Anne Versteeg

benefits of surgery to the associated risks. Future studies assessing the relation between the occurrence of adverse events, HRQOL, and associated costs are required.

Advances in surgical techniques have led to the development of less invasive surgical techniques. The potential advantages of less invasive spine surgery include a decreased risk of complications, reduced loss of blood and improved recovery time as a result of less post-operative pain due to the smaller incisions and less soft tissue dissection [36]. The literature regarding less invasive surgical procedures in patients with spinal metastases is however still limited. Chapter 8 assessed the incidence of adverse events following percutaneous pedicle screw fixation for spinal metastases. A multicenter retrospective review of 101 neurologically intact patients who underwent percutaneous pedicle screw fixation for spinal metastases was performed. A total of 30 adverse events in 18 patients were identified. The lower incidence of adverse events suggests a benefit of using a less invasive surgical approach in this patient population. However, it should be noted that less impactful adverse may not have been accounted for in this retrospective review, which also contributes to the lower incidence.

Controversy exists regarding the indication for less invasive spine surgery in patients with spinal metastases. Some authors propose that less invasive surgery should be limited to patients in bad clinical shape. Others, including the author’s current institution, feel that a less invasive approach should be used whenever possible to decrease the risk of complications and enhance patient recovery. A future study comparing the difference in adverse events between minimal invasive surgery and conventional open surgery should therefore consider the potential influence of selection bias.

advances in treatment strategy
Currently, standard of care for patients with unstable spinal metastases consists of stabilizing surgery followed by EBRT, or SBRT, after a minimum of two weeks. The time interval between surgery and radiotherapy is considered necessary based on the high incidence of wound healing complications that were reported when surgery and EBRT were combined within a week [6]. The wound healing process is a complex cascade of inflammation, proliferation and tissue-maturation, which is vulnerable for disruption due to radiation exposure, especially in the early phases [7].

Dose delivery with EBRT is non-conformal and is performed with a single posterior-anterior beam or with a two-beam approach with a posterior-anterior and anterior-posterior beam. The maximum dose to the spinal metastasis with EBRT is limited by the radiation tolerance of the surrounding organs at risk. Moreover, due attenuation the radiation dose delivered to structures present in the pathway in front of the spinal metastasis, including soft tissues in the surgical field, is higher compared with the dose delivered to the spinal metastasis [9]. SBRT, on the other hand, allows highly conformal delivery of the radiation dose. The radiation dose to the spinal metastases can be increased up to ablative radiation doses while limiting the dose to the surrounding tissues. The conformal dose delivery with SBRT also substantially reduces the radiation dose to the posterior surgical area, and may be even further decreased with active sparing of the surgical area during treatment planning. The aim of the study described in Chapter 9 was to compare the radiation dose to the surgical area with EBRT, standard SBRT, and SBRT with active sparing of the surgical area. As expected, the mean radiation dose in the surgical area was significantly lower with the use of SBRT, with and without active sparing of the surgical area, compared to the use of EBRT. Active sparing of the surgical area with SBRT resulted in a further decrease in mean radiation dose to the surgical area. It is presently not known if the additional sparing of the surgical area with SBRT has a clinically relevant impact on the risk of wound complications compared to SBRT without active sparing of the surgical area. However, considering the feasibility of active sparing of the surgical area without compromising the radiation dose to the target spinal metastasis and other organs at risk, we tentatively recommend to use this type of SBRT planning strategy to minimize the risk of wound complications due to radiation injury.

