Nikki Ijzerman

PART 2: ANGIOSARCOMA

Chapter 11 provides a systematic review of the literature on the role of neoadjuvant systemic treatment of angiosarcoma. The literature showed a beneficial role of neoadjuvant chemotherapy on downsizing of the tumour resulting in an improvement in the rate of free resection margins, especially in patients with cardiac or cutaneous angiosarcoma. However, no definitive conclusions on survival can be drawn based on the available literature lacking any prospective randomized studies in this setting. We advise that neoadjuvant chemotherapy should be considered, since this could lead to less mutilating resections and a higher rate of free resection margins. In the future, an international angiosarcoma registry could help to develop guidelines for this rare disease.

In Chapter 12 of this thesis the PropAngio study protocol is described. Recently, propranolol has effectively been repurposed for the treatment of infantile hemangioma. Angiosarcoma has several similarities with hemangioma, including its high β-adrenergic receptor expression and the supposedly important role of vascular endothelial growth factor in malignant growth. Propranolol has been administered small-scale in individual angiosarcoma cases with promising results. The goal of this neoadjuvant window-of-opportunity study is to prospectively evaluate the activity of propranolol monotherapy in patients with cutaneous angiosarcoma. Fourteen patients with primary, recurrent or metastatic cutaneous angiosarcoma will be included. Propranolol will be administered orally in an escalating dose during three to six weeks, before the initiation of standard treatment. The primary endpoint is clinical response and histological response will be determined as secondary endpoint. The study, currently enrolling patients, will be considered positive when at least three patients have a response to propranolol.

In conclusion, we feel this thesis has contributed to further personalising the treatment of GIST and angiosarcoma patients. In the future, a more personalised, centralised, mutation-tailored treatment of GIST patients should be pursued. Besides that, further research on GIST and angiosarcoma biology, clinical behaviour and treatment is warranted to improve survival.

General Discussion and Future Perspectives

Both GIST and angiosarcoma are rare tumour types, exposing patients and researchers to several challenges. Randomized controlled trials (RCTs) are generally considered as the best tool for comparing the outcomes of patient groups receiving different cancer treatments. However, RCTs often require a large sample size for powered results. Since soft tissue sarcomas (STS) represent less than 1% of all cancers 1, 2, inclusion of a large number of STS patients in RCTs is almost impossible within reasonable timelines and takes many years, slowing down the advancements made in sarcoma treatment. Besides, since the patient group is relatively small compared to – for example – breast cancer patients, the incentive for pharmaceutical companies to develop new targeted medicines for sarcoma patients is smaller. To overcome these challenges, a strong international collaboration is warranted to boost STS patient inclusion in clinical studies and to combine patient data to enlarge the sample size of retrospective studies. In this general discussion, several other priorities in the treatment of GIST and angiosarcoma patients are discussed, as well as its future perspectives.

Centralised treatment
Because of their rarity and frequent need of multimodal treatment, management of GIST should be carried out in a centralised manner: in a specialised centre with expertise in the treatment of GIST and treating a high number of GIST patients 3. The treatment team should involve dedicated pathologists, radiologists, surgeons, radiation oncologist and medical oncologists.

In Chapter 6 of this thesis, the presentation and treatment of rectal GIST patients in general hospitals were compared to rectal GIST patients treated in specialised centres. Perioperative GIST tumour rupture is an established adverse prognostic factor 3, 4. Despite the rectal GIST tumours being smaller in general hospitals with less extensive surgery, the proportion of patients with perioperative tumour rupture was notably higher in general hospitals (37% vs. 5%, p<0.001). This suggests that the quality of surgery of rectal GIST was superior in specialised centres. Although the European Society for Medical Oncology (ESMO) guidelines dating from respectively 2021 3, 5 and 2018 advise to treat GIST patients in specialised centres, in 2017-2018 only 31% of all GIST patients who received surgery in the Netherlands was operated on in a specialised centre 6. Larger tumours are associated with a higher rupture risk 7. Nevertheless, only 35% of the patients with a large GIST (>5cm) was operated on in a specialist centre in the Netherlands 6. Notwithstanding the fact that the proportion of GIST patients receiving surgery in a specialised centre did increase compared to 2009-2010 (17% surgery in specialised centre, 19% >5cm in specialised centre), additional efforts should be made to centralise the surgical treatment of GIST patients in the Netherlands.

