sites, focusing on four main topics: 1) indications and patient selection methods; 2) reimbursement; 3) on-going or planned studies, 4) annual number of patients treated with PT. RESULTS: Of 22 centres, 19 (86%) responded. In total, 4233 adult patients are currently treated across Europe annually, of which 46% consists of patients with central nervous system tumours (CNS), 15% head and neck cancer (HNC), 15% prostate, 9% breast, 5% lung, 5% gastrointestinal, 4% lymphoma, 0.3% gynaecological cancers. CNS are treated in all participating centres (n = 19) using PT, HNC in 16 centres, lymphoma in 10 centres, gastrointestinal in 10 centres, breast in 7 centres, prostate in 6 centres, lung in 6 centres, and gynaecological cancers in 3 centres. Reimbursement is provided by national health care systems for the majority of commonly treated tumour sites. Approximately 74% of centres enrol patients for prospective data registration programs. Phase II-III trials are less frequent, due to reimbursement and funding problems. Reasons for not treating certain tumour types with PT are lack of evidence (30%), reimbursement issues (29%) and/or technical limitations (20%). CONCLUSION: Across European PT centres, CNS tumours and HNC are the most frequently treated tumour types. Most centres use indication protocols. Lack of evidence for PT and reimbursement issues are the most reported reasons for not treating specific tumour types with PT.

A Nordic-Baltic perspective on indications for proton therapy with strategies for identification of proper patients.

The beneficial effects of protons are primarily based on reduction of low to intermediate radiation dose bath to normal tissue surrounding the radiotherapy target volume. Despite promise for reduced long-term toxicity, the percentage of cancer patients treated with proton therapy remains low. This is probably caused by technical improvements in planning and delivery of photon therapy, and by high cost, low availability and lack of high-level evidence on proton therapy. A number of proton treatment facilities are under construction or have recently opened; there are now two operational Scandinavian proton centres and two more are under construction, thereby eliminating the availability hurdle. Even with the advantageous physical properties of protons, there is still substantial ambiguity and no established criteria related to which patients should receive proton therapy. This topic was discussed in a session at the Nordic Collaborative Workshop on Particle Therapy, held in Uppsala 14-15 November 2019. This paper resumes the Nordic-Baltic perspective on proton therapy indications and discusses strategies to identify patients for proton therapy. As for indications, neoplastic entities, target volume localisation, size, internal motion, age, second cancer predisposition, dose escalation and treatment plan comparison based on the as low as reasonably achievable (ALARA) principle or normal tissue complication probability (NTCP) models were discussed. Importantly, the patient selection process should be integrated into the radiotherapy community and emphasis on collaboration across medical specialties, involvement of key decision makers and knowledge dissemination in general are important factors. An active Nordic-Baltic proton therapy organisation would also serve this purpose.

Initial experience with introducing national guidelines for CT- and MRI-based delineation of organs at risk in radiotherapy.

A fundamental problem in radiotherapy is the variation of organ at risk (OAR) volumes. Here we present our initial experience in engaging a large Radiation Oncology (RO) community to agree on national guidelines for OAR delineations. Our project builds on associated standardization initiatives and invites professionals from all radiotherapy departments nationwide. Presently, one guideline (rectum) has successfully been agreed on by a majority vote. Reaching out to all relevant parties in a timely manner and motivating funding agencies to support the work represented early challenges. Population-based data and a scalable methodological approach are major strengths of the proposed strategy.

Real-World Use and Outcomes of Olaparib: a Population-Based Cohort Study.