The current standard practice, i.e. surgery followed by radiotherapy after a two-week interval, has several downsides. First, the time interval between surgery and radiotherapy delays the time until radiotherapy-induced pain relief. Second, the surgical implants induce scatter artifacts on planning computed tomography (CT) and magnetic resonance imaging (MRI) examinations, which prohibit accurate planning and delivery of radiation [37]. Third, in case of postoperative SBRT additional invasive imaging procedures, such as a CT myelogram, are necessary for accurate treatment planning. Fourth, in case of EBRT, multiple hospital visits are often needed for the administration of hyper-fractionated radiation schemes. Finally, only in about 60% of the patients, pain relief is achieved [38]. An alternative treatment strategy, which could potentially lead to faster pain relief in a higher proportion of patients with less hospital visits, is described in Chapter 10. Here, safety and feasibility of SBRT followed by stabilizing surgery within 24 hours for patients with symptomatic unstable spinal metastases is demonstrated. Combining SBRT and surgery within 24 hours has several advantages for the patient. Both treatments can be performed within one hospital admission and the radiotherapy induced pain relief may be experienced (approximately two weeks) earlier. If necessary, systemic treatment can also be initiated earlier. In addition, the use of pre-operative SBRT may reduce the vitality of malignant cells, thereby decreasing the risk of tumor spread as a result of surgical manipulation of the tumor. The results of this first-in-man study are promising but some limitations should be considered. Planning both treatments within a 24 hour time frame requires excellent collaboration between spine surgeons and radiation oncologists. This treatment strategy is not suitable for patients requiring emergency surgery (<24 hours) for symptomatic MESCC because of the required time that is necessary to plan and complete the work-up for both treatments. Future studies should investigate if this new treatment strategy not only decreases the treatment burden for the patient but also results in superior clinical and patient reported outcomes compared to the current standard of care. future perspectives The increasing incidence of patients with spinal metastases and the expanding treatment options to relieve symptoms and to maintain or improve quality of life, will lead to a further increase in the application of surgery and radiotherapy for spinal metastases in the near future. In light of the advances in treatment strategies of the last two decades, a further shift towards less extensive open surgical procedures and minimal invasive surgical procedures can be expected. Historically, resection of a spinal metastasis was considered if the pertaining spinal metastasis was the only (visible) metastatic site. Currently, we consider a solitary spinal metastasis as not truly being a solitary metastasis. Even though the solitary spinal metastasis is the only visible metastatic site, it is very likely that other sites harbour undetectable (micro-)metastases. Extensive tumor resections with curative intents, accompanied with high risks of peri-operative and post-operative adverse events, and post-operative morbidity are not desirable when the procedure is not curative. Instead, conventional open procedures or minimal invasive approaches may be limited to procedures to decompress the neurological structures and to stabilize the spine. Pre-operative or post-operative SBRT is an important adjuvant treatment to both open and minimal invasive surgical procedures to achieve durable local tumor control [4]. Limiting the surgical invasiveness, while still achieving the goals of decompression of the spinal cord, stabilization of the spinal column and achievement of durable local tumor control may improve patient quality of life and disease control. Furthermore, we predict a shift towards more patient-centered care, with different medical specialists collaborating for and together with the patient to optimize treatment. With the increased attention for patient reported outcomes to evaluate treatment, there is also a trend towards evaluating patient satisfaction with treatment using patient reported experience measures (PREMS) [39, 40]. Patient satisfaction is a complex multidimensional construct and an interplay between pre-treatment expectations, severity of pre-treatment symptoms and post-treatment outcomes [41]. It is important to gain insight in both perceived satisfaction with treatment for spinal metastases, and factors that are related with satisfaction to improve patient counselling and outcomes. Recently Versteeg et al. [unpublished results] conducted a study to assess satisfaction with the outcomes of treatment for spinal metastases using the separate set of post-therapy questions of the SOSGOQ2.0. At 12 weeks post-treatment, 83% of the surgically treated patients and 77% of the patients who underwent radiotherapy reported to be satisfied with the outcomes of their treatment. A distinct difference in changes in HRQOL (pre-treatment vs. post-treatment) was observed between satisfied and dissatisfied patients, with dissatisfied patients experiencing only slight improvements in HRQOL. An important aspect of patient satisfaction and HRQOL is the relation with pre-treatment expectations [42, 43]. Quality of life has therefore previously been considered as the appraisal of the current level of functioning compared to what is perceived to be ideal or possible (expectations) [42, 43]. In order to optimize post-treatment quality of life, we also need to optimize patient counselling towards realistic expectations [42]. It is imperative that patients understand the goals and limitations of treatments in order to make an informed treatment decision. Previous studies have shown that both physicians and patients are overly optimistic about life expectancy and patients having unrealistic beliefs about the effectiveness of treatments [44]. Two recent studies demonstrated that the majority of patients with final stage lung or rectal cancer receiving palliative radiotherapy or chemotherapy reported that their treatment was likely to cure them [45, 46]. Patients are willing to accept invasive and toxic treatments if there is a chance of cure, even if this chance is as small as 1% [45]. When the treatment goal is palliative, however, the willingness to accept the same treatment decreases [46]. A study by Mitera et al. [47] explored the expectations of patients with spinal metastases regarding palliative radiotherapy and demonstrated that 35% of the patients were unaware of the severity of their disease. Furthermore, 20% of the patients expected that radiotherapy targeting the spinal metastases would have a systemic effect and be able to cure their cancer [47]. To improve treatment counselling of patients with spinal metastases, it is imperative to understand patients’ expectations and perceptions of received treatment. Yet, to the best of our knowledge, the expectations and level of understanding of patients facing surgical treatment for spinal metastases are currently unknown. A study evaluating patients’ expectations regarding surgical and/or radiotherapy for treatment is currently being designed to develop a new questionnaire to assess pre-treatment expectations. In the future, evaluation of patient’s expectations may aid in improved patient counselling and patient selection. CONCLUSION In conclusion, the decision for surgery, radiotherapy or a combination of both for the treatment of spinal metastases is complex. The introduction of the SINS has assisted to standardize the assessment of neoplastic spinal instability and to improve communication among physicians. Yet the predictive value of the SINS for treatment outcome requires further research. The main goal of treatment for patients with spinal metastases is to improve their quality of life; use of the spine oncology specific SOSGOQ2.0 HRQOL measure will aid in the accurate evaluation of the impact of different treatment strategies on HRQOL. The results of the studies presented in this thesis showed that surgery with or without additional radiotherapy is associated with clinically meaningful improvements in quality of life in carefully selected patients with (potentially) unstable spinal metastases. The benefits of surgery should however be weighed against the risks of adverse events. In terms of optimizing treatment strategies, we demonstrated that the combination of SBRT and surgical stabilization within 24 hours for spinal metastases is safe and feasible. Whether this new combined treatment strategy results in superior outcomes compared to current standard of care remains to be determined.