University of Groningen Improving long-term morbidity and treatment outcomes in patients with rare malignancies Stelwagen, Johannes

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Improving long-term morbidity and treatment outcomes in patients with rare malignancies

Stelwagen, Johannes

DOI:

10.33612/diss.170823907

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2021

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Stelwagen, J. (2021). Improving long-term morbidity and treatment outcomes in patients with rare

malignancies. University of Groningen. https://doi.org/10.33612/diss.170823907

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SUMMARY

Rare malignancies constitute about one-fourth of all cancer types (1). The prognosis of patients with such tumours depends on the rare tumour type, and thus some patients will receive long-lasting care and follow-up by their team of oncological healthcare professionals. Patients with metastatic testicular cancer, treated with a combination of surgery and cisplatin-based chemotherapy have 10-year survival rates of up to 80% (2). In these successfully treated patients, long-lasting follow-up – after the initial focus of a tumour recurrence – is mainly aimed at preventing or treating adverse late treatment effects. Second primary malignancies, cardiovascular disease, neurotoxicity, and pulmonary toxicity are potential late treatment effects (3). For patients with metastatic neuroendocrine tumours (NET), long-term curation rates are far worse, with a median overall survival of 54 months (4). A relatively indolent nature frequently characterises NETs. Some patients with NET can remain symptom-free for many years, while others experience symptomatic disease with a wide variety of complaints. Gastrointestinal complaints, such as diarrhoea, abdominal pain, and cramping, are most frequent (5). These symptoms can be caused by hormone hypersecretion by the tumour, side-effects of systemic or local treatments, abdominal surgery, or the mechanical effects of the tumour. Complaints can persist for years given the indolent nature of NET, and they can severely impact the quality of life in an otherwise oncologic stable setting (6). Neuroendocrine carcinomas are aggressive tumours that can originate almost anywhere in the body (7). However, irrespective of the primary tumour location, the prognosis is generally poor, with a median overall survival OS of 34 months for localised disease and 5 months for patients with metastases (8). Given the dismal prognosis of these patients, research focusses on improving the outcome for these patients.

This thesis aims to investigate – in patient populations with rare malignancies – options to progress treatment results, alleviate long-term adverse treatment effects, and improve health-related quality of life.

Chapter 1 provides a general introduction to the topic and outlines the thesis. In chapter 2, we studied cardiovascular morbidity in testicular cancer survivors after cisplatin-based chemotherapy beyond 20 years post-treatment. Testicular cancer survivors and age-matched healthy controls were invited for a study visit.

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The assessment included vascular stiffness with ultrasound measurement of carotid-femoral pulse wave velocity (cf-PWV). We included 127 testicular cancer survivors consisting of a chemotherapy group (70 patients) and an orchiectomy only group (57 patients) along with 70 controls. The cf-PWV (m/s) was higher in testicular cancer survivors than in controls (geometrical mean 8.05 (SD 1.23) vs 7.60 (SD 1.21), p = 0.04), and was highest in the chemotherapy group (8.39 m/s). In the chemotherapy group, cf-PWV increased more rapidly as a function of age compared to controls (regression coefficient b 7.59 x 10-3 vs 4.04 x 10-3; p = 0.03). We concluded that very long-term testicular cancer survivors treated with cisplatin-based chemotherapy show increased signs of vascular damage. This is compatible with “accelerated vascular ageing”, and survivors continue to be at risk for cardiovascular morbidity. These findings support life-long intensive cardiovascular risk management. Subsequently, in a further analysis of the same observational cross-sectional study, neurocognitive impairment as a potential late treatment effect was investigated (chapter 3). This assessment and analysis included cognitive testing of testicular cancer survivors treated with orchiectomy and chemotherapy (n=66), orchiectomy and subsequent radiotherapy (n=53) or orchiectomy only (n=65) and age-matched healthy controls (n=70). Formal cognitive testing included an auditory verbal learning test, letter and category fluency tests, and the Trail Making Test. Self-perceived cognitive functioning was assessed with the Cognitive Failure Questionnaire. Sixteen percent of the testicular cancer survivors were cognitive impaired and 10% of the controls (p = 0.56). The cumulative Z-scores per individual were lower in testicular cancer survivors – resulting in a negative mean sum of Z-scores (mean -0.85; 95% CI -1.39 to -0.33) – compared to the controls with a positive-sum of Z-scores (mean 0.67; 95% CI -0.21 to 1.57, p < 0.01). In univariate analysis, presence of hypogonadism (β -1.50, p <0.01), high c-PWV (β -0.35, p = 0.09) and high advanced glycation end products (β -1.27, p = 0.02) were associated with lower cognitive scores. Advanced glycation end-products [AGEs] (β -1.17, p = 0.03) remained a significant predictor in multivariate analysis (Model R2_{0.31, p <0.01).}

This suggests an accelerated cognitive ageing process in testicular cancer survivors, potentiated through neurological and/or vascular damage. We concluded long-term testicular cancer survivors performed worse on cognitive tests compared to controls. Cardiovascular risk management during follow-up and treatment of hypogonadism with testosterone supplementation may alleviate this long-term cognitive decline. Whether AGEs could serve as a biomarker for long-term cognitive decline still needs to be prospectively investigated.

