The solitary versus supported experience: Care inequality between rare and common cancer patients.

OBJECTIVE: Patients with a rare cancer (RC) often have a more complex disease trajectory than patients with a common cancer. Research involving both patient groups is needed to identify differences and resemblances. In this study, we aimed to explore and compare experiences, needs and quality of life of patients with rare and common cancer throughout the disease trajectory. METHODS: A qualitative focus group study was conducted, including patients with rare and common cancer (n = 25). Participants were purposively selected to reflect heterogeneity of cancer types. A semi-structured topic list was used. Focus groups (n = 4) were recorded, transcribed verbatim and analysed, using thematic analysis. RESULTS: Three themes were identified emphasizing care inequality between patients with rare and common cancer: (1) The solitary experience: lack of information and support impact the RC patient, (2) Sudden impact, but recognition reduces the common cancer burden, and (3) Absence of psychosocial care requires being empowered as a cancer patient. CONCLUSIONS: Patients with RC are faced with enormous challenges due to the high impact of their solitary experience on their quality of life, while patients with common cancer generally experience social support and recognition alleviating their burden. Centralisation of care for patients with RC is needed and tailored psychosocial care should be provided to overcome inequalities.

Long-term survival in patients with gastroenteropancreatic neuroendocrine neoplasms: A population-based study.

BACKGROUND: Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) comprise a group of rare malignant tumours with heterogeneous behaviour. This study aimed to assess long-term survival and prognostic factors associated with survival, in order to optimise counselling. PATIENTS AND METHODS: This population-based study included all GEP-NENs diagnosed between 1989 and 2016 in the Netherlands, selected from the Netherlands Cancer Registry. Overall survival (OS) and relative survival (RS) were calculated. A Cox Proportional Hazard analysis was used to identify prognostic factors (gender, age, tumour stage, location and treatment) for OS. Analyses were stratified by metastatic disease status and tumour grade. RESULTS: In total, 9697 patients were included. In grade 1, 2 and 3 non-metastatic GEP-NENs (N = 6544), 5-year OS and RS were 81% and 88%, 78% and 83%, and 26% and 30%, respectively. In grade 1 non-metastatic GEP-NENs 10-year OS and RS were 68% and 83%. In grade 1, 2 and 3 metastatic GEP-NENs (N = 3153), 5-year OS and RS rates were 47% and 52%, 38% and 41%, and 5% and 5%, respectively. The highest (relative) survival rates were found in appendicular and rectal NENs, demonstrating 10-year OS and RS of 87% and 93%, and 81% and 95%, respectively. CONCLUSIONS: These long-term follow-up data demonstrate significant differences in survival for different grades, tumour stage, and primary origin of GEP-NENs, with the most favourable overall and RS rates in patients with non-metastatic grade 1 appendicular and rectal NENs. This study demonstrates unique long-term OS and RS rates using combined stratification by tumour site, grade and stage.

The gap between rare and common cancers still exists: Results from a population-based study in the Netherlands.

INTRODUCTION: Epidemiological discrepancies exist between rare and common cancers. The aim of this population-based study was to compare rare versus common adult solid cancers in the Netherlands, by providing incidence, prevalence and survival rates, evaluating trends in survival and comparing individual entities within domains and families. METHODS: All adult patients with malignant solid cancers in the Netherlands between 1995 and 2019 were identified from the Netherlands Cancer Registry. Data on patient, tumour and treatment characteristics were collected, and relative survival and survival trends were analysed. RESULTS: A total of 170,628 patients with rare adult solid cancers and 806,023 patients with common adult solid cancers were included. Rare cancers accounted for 18% of all cancer diagnoses (mean incidence), and 15% of the total ten-year cancer prevalence during 2010-2019. Overall 5-year survival was worse for rare cancers than for common cancers (52.0% versus 68.7%). Between 1995-1999 and 2015-2019, 5-year survival rates for rare cancers increased to a lesser extent (from 46.2% to 52.6%, i.e. 6.4%) than for common cancers (56.9%-70.1%, i.e. 13.2%), and for most rare cancer domains compared to common cancer domains. The majority of rare cancer entities did not show an improvement in 5-year survival. Differences for individual entities between domains and families were found. CONCLUSION: Differences in survival between rare and common cancers indicate major challenges for rare cancer care and emphasise that improvement is highly needed. Observed inequalities need to be overcome by investing in early diagnosis, novel therapies, scientific research and in establishing centres of expertise.