BACKGROUND: Although olaparib, the first poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor approved, has been used in routine clinical practice for over three years, little has been published on its uptake, utilization patterns, and clinical outcomes. OBJECTIVE: To examine real-world use and outcomes of olaparib treatment in Swedish patients during the first three years following regulatory approval. PATIENTS AND METHODS: This is a population-based cohort study using data from the Swedish national registers. All individuals initiating olaparib treatment from regulatory approval to 31 December 2017 were included. The extent of off-label use was assessed based on recorded diagnoses. Ovarian cancer patients were followed until death or the end of the study period. Starting dose and dose adjustments were assessed. Time to olaparib discontinuation and overall survival were plotted using Kaplan-Meier survival curves. RESULTS: We identified 109 patients to whom olaparib was dispensed in Sweden during the study period. Nine of these were prescribed olaparib off-label for either breast or prostate cancer and were excluded from further analyses. Median age among the remaining 100 patients with ovarian cancer was 59 years (range: 42-83). Almost all patients (96%) started on the recommended dose (400 mg [eight capsules] taken twice daily). Dose reductions were explicitly recorded for 14% of patients. Median time to discontinuation was 289 days (95% confidence interval [CI]: 226; 338). Median overall survival from olaparib initiation was 1002 days (95% CI: 676; not calculable). CONCLUSIONS: To our knowledge, this is the first population-based study of olaparib real-world use and outcomes. During the first three years following regulatory approval, olaparib was mainly prescribed to ovarian cancer patients. Ovarian cancer patients stayed on olaparib for a median of 9.5 months and the treatment appeared to be well tolerated.

[Survival increases for all cancer diagnoses - but inequality persists]. / Överlevnaden ökar vid all cancer ­ men ojämlikheten kvarstår - Konceptet ¼rätt resurser med rätt åtgärd till rätt patient vid rätt tillfälle« måste få genomslag.

New data show a continuously increased five-year survival for almost all analyzed cancer diagnoses since 1990. It has to be emphasized that the figures are uncertain due to the limited number of patients. The variation is huge and the greatest improvements are seen not least among the three major tumor diseases (breast, colorectal and prostate cancer), where the society, industry and research bodies made the biggest investments over the years. The causes of improved survival can be sought in several areas, such as earlier detection and better treatments. In addition to survival estimates, it is also always of importance to consider aspects around patient related outcome, such as quality of life.

Long-term survival in women with borderline ovarian tumors: a population-based survey of borderline ovarian tumors in Sweden 1960-2007.

INTRODUCTION: We conducted an evaluation of incidence and survival of women with borderline ovarian tumors in Sweden. MATERIAL AND METHODS: All women diagnosed with borderline ovarian tumor in the Swedish Cancer Register 1960-2007 (n = 6252) combined with follow up in the Swedish Death Registry to 1 July 2009 were included. Estimation of age-standardized relative survival rate according to time periods for diagnosis. RESULTS: The incidence of borderline ovarian tumors increased during the study period, with a steep increase during the 1980s. The age standardized 5-year relative survival including all borderline tumors diagnosed 2000-07 was 97% (95% CI 92-99%). In women aged ≤64 years, the 10-year relative survival related to age at diagnosis of borderline tumors ranged from 95 to 98% and was 89% in women aged 65-74 years. In a multivariable analysis including age and decade of diagnosis relative survival for every decade increased. The 10-year relative survival in women with mucinous and serous borderline tumors did not differ significantly (p = 0.121). CONCLUSIONS: Results of the present study are reassuring about long-term survival in women with borderline ovarian tumors. The age-standardized relative survival rate increased across time periods for diagnosis. There was no difference in long-term survival between mucinous and serous borderline ovarian tumors.

[Hope for improvement of survival in ovarian cancer]. / Hopp om förbättring av överlevnad i ovarialcancer.

Ovarian cancer is the most common cause of death from a gynecologic cancer. Every year around 700 women contracts ovarian cancer in Sweden. The overall survival is among the highest in Europe, but still long term relative survival is only 46%. It is a long-held myth that ovarian cancer is a disease without symptoms. Almost 90% of women have symptoms, even in the early stages. Symptoms that should arise suspicion of ovarian cancer and initiate diagnostic work-up are continuous abdominal extension, early feeling of satiety, pelvic or abdominal pain, urinary urge and postmenopausal bleeding. Women's awareness of symptoms and willingness to seek medical advice and the organization of the health care system are important factors determining cancer survival. Ovarian cancer is a heterogeneous group of diseases with different tumor traits and prognosis. Personalized medicine and preventive measures recognizing recent knowledge about tumor biology will positively affect survival.

