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

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University of Groningen

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

Stelwagen, Johannes

DOI:

10.33612/diss.170823907

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Publication date:

2021

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Citation for published version (APA):

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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Chapter 1

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BACKGROUND

More than 100 different rare tumour types exist, and any part of the body can be affected.1_{These malignancies have a wide variety of clinical courses, treatment}

options, and prognosis. Some malignancies – such as testicular cancer and neuroendocrine tumours (NET) – require long-lasting care and follow-up by an oncologist.

For patients with metastatic testicular cancer, 10-year survival rates after cisplatin combination chemotherapy and surgery are up to 80% despite the tumour’s aggressive nature.2_{In the successfully treated patients, long-lasting follow-up}

focusses on recurrence of the disease and aims to prevent or treat adverse late treatment effects such as second primary malignancies, cardiovascular disease, nephrotoxicity, and pulmonary toxicity, influencing health-related quality of life.3

For patients with NETs, long-term curation rates are much lower when diagnosed with metastases. In contrast to testicular cancers, these tumours are characterised by an indolent nature, illustrated by a median overall survival of 54 months for patients with a metastatic NET.4_{Even when having metastatic disease, these}

patients can remain symptom-free while others experience symptoms 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. These complaints can persist for years, given the indolent nature of NETs, and they can severely impact the quality of life in an otherwise oncologic stable setting.6

Summarising, many patients – with testicular cancer or a NET – share long-lasting oncological follow-up care. During these visits, next to the tumour’s recurrence, attention is paid to chronic disease or treatment related symptoms. These patients are, given the rarity of their diseases, often treated in expert centres. This facilitates performing research to improve short and long-term outcomes of these patients. This research can focus on several aspects, such as cardiovascular morbidity and health-related quality of life.

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On the other end of the prognostic spectrum are patients with neuroendocrine

carcinomas. These tumours can arise as primary malignancy or due to neuroendocrine transdifferentiation following treatment for adenocarcinomas. Although sharing rarity with testicular cancer and NETs, neuroendocrine carcinomas show a drastically different clinical course. They are aggressive tumours that can originate almost anywhere in the body.7_{Irrespective of primary tumour location,}

a patient’s prognosis is generally poor with a median overall survival of 34 months for localized disease and five months for metastatic disease.8_{Given the dismal}

prognosis of these patients, research focusses on improving treatments. Therefore, steps are taken to expand potential treatment modalities beyond the currently used cisplatin-based chemotherapy regimens.

Aim of this thesis

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

Outline of this thesis

Late effects of cisplatin-based chemotherapy in testicular cancer survivors include cardiovascular morbidity, but little data is available beyond 20 years post-treatment. In chapter 2, our objective was to assess vascular damage in

very long-term testicular cancer survivors. Testicular cancer survivors treated with orchiectomy plus chemotherapy (n=70) or orchiectomy only (n=75) and age-matched healthy controls (n=70) participated. The minimal follow-up duration after treatment for testicular cancer had to be 20 years. Patients above 70 years of age were not eligible. The assessment included vascular stiffness with ultrasound measurement of carotid-femoral pulse wave velocity (cf-PWV) and several other vascular- and ageing biomarkers, including intima-media thickness, von Willebrand Factor, presence of albuminuria, coagulation markers, and advanced glycation end products. Like vascular morbidity, impaired cognitive function may be a late

and essential effect of cisplatin-based chemotherapy (CT) or radiotherapy (RT), negatively affecting testicular cancer survivors’ daily lives. Therefore, in a second analysis of the same observational cross-sectional study, our objective was to assess neurocognitive impairment as a potential late treatment effect (chapter 3).

Data were collected from testicular cancer survivors treated with orchiectomy plus chemotherapy (n=66), orchiectomy plus radiotherapy (n=53) or orchiectomy only

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Chapter 1

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(n=65) and age-matched healthy controls (n=70). Formal cognitive testing included: auditory verbal learning test, letter fluency, category fluency tests, and the Trail Making Test; self-perceived cognitive functioning was assessed with the Cognitive Failure Questionnaire.