Experiences of healthcare professionals with support for mesothelioma patients and their relatives: Identified gaps and improvements for care.

OBJECTIVE: To assess perspectives and experiences of healthcare professionals and other relevant stakeholders regarding psychosocial support and palliative care in mesothelioma patients and their relatives, to identify gaps and to explore potential improvements in current healthcare. METHODS: Individual, semi-structured interviews were conducted with healthcare professionals and other relevant stakeholders. Interviews were transcribed verbatim and analysed thematically using ATLAS.ti. RESULTS: In total, 16 respondents participated in an interview (69% women; mean age: 51.8 years (SD 12.41; range 28-75)). Four key themes were identified: (1) availability of tailored psychosocial and palliative care, (2) timely integration and organisation of psychosocial support and palliative care, (3) differences in provided support and care between healthcare professionals and hospitals and (4) training of healthcare professionals and stakeholders on psychosocial problems. CONCLUSION: Our study showed that psychosocial support and palliative care for patients with mesothelioma could be improved. A more fluent transition between primary and secondary cancer care and early integration of psychosocial support and palliative care is advised. Lastly, more attention is needed for psychosocial and palliative care in the basic medical training of healthcare professionals.

The psychosocial impact of living with mesothelioma: Experiences and needs of patients and their carers regarding supportive care.

OBJECTIVE: Mesothelioma is a rare cancer with a poor prognosis caused by exposure to asbestos. Psychosocial support and care for mesothelioma patients and their carers is limited and not tailored to their specific needs. The aim of this study was to explore patients' and carers' needs and experiences regarding psychosocial support and their coping mechanisms dealing with psychosocial problems. METHODS: A qualitative study was performed using semi-structured interviews with both mesothelioma patients and their carers. Participants were recruited through two specialised hospitals and two patient organisations. All interviews were transcribed verbatim and thematically analysed. RESULTS: Ten patients (70% male, mean age 67.7) and five carers (20% male, mean age 65) participated in the study. The main themes identified for patients were active coping, limited needs and limited knowledge and awareness about psychosocial support. The main themes for carers were passive coping and 'it's all about the patient'. CONCLUSION: Mesothelioma patients do not seem to have high needs for psychosocial support, whereas carers do. However, knowledge about and awareness of psychosocial support is low among mesothelioma patients. The findings from this study should be used to adjust guidelines for psychosocial support in mesothelioma patients and their carers.

Unmet supportive care needs of patients with rare cancer: A systematic review.

OBJECTIVE: Patients with rare cancers may experience different unmet needs than those with common cancer. The objective of this systematic review was to (1) investigate unmet supportive care needs of rare cancer patients throughout the disease trajectory and (2) identify predictive factors for these unmet needs. METHODS: PubMed, PsycINFO and CINAHL were searched for publications (January 2011 to March 2021) focusing on unmet needs of patients with rare cancer. Two reviewers independently selected studies, extracted data and performed quality assessment. Findings were synthesised. RESULTS: The search yielded 4,598 articles, of which 59 articles met eligibility criteria and 57 were of medium or high quality. Rare cancer patients most frequently reported unmet needs in the healthcare system and information domain (up to 95%), followed by the psychological domain (up to 93%) and the physical and daily living domain (up to 80%). Unmet needs were mainly reported in the posttreatment phase. The most frequently identified predictors were higher anxiety, younger age and higher neuroticism. CONCLUSION: Patients with rare cancer have unmet needs throughout their disease trajectory. Supportive care needs of rare cancer patients should be addressed individually, depending on the rare cancer subdomain and phase of disease and from diagnosis onwards.

Differences in health care experiences between rare cancer and common cancer patients: results from a national cross-sectional survey.