GIST patients are treated with tyrosine kinase inhibitors (TKIs) in the neoadjuvant, adjuvant and palliative treatment setting 3. Common side effects of imatinib and sunitinib are diarrhoea, nausea, vomiting, oedema, fatigue and haematological disorders such as anemia 8. With more than 200 registered medical oncologists in the Netherlands 6 and only 400 new GIST diagnoses per year in the Netherlands 9 – who are mostly treated in GIST expertise centres – a medical oncologist in a general hospital usually only sees a handful of GIST patients during their career. This lack of experience in general hospitals could negatively influence the (systemic) treatment of GIST patients. Also, especially for other uncommon but severe side effects from TKIs, such as neurocognitive adverse effects for avapritinib 10 or severe liver injury for regorafenib 11, it could be beneficial for patients to be treated by medical oncologists specialised in sarcoma. As a result of their experience in the management of these side effects, specialised medical oncologists might be more aware in timely diagnosing of severe side effects, early dose modification and prompt prescription of treatment, to prevent TKI interruption which can negatively influence clinical outcome.

With an annual incidence of only around 50 patients in the Netherlands per year 6, oncology doctors in general hospitals only see a few angiosarcoma patients during their career. A successful angiosarcoma treatment begins with a timely and accurate diagnosis, what is most likely done by a team of angiosarcoma experts working in specialised sarcoma centres. Therefore, angiosarcoma patients should be referred to specialised centres. Another advantage of centralised treatment of angiosarcoma patients is that all angiosarcoma patients may be asked to participate in clinical trials and registries of specialist centres, which will eventually contribute to further elucidating angiosarcoma characteristics and hopefully also improve angiosarcoma survival.

Future efforts should be made to centralise the treatment of GIST and also angiosarcoma patients in the Netherlands. To motivate doctors in general hospitals to refer their patients to a specialised centre or to treat their patients under supervision of a specialised centre, it could be helpful to perform a nationwide study with data from the national cancer registry to compare the current characteristics and outcome of patients treated in a general hospital with patients in a specialist centre. Furthermore, this could help to identify patient factors that definitely qualify that patient for centralised treatment.

