Quality assurance of the PREOPANC trial (2012-003181-40) for preoperative radiochemotherapy in pancreatic cancer

Pancreatic cancer is the fourth largest cancer-related cause of death worldwide, with an overall 5‑year survival rate of 2–7% [1‐4]. Although approximately 15% of patients are diagnosed with a seemingly resectable tumour, 10–35% of these tumours prove to be irresectable during explorative laparotomy [5]. Also, although some studies suggest that the percentage of resectable tumours may be increased by preoperative radiochemotherapy, those studies were mainly single-arm phase II trials and many did not report using the intention-to-treat approach [5].

The Dutch Pancreatic Cancer Group (DPCG) started the multicentre, randomised, controlled PREOPANC trial (Netherlands Trial Registry: NTR 3709), which became open for accrual in April 2013 [6]. In this phase III trial, patients with (borderline) resectable pancreatic tumours are randomized between (1) direct explorative laparotomy and (2) preoperative radiochemotherapy followed by explorative laparotomy.

For pancreatic cancer, it is well known that target volume delineation can be difficult [7]. In our department, the planning CT scan is combined with a contrast medium and a four-dimensional CT scan (4DCT) to determine the respiratory-induced motion of the tumour and neighbouring organs [8]. Because of the large day-to-day variation in tumour position, in our clinic we currently use intratumoural fiducial markers for delineation and daily online position verification [8‐12]. The radiation oncologist delineates the gross tumour volume (GTV) on the CT scan and expands this volume to encompass the GTV in all respiratory phases. This expanded volume is defined as the internal gross tumour volume (iGTV). The iGTV combined with an additional margin forms the internal clinical target volume (iCTV), which is then expanded to create the planning target volume (PTV).

A dummy run procedure at the beginning of a clinical trial is a good tool to improve protocol compliance with the radiotherapy prescriptions and to improve uniformity of the treatment. In multicentre trails, a dummy run can diminish heterogeneity in treatment quality and can also be used to detect correctable variations in treatment [13‐18].

The aim of this dummy run procedure was to evaluate compliance with the radiotherapy protocol, and the uniformity of delineation and treatment planning, among institutions participating in the DPCG PREOPANC trial.

All 11 institutions submitted the delineation and treatment plan for the ‘dummy’ patient and the questionnaire.

In multicentre clinical trials, variation in protocol interpretation and noncompliance are well-known pitfalls that may lead to protocol deviations and discrepancies between participating institutions. A modern protocol prescription of radiotherapy leaves some freedom with regard to radiation technique, but clearly describes target volumes, dose requirements and constraints for OARs [23]. Quality assurance in the form of a dummy run can be beneficial because this can minimise clinical variations in treatment within the trial. Previous dummy run studies (in various tumour groups) showed that a dummy run ensures optimal radiotherapy delivery based on recommendations and protocol adaptations [13, 15, 16]. Our results showed acceptable deviations, i. e. essentially, inevitable interobserver variations in target delineation, and no prescription adaptations were required for the PREOPANC protocol. Because no adaptations to the protocol were required we did not repeat the dummy run and did not perform a central review of individual patients prospectively.

In the present dummy run, we considered our assessment (EV, GT) as the standard for evaluation of the pancreatic tumour delineations of the ‘dummy’ patient. Consultation between the QA team and the diagnostic radiologist concerning the borders of the tumour took place before evaluation of the delineations. We are aware that no gold standard is available for the delineation of pancreatic tumours and that evaluation of the delineations by two clinicians is subjective and prone to error. Creating a consensus delineation with more observers as a gold standard may be helpful, as was shown in cervical cancer [24]. In pancreatic cancer, the study of Carvatta et al. [25] proposed guidelines for high-risk nodal areas and CTV delineation, showing acceptable interobserver variation. No guideline is available for the GTV delineation in pancreatic cancer and large interobserver variation in pancreatic cancer delineation is reported [26, 27]. For that reason, we did not provide a reference contour.