BACKGROUND: Patients with rare cancers face challenges in the diagnostic and treatment phase, and in access to clinical expertise. Since studies on health care experiences of these patients in comparison to patients with more common cancers are scarce, we aimed to explore these differences. METHODS: Data were cross-sectionally collected among (former) adult cancer patients through a national online survey in the Netherlands (October 2019). Descriptive statistics were reported and subgroups (rare vs. common patients) were compared. RESULTS: In total, 7343 patients (i.e., 1856 rare and 5487 common cancer patients) participated. Rare cancer patients were more often diagnosed and treated in different hospitals compared to common cancer patients (67% vs. 59%, p < 0.001). Rare cancer patients received treatment more often in a single hospital (60% vs. 57%, p = 0.014), but reported more negative experiences when treated in multiple hospitals than common cancer patients (14% vs. 9%, p < 0.001). They also more often received advise from their physician about the hospital to go to for a second opinion (50% vs. 36%, p < 0.001), were more likely to choose a hospital specialized in their cancer type (33% vs. 22%, p < 0.001), and were more willing to travel as long as necessary to receive specialized care than common cancer patients (55% vs. 47%, p < 0.001). CONCLUSIONS: Rare and common cancer patients differ in their health care experiences. Health care for rare cancer patients can be further improved by proper referral to centers of expertise and building a clinical network specifically for rare cancers.

Unique Metastatic Patterns in Neuroendocrine Neoplasms of Different Primary Origin.

INTRODUCTION: Neuroendocrine neoplasms (NEN) can originate in different organs, for example, the gastroenteral tract (GE), pancreas (Pan), or lungs (L). Our aim was to examine metastatic patterns for patients with NEN of various primary origins with a special focus on brain metastases to indicate utility for screening. METHODS: All NEN patients except for small cell lung cancer registered in the Netherlands Cancer Registry from 2008 to 2018 were selected. Metastatic patterns at initial diagnosis for NEN with different primary origins were compared. In a subcohort of patients from 2 referral hospitals (2014-2019), additional information on, for example, development of metastases after initial presentation was available. RESULTS: In the nationwide cohort, 4,768/11,120 (43%) patients had metastatic disease at diagnosis (GE: 1,504/4,710 [32%]; Pan: 489/1,150 [43%]; and L: 1,230/2,978 [41%]). For GE- and Pan-NEN, the most prevalent metastatic site was the liver (25 and 39%), followed by distant lymph nodes (8 and 8%), whereas only few patients with brain metastases were identified (0% in both). In contrast, for L-NEN, prevalence of metastases in the liver (19%), brain (9%), lung (7%), and bone (14%) was more equal. In the reference network cohort, slightly more NEN patients had metastatic disease (260/539, 48%) and similar metastatic patterns were observed. CONCLUSION: Almost half of NEN patients were diagnosed with synchronous metastatic disease. L-NEN have a unique metastatic pattern compared to GE- and Pan-NEN. Remarkably, an important part of L-NEN metastases was in the brain, whereas brain metastases were almost absent in GE- and Pan-NEN, indicating utility of screening in L-NEN.

Importance of Complete Pathology Reporting for Neuroendocrine Carcinoma: WHO Guidelines Are a Good Start but Not Enough.

BACKGROUND: Neuroendocrine carcinomas (NECs) are diagnosed through a combination of immunohistochemistry (IHC) and morphology according to WHO guidelines. The presence of these crucial components for classification in the pathology report is critical for appropriate understanding of the report especially since terminology and definitions of NEC have been changing a lot lately. OBJECTIVES: The aim of this study is to assess the effect of WHO 2010 on the quality of pathology reporting for NEC and to assess the relevance of the criteria demanded. METHODS: Patients registered with a NEC (gastrointestinal or unknown origin) in the Netherlands Cancer Registry (NCR) between 2008 and 2012 were included. Local pathology reports were reviewed for reporting of morphology and IHC comparing 2008-2010 (baseline) with 2011-2012. The diagnosis of NEC was confirmed according to WHO 2010, if synaptophysin or chromogranin were positive in a majority of cells and Ki-67 or mitotic count confirmed a grade 3 tumour. RESULTS: 591 patients were registered with a NEC in the NCR. 436 pathology reports were reviewed. 62.2% of reports described morphology, IHC and grading in accordance with WHO 2010. Reporting of these parameters increased from 50.0% in 2008 to 69.2% in 2012. Large-cell NEC could be confirmed in 45.0% of patients, increasing from 31.7% in 2008 to 56.7% in 2012 (p = 0.02). Other diagnoses included neuroendocrine tumour (NET) G1/2 13.3%, small-cell carcinoma 2.8%, no neuroendocrine neoplasm (NEN) 17.7%, NEN grade unknown 21.3%. Mean survival was 1.1 years in large cell NEC versus 2.2 years in NET G1/2 (p = 0.005). CONCLUSION: Implementation of the WHO 2010 guideline is associated with a significant increase in reporting parameters needed for classification. Stratification of patients is more reliable based on reports containing all parameters. Guidelines alone however are not enough to warrant complete reporting; synoptic reports might be needed.