Mutation tailored treatment
Another form of personalised medicine in cancer patients is mutation tailored treatment. ESMO guidelines recommend mutational analysis for every GIST patient (except non-rectal GIST <2 cm) to tailor potential future systemic treatment 3. The presence of specific mutations in GIST patients could have implications for the treatment. Therefore, mutation analysis does not only have consequences for patients with advanced GIST, but also for patients getting neo-adjuvant or adjuvant therapy with imatinib. First of all, patients with a KIT exon 9 mutation should get a higher dose of imatinib (800 mg instead of 400 mg once daily (OD)). Several years ago, two imatinib dosing strategies (800 mg OD vs. 400 mg OD) were compared in clinical trials in all GIST patients 12, 13. Data from these studies were combined and a meta-analysis was performed in 1,640 advanced GIST patients treated with imatinib 14. In the entire group, a small but significant difference in progression free survival (PFS) was found in benefit of the 800 mg arm (400 mg arm HR 0.89, 95% confidence interval 0.79-1.00, p=0.04), but no difference in overall survival (OS). On the other hand, patients harbouring a KIT exon 9 mutation had a substantial PFS benefit once treated with the higher imatinib dose. Based on these results, sarcoma clinicians prefer to use the 800 mg dose for KIT exon 9 mutated GIST patients, even in the adjuvant treatment setting 3. Furthermore, several mutation profiles in GIST patients have shown to be primary-resistant to imatinib. These mutation profiles concern the PDGFR D842V mutation, neurofibromatosis type 1 (NF1) associated GIST, SDH deficient GIST, BRAF mutation, NTRK rearrangements and wildtypes 15. For these patients, no (neo) adjuvant imatinib should be given. Finally, relatively new agents were registered for specific GIST mutation subgroups. For GIST patients with a PDGFR D842V mutation (8% of all GIST 16), avapritinib has shown efficacy 17, 18. Advanced PDGFR D842V patients treated with avapritinib had an adjusted median PFS of 29.5 months in a retrospective analysis, which is considerably longer than the median PFS of 3.4 months for PDGFR D842V patients treated with other TKIs 18. Therefore, all GIST patients with a PDGFR D842V mutation and TKI indication should be treated with avapritinib instead of other TKIs. Furthermore, NTRK inhibitors, such as larotrectinib, have shown efficacy in NTRK-fusion mutated GIST patients 19 and BRAF inhibitors in BRAF mutated GIST patients 20. The fact that therapy response differs for different GIST mutation types, provides a strong rationale for mutation tailored therapy. As a result, ESMO guidelines incorporated mutation analysis as standard part of GIST treatment 3. However, in a retrospective study from the Netherlands with 756 GIST patients diagnosed in 2017-2018, only 49% of all patients was found to receive mutation analysis 21. A significant majority of these patients was treated in a specialised centre (76%, p<0.001). From the high risk or metastatic patients who had mutation analysis (n=159), the frequency of mutation analysis was significantly higher in specialised centres (96%) compared to non-specialised centres (75%, p<0.001), providing another argument for centralised treatment of (high risk) GIST patients. For approximately 1% of GIST patients no driver mutation is found 16. In future research, it would be interesting to perform whole genome sequencing (WGS) on tissue from these so-called wildtype GIST patients, in order to reveal uncommon genetic alterations that are prone for treatment with (off-label) agents. Not only for GIST patients, but also for the treatment of angiosarcoma a lot of advances could be made by a better mutational profiling of the disease. This could help to identify potential treatment targets. Since angiosarcoma is such a rare disease, only relatively small cohort studies investigating the genomic landscape of angiosarcoma are available 22, 23. In the Angiosarcoma Project, WGS was performed on 47 angiosarcoma tumours and mutations in KDR, TP53 and PIK3CA were recurrently found 22. In a cohort described by Huang et al., MYC amplification was found in most secondary angiosarcoma tumours (28/31, 90%) 23. Nevertheless, the genomic landscape of angiosarcoma tumours is heterogeneous. This heterogeneity clearly introduces challenges in the development of targeted therapies in angiosarcoma patients. Future efforts should be made to further characterise the genomic landscape of angiosarcoma in order to enhance treatment strategies. Dosing of TKIs in GIST patients Systemic treatment with TKIs is an important part of GIST treatment. GIST patients are treated with TKIs in the neoadjuvant, adjuvant and palliative treatment setting 3. Imatinib is indicated in the neoadjuvant, adjuvant and first line palliative treatment setting. In the palliative setting, sunitinib is registered as second line treatment, regorafenib as third line treatment, and ripretinib as fourth line treatment 24-27. Furthermore, avapritinib is registered as effective treatment for patients with a PDGFR D842V mutated GIST 17, 18. In previous studies on the pharmacokinetics (PK) of imatinib and sunitinib, the importance of adequate dosing of these TKIs was underlined when an exposure-response relationship was established. Patients with an imatinib trough level above the threshold of 1,100 ng/mL had an almost three times longer time to progression (TTP) compared to patients with levels below this threshold (i.e. 30 months vs. 11 months) 28. Also for sunitinib in GIST patients, a high exposure was associated with a longer TTP compared to a low exposure (median TTP 290 days vs. 150 days) 29. Besides, there is a large inter- and intra-patients variability in drug exposure 28, 30-32. Also after long-term imatinib treatment a decrease in imatinib levels of approximately 29% was seen 33. The high variability in drug exposure combined with the established exposure-response relationship, forms the rationale for routinely measuring the drug exposure. If the measured drug exposure (trough level) is below the target, dose modifications can be performed to achieve adequate drug exposure defined by trough levels above the established targets. Dose modifications based on trough levels is called Therapeutic Drug Monitoring (TDM). TDM has shown to be feasible in routine clinical practice in the Netherlands for imatinib (chapter 8) and sunitinib 34. More importantly, in a recent Dutch prospective, multicentre study including 552 evaluable patients using 24 oral targeted therapies, TDM showed to be feasible as well 35. In this study, the proportion of underexposed patients was reduced by 39% compared with historical data 35. Future efforts should be made to implement TDM in routine clinical care in all centres prescribing TKIs to enable adequate exposure and extend TKI treatment. Follow-up strategy Current follow-up of GIST patients is done by routine CT-scanning to evaluate tumour response to therapy or to screen for recurrence after surgery. Nowadays, circulating tumour DNA (ctDNA) is increasingly valued as a highly sensitive, non-invasive tumour-specific biomarker of metastatic disease in several tumour types 36, 37. In GIST ctDNA might also be useful as a tool to screen for tumour recurrence or progression of disease. CtDNA could be used as a biomarker by measuring changes in both the fractional abundance and levels of known