The volumes of GTV and iGTV can be used as an objective measure to indicate variation [28]. Our results show that, for this ‘dummy’ patient, the mean iGTV volume of the pancreatic tumour was 41.5 cm³, with a ratio between the largest and the smallest iGTV of 4.0. Two earlier dummy runs, in three different cases of pancreatic cancer, reported ratios of the largest to the smallest GTV volume of 9, 3 and 6.8 [29, 30]. In the present study, the questionnaire revealed that there is little experience in the Netherlands with preoperative radiotherapy of pancreatic tumours. The variation in delineation between observers may decrease in time when institutions gain more experience.

Tumour extension outside the pancreas is an important problem in the delineation of the GTV. Tumour extension may result in only slight differences in density compared with the surrounding fat tissue [29]. Also, no delineation guidelines are available for pancreatic cancer, only for postoperative radiotherapy of pancreatic cancer [31].

In our study, institution #10, applied the CTV margin before expanding the GTV to account for respiratory motion. This suggested that the CTV was manually expanded in the 10 respiratory phases to include the visible tumour; this means that the microscopic tumour extensions are not properly accounted for in the CTV. As a result, the PTV margin used may be insufficient to account for all remaining uncertainties. In this institution, the PTV volume (241 cm³) was not the smallest of all the institutions. On an annual basis, this institution treats (on average) only 5 patients with pancreatic cancer, implying that the experience in delineation can be considered only moderate as compared with the other institutions. Unfortunately we only noticed this deviation in a later stage of the study, so this feedback was reported in a later stage of the dummy run to the concerned institution. The consequences of the minor deviations in iGTV delineation for the PREOPANC trial outcome are unclear, as the impact of interobserver variation on a trial outcome is not yet fully explored [28]. However, by producing a clear protocol and using a dummy run to test protocol compliance we aimed to reduce this variation between institutions. RTOG studies reporting on deviations in delineation in pancreatic trials showed unacceptable deviations in around 5% of the cases in a total of four studies, without knowing the impact on outcome [32]. In a multivariate analysis, one study showed that the radiation therapy quality assurance (per-protocol failure of adherence to guidelines) was significant for survival of patients with pancreatic tumours [33].

One of our institutions used conformal 3‑field treatment planning, with a CI of 1.52 and higher doses to the spinal cord and left kidney compared with the other institutions. This illustrates that conformity and OAR sparing can be improved with techniques such as VMAT or IMRT, as described by Nabavizadeh et al. [34]. These latter authors showed that the conformity for both VMAT and IMRT techniques was superior compared with a 3D-CRT technique. VMAT provided a comparable CI to IMRT, with reduced mean doses to the PTV and an overall reduction in treatment time [34].

It is known that respiratory-induced abdominal tumour motion can be substantial. Almost all our institutions used 4DCT in the treatment of patients with pancreatic cancer, taking into account the differences in position of the GTV during the respiratory cycle. This can result in better coverage of the pancreatic tumour within one fraction. Intratumoural fiducial markers and daily online position verification are used to compensate for day-to-day position variation [11, 35]. The above-mentioned procedures in radiotherapy of pancreatic cancer are recommended in the PREOPANC trial. Also, the interobserver variation in pancreatic tumour delineation is currently being quantified in the Netherlands, by means of a study comparing delineation on 3DCT and 4DCT.

Unfortunately, no quantitative evaluation of the variation in delineations, such as the kappa index, could be performed with the software used for the present study. This is a limitation of this study. The kappa index can be used for measuring observer agreement when there is no gold standard [36]. However the added value of the kappa index in this study would be limited since we only had a single dummy patient. No other radiotherapy quality assurance measures were undertaken, as the compliance to protocol prescriptions was acceptable and the observed deviations were inevitable interobserver variations in target delineation. Although guidelines are available for the postoperative setting [31], no gold standard exists for preoperative target delineation for pancreatic cancer. Also, since extensive QA procedures are known to hamper accrual [37], we considered the value of adding prospective individual case review (or other measures) to be too small to implement them.

In this dummy run, all participating institutions were allowed to continue participation in the PREOPANC trial since their compliance to the radiotherapy protocol had acceptable deviations, all of which were due to inevitable interobserver variation in target delineation. A few recommendations were made. Further studies are required to improve visualisation of pancreatic cancer and the delineation tools used, in order to decrease target delineation variation between individual clinicians.