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Similar to patients with testicular cancer, patients with NETs are exposed to long-term morbidity. Patients with NET are at risk for vitamin deficiencies and poor nutritional status due to excessive serotonin production, diarrhoea, gastrointestinal surgery, and or treatment with somatostatin analogues. We performed a feasibility study described in chapter 4a to explore if supplementation of vitamin deficiencies and personalised dietary advice could be executed. We included 15 patients with NET – a participation rate of 75% –treated with somatostatin analogues for at least 6 months. Nine patients had one or more vitamin A, D, E, K, B12, or B3 deficiency and got supplementation of deficient vitamins and received dietary counselling during the complete study course of 18 weeks. The drop-out rate was 17%, and no intervention-related adverse events occurred. Subsequently, we performed a well-powered trial in 53 patients with NET and investigated the efficacy of the dietary counselling and vitamin supplementation (chapter 4b). This study’s primary endpoint was the change in the proportion of patients with normal vitamin values at the end of the study period. Nutritional state, QoL and levels of distress were secondary endpoints. At baseline, 72% of patients had one (34%) or more (38%) vitamin deficiencies. At 18 weeks, this percentage decreased to 29% (p = 0.004). Deficiencies of fat-soluble vitamins – mainly vitamin D and K – were with 66% of the patients affected most common at baseline. Vitamin B12 deficiency occurred in five patients at baseline and vitamin B3 deficiencies in 11 patients. Median cancer-specific QoL was high and did not change (at baseline 75 (range 50 – 100) at study end 75, range 42 – 100). We concluded that patients with NETs frequently have fat-soluble, B3, and B12 vitamin deficiencies that can successfully be supplemented. Long-term fat-soluble vitamins and vitamin B12 and B3 deficiencies can cause severe symptoms. Therefore, repetitive evaluation of vitamin A, D, E, K, B3, and B12 status and supplementing deficiencies is recommended in patients with NETs. In chapter 5, the efficacy of a web-based system consisting of self-screening of problems and care needs in patients with NETs is studied. Patients were randomised between the standard of care (n=49) or additional access to the web-based system (n=53) during a study period of 12 weeks. Participants completed questionnaires on levels of distress, perception and satisfaction of received information, quality of life, and empowerment. Of the 91 patients who completed the study, 46 (12 newly diagnosed) patients were randomised to the intervention group. The median levels of distress and the median global scores on perceived information and satisfaction did not change, in both the intervention and control group. Out of all

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newly diagnosed participants, 56% of patients wished to receive more information on NETs. Remarkably, while at the end of the study period, this percentage declined to 15% for patients in the control group and it rose to 64% in the patient group who had access to the web-based information system.

Given the dismal prognosis, treatment results for patients with extrapulmonary neuroendocrine carcinomas (EPNECs) have to improve. Chapter 6 provides a literature overview where we describe new treatment modalities for EPNECs and the improved understanding of the tumour pathogenesis and molecular alterations. To this end, we performed a search of the current literature on treatment outcomes for EPNECs with the current modalities of surgery, radiotherapy and platinum-based chemotherapy, and new modalities, including immune checkpoint inhibitors. Our search included literature about the transdifferentiation of certain adenocarcinomas into neuroendocrine carcinomas and the molecular mechanisms underlying the EPNEC development. EPNECs of different organ primaries have many similarities in tumour biology. The same is true for EPNECs originating from various epithelial cancers through neuroendocrine differentiation. Therefore, we recommend including patients with EPNECs from different primary tumour sites in clinical trials. Anecdotal evidence points to the efficacy of some potential treatment modalities regardless of primary tumour location (e.g., B-Rapidly Accelerated Fibrosarcoma (BRAF) inhibitors). More extensive site-specific data is also available for new modalities such as alisertib for prostate NECs. The pooling of EPNECs, independent of the primary tumour site, has helped demonstrate the efficacy of immune checkpoint inhibitors , and this approach could also help define the role of other new drugs.

