Stereotactic ablative radiotherapy (SABR) as primary, adjuvant, consolidation and re-treatment option in pancreatic cancer: scope for dose escalation and lessons for toxicity

Pancreatic cancer is characterised by debilitating symptoms caused by local disease advance, high rates of metastatic progression and dismally close incidence and mortality rates. Median overall survival (OS) from diagnosis for all patients is less than 5 months, ~ 20% of patients overall survive more than 1 year and ~ 5% survive more than 5 years [1‐4]. Standard treatment options include single or multi-agent chemotherapy or chemoradiotherapy. For the small minority of patients diagnosed with earlier stage resectable disease, radical surgical resection offers the best chance of long-term survival with reported 5-year survival rates of ~ 20% [5]. However, the disease is typically diagnosed at more advanced stages: ~ 45% of patients present with metastatic disease that has a median OS of ~ 2–5 months, and ~ 30% present with inoperable localized or locally advanced pancreatic cancer (LAPC) that has an intermediate status and prognosis [1‐4]. For the latter subset of patients, conversion to resectability currently offers the best outcome [5‐7]: nevertheless, median OS reported in LAPC randomised trials remains poor at 7–15 months [8‐10].

Modern conformal radiotherapy has a central role in pancreatic cancer disease control to: 1) palliate symptoms and prevent local progression that causes morbidity and may be causal of death [11]; 2) increase the chances of achieving secondary resectability [6, 7]; and 3) extend median survival time [12‐15]. However, conventional chemoradiotherapy regimens can be long (~ 5.5 weeks) and arduous with only a modest or no overall survival gain [16]. Furthermore, the radiation doses that can be delivered safely are limited by toxicity to adjacent abdominal structures such that local control rates can be low [8, 15, 17, 18], repeat treatment upon relapse is inhibited, and treatment toxicity may be high and exacerbated by concomitant chemotherapeutics [14, 19‐22].

Stereotactic ablative body radiotherapy (SABR) may be used as an alternative, adjunct, consolidation or re-treatment option to conventional therapies in pancreatic cancer. High dose radiotherapy can be delivered in conveniently few fractions, with rapid dose fall-off outside the delineated tumour volume [23, 24]. This offers the potential for increased local tumour control and reduced toxicity, and additionally introduces the valuable possibility of tumour re-irradiation. Due to the highly conformal target volumes delineated, the high doses delivered and the proximity of adjacent radiosensitive organs-at-risk (OAR — duodenum, stomach, small bowel, liver, kidneys and spinal cord), accurate on-treatment tumour targeting is imperative.

Previous studies have pioneered the use of SABR in pancreatic cancer in various regimens, including as a single boost adjunct to chemotherapy or chemoradiotherapy or for re-treatment following local failure [20‐22, 25‐37]. The majority have shown relative efficacy for local control with reasonable toxicity, as well as benefits such as convenience and good pain relief [37]. Furthermore, receipt of SBRT compared with conventionally fractionated radiotherapy has shown significantly improved OS for locally advanced disease [38]. However, comparisons, interpretations and treatment optimisation of SABR in pancreatic cancer have been difficult as different planning, delivery and dosimetry methodologies have been used. As a result, local control has been reported as excellent in some studies [22, 25, 29, 31], but not in others [20, 21] and toxicity has been reported to be low in some studies [26, 33], but significant or unacceptable in others [20‐22, 25, 28, 36, 39]. With the aim of increasing understanding and enabling treatment improvements for inoperable, non-metastatic pancreatic cancer, in our real-world series of patients we sought to: 1) review patient outcomes following SABR treatment for a range of indications 2) comprehensively examine the contribution of patient, planning, delivery and radiobiological variables upon the toxicity and efficacy of fractionated SABR and 3) use radiobiological modelling to compare SABR treatment to a conventional comparator regimen.

