While radiotherapy was considered an important treatment modality in locally advanced pancreatic cancer for several decades, the presentation of the LAP 07 trial results have impressed a concept that radiotherapy provides no benefit in this patient group. Further analysis however, revealed that the use of radiotherapy in the LAP 07 trial was associated with better local control and a greater chemotherapy-free interval, both meaningful palliation benefits. Further, the initiation of radiation was delayed by a four month period of induction treatment that employed a drug with only an 8% response rate, and progression free survival control of 3.1 months. A detailed review of the literature to date demonstrates that modern radiotherapy in locally advanced pancreatic cancer has a significant local effect, is well tolerated and associated with improved quality of life through providing durable local control, and in a subset population, resulting in long-term survival. Perhaps the most important conclusion of the LAP 07 study, which was very well conducted, is that delaying a local therapy for four months is not an effective sequencing strategy when the induction treatment is of borderline efficacy in a cancer with a rapid progression characteristic. While newer agents are improving survival, the outlook remains dismal. Optimising the integration of radiation needs to be a priority to define how this modality can assist the modest gains that have come about from a very large number of chemotherapy sequencing studies.
Pancreatic cancer is the tenth most common cancer diagnosed in Australian men and women, but is the fourth most common cause of cancer mortality.1 At diagnosis, approximately one third of patients present with locally advanced disease and approximately half with metastatic disease, leaving only 10 to 20% suitable for resection.2 As a group, locally advanced pancreatic cancers (LAPCs) tend to be characterised by their proximity to critical vascular structures, rendering them unsuitable for resection, even in the absence of gross metastatic disease. LAPC is associated with poor survival, approximately 5 to 11 months.3
LAP 07 trial design and endpoints
The results of the LAP 07 trial were presented at the 2013 American Society of Clinical Oncology Annual Meeting. In this large trial, patients of good performance status with LAPC (n = 442) were first randomised to four months of gemcitabine (1000mg/m2/week x3) with or without erlotinib (100mg/day). Patients who did not have disease progression were further randomised to radiotherapy treatment of 54 Gy, with concurrent capecitabine (1600mg/m2/day), or two additional months of the same chemotherapy.4 Patients who received erlotinib at first randomisation continued with this drug from the completion of protocol until further disease progression. The primary objective was to assess whether chemoradiotherapy increased overall survival.
LAP 07 shortcomings
A widely reported outcome from the study, median overall survival for the chemotherapy only arm was 16.5 months, appeared very good. This is misleading however, as it relates to the outcome for the selected 61% of patients who remained eligible to progress to the four month second randomisation point. Two thirds of the patients who did not proceed to second randomisation (26% of all patients) had disease progression, and one tenth had treatment toxicity.
At the time of the LAP 07 trial development, single agent gemcitabine was the standard of care for metastatic pancreatic cancer. This stems from an initial landmark study that showed improved median survival with gemcitabine compared to 5-fluorouracil (5-FU) by approximately five weeks (5.6 months versus 4.4 months), and improved clinical benefit (based on a non-validated health-related quality of life tool) in patients with advanced pancreatic cancer.5 Multiple other studies have replicated the additional but modest benefit of this drug in locally advanced and metastatic pancreatic cancer, including progression-free survival of 3.1 months and a response rate of 8.2%.6
The LAP 07’s investigation of the role of erlotinib concluded that its use was not beneficial in LAPC. The added toxicity was quite substantial, with 37.3%, 32.9%, 24.5% and 6.6% experiencing grade 3 or 4 neutropaenia, coughing, dyspnoea and diarrhoea respectively. This is in contrast to just 5.9% of patients treated with radiotherapy experiencing grade 3 or 4 nausea.
Common induction program practices prior to the study employed neoadjuvant periods of 1-2 months, as it was recognised that occult metastatic disease could present quite quickly in this condition. It was hypothesised that extending the neoadjuvant period might improve the selection of patients who would benefit from the addition of radiotherapy. However, no benefit to survival was observed by extending the period to four months, which exceeded the median progression-free survival of 3.1 months.
Radiotherapy has a useful response rate and increases R0 rates
Multiple phase 1 and 2 trials (summarised in table 1) demonstrate improved response rates and increased R0 resection rates with neoadjuvant chemoradiotherapy. In one retrospective study of patients with borderline and LAPC (n = 41), investigators attempted to compare the relative contributions of neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy to outcomes.7 Patients receiving radiotherapy (58.5%) were treated to a dose of 45 Gy to 50.4 Gy, with concurrent gemcitabine, cisplatin or capecitabine at radiosensitising doses. Patients treated with chemotherapy only received gemcitabine alone, or gemcitabine in combination with capecitabine or oxaliplatin. A complete pathological response was only attained in patients receiving radiotherapy – 12% of patients vs 0% for chemotherapy alone. The addition of radiotherapy significantly increased the likelihood of a partial response – 46% vs 17% (P = 0.03). The use of radiotherapy more than doubled the R0 surgical resection rate – 96% vs 35% (P < 0.0001).