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FUTURE PERSPECTIVES

Long-term adverse treatment effects in testicular cancer survivors

Testicular cancer treatment-related complications, including second primary malignancies, cardiovascular disease (CVD), hypogonadism, anxiety, depression, cognitive impairment, peripheral neuropathy and chronic cancer-related fatigue, have emerged as critical survivorship issues. Our observational cross-sectional study among long-term testicular cancer survivors described long-term cardiovascular and cognitive morbidity (chapters 2 and 3). Our results show two major contributing factors in long-term sequelae’s aetiology after testicular cancer treatment: accelerated vascular ageing and presence of (subclinical) primary hypogonadism. The phenomenon of “accelerated vascular ageing” may be caused by direct vascular damage through cisplatin-based chemotherapy – increasing the vascular age at the time of treatment – only to become symptomatic after years of additional ageing (9). Also, cisplatin-based chemotherapy causes an increase in known CVD risk factors leading to CVD in testicular cancer survivors earlier than expected (10). These effects might be further worsened by long-term circulating platinum, detectable up to 20 years after administration of cisplatin-based chemotherapy (11). Therefore, high-risk populations such as testicular cancer survivors treated with platinum-based chemotherapy may benefit from a more intensive CVD risk factor management to reduce long-term cardiovascular morbidity. Interventions such as physical exercise have repeatedly shown efficacy in preventing and reversing age-related arterial stiffness in patients with vascular risk factors (12–14). Its clinical benefit in the oncological setting is currently explored in a randomised controlled trial (NCT01642680). Another contributing pathophysiologic factor could be low serum testosterone. Hypogonadism after hemicastration and subsequent gonadal toxic treatment with chemotherapy increase the risk to develop insulin resistance, metabolic syndrome and cardiovascular disease. Two randomised controlled trials aim to reduce complaints of hypogonadism and the prevalence of metabolic syndrome. These trials are currently recruiting patients treated for testicular cancer with low serum testosterone, who are then randomised between testosterone supplementation or placebo after completion of their cancer treatment. (NCT02991209 and NCT03339635). Of note, it remains challenging to identify those testicular cancer survivors that may benefit from interventional strategies. Adding arterial stiffness in CVD risk assessment after treatment completion may help identify those testicular cancer survivors that might

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benefit from a more intensive CVD risk management. Arterial stiffness has an added value in CVD risk assessment compared to conventional risk factors alone (e.g., age, sex, blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking status and diabetes). A systematic review – including 16 prospective studies with more than 17.000 participants – showed that the addition of arterial stiffness improved the 10-year CVD risk classification by 13% (15).

Consequently, arterial stiffness assessment is currently recommended in guidelines to improve CVD risk stratification (16). Future studies to investigate the effect of a more intensive CVD risk management based on risk stratification, including arterial stiffness, are needed. To improve cognitive function, two placebo-controlled trials, including patients with low serum testosterone and cognitive impairment – without a history of testicular cancer – found beneficial effects in cognitive function from testosterone replacement therapy compared to placebo (17,18). Future studies are needed to investigate whether this strategy can improve cognitive functioning in testicular cancer survivors with hypogonadism and cognitive impairment.

Another unanswered question in cancer survivorship care is the course of the reported late treatment effects. It remains unclear if these are immediate treatment effects – which persist and slowly worsen over time – or if they are late effects becoming manifest after many years of follow-up . Regarding cognitive impairment among testicular cancer survivors, for example, it may be both. During chemotherapy for testicular cancer, there are reports of an initial decline of cognitive function, followed by a normalisation 6 to 18 months after chemotherapy (21,22). Long-term outcomes – with a median follow-up duration of 11 to 14 years – do report compromised cognitive function (23,24), supporting a chronic component in the aetiology of cognitive impairment among testicular cancer survivors. Biomarkers – such as serum levels of testosterone or AGEs in the skin – may help identify testicular cancer survivors prone to long-term cognitive sequelae (chapter 2 and 3). Prospective, longitudinal data are needed to answer questions regarding the course of potential biomarkers of long-term adverse events in testicular cancer survivors. With timely detection and treatment of long-term complications, such studies can be executed by collaboration between oncologists and general practitioners (25). Currently, a study including curatively treated testicular cancer patients examines the safety and feasibility of a shared

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care survivorship care plan to follow-up patients in close collaboration with their general practitioner (NCT01783145).