Panitumumab and pegylated liposomal doxorubicin in platinum-resistant epithelial ovarian cancer with KRAS wild-type: the PaLiDo study, a phase II nonrandomized multicenter study.

OBJECTIVE: The increasing number of negative trials for ovarian cancer treatment has prompted an evaluation of new biologic agents, which in combination with chemotherapy may improve survival. The aim of this study was to investigate the response rate in platinum-resistant, KRAS wild-type ovarian cancer patients treated with pegylated liposomal doxorubicin (PLD) supplemented with panitumumab. PATIENTS AND METHODS: Major eligibility criteria were relapsed ovarian/fallopian/peritoneal cancer patients with platinum-resistant disease, measurable disease by GCIG CA125 criteria and KRAS wild-type. Patients were treated with panitumumab 6 mg/kg day 1 and day 15 and with PLD 40 mg/m2 day 1, every 4 weeks. RESULTS: Forty-six patients were enrolled by 6 study sites in this multi-institutional phase II trial. The response rate in the intention-to-treat population (n = 43) was 18.6%. Progression-free and overall survival in the intention-to-treat population was 2.7 months (2.5-3.2 months, 95% confidence interval) and 8.1 months (5.6-11.7 months, 95% confidence interval), respectively. The most common treatment-related grade 3 toxicities included skin toxicity (42%), fatigue (19%), and vomiting (12%). CONCLUSIONS: The combination of PLD and panitumumab demonstrates efficacy in platinum refractory/resistant patients but the skin toxicity was considerable.

Correlation of HLA-A02* genotype and HLA class I antigen down-regulation with the prognosis of epithelial ovarian cancer.

BACKGROUND: In recent years, evidence is accumulating that cancer cells develop strategies to escape immune recognition. HLA class I HC down-regulation is one of the most investigated. In addition, different HLA haplotypes are known to correlate to both risk of acquiring diseases and also prognosis in survival of disease or cancer. We have previously shown that patients with serous adenocarcinoma of the ovary in advanced surgical stage disease have a particularly poor prognosis if they carry the HLA-A02* genotype. We aimed to study the relationship between HLA-A02* genotype in these patients and the subsequent HLA class I HC protein product defects in the tumour tissue. MATERIALS AND METHODS: One hundred and sixty-two paraffin-embedded tumour lesions obtained from Swedish women with epithelial ovarian cancer were stained with HLA class I heavy chain (HC) and ß(2)-microglobulin (ß(2)-m)-specific monoclonal antibodies (mAb). Healthy ovary and tonsil tissue served as a control. The HLA genotype of these patients was determined by PCR/sequence-specific primer method. The probability of survival was calculated using the Kaplan-Meier method, and the hazard ratio (HR) was estimated using proportional hazard regression. RESULTS: Immunohistochemical staining of ovarian cancer lesions with mAb showed a significantly higher frequency of HLA class I HC and ß(2)-m down-regulation in patients with worse prognosis (WP) than in those with better prognosis. In univariate analysis, both HLA class I HC down-regulation in ovarian cancer lesions and WP were associated with poor survival. In multivariate Cox-analysis, the WP group (all with an HLA-A02* genotype) had a significant higher HR to HLA class I HC down-regulation. CONCLUSIONS: HLA-A02* is a valuable prognostic biomarker in epithelial ovarian cancer. HLA class I HC loss and/or down-regulation was significantly more frequent in tumour tissues from HLA-A02* positive patients with serous adenocarcinoma surgical stage III-IV. In multivariate analysis, we show that the prognostic impact is reasonably correlated to the HLA genetic rather than to the expression of its protein products.

The common Scandinavian human leucocyte antigen ancestral haplotype 62.1 as prognostic factor in patients with advanced malignant melanoma.