Radiotherapy reduces local failure
Huguet et al in a recent review of the role of chemoradiotherapy in LAPC, identified three-dimensional (3D) -conformal radiotherapy as an ‘active, well-tolerated regimen’, and given that LAPC was rarely downstaged with contemporary treatment programs, the goal of treatment should be palliative with aims of prolonging survival, disease control and symptom palliation.8 The palliative benefits of chemoradiotherapy compared to no chemoradiotherapy in LAPC were demonstrated in one prospective trial (n = 31), with improved Karnofsky’s performance status (77.1 vs 65.5, P < 0.0001), reduced days in hospital (12.3 days vs 19.0 days, P < 0.05) and pain relief (response rate 80%, median duration 5.2 months).9 This was in addition to a survival benefit (median survival 6.4 months vs 13.2 months, P = 0.0009). Closer analysis of the LAP 07 data reveals reduced local progression with radiotherapy.10 With improved local control there would be potential to avoid biliary or gastric outlet obstruction, and hence avoid stenting or surgical procedures.
Radiotherapy improves chemotherapy free interval
Patients in the LAP 07 trial who received chemoradiotherapy achieved a greater chemotherapy-free interval than those who did not receive radiotherapy.10 The median time to re-introduction of chemotherapy was 5.2 months versus 3.2 months.
Radiotherapy is associated with long-term survivors
The notion that we should include the presence of a tail of longer term survival as an endpoint in pancreatic cancer was emphasised at the recent American Society of Clinical Oncology plenary update of a randomised phase 3 study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone, in patients with metastatic adenocarcinoma of the pancreas (MPACT).11 Longer-term follow-up of this study, which has established the combination of nab-Paclitaxel and gemcitabine as a new standard of therapy for locally advanced and metastatic cancer, emphasised three year survival of 4%. The authors’ experience (manuscript in preparation) of 124 patients with histologically confirmed locally advanced inoperable pancreatic cancer, employing only one cycle neoadjuvant gemcitabine prior to 3D-conformal radiotherapy (54 Gy with concurrent 5-FU), found three year survival of 13% and five year survival of 6%. Prospective randomised control trials of chemoradiotherapy in LAPC to date have generally not reported on survival rates beyond 1-2 years. The identification of a small but not insignificant ‘tail’ of long-term survivors is only apparent if we look.
Radiation technique is vital
The importance of consistent technical expertise is recognised in the surgical literature. The same applies to any radiotherapy technique. A good example of this is seen in the European Study Group for Pancreatic Cancer (ESPAC) 1 study, a randomised trial of adjuvant chemoradiotherapy and chemotherapy after resection of pancreatic cancer, where the median survival of patients assigned to chemoradiotherapy was worse than those assigned to observation – 13.9 months vs 16.9 months.12 At that time, radiation was rarely, if ever, employed at most centres and there was very little engagement with expertise. There was no funding to undertake radiation technique quality assurance, and the protocol description was confined to a brief paragraph that referred to a crude Gastrointestinal Tumor Study Group radiation technique developed in the 1970s.13 This was in contrast to the robust contemporary standards of surgical practice that were well developed, as well as the widespread familiarity of chemotherapy protocols. Their minimalist approach to radiation quality assurance appears to have resulted in poor survival, worse than no treatment at all.14 Bydder and Spry further suggested that the observed detriment to survival might be accounted for by inadvertent coverage of the kidneys in close proximity, leading to their later and premature failure.14 With such confounding factors, this study does not exclude the role of radiotherapy in this setting. Rather, it suggests the ESPAC-1 radiotherapy technique should not be employed and further highlights the great need to develop safe future radiotherapy techniques and robust quality assurance processes.
Improved results with advances in modern techniques
Contemporary anatomically targeted radiation programs have now been set up to be safe and avoid adverse late renal or hepatic damage.15,16,17
We have previously identified the importance of ‘dummy run’ testing of new centres, which exposed unexpected misunderstandings of protocol writing, allowing them to be addressed.17 Additionally, development of quality assurance assessment tools address the very complex data sets that represent modern computer planning.18
Intensity-modulated radiotherapy (IMRT) is a technique which uses multiple non-coplanar beams of non-uniform intensity, leading to better conformality of dose to the target volume, and less dose to adjacent critical structures, thereby reducing potential toxicities and allowing for dose escalation. This was used in a recent LAPC trial to a dose of 55 Gy to 60 Gy, in 25 fractions;19 even with concurrent full dose gemcitabine, this combined treatment was well tolerated and achieved a median survival of 14.8 months and two year overall survival of 30%. Superior dosimetry is achievable with volumetric-modulated arc radiotherapy, a type of IMRT in the treatment of pancreatic cancer, which may translate to better toxicity profiles and the potential for dose escalation.20
Diaphragmatic movement is transmitted to the pancreas hence this target moves during the treatment; the limits of this motion increase the size of the target needed to be treated and thereby increase treatment toxicity. Four-dimensional computed tomography (CT) can reliably reduce the margin necessary for treating pancreatic cancer, reducing dose to adjacent organs.21 Until recently, the radiation target was determined by a CT-defined target based on CT abnormality and standard anatomical risk patterns. Positron emission tomography (PET) in other cancer situations e.g. lung, has already changed the approach to target delineation. While current PET tracers are only uncommonly useful, we are likely to see more confident target delineations with future development, which will improve treatment efficacy, possibly allowing radiotherapy dose escalation and simultaneous normal tissue toxicity reduction.22,23
Impact of stage migration from improved imaging
In the last two decades, increased utilisation of CT, improvements in multidetector CT technology, and increased utilisation and expertise in reporting of magnetic resonance imaging (MRI) and PET in pancreatic cancer have led to improved detection of smaller primary disease, hence earlier detection. Furthermore, improvement in the assessment of the vascular involvement selects out truly inoperable patients along with the better assessments of previously occult metastatic diseases.24 The impact of better staging not only helps our patient selection, it improves outcome even when there has been no true treatment effect by this better selection. This is the process of stage migration (the Will Rogers phenomenon*);25 patients that would not have been identified as having gross distant metastases are now identified and treated as metastatic cancer patients, thereby improving the outcomes in non-metastatic and metastatic populations. In the 1990s, phase 3 trial data found gemcitabine achieved a median overall survival for non-operable patients of 5.6 months,5 contrasting with more recent improved outcomes, employing the same regimen of 6.6 months.11 It is likely that the Will Rogers effect is a major contributor to this survival improvement.
