Comparing conVEntional RadioTherapy with stereotactIC body radiotherapy in patients with spinAL metastases: study protocol for an randomized controlled trial following the cohort multiple randomized controlled trial design

Bone metastases are a frequent distant manifestation of cancer, with the spinal column being the most common site [1]. Spinal metastases can induce cancer-related pain, mechanical instability, and neural compression, thereby causing morbidity and impacting on quality of life (QOL). Treatment is aimed at pain relief and prevention of neurological deficits. The treatment for most patients with symptomatic spinal metastases is standard external beam radiotherapy [2], which is moderately effective: around 60% of patients who undergo external beam radiotherapy experience pain relief [3]. Furthermore, pain relief is often incomplete with complete pain response rates ranging from 0 and 23% [3] and one in five patients needs re-irradiation [4]. Escalating the dose to the metastatic site might improve the pain response and prolong the duration of pain relief [5]. Dose escalation to spinal tumors using standard radiotherapy is complicated by the low tolerance of the spinal cord to radiation. Stereotactic body radiotherapy (SBRT) is able to deliver precise high-dose radiation to spinal metastases in single or multiple fractions, while sparing surrounding healthy tissues. Phase I and II studies have suggested that, for selected groups of patients, SBRT for spinal metastases may be accurate, safe, and effective [5, 6], with complete pain response in 54% of patients six months after SBRT [7]. Other authors even reported overall pain response rates around 90% [8‐10]. To date however, no randomized controlled studies have been performed so equipoise still exist on the effectiveness of SBRT in comparison to standard radiotherapy. Therefore, we designed a pragmatic randomized controlled trial to compare conVEntional RadioTherapy with stereotactIC body radiotherapy in patients with spinAL metastases (VERTICAL) following the CONSORT statement [11].

In this report, we present the rationale and design of the VERTICAL trial. In this randomized study, we investigate whether SBRT can increase the proportion of patients with (complete or partial) pain response. Although standard radiotherapy is moderately effective in achieving pain relief in most patients with spinal metastases, up to 40% of patients do not experience any pain relief and complete response occurs in only 30% of responders [3]. Presently, it is not exactly understood why some patients do not respond (adequately) to standard radiotherapy. A factor that may play a role in the suboptimal response to standard radiotherapy is the way the radiation dose is delivered. Barton and colleagues [28] showed that the dose received by the vertebral column using standard radiation techniques varies by up to 50%. For instance, when using a direct posteroanterior field to deliver 8 Gy at a depth of 5 cm, metastases located in deep vertebrae receive less than 50% of the prescribed dose. This is important, since 4 Gy in one fractions is proven to be less effective than 8 Gy [29‐31]. If there is indeed a threshold dose below which pain relief is less likely and of slower onset, it may be important to ensure that the vertebral metastasis receives the dose intended. However, the low tolerance of the spinal cord to radiation limits the standard radiation dose to a level that below the optimal therapeutic dose thus providing a less than optimal response. Precise confinement of the radiation dose, even including dose escalation in addition, should increase the probability of pain relief while the risk of injury to the spinal cord is minimized. Several retrospective and prospective phase II studies have indeed shown the safety and efficacy of SBRT in spinal metastases [5, 6].

Most studies on spinal SBRT included a heterogeneous patient population, including previously unirradiated patients, patients who needed reirradiation, and post-operative SBRT, and these categories include patients with or without solitary spine metastases [8, 32]. We include all unirradiated patients with spinal metastases including patients with diffuse metastases, and mild neurological complaints. In this way, we deliberately chose a pragmatic approach since we expect that this would be the patient population that is going to be treated once the benefits of SBRT would have been established. In order to investigate the effect of SBRT without the effect of additional treatments, we however exclude patients who received previous standard or stereotactic body radiotherapy or surgery to the index site. As pragmatic trials investigate the effectiveness of medical treatment strategies under usual conditions, the standard strategy (i.e. 8 Gy in a single fraction, or for selected patients 30 Gy in 10 fractions) will be compared to the SBRT strategy (which includes more dose schedules). Still, the biological effective dose (BED) of the three dose regimen is much higher compared to the BED of the conventional dose regimen. If there is a difference in pain response after SBRT compared to standard radiotherapy, we should be able to detect that differences despite the use of multiple radiation dose schedules. Traditionally, stereotactic radiotherapy in metastatic bone disease is intended for patients with spinal metastases. However, SBRT is increasing being applied in the treatment of non-spine osseous metastases [33]. Since spinal metastases are similar to non-spine osseous metastases in terms of bone involvement and pain relief after standard radiotherapy [34, 35], the response after SBRT in spinal and non-spine osseous metastases is likely to be similar as well. Therefore, we have extended the VERTICAL inclusion criteria to patients with non-spinal bony metastatic disease.