Improving long-term health status in patients with neuroendocrine

tumours

Patients with NETs are at risk for fat-soluble vitamin deficiencies, vitamin B12 and B3 deficiencies, and poor nutritional status (26). This is due to excessive serotonin production, diarrhoea, gastrointestinal surgery, and treatment with somatostatin analogues (SSA) (27). Firstly, we performed a feasibility study to improve fat-soluble vitamins, vitamin B3, and vitamin B12 status (chapter 4a). In the subsequent well-powered clinical trial (chapter 4b), we investigated if it was possible to reduce the number of patients with NET and deficient vitamin A, D, E, K, B3, and B12. We showed that the proportion of patients with above-mentioned adequate vitamin levels improved from 38% to 66%. As long-term fat-soluble vitamin deficiencies and vitamin B12 and B3 deficiencies can cause severe symptoms, we concluded that repetitive evaluation of the vitamin A, D, E, K, B3, and B12 status and supplementing deficiencies should be recommended in patients with NETs. However, we could neither demonstrate a reduction in symptoms linked to vitamin deficiencies nor improve the quality of life in such a short study period. Other studies in patients with NETs – mostly focussed on vitamin D – report normalising single vitamin levels (28–31), also fail to reduce morbidity after vitamin supplementation. Well-designed trials with a sufficient follow-up duration are needed to define further the benefit of vitamin supplementation in patients with NET. Another essential element warranting further research consists of dietary guidance. This is relevant as malnourishment is associated with poorer outcomes in progression-free survival and QoL in patients with NETs (32,33). However, it is unknown whether addressing this malnutrition leads to improved survival in patients with NETs. There are indications that dietary consultation improves nutritional status, particularly in patients dealing with anorexia, steatorrhea, and pancreatic enzyme supplements, bowel stenosis, or abdominal complaints due to hormone hypersecretion. Therefore, future investigations must standardise methodology on dietary support and investigate its added value in the care for patients with NETs.

In this thesis, we describe a study on a web-based tailored information and support system for patients with NETs (chapter 5). We found seemingly conflicting results. Although 55% of patients wished to receive more information at baseline,

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we observed no difference in median distress level and median global score on perceived information and satisfaction between the intervention and control groups. These results contrast with other web-based systems investigated in patients with advanced cancer where participants were assigned to an online program in which they could self-report symptoms (34). This difference might be due to direct communication with a healthcare provider participant had access to their web-based system. Without active consultation regarding the provided information on NET diagnosis, symptoms, and treatment, its complexity might only raise more questions. This would also explain our observation. In chapter 5, fewer patients in the control group wished to receive more information at the end of the study than our intervention group. Another study with a web-based system to assist patients with cancer in reducing symptom distress reported that their system’s most valuable component was e-mail communication with nurses (34). These findings, including the results described in chapter 5, suggest an interactive function in web-based systems can have additional value for patients with NET. We are currently performing a single centre, randomised interventional study including patients with a NET grade 1 or 2, irrespective of disease stage and treatment intent. Patients are randomised between standard care – including access to a web-based information system – and standard care complemented with access to a healthcare provider to help interpret the information provided (METc 2018/297).

Improving outcomes in extrapulmonary neuroendocrine carcinomas

EPNECs remain challenging to treat due to their aggressive nature and rarity. EPNECs of different organ primaries have many similarities in their tumour biology. Understanding the cellular and molecular basis underlying neuroendocrine transdifferentiation of epithelial cancers is of clinical significance. Instead of primary tumour location, molecular signatures of various neuroendocrine carcinomas and common sensitivity profiles could serve to guide treatment. This approach has helped to demonstrate the efficacy of immune checkpoint inhibitors. We, therefore, recommend including patients with EPNECs in clinical trials independent of the primary tumour site.

Improving oncological care in patient populations with rare

malig-nancies

Rare cancers, like all cancers, need a timely and appropriate diagnosis and optimal treatment strategies. In this heterogeneous group of diseases, each

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rare malignancy requires specific attention during both treatment and follow-up. Firstly, the centralisation of rare cancer patients to dedicated reference centres is recommended to increase the number of patients treated in these centres to ensure physician expertise. This facilitates in depth-analysis of patient data and clinical studies that is particularly crucial for rare cancers, such as NETs and EPNECs. The studies are often of limited impact due to low patient numbers or incomplete data sets. Moreover, the published studies on NETs and EPNECs, which usually concern retrospective research, are difficult to compare due to the heterogenous design of databases and the variation over time in classification and selection of patient populations. Therefore, prospective collaborative studies of methodologically adequate quality are urgently needed to identify predictors of the course of the disease and enable personalized patient care. Furthermore, biomarker research is exceptionally important in rare cancers, from both a medical perspective and a health care cost perspective. Biomarkers could guide treatment strategies and/or identify patients at risk for long-term adverse treatment effects. To ensure continuity of cancer care and the best possible treatment for patients, cooperation between oncologists and general practitioners (GPs) is necessary. GPs’ tasks in cancer care range from prevention, cancer screening and diagnosis, and the treatment of side-effects during therapy, shared follow-up and survivorship care, to end-of-life care. Creating a disease-specific shared-care model, including each healthcare provider’s contribution to a patient’s treatment, ensures effective cooperation between GPs and oncologists. A prospective study including 163 patients with metastatic testicular cancer after completion of chemotherapy that resulted in complete remission examines the safety and feasibility of a shared care survivorship care plan (NCT01783145). For patients with NETs or EPNECs, such a model still needs to be developed and investigated.

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