mutants in cell free plasma by digital droplet PCR (ddPCR). The fractional abundance is a percentage based on the ratio between mutant and wild type droplets. Once tumours are growing, both the fractional abundance as well as the levels of known mutants in cell free plasma are increasing, whereby ctDNA could be used as a biomarker to assess response. The assessment of ctDNA in blood has several advantages. Firstly, a simple blood draw could replace an invasive tumour biopsy, which is indicated in case of progressive disease to determine the type of (resistant) mutation. Secondly, therapy is stopped and switched to the next treatment line after progressive disease is identified on the CT-scan in current clinical practice. At that moment, therapy resistant tumour clones have already been developed causing growth of the tumour lesions. By routinely measuring ctDNA, secondary resistant mutations might be measured at an earlier stage, possibly even before the tumour develops definite resistant tumour clones. Finally, the assessment of ctDNA could avoid certain disadvantages of CT-scanning, such as radiation burden and high costs. Since 2014, the Dutch GIST Consortium is trying to establish the role of ctDNA measurements during the follow-up of GIST patients by means of the GALLOP study and GALLOP-11 study (NCT03780400). In the first part of the study, the GALLOP study, a ddPCR assay was developed that is able to measure 80% of all KIT exon 11 mutations in theory, translating to around 56% of all KIT mutations 21. Furthermore, a bio-databank was set-up, that currently stores ctDNA samples of more than 400 patients. In the second part of the GALLOP project –the recently started GALLOP-11 study– this ddPCR assay will be validated by comparing the results from the ddPCR measurement to the result from the routinely performed CT-scans. In addition to the validation of the KIT exon 11 ddPCR assay, efforts will be made to develop other ddPCR assays that are able to measure other GIST mutations. In the future, the most manageable device to measure ctDNA in GIST patients should be able to trustworthy pick up and quantify all possible mutations in the ctDNA (primary and secondary mutations). Another topic that should be part of the standard follow-up of cancer patients is to discuss uncommon side effects during follow-up visits and to also address important questions of life during follow-up visits. Side effects of anti-cancer treatment can have a tremendous impact on quality of life. Common side effects, such as diarrhoea, nausea and laboratory abnormalities, are nearly always addressed during outpatient follow-up visits. Discussing uncommon side effects, such as taste and smell disturbances, is something that is done less often. Nonetheless, the prevalence of these disturbances is quite high (chapter 9) and daily life and quality of life are affected by these side effects in a considerable number of patients. Furthermore, the psychosocial impact of their disease on life often remains an underexposed topic during outpatient visits (chapter 2). This is probably (at least partly) explained by the limited consultation time. During the already limited consultation time, the treating physician needs to chart the health status and discuss the results of investigations and potential clinical studies. In the future, more financial support should be dedicated to provide patients with extra guidance by a social worker or specialised nurse. During these extra consultations, important quality of life issues can receive extra attention. Since your quality of life determines your happiness and is therefore such an important facet of life, these extra consultations should be implemented as part of the standard treatment and follow-up strategy. New treatment strategies The development of new drugs will probably play an important role in the future improvement of GIST and angiosarcoma treatment and survival. The recent registration of ripretinib and avapritinib shows the ongoing relevance of the development of new TKIs for GIST treatment. For angiosarcoma, newer drugs such as checkpoint inhibitors have shown quite good responses, especially for cutaneous angiosarcoma 22, 38-40. Immunotherapy agents are therefore interesting candidates to investigate in order to improve the treatment of angiosarcoma in both the neoadjuvant as palliative treatment setting. Besides the development of new drugs, re-use of existing drugs for an indication outside their label –also called drug repurposing– could be another strategy to improve the treatment of cancer patients. An example is the study on the repurposing of propranolol for the treatment of angiosarcoma (chapter 12); the results of which are still awaited. Data driven research and eHealth As with other rare cancers, the limited availability of reliable data is one of the main barriers to conduct angiosarcoma research. Considering this barrier and the challenges in performing a randomized controlled trial in rare tumour types, an international registry with data on angiosarcoma could be a very valuable source of information. Such an easily accessible registry could help to develop international treatment guidelines, identify new treatment targets and elucidate angiosarcoma characteristics. Several years ago, a project was set-up to collect angiosarcoma patient data in the United States: the Angiosarcoma Project. In this project, patients were invited to participate via social media and patient advocacy groups and gave their consent online, after which their data were collected. Patients are hereby collaborating with and facilitating in the research that is done, making it a very innovative patient-partnered approach 22. Expansion of these kind of databases to other countries, would help in the design and execution of new randomized trials, to increase patient numbers, and provide internationally accepted treatment guidelines. Furthermore, an important part of future health care lies in the implementation of more eHealth features. According to the definition of e-health as stated by the European Union, eHealth refers to ‘tools and services that use information and communication technologies to improve prevention, diagnosis, treatment, monitoring and management of health and lifestyle’ 41. Potential tools and services that could help to improve patient care are a web-based appointment system, home measurements of for example blood pressure, online reporting of side effects, and online question and answer by treating physicians. These tools might improve patient care for patients and could also give physicians and researchers extra insights. CONCLUDING REMARKS In conclusion, this thesis has contributed to personalising the treatment of GIST and angiosarcoma patients. In the future, a personalised, centralised, mutation-tailored treatment of GIST patients should be pursued. In the follow-up strategy of GIST patients, there seems to be a role for TDM and there might be a role for routinely measuring ctDNA. Extra consultation time should be cleared to create room to discuss important quality of life topics in cancer patients. New drugs or repurposed drugs are needed to improve GIST and angiosarcoma treatment. Furthermore, international data registries could help to further elucidate characteristics of rare tumour types. Finally, future eHealth tools might improve patient care for patients and could also give physicians and researchers additional insights.