To our knowledge, six other randomized studies on spinal SBRT are currently being conducted (Table 3) [36‐41]. Only two other trials require both CT and MRI imaging for the delineation of the spinal metastases [37, 38], however, these trials delineate the whole bony compartment (i.e. the CTV) that contains the metastasis instead of using an simultaneous integrated boost approach. They also have strict instructions on how to apply the standard and stereotactic body radiotherapy in contrast to our more pragmatic approach, offering radiation oncologists leeway in fractionation schedule. Furthermore, the VERTICAL trial distinguishes itself from these trials by applying the cmRCT design. The cmRCT design was proposed as a variant of classic pragmatic randomized controlled trials (RCTs) and addresses some common difficulties associated with those RCTs, such as disappointment bias, drop-outs, slow recruitment, and poor generalizability [13]. Patients and doctors often have a strong preference for the experimental treatment that has not proven to, but is expected to be superior. Investigators of the RTOG 0631 trial indeed experience that patients and their physicians prefer the SBRT treatment over standard radiotherapy [Samuel Ryu, personal communication]. Consequently, patients allocated to the standard arm may show disappointment when reporting outcomes. This is of particular concern since the primary endpoint consists of a subjective outcome (i.e. pain scores). By using the cmRCT design however, control patients are unaware of being allocated to the control arm, which will prevent disappointment bias in observed outcomes. Furthermore, standard of care is likely to be unaffected by treatment allocation and will therefore better resemble routine practice. We also expect lower drop-outs rates since patients in the control arm are not likely to withdraw from standard care, which may be of particular interest in this fragile patient population. Because of this fragility, researchers in this field should make an effort to optimize recruitment rates. The use of the cmRCT design may foster recruitment rates by its unique informed consent procedure. A reason not to take part in classic randomized studies might be that patients cannot be guaranteed to receive the desired experimental treatment. Furthermore, once participating, patients are often allowed to participate in one trial at a time only. By contrast, patients participating in a cmRCT study give broad informed consent to participate in randomized trials, but not to specific trials which may increase recruitment rates. Moreover, the cmRCT cohort offers an infrastructure which allows the conduct of randomized trials simultaneously. Finally, recruitment in cohort studies is usually more manageable compared with recruitment in RCTs. The inclusion rates in the PRESENT cohort for example are promising: the participation rate is 83%, and 88% of the participating patients have given informed consent for broad randomization to experimental interventions. The use of a cohort in cmRCT studies offers more potential advantages. Palliative patients willing to participate in randomized trials often represent a relatively healthier and higher-educated subgroup. By using a cohort as a recruitment pool for RCTs, a more routine population is included since recruitment for cohort studies is generally less selective. Moreover, the cohort provides information on baseline characteristics and outcome measurements (i.e. the regular cohort measures) of drop-outs, which is essential in the data analysis. Patients allocated to the control arm, are cohort participants who receive the current standard of care (i.e. standard radiotherapy in the PRESENT case). In our department, the standard of care for patients with bone metastases will change from standard radiotherapy to automatically generated conformal treatment plans. Would the VERTICAL trial have been conventionally conducted, this could have been problematic since control patients in the VERTICAL trial would then have been withhold from standard of care. However, the cmRCT design has the advantage that experimental interventions are compared with the most up-to-date standard of care, instead of competing with outdated treatments, which is often the case in completed classic RCTs. Finally, a valuable feature of the cmRCT design is the opportunity to evaluate and quantify the acceptance rates of the offered treatment (i.e. SBRT). This offers new insights into patient preferences and reasons for refusal of SBRT. We feel that prevention of disappointment bias, more efficient and less selective patient recruitment, up-to-date standard of care, and quantifying patients’ preference could significantly improve trials conducted according to the cmRCT design.

In conclusion, the VERTICAL study is a pragmatic randomized trial, following the cmRCT design, which compares stereotactic radiotherapy with standard radiotherapy in patients with spinal metastases in terms of pain response, with the ultimate goal to improve quality of life.