This study was the first to use LQ modelling to assess pancreatic SABR efficacy and to comprehensively examine the influence of patient and planning factors on toxicity and outcome. The study was conducted in a ‘real-world’ patient series, which is crucial for understanding treatment effectiveness and safety in everyday clinical practice. Our results support SABR as an encouraging modality for locally inoperable pancreatic cancer, with particular benefits as a re-treatment, consolidation or salvage boost, or as an alternative treatment for patients with poor PS or co-morbidity. Although toxicity was low and survival was better than expected — especially considering nearly half of patients were treated more than 6-months after primary treatment — both FFLP survival analysis and LQ modelling showed scope to improve local control through dose escalation. The few serious incidences of late duodenal toxicity indicate that this would need to be approached cautiously with increased stringency on duodenal protection through highly detailed individualised planning.

Low toxicity was obtained that was better than many other SABR studies [20‐22, 25, 28, 36], despite larger PTVs and higher prescription doses in this study. This indicates planning methods and on-treatment dynamic targeting with Synchrony® were generally good and consistent with other studies [20, 25, 27‐30, 32, 34, 36]. The main limitation when examining patient and treatment factors in relation to toxicity was the low incidence of late and Grade 3+ toxicity events: multiple testing is acknowledged as an additional limitation. The only factors that showed association with acute toxicity were number of fiducials (p = 0.0002) and treatment purpose (p = 0.064). The former aligns with our previous dose-volume histogram study of duodenal risk in an overlapping cohort of pancreatic SABR patients that showed increased toxicity risk for patients with single or no fiducial [47]. The latter is probably due to the patients who were re-treated who had one or more sub-optimal treatment factors (unusually large or small PTV and/or tightly adjacent OAR and/or only one fiducial and/or breached OAR constraints) and thus a higher risk of treatment toxicity was expected. Number of fiducials also associated with late toxicity [47]. Other variables that associated with late toxicity were increased treatment duration period (> 3 days), treatment delivery time (mins), and coverage: (%): however, we consider these factors to be associative rather than causal for late toxicity for several reasons. First, the main reason for serious duodenal toxicity in three patients was breached duodenal OAR constraints. Second, the uneven distribution noted for treatment delivery time and late treatment toxicities is mainly because two patients who showed Grade 2 late treatment toxicities had lower than average treatment times. Third, the association between treatment duration and percentage coverage likely reflects purposeful selection of these parameters because of recognised increased duodenal toxicity risk due to individual medical, anatomical planning and delivery challenges. For example, SABR is known to be least successful when the treatment volume is large and the ‘dose-cloud’ is not tightly conformal, and to be sub-optimal when fewer fiducials are used compromising the accuracy of dynamic tumour tracking. As such, it is notable that of the four patients that suffered duodenal toxicity, two had large PTV (> 100 cc), and the other two (who were treated palliatively > 6 months after primary therapy for recurrent disease) had only one fiducial implanted for on-treatment tumour tracking and were purposefully prescribed treatment over 5 days because of anticipated toxicity risk. Moreover, three of the patients who suffered duodenal toxicity breached the preferred duodenal OAR dose constraints, with the volume of duodenum receiving > 15 Gy considerably exceeding limits correlated with duodenal toxicity [36]. Increased vigilance and stringency to duodenal dose constraints, particularly for patients with large PTV, distorted anatomy, closely adjacent OAR, or fewer fiducials, is therefore appropriate. Indeed, our recent dose-volume histogram duodenal risk map study of duodenal risk in an overlapping cohort of pancreatic SABR patients showed a 10% risk level for Grade 3–4 duodenal haemorrhage or stricture when D1 cc = D31.4 Gy [47]. Furthermore, we found that the use of multiple fiducials showed ~one-fifth of the risk for Grade 3–4 duodenal complications compared with single fiducial or Xsight® Spine tumour tracking. As such, we advocate implanting at least four fiducials and using three or more stable fiducials for optimal tumour tracking during treatment delivery and, based on estimated 10% duodenal risk levels, now impose the stringent duodenal constraint of D1.0 cc < 31.4 Gy for all pancreatic patients treated with ≤30 Gy in three fractions. Concomitantly, in response to collective experience, we have revised our duodenal D0.035 cc constraint to the higher limit of 24 Gy [47]. It is additionally noted that the incorporation of more extensive measures for duodenal assessment during individualised planning/schedules, such as Lyman modelling for normal tissue complication probability [36], late complications [44] or Red Shell volume calculation [48] may also be helpful in the prevention of duodenal toxicity.