PURPOSE: We have previously demonstrated an association of the human leukocyte antigen (HLA), HLA-A2 allele with ovarian and prostate cancer mortality as well as a segregation of the ancestral HLA haplotype (AHH) 62.1 [(A2) B15 Cw3 DRB1*04] in patients with stage III-IV serous ovarian cancer. The objective of the present study was to determine the role of the HLA phenotype on the prognosis in stage III-IV malignant melanoma patients. PATIENTS AND METHODS: A cohort of metastatic malignant melanoma patients (n = 91), in stage III (n = 26) or IV (n = 65) were analysed for HLA-A, -B, -Cw and -DRB1 types by PCR/sequence-specific primer method. The frequencies of HLA alleles in the patients were compared to that of healthy Swedish bone marrow donors. The effect of HLA types on prognosis was defined by Kaplan-Meier and Cox analysis. RESULTS: The presence of the AHH 62.1 in clinical stage IV patients was significantly and independently associated with the worst survival rate recorded from the appearance of metastasis (HR = 2.14; CI = 1.02-4.4; P = 0.04). In contrast, the period from the primary diagnosis to metastasis was the longest in patients with this haplotype (HR = 0.40; CI = 0.17-0.90; P = 0.02). CONCLUSIONS: Melanoma patients in our cohort with 62.1 AHH which is associated with autoimmune diseases have an initial strong anti-tumour control with longer metastasis-free period. These patients have rapid progression after the appearance of metastasis, responding poorly to chemo- or/and immunotherapy. This apparently paradoxical clinical process could be due to the interplay between tumour clones escape and immune surveillance ending up with a rapid disease progression.

Ovarian epithelial neoplasia after hormonal infertility treatment: long-term follow-up of a historical cohort in Sweden.

OBJECTIVE: To study the association between hormonal infertility treatment and ovarian neoplasia. DESIGN: Historical cohort study. SETTING: Three university hospitals in Sweden. PATIENT(S): A total of 2,768 women assessed and treated for infertility and infertility-associated disorders between 1961 and 1975. INTERVENTION(S): Exposed women received clomiphene citrate and/or gonadotropins. MAIN OUTCOME MEASURE(S): Incidence of ovarian neoplasia. RESULT(S): No overall excess risk of invasive ovarian cancer emerged compared with the general population. In women with gonadotropin treatment for non-ovulatory disorders, the risk was elevated (standardized incidence ratio [SIR] = 5.89; 95% confidence interval [CI] 1.91-13.75); four of the five cases reported hCG treatment only, rendering the biological plausibility uncertain. Multivariate analysis within the cohort indicated that treatment with gonadotropins only was associated with an increased risk of invasive cancer (relative risk = 5.28; 95% CI 1.70-16.47). For borderline tumors, a more than threefold overall increase of tumors (SIR = 3.61; 95% CI 1.45-7.44) was noted; women exposed to clomiphene because of ovulatory disorders showed the highest risk (SIR = 7.47; 95% CI 1.54-21.83). CONCLUSION(S): Our findings of increased risk of ovarian cancer after gonadotropins and of borderline tumors after clomiphene treatment need to be interpreted with caution. However, concern is raised, and further research on the long-term safety particularly of modern hormonal infertility treatment in IVF programs is warranted.

Predictors of ovarian cancer survival: a population-based prospective study in Sweden.

Ovarian cancer is the leading cause of death from gynecologic malignancies among women worldwide. Little is known about reproductive factors or lifestyle determinants and ovarian cancer prognosis. The objective of this study was to examine whether ovarian cancer survival is influenced by reproductive history, anthropometric characteristics, prediagnostic life-style factors and family history of breast or ovarian cancer. The study population consisted of 635 epithelial ovarian cancer (EOC) cases derived from a nationwide population-based case-control study conducted in Sweden between 1993 and 1995. Exposure data on prediagnostic factors of interest were collected through questionnaires at the beginning of the parent study. Clinical data were abstracted from medical records. Cases were followed-up by means of record linkage to nationwide registers until December 31, 2002. Cox proportional hazard regression model was used to estimate the prognostic effect of each factor in terms of hazard ratios (HR) and 95% confidence intervals (CI), following adjustment for age at diagnosis, FIGO tumor stage and WHO grade of tumor differentiation. Tumor characteristics significantly influenced the risk of death from EOC. After adjustment for these, no clear associations were detected between reproductive history (parity, age at first or last birth, oral contraceptive use, age at menarche or menopause), anthropometric characteristics (body size and shape in different periods of life), lifestyle factors before diagnosis (alcohol consumption, smoking and physical activity over lifetime), nor family history of breast cancer or ovarian cancer and EOC survival. Our findings indicate that these prediagnostic factors do not influence the EOC survival. Nevertheless, among women with early stage disease (FIGO stage I and II), there was some indication that overweight in young adulthood or recent years increased the risk of death, while physical activity in young adult life appeared to reduce the risk of death due to EOC.