*In the Will Rogers Phenomenon, stage migration and new diagnostic techniques are recognised as a source of misleading statistics for survival in cancer. Patients who previously would have been classified in a “good” stage migrate to a “bad stage” with the new identification of metastases with improved techniques. The prognosis of those migrated (although worse than those in the good-stage group) is better than those in the bad-stage group; thereby improving the survival rates of both groups without improvement of individual outcomes.
Importance of durable local control with improving systemic treatments
Multiagent nab-paclitaxel and FOLFIRINOX has resulted in improved survival compared to gemcitabine alone in metastatic pancreatic cancer, 8.7 months vs 6.6 months, and 11.1 months vs 6.8 months respectively.11,26 As in other tumour sites, the role of local control in improving overall survival may become evident as systemic treatment improves.
The vast experience from breast cancer research has demonstrated improved systemic treatments leading to improved survival for localised disease.27 With the arrival of effective systemic treatments in breast cancer, achieving local control was thought to have limited impact on survival because of the view that a local recurrence could be treated, and that local recurrence was not thought to lead to metastatic disease. The evidence however, shows that improved local control in non-metastatic breast cancer actually improves overall survival.27 In the Early Breast Cancer Trialists’ Collaborative Group meta-analysis of local therapy, for every four local recurrences prevented by loco-regional radiotherapy, one death from breast cancer was avoided.28 In the setting of LAPC and improving effectiveness of systemic treatment, improving local control will become an important factor in improving survival.
Paucity of radiotherapy data
There have been huge resources employed to study the effect of minor variations to drug sequencing and combinations using the clinical trial method. These collaborations have encouraged the rapid development of widespread familiarity with and expertise in the safe and effective use of systemic agents in this condition. In contrast, there have been very few resources employed to develop the optimal utilisation of radiotherapy, hence expertise is rare and largely confined to few centres who publish their own data.
A search of the PUBMED database from 1950 until October 2015, combining the MESH terms ‘pancreatic neoplasms’ with ‘chemotherapy’, ‘biological agents’ or ‘immunotherapy’, and limiting search to human phase 2 or 3 trials, excluding irrelevant trials (focused only on resectable, borderline resectable or metastatic disease), yields 338 trials, 42 of which were phase III. A similar search combining MESH terms ‘pancreatic neoplasms’ with ‘radiotherapy’, but excluding trials on stereotactic body radiotherapy and intraoperative radiotherapy, yields 53 trials, making up less than 15% of the available data for management of LAPC. While few of the systemic treatment studies have changed systemic treatment directly, the knowledge base has helped optimise schedules and sequencing, and helped foster expertise and familiarity. This contrasts with the paucity of data to define how to sequence and integrate radiotherapy in LAPC.
A summary of what LAP 07 showed us
The LAP 07 experience showed us that a program that delays the commencement of radiation by four months in patients with locally advanced disease does not improve overall survival. The induction period had been extended in this study from a common one month period to four months, based on a belief that this would identify occult liver metastases and hence improve selection. The progression-free survival for the drug was 3.1 months, however, less than the induction period, matched by a response rate of 8%. Nonetheless, the study did establish the safety and protocol compliance of study collaborators (radiation therapy quality assessment identifying on 18% of major deviations from radiotherapy protocol).4 It also confirmed that the radiation program was minimally toxic and there were clear palliative benefits of improved local control, and beneficial delay to time of recommencement of chemotherapy.10
Locally advanced pancreatic cancer has a poor outlook. Advances in radiotherapy technique and expertise in locally advanced pancreatic cancer have resulted in improved tolerance and benefits in palliation, such as improved local control and increasing time off chemotherapy. Furthermore, in a small but not insignificant number the potential for long-term survival has been observed. With the introduction of more effective systemic treatments, more studies are needed to identify the optimal integration of radiotherapy and further define the most effective sequencing strategy to improve quality of life and survival.