Compared to long-term morbidity in the curative setting for patients with testicular cancer, patients with metastatic NET often experience long-term morbidity in the non-curative setting. These patients are at risk for certain vitamin deficiencies and poor nutritional status due to excessive serotonin production, diarrhoea, gastrointestinal surgery, and or treatment with somatostatin analogues. Therefore, in chapter 4A we describe a feasibility study in which patients with NETs treated

with somatostatin analogues for at least 6 months were included. This study’s primary endpoint was the change in the proportion of patients with normal fat-soluble vitamin values and vitamin B3 and B12 values at the end of the study period. Furthermore, as secondary endpoints, nutritional state, quality of life, and levels of distress were assessed. The patients underwent dietary counselling and got vitamin supplementation in patients using a somatostatin analogue for more than 6 months. Participants were counselled by a dietician and received supplementation of deficient vitamins A, D, E, K, B12, and B3. Vitamin A, D, E, K, and B12 levels in blood, and vitamin B3 levels in urine, were measured at baseline, after four weeks, and after 18 weeks. Subsequently, we performed a trial in 53 patients with NETs and investigated the efficacy of the beforementioned dietary counselling and vitamin supplementation (chapter 4B).

Adequate information throughout a patients’ diagnostic, treatment, and follow-up process is an essential aspect of supportive care. Adequate information provision is associated with better health-related quality of life and lower distress levels in cancer patients. Therefore, our objective in chapter 5 was to assess the efficacy

of a web-based system consisting of self-screening of problems and care needs in patients with neuroendocrine tumours. Patients were randomized between the standard of care (n=49) or additional access to the web-based system (n=53) and followed 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.

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The poor prognosis for patients with extrapulmonary neuroendocrine carcinomas

(EPNECs), illustrates the need to improve their treatment. Chapter 6 provides a

literature overview where we describe new treatment modalities – including immune checkpoint inhibitors – for EPNECs and the improved understanding of the tumour pathogenesis and molecular alterations. To this end, we performed we searched PubMed on treatment outcomes for EPNECs with the current modalities of surgery, radiotherapy and platinum-based chemotherapy, and new modalities, including immune checkpoint inhibitors. Moreover, we verified ClinicalTrials.gov for clinical trials. Our search also included studies about adenocarcinomas’ transdifferentiation into neuroendocrine carcinomas and the molecular mechanisms underlying EPNEC development.

Finally, the results of this thesis are summarized and discussed in chapter 7. A

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REFERENCES

1. Gatta G, Van Der Zwan JM, Casali PG, Siesling S, Dei Tos AP, Kunkler I, et al. Rare cancers are not so rare: The rare cancer burden in Europe. Eur J Cancer. 2011;47:2493–511. 2. Hanna N, Einhorn LH. Testicular cancer: A reflection on 50 years of discovery. J Clin

Oncol. 2014;32:3085–93.

3. Kerns SL, Fung C, Monahan PO, Ardeshir-Rouhani-Fard S, Abu Zaid MI, Williams ALM, et al. Cumulative burden of morbidity among testicular cancer survivors after standard cisplatin-based chemotherapy: A multi-institutional study. J Clin Oncol. 2018;36:1505–12. 4. Mocellin S, Nitti D. Gastrointestinal carcinoid: Epidemiological and survival evidence

from a large population-based study (n = 25 531). Ann Oncol. 2013;24:3040–4. 5. Wolin EM, Leyden J, Goldstein G, Kolarova T, Hollander R, Warner RRP. Patient-reported

experience of diagnosis, management, and burden of neuroendocrine tumors: Results from a large patient survey in the United States. Pancreas. 2017;46:639–47.

6. Strosberg J, Wolin E, Chasen B, Kulke M, Bushnell D, Caplin M, et al. Health-related quality of life in patients with progressive midgut neuroendocrine tumors treated with

177_{Lu-dotatate in the phase III NETTER-1 trial. J Clin Oncol. 2018;36:2578–84.}

7. Kim JY, Hong S, Ro JY. Annals of diagnostic pathology recent updates on grading and classification of neuroendocrine tumors. Ann Diagn Pathol. 2017;29:11–6.

8. Sorbye H, Baudin E, Raymond E, Wiedenmann B, Niederle B, Sedlackova E, et al. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103:186–94.

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