Use of hormone replacement therapy before and after ovarian cancer diagnosis and ovarian cancer survival.

Use of hormone replacement therapy (HRT) has been hypothesized to affect survival of epithelial ovarian cancer (EOC). We studied 5-year survival in patients with invasive EOC and borderline ovarian tumors (BOT) according to HRT use before and after diagnosis in a prospective nation-wide cohort study of 799 women diagnosed with EOC (n = 649) and BOT (n = 150) aged 50-74 years in 1993-1995 in Sweden. Cox regression was used to obtain multivariate age-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Multivariate models included indicator variables for age, tumor stage, grade and histological subtype. After 5 years of follow-up, 45% of the patients with EOC and 93% of the patients with BOT were alive. For women with BOT there were no associations between HRT-use pre- or postdiagnosis and survival. There was no overall difference in 5-year EOC survival according to use HRT before diagnosis (multivariate HR = 0.83, 95% CI = 0.65-1.08), except for serous EOC (HR = 0.69, 95% CI = 0.48-0.98). Analyses of different HRT preparations, duration and recency of use did not reveal any variations in pattern of survival. We observed a better survival for EOC-patients who used HRT after diagnosis (multivariate HR = 0.57, 95% CI = 0.42-0.78). We conclude that HRT-use prior to diagnosis of EOC does not affect 5-year survival, except for a possible survival advantage in serous EOC. Women using HRT after diagnosis had a better survival than women with no use, but we cannot rule out that this latter finding may reflect a subtle selection process.

Human leucocyte antigen (HLA) A2 as a negative clinical prognostic factor in patients with advanced ovarian cancer.

OBJECTIVES: Major histocompatibility complex antigens are mandatory for the immune response, and a genetic imbalance may be linked to tumor escape. We have previously characterized a cluster of ovarian cancer patients with high incidence of HLA-A2. To find a prognostic relevance, the presence of HLA-A2 was correlated to defined clinical parameters. METHODS: A population-based set of 97 patients with confirmed epithelial ovarian cancer were recorded in a database by age, histology, stage, surgery and treatment. At the time the study was initiated, the majority of the patients were not alive and HLA-A2 expression was therefore determined by PCR/sequence-specific oligonucleotide hybridization using DNA extracted from paraffin-imbedded tissue specimens. RESULTS: 88 patients with a median age of 65 years (36-87) could be evaluated. 44% were serous adenocarcinomas, 28% endometrioid, 6% mucinous, 13% clear cell carcinomas, 7% undifferentiated and 2% other epithelial tumors. Stages I-II comprised 33% and stages III-IV 67%. In stages III-IV and serous histology, 73% were HLA-A2 positive. Cox analysis, in this group, showed high univariate (HR7.16; CI 2.04-25.03; P = 0.002) and multivariate (HR 6.8; CI 2.10-22.4; P = 0.001) Hazard Ratios. None of the HLA-A2 positive patients survived 5 years, compared to more than 50% of the HLA-A2 negative patients. CONCLUSIONS: HLA-A2 is a negative factor for survival in women with serous adenocarcinomas of the ovary in stages III-IV. This finding has implications for clinical patient management. Association with known oncogenes needs further analysis.

Correlation between HLA-A2 gene frequency, latitude, ovarian and prostate cancer mortality rates.