Extra-Pulmonary Neuroendocrine Carcinomas: A Population-Based Study in the Netherlands.

BACKGROUND: Extra-pulmonary neuroendocrine carcinomas (EP-NEC) are rare tumours that require expertise for correct and timely diagnosis, which is essential for clinical decision making. The number of patients affected, treatment given, and the proportion surviving the disease is based on limited evidence. The aim of this study is to retrospectively analyse the incidence, treatment, and relative survival (RS) of EP-NEC patients in the Netherlands. METHODS: Patients diagnosed between 2008-2012 with EP-NEC or NEC with unknown primary site (UP-NEC) were selected from the Netherlands Cancer Registry based on combinations of tumour localisation and morphology code. Incidence was studied using the European standardised (ESR) and world standardised rates, and RS was calculated using the Ederer II method. RESULTS: In total, 1,544 cases were analysed, 1,045 EP-NEC and 499 UP-NEC. For EP-NEC, the incidence was 1.0 per 100,000 person-years (ESR), the mean age was 68 years, and the male to female ratio was 1: 0.6. Most frequent EP-NEC localisations were the bladder and the gastrointestinal tract, and the treatment most frequently given was surgery in combination with chemotherapy. The overall 5-year RS was 38% for patients with local/regional disease (n = 447), and 7% for patients with extensive disease (n = 582). For UP-NEC patients (n = 499), the 5-year RS was 6%. CONCLUSIONS: This study is the first nationwide study presenting an increase in the incidence of EP-NEC patients from 196 to 260 cases annually in the Netherlands. The best 5-year RS was found for EP-NEC patients with local disease located in the bladder, where the worst 5-year RS was found for patients with disease located in the oesophagus.

Data quality in rare cancers registration: the report of the RARECARE data quality study.

PURPOSE: Rare cancers represent 22% of all tumors in Europe; however, the quality of the data of rare cancers may not be as good as the quality of data for common cancer. The project surveillance of rare cancers in Europe (RARECARE) had, among others, the objective of assessing rare cancer data quality in population-based cancer registries (CRs). Eight rare cancers were considered: mesothelioma, liver angiosarcoma, sarcomas, tumors of oral cavity, CNS tumors, germ cell tumors, leukemia, and malignant digestive endocrine tumors. METHODS: We selected data on 18,000 diagnoses and revised, on the basis of the pathologic and clinical reports (but not on pathologic specimens), unspecified morphology and topography codes originally attributed by CR officers and checked the quality of follow-up of long-term survivors of poor prognosis cancers. RESULTS: A total of 38 CRs contributed from 13 European countries. The majority of unspecified morphology and topography cases were confirmed as unspecified. The few unspecified cases that, after the review, changed to a more specific diagnosis increased the incidence of the common cancer histotypes. For example, 11% of the oral cavity epithelial cancers were reclassified from unspecified to more specific diagnoses: 8% were reclassified as squamous cell carcinoma (commoner) and only 1% as adenocarcinoma (rarer). The revision confirmed the majority of long-term survivors revealing a relative high proportion of mesothelioma long-term survivors. The majority of appendix carcinoids changed behavior from malignant to borderline lesions. CONCLUSIONS: Our study suggests that the problem of poorly specified morphology and topography cases is mainly one of difficulty in reaching a precise diagnosis. The awareness of the importance of data quality for rare cancers should increase among registrars, pathologists, and clinicians.

Methodological aspects of estimating rare cancer prevalence in Europe: the experience of the RARECARE project.