As all patients were inoperable and non-metastatic, they would be expected to have similar prognostic outcomes to intermediate stage patients and may reasonably be compared with similar intermediate stage cohorts in the literature. Overall survival following SABR was good considering that 48% of patients were treated > 6 months after primary therapy, indicating that SABR may be extending survival times for patients with residual or relapsed local disease. The median OS of 8.4 months is comparable to that of first line chemoradiotherapy treatments in randomised LAPC trials [9, 10, 49] and the actuarial 1 year OS of 39% is comparable [29‐31, 33] or better than [21, 22, 25, 32] other studies of SABR in LAPC. However, the FFLP of 43% at 1 year is lower in comparison to other SABR studies [20‐22, 25‐35], where some achieved FFLP rates of 70–94% at 1 year [22, 25, 29, 32]. Although the low FFLP rate is likely to have been negatively influenced by the fact that almost half of patients were treated > 6 months after primary therapy to residual or relapsed disease, it also suggests that higher rates of local control may be achievable with SABR. The lack of any association of treatment factors with FFLP in log-rank or multi-variate analysis indicates that neither current planning or delivery methods are contributing to local failure. Both PTV size and treatment course duration (days) associated with OS. The relationship between size and OS is not clear and may be related to disease advance, and the association with treatment days likely reflects purposeful selection of a longer treatment course for re-treat/palliative/relapse patients with more advanced disease and worse PS.

Although there are limitations to LQ modelling when extrapolating from schedules involving conventional fraction sizes to those involving larger fractions, the results indicated that 50% of the patients treated received a minimum PTV dose that was less potent than a comparator standard conformal radiotherapy regimen. The main reason was because prescribed SABR dose was delivered to a patient individualised isodose line to balance target volume coverage with adjacent OAR risk, whereas conformal RT is delivered to the minimum 95% isodose within the PTV. It is additionally notable that the reference schedule of 50.4 Gy in 28 fractions over 5.5 weeks is associated with a tumor BED of ~ 40.5 Gy. This is considered likely to eradicate only the smallest tumour of moderate radiosensitivity, whereas pancreatic tumours are typically moderately sized and relatively radioresistant. Recent analysis of clinical radiation dose response in pancreatic cancer using LQ modelling has indicated that a BED of ~ 40.5 Gy may achieve > 50% local control [18]. A BED > 70 Gy was calculated to achieve significant tumour response (size reduction consistent with complete or partial response) and thus a schedule of three fractions, each delivering 9.2 Gy, was proposed accordingly for SABR [18]. Recent studies have provided support for the feasibility, similar toxicity and potential increased local control with escalated dose [50]. In our study, the lack of association of toxicity with maximum dose to PTV or prescription dose indicates that a higher overall dose is unlikely to affect toxicity if measures to limit duodenal dose are emphasized. Together these data indicate need and scope to escalate SABR doses to achieve minimum PTV doses > 22.5 Gy and optimal BED > 70 Gy for improved efficacy. Our revised duodenal D0.035 dose constraint to the higher value of 24 Gy will allow greater scope for dose escalation. The recent adoption of 5–6 fraction SABR regimens are additionally anticipated to improve toxicity profiles. However, given the ongoing risk for serious duodenal toxicity in a proportion of patients, dose escalation would need to be implemented with great care and awareness of risk for individual patients.

CyberKnife® treatment was well tolerated and survival in the cohort was encouraging, supporting SABR as a good treatment option in the primary, adjuvant or re-treatment setting. The LQ modelling results and relatively low FFLP indicate scope for dose escalation to improve local control and survival. However, to avoid serious duodenal toxicity a cautious approach needs to be taken, incorporating careful assessment of individual patients for dose escalation suitability and concomitant enhanced stringency on duodenal protection.