Molecular-target therapies are novel approaches to the treatment of prostate and ovarian cancer, but to ensure the best response, a very careful selection of patients, based on immunological characteristics, must be performed. We screened for HLA type, 24 patients with advanced ovarian cancer and 26 patients with hormone-refractory prostate cancer, in order to be recruited to vaccine protocols. HLA typing was performed with PCR in ovarian cancer patients and with serological assay in prostate cancer patients. The results were then extended to a population level, comparing the HLA genotype frequencies in Europe with ovarian and prostate cancer mortality rates. An overrepresentation of HLA-A2 phenotype was observed in both patient groups compared to the normal Swedish population (p = 0.01). As it is already known, the higher phenotype frequency of this allele found in Scandinavian countries decreases significantly as one moves further south in Europe. Ovarian and prostate cancer mortality rates decrease as well as the demographic changes in HLA-A2. These observations have to be confirmed by more extended investigations in order to elucidate if HLA-A2 higher frequency is already present at the diagnosis (risk factor) or is selected during the course of the disease (prognostic factor). Moreover, this fact would suggest different strategies for specific immunotherapy in addition to first line conventional treatments.

Risk of ovarian cancer in breast-cancer patients with a family history of breast or ovarian cancer: a population-based cohort study.

BACKGROUND: Patients with breast cancer who have mutations in the high penetrance genes BRCA1 and BRCA2, have an increased risk of ovarian cancer. Because these mutations are rare, easily obtained information such as age and family history of breast or ovarian cancer might be preferable for assessment of ovarian cancer risk in clinical practice. METHODS: We linked data from the Swedish Cancer Register to the Swedish Generation Register and generated a cohort of 30552 breast-cancer patients born after 1931, with information on breast and ovarian cancer diagnosis from 146117 first-degree relatives. Standardised incidence ratios (SIRs) with 95% CIs were calculated with nationwide rates of ovarian cancer, adjusted for age and calendar year. FINDINGS: During a mean follow-up of 6 years, 122 incident ovarian cancers were identified in the cohort, yielding an overall SIR of 2.0 (95% CI 1.6-2.4). The risk was higher in breast-cancer patients diagnosed before the age of 40 years, with a family history of breast cancer (5.6; 1.8-13.1) or ovarian cancer (17.0; 3.5-50.0). A consistently increased risk was noted in patients with a relative who was diagnosed before the age of 50 years, with either breast or ovarian cancer. Women with a family history of ovarian cancer have an almost 10% risk of developing ovarian cancer before the age of 70. INTERPRETATION: In young women with breast cancer, the risk of ovarian cancer is greatly raised when a family history of breast or ovarian cancer is present. Close medical surveillance, and perhaps even prophylactic oophorectomy, might be justified in high-risk groups.

p53 mutations in leukemia and myelodysplastic syndrome after ovarian cancer.

PURPOSE: Although p53 mutations occur in alkylating agent-related leukemias, their frequency and spectrum in leukemias after ovarian cancer have not been addressed. The purpose of this study was to examine p53 mutations in leukemias after ovarian cancer, for which treatment with platinum analogues was widely used. EXPERIMENTAL DESIGN: Adequate leukemic or dysplastic cells were available in 17 of 82 cases of leukemia or myelodysplastic syndrome that occurred in a multicenter, population-based cohort of 23,170 women with ovarian cancer. Eleven of the 17 received platinum compounds and other alkylating agents with or without DNA topoisomerase II inhibitors and/or radiation. Six received other alkylating agents, in one case, with radiation. Genomic DNA was extracted and p53 exons 5, 6, 7, and 8 were amplified by PCR. Mutations and loss of heterozygosity were analyzed on the WAVE instrument (Transgenomic) followed by selected analysis by sequencing. RESULTS: Eleven p53 mutations involving all four exons studied and one polymorphism were identified. Genomic DNA analyses were consistent with loss of heterozygosity for four of the mutations. The 11 mutations occurred in 9 cases, such that 6 of 11 leukemias after platinum-based regimens (55%) and 3 of 6 leukemias after other treatments (50%) contained p53 mutations. Two leukemias that occurred after treatment with platinum analogues contained two mutations. Among eight mutations in leukemias after treatment with platinum analogues, there were four G-to-A transitions and one G-to-C transversion. CONCLUSIONS: p53 mutations are common in leukemia and myelodysplastic syndrome after multiagent therapy for ovarian cancer. The propensity for G-to-A transitions may reflect specific DNA damage in leukemias after treatment with platinum analogues.