This paper describes the usage and the performance evaluation of the completeness index method in the 'Surveillance of Rare Cancers in Europe project' (RARECARE) for estimating rare cancer prevalence in Europe. The 15-year prevalence at 1st January 2003 for 255 cancers is obtained from a pool of 22 RARECARE cancer registries (CRs). Incidence and survival models are applied to the RARECARE database to estimate the parameters from which the completeness indices are calculated. Complete prevalence is obtained adjusting the observed 15-year prevalence by the completeness index, to account for those cancer survivors diagnosed before the CR activity started. Main factors influencing the performance of the completeness index method for rare cancers are the same as for common cancers: age distribution of incidence and lethality of the cancer. For cancers occurring in the elderly, with low survival rates and consequently a restricted number of long-term survivors we obtained completeness indices higher than 0.9. Values lower than 0.7 correspond to those cancers with good prognosis and/or incidence more concentrated at the younger ages, indicating that 15 years of follow up are insufficient to detect all prevalent cases. Validation analysis shows that for a restricted subgroup of rare cancers with very low incidence and low survival, the completeness indices were not able to adequately correct the observed prevalence even considering a registration period of 20 years. On average, sensitivity analyses show a slight overestimation of complete prevalence for rare and common cancers whose increasing incidence is known in literature. RARECARE is the largest project on rare cancers conducted to date. Improving health care programs for cancer survivors is a public health priority and prevalence data which provides important information in this field should be regularly asked to Member States and included in the EU health statistics.

Adrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993.

BACKGROUND: The reported annual incidence of adrenocortical carcinoma (ACC) is 0.5-2.0 cases per million individuals. Updated population-based studies on incidence are lacking. The aim of this nationwide survey was to describe the incidence and survival rates of ACC in the Netherlands. Secondary objectives were to evaluate changes in both survival rates and the number of patients undergoing surgery. METHODS: All ACC patients registered in the Netherlands Cancer Registry (NCR) between 1993 and 2010 were included. Data on demographics, stage of disease, primary treatment modality and survival were evaluated. RESULTS: Included were 359 patients, 196 of whom were female (55%). Median age at diagnosis was 56 years (range 1-91). The 5-year age-standardised incidence rate decreased from 1.3 to 1.0 per one million person-years. Median survival for patients with stage I-II, stage III and stage IV disease was 159 months (95% confidence interval (CI) 93-225 months), 26 months (95% CI: 4-48 months) and 5 months (95% CI: 2-7 months), respectively (P<0.001). Improvement in survival was not observed, as reflected by the lack of association between survival and time of diagnosis. The percentage of patients receiving treatment within 6 months after diagnosis increased significantly from 76% in 1993-1998 to 88% in 2005-2010 (P=0.047), mainly due to an increase in surgery for stage III-IV patients. CONCLUSION: These nationwide data provide an up-to-date survey of the epidemiology of ACC in the Netherlands. A trend towards a decreasing overall incidence rate was observed. Survival rates did not change during this period despite an increased number of surgical procedures.

Rare neuroendocrine tumours: results of the surveillance of rare cancers in Europe project.

Because of the low incidence, and limited opportunities for large patient volume experiences, there are very few relevant studies of neuroendocrine tumours (NETs). A large population-based database (including cancer patients diagnosed from 1978 to 2002 and registered in 76 population-based cancer registries [CRs]), provided by the project 'surveillance of rare cancers in Europe' (RARECARE) is used to describe the basic indicators of incidence, prevalence and survival of NETs, giving a unique overview on the burden of NETs in Europe. NETs at all cancer sites, excluding lung, were analysed in this study. In total over 20,000 incident cases of NETs were analysed and a data quality check upon specific NETs was performed. The overall incidence rate for NETs was 25/1,000,000 and was highest in patients aged 65 years and older with well differentiated endocrine carcinomas (non-functioning pancreatic and gastrointestinal) (40 per 1,000,000). We estimated that slightly more than 100,000 people were diagnosed with NETs and still alive in EU27 at the beginning of 2008. Overall, NETs had a 5 year relative survival of 50%; survival was low (12%) for poorly differentiated endocrine carcinoma, and relatively high (64%) for well differentiated carcinoma (not functioning of the pancreas and digestive organs). Within NETs, endocrine carcinoma of thyroid gland had the best 5-year relative survival (82%). Because of the complexity and number of the different disciplines involved with NETs (as they arise in many organs), a multidisciplinary approach delivered in highly qualified reference centres and an international network between those centres is recommended.

Rare thoracic cancers, including peritoneum mesothelioma.

