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2018 Joanne van der Velden

Towards personalized treatment for patients with bone metastases

 

Many patients with cancer develop bone metastases with pain as an important symptom impacting on quality of life. Conventional radiotherapy is the standard local treatment, effective in a small majority of patients (61%). This means that a large portion of patients does not respond to radiotherapy. New interventions or combination of conventional treatments are needed.
Furthermore, it is important to identify those patients who are not likely to respond. For that purpose, we developed a clinical risk score. Primary tumor, performance status, and baseline pain score are associated with pain response. With a corrected c-statistic of 0.63, the risk score is only modestly able to discriminate good and poor responders, showing the need for better predictors. A possible factor that could be predictive for pain response in patients with spinal metastases is the degree of spinal (in)stability. It might be that pain caused by mechanical instability is not well treated by radiotherapy compared with pain resulting from local tumor activity. In patients with increasing spinal instability, radiotherapy might then be less effective. An association between spinal stability and a complete pain response after radiotherapy was found, supporting this hypothesis.
As stereotactic radiotherapy (SBRT) promises better and longer duration of symptom relief, its use is increasing rapidly. Overall, SBRT for bone metastases is associated with higher rates of pain response than have been reported following conventional radiotherapy. Also, local control seems excellent. These improved outcomes, however, may very well be the result of study methodology and patient selection. Randomized trials are required to formally evaluate the impact of SBRT for bone metastases. Therefore, the VERTICAL trial was initiated to quantify the effect of SBRT in patients with bone metastases by following the ‘cohort multiple Randomized Controlled Trial’ design. This design addresses common difficulties associated with pragmatic RCTs, such as reporting bias in patients allocated to the control arm, slow recruitment, and poor generalizability. We evaluated methodological challenges of conducting a cmRCT and argued that equally valid results can be obtained from trials conducted within cohorts as from pragmatic RCTs. Whether this design is more efficient depends on the amount and nature of non-compliance in the intervention arm.
SBRT involves high precision, high dose delivery to the target volume while sparing healthy tissues. Accurate and consistent delineation of the target volume is therefore crucial in SBRT, for which knowledge of the inter-observer differences in tumor volume delineation is needed. In our delineation study, considerable differences in interpretation of the tumor volumes were found. The use of MRI result in the highest inter-observer agreement. After spinal SBRT, a serious adverse effect is the occurrence of compression fractures. Prevention of these fractures is challenging because the metastatic lesion lies within the bone to be radiated. A simultaneous integrated boost (SIB) approach was proposed, designed to spare bone surrounding the metastasis to mitigate this risk. Follow-up data of patients who are treated with a SIB SBRT approach are needed to confirm the hypothesis of less fractures by sparing the surrounding relatively healthy bone.

Key words
Bone metastases; palliative radiotherapy; stereotactic radiotherapy; SBRT; prospective cohort; cmRCT

Main conclusions
•    The majority of patients with painful bone metastases experience pain relief after conventional radiotherapy.
•    It is difficult to identify the patients who are unlikely to respond to palliative radiotherapy.
•    The SINS is suitable for discriminating patients for referral to a radiation oncologist or an orthopedic surgeon, but it does not predict clinical outcomes.
•    MRI is more reproducible than CT in delineation of bone metastases.
•    The simultaneous integrated boost approach leads to better sparing of healthy bone and has the potential to reduce the risk of vertebral compression fractures.
•    Stereotactic radiotherapy for bone metastases seems to result in higher pain response and local control rates, but this may very well be the result of study methodology and patient selection.
•    The cmRCT design may improve trials by prevention of reporting bias, more efficient patient recruitment, quantification of patients’ preference, and up-to-date standard of care, also in the palliative setting.
•    Results from single trials conducted within cohorts are theoretically as valid as those from pragmatic, classic randomized controlled trials.

Subject doctoral thesis (Dutch)
Op weg naar een behandeling op maat voor patiënten met botmetastasen

Short summary (Dutch)
Op weg naar een op het individu gerichte behandeling voor patiënten met botmetastasen
Bij veel patiënten met kanker zaait de ziekte uiteindelijk uit naar de botten met negatieve gevolgen voor de kwaliteit van leven. Traditioneel worden deze patiënten op dezelfde manier behandeld: meestal met conventionele radiotherapie. De groep patiënten met botmetastasen is zo heterogeen dat elke patiënt een behandeling op maat verdient. Een risicoscore om patiënten te identificeren die niet zullen reageren op bestraling zou daarin kunnen helpen. Het blijkt dat de primaire tumor, conditie en pijnscore geassocieerd zijn met pijnrespons, maar helaas kunnen we met deze gegevens slechts matig onderscheid maken tussen een patiënt die wel reageert en een patiënt die pijn blijft houden. In het in Utrecht opgerichte PRESENT cohort blijkt dat een kleine meerderheid van patiënten (61%) verlichting van de pijn ervaart na bestraling. Dit betekent ook dat veel patiënten geen effect merken. Het lijkt erop dat de pijnrespons en lokale controle na hoge precisiebestraling (stereotactische radiotherapie) beter is, maar is het belangrijk om te weten dat de onderzoeksmethoden niet altijd even goed waren, en dat met name patiënten in een goede conditie onderzocht. Gerandomiseerde studies zijn dus nodig om stereotactische radiotherapie eerlijk te kunnen vergelijken met conventionele radiotherapie. Dat doen we in de VERTICAL trial, de eerst trial binnen het PRESENT cohort, opgezet volgens het ‘cohort multiple Randomized Controlled Trial’ design. Het cmRCT design heeft een inclusieprocedure die op de patiënt is gericht, wat ervoor kan zorgen dat studies sneller vol zitten en er minder patiënten teleurgesteld worden. We verwachten de resultaten van de VERTICAL studie over een jaar.

 

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