Rare thoracic cancers include those of the trachea, thymus and mesothelioma (including peritoneum mesothelioma). The aim of this study was to describe the incidence, prevalence and survival of rare thoracic tumours using a large database, which includes cancer patients diagnosed from 1978 to 2002, registered in 89 population-based cancer registries (CRs) and followed-up to 31st December 2003. Over 17,688 cases of rare thoracic cancers were selected based on the list of the RACECARE project. Mesothelioma was the most common tumour (19 per million per year) followed by epithelial tumours of the trachea and thymus (1.3 and 1.7, respectively). The age standardised incidence rates of epithelial tumours of the trachea was double in Eastern and Southern Europe versus the other European regions: 2 per million per year. Epithelial tumours of the thymus had the lowest incidence in Northern and Eastern Europe and UK and Ireland(1) and somewhat higher incidence in Central and Southern Europe.(2) Highest incidence in mesothelioma was seen in UK and Ireland(23) and lowest in Eastern Europe.(4) Patients with tumours of the thymus had the best prognosis (1-year survival 85%, 66% at 5 years). Five year survival was lowest for the mesothelioma 5% compared to 14% of patients with tumours of the trachea. Mesothelioma was the most prevalent rare cancer (12,000 cases), followed by thymus (7000) and trachea (1400). Cancer Registry (CR) data play an important role in revealing the burden of rare thoracic cancers and monitoring the effect of regulations on asbestos use and smoking related policies.

Carcinoma of endocrine organs: results of the RARECARE project.

The rarity or the asymptomatic character of endocrine tumours results in a lack of epidemiological studies on their incidence and survival patterns. The aim of this study was to describe the incidence, prevalence and survival of endocrine tumours using a large database, which includes cancer patients diagnosed from 1978 to 2002, registered in 89 population-based cancer registries (CRs) with follow-up until 31st December 2003. These data give an unique overview of the burden of endocrine carcinomas in Europe. A list of tumour entities based on the third International Classification of Diseases for Oncology was provided by the project Surveillance of rare cancer in Europe (RARECARE) project. Over 33,594 cases of endocrine carcinomas were analysed in this study. Incidence rates increased with age and were highest in patients 65 years of age or older. In 2003, more than 315,000 persons in the EU (27 countries) were alive with a past diagnosis of a carcinoma of endocrine organs. The incidence of pituitary carcinoma equalled four per 1,000,000 person years and showed the strongest decline in survival with increasing age. Thyroid cancer showed the highest crude incidence rates (four per 100,000 person years) and was the only entity with a gender difference: (female-to-male ratio: 2:9). Parathyroid carcinoma was the rarest endocrine entity with two new cases per 10,000,000 person years. For adrenal carcinoma, the most remarkable observations were a higher survival for women compared to men (40% compared to 32%, respectively) and a particularly low relative survival of 24% in patients 65 years of age or older. More high quality studies on rare cancers, with additional information, e.g. on stage and therapeutic approach, are needed and may be of help in partly explaining the observed variation in survival.

Rare cancers are not so rare: the rare cancer burden in Europe.

PURPOSE: Epidemiologic information on rare cancers is scarce. The project Surveillance of Rare Cancers in Europe (RARECARE) provides estimates of the incidence, prevalence and survival of rare cancers in Europe based on a new and comprehensive list of these diseases. MATERIALS AND METHODS: RARECARE analysed population-based cancer registry (CR) data on European patients diagnosed from 1988 to 2002, with vital status information available up to 31st December 2003 (latest date for which most CRs had verified data). The mean population covered was about 162,000,000. Cancer incidence and survival rates for 1995-2002 and prevalence at 1st January 2003 were estimated. RESULTS: Based on the RARECARE definition (incidence <6/100,000/year), the estimated annual incidence rate of all rare cancers in Europe was about 108 per 100,000, corresponding to 541,000 new diagnoses annually or 22% of all cancer diagnoses. Five-year relative survival was on average worse for rare cancers (47%) than common cancers (65%). About 4,300,000 patients are living today in the European Union with a diagnosis of a rare cancer, 24% of the total cancer prevalence. CONCLUSION: Our estimates of the rare cancer burden in Europe provide the first indication of the size of the public health problem due to these diseases and constitute a useful base for further research. Centres of excellence for rare cancers or groups of rare cancers could provide the necessary organisational structure and critical mass for carrying out clinical trials and developing alternative approaches to clinical experimentation for these cancers.