THE ECOG E4201 study adds another piece of information to a growing body of evidence pointing strongly to the importance of local control and the role of radiotherapy in unresectable pancreatic cancer. Based on this evidence, we believe radiotherapy should be used routinely in this setting.
The role of radiotherapy in unresectable adenocarcinoma of the pancreas has been in question for the past three decades. Radiotherapy can palliate common symptoms such as pain, duodenal ulceration and bleeding but its impact on survival has not been clear. Whereas older trials were inconclusive, the recent phase III trial reported by Loehrer et al.[1] has shown that radiotherapy improves overall survival when added to gemcitabine. Patients with non-metastatic unresectable adenocarcinoma of the pancreas were randomly assigned to receive gemcitabine alone (1000 mg/m2 per week for 6 weeks, followed by 1 week rest, then five more cycles of 1000 mg/m2 for 3 out of 4 weeks) or gemcitabine (600 mg/m2 per week) concurrently with three-dimensional conformal radiotherapy (50.4 Gy in 28 fractions) followed by additional gem-citabine (five cycles of 1000 mg/m2 for 3 out of 4 weeks). The study was closed early owing to poor accrual but, in the 74 patients enrolled, median survival improved from 9.2 months to 11.1 months (P=0.017). This came at a cost of increased frequency of grade 4 toxic effects (although combined grade 3 or 4 toxic effects were the same in each arm). These results lend support to the notion that radiation therapy improves the survival of patients with unresectable pancreatic cancer through intensification of local therapy, given that uncontrolled local growth is the cause of death in 30% of patients with this malignancy.[2]
The trial conducted by Loehrer et al.[1] is one of two trials conducted in this decade addressing the question of whether radiotherapy can be of benefit in unresectable adenocarcinoma of the pancreas. The other study, the Fédération Francophone de Cancérologie Digestive and Société Française de Radiothérapie Oncologique (FFCD–SFRO) trial3 showed a worse survival (8.6 months vs 13 months; P=0.03) when chemoradiotherapy was added to gemcitabine. However, the chemoradiotherapy regimen tested in that trial (60 Gy in 30 fractions in 6 weeks concomitant with a 5-fluorouracil infusion [300 mg/m2 per day] days 1–5 for 6 weeks and cisplatin [20 mg/m2 per day] days 1–5 on weeks 1 and 5) was highly toxic (65.5% grade 3 or 4 toxic effects) and, no doubt, contributed to the worse outcome.
Unfortunately, radiotherapy has been used suboptimally in this disease. The sensitivity of the organs to radiotherapy in the upper abdomen has limited the radiation dose to ineffective levels, and attempts to increase the radiation dose have been unsuccessful, resulting in high morbidity and mortality.[4]
An alternative strategy is to use radiosensitising drugs that enhance the effect of radiation preferentially within the tumour. The two drugs that are used most commonly with radiation in the treatment of pancreatic cancer, gem-citabine and 5-FU, both appear to decrease the ability of cancer cells to repair radiation-induced DNA damage.[5] At the University of Michigan we have carried out a series of trials using full therapeutic doses of gem-citabine – a potent radiosensitiser[6] – and concurrent three-dimensional conformal radiotherapy to maximise systemic and local control. However, toxicity has prevented the escalation of the radiation dose beyond 36 Gy in 2.4 Gy fractions even when only the tumour was targeted and clinically negative lymph nodes were excluded.[7]
An option that might allow delivering an increased radiation dose to the pancreas without exposing the dose-limiting organs to toxic levels of radiation is intensity-modulated radiotherapy (IMRT).[8] For example, we recently completed a trial in which we used IMRT to simultaneously reduce the dose to the stomach and intestines and increase the dose in the tumour in patients with unresectable pancreatic cancer. We have established that high-dose radiotherapy (55 Gy in 25 fractions) can be delivered safely with concurrent full-dose gemcitabine, with the use of IMRT delivered during breath hold. The rate of severe toxicity (24%) observed when using this chemoradiotherapy dose[9] compares favourably with toxic effects reported with other contemporaneous regimens. In addition, there are encouraging signals of efficacy; the median overall survival and two-year overall survival in this trial[9] (14.8 months and 30%, respectively) are significantly better (hazard ratio = 0.63, log-rank P=0.028) than historical controls (11.2 months and 13%, respectively).[10] These results also compare favourably with other contemporary phase II and phase III trials in this patient population, with either 5-FU-based or gemcitabine-based chemotherapy. High-dose radiotherapy also improved the two-year local control from 38% (historical controls)[10] to 59%.9 Most importantly, 12 of 50 patients (24%) receiving high-dose radiotherapy were able to undergo resection with good outcomes; 10 patients (83%) had R0 resection and five patients (42%) had a major pathological response. The median survival in these patients who had undergone resection was 32 months.[9]
Thus, the results from the Eastern Cooperative Oncology Group (ECOG) trial1 coupled with the finding that a significant proportion of patients with pancreatic cancer die of complications of uncontrolled growth,[2] and results showing improved local control and survival in patients receiving high-dose radiotherapy, suggest a new paradigm. The question now is not whether radiotherapy is of benefit in this disease but rather how to make it more effective and how to combine it optimally with systemic therapies. “The question now is not whether radio-therapy is of benefit in this disease but rather how to make it more effective”
A number of strategies can be explored to further intensify local therapy. Firstly, improvements in radiotherapy planning and delivery: we need to improve targeting of the tumour while avoiding the critical normal tissues and to incorporate individual susceptibilities to radiation toxicity into treatment planning. Secondly, we have to explore the use of novel tumour-specific radiosensitisers: with so many targeted agents in the pipeline, this strategy is more promising than ever. Potential candidates include CHK1 inhibitors, nab-paclitaxel, PARP inhibitors, MEK inhibitors, and many others. Thirdly, we have to carefully study the potential role of surgery in selected patients.
Finally, potential progress can be made by individualising therapy. One such effort underway is an attempt to use the status of SMAD4 (also known as DPC4) to select patients for intensive local therapy versus intensive systemic therapy. Loss of DPC4 is associated with a widely metastatic phenotype, while patients with intact DPC4 are more likely to die of local complications.[2] Thus, in a currently planned national trial, DPC4 status will be determined upfront by cytology. Patients with intact DPC4 will be randomly assigned to receive an intensive or a standard chemoradiotherapy regimen (following 12 weeks of gemcitabine) whereas patients with DPC4 loss will be randomly assigned to receive FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) versus gemcitabine (followed by standard chemoradiotherapy) for two weeks.
In summary, the current ECOG trial adds one more piece of information to a growing body of evidence pointing strongly to an important role of radiotherapy in local control for unresectable pancreatic cancer. Future advances could come from better selection of patients for intensive local therapy using molecular biomarkers.
References
1. PJ Loehrer Sr et al. (2011) Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. JCO 29:4105–12
2. CA Iacobuzio-Donahue et al. (2009) DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. JCO 27:1806–13
3. B Chauffert et al. (2008) Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000–01 FFCD/SFRO study. Ann Oncol 19:1592–99
4. HM Ceha et al. (2000) Feasibility and efficacy of high dose conformal radiotherapy for patients with locally advanced pancreatic carcinoma. Cancer 89:2222–29
5. DS Shewach and TS Lawrence. (2007) Antimetabolite radiosensitizers. JCO 25:4043–50
6. TS Lawrence, EY Chang and TM Hahn. (1996) Radiosensitization of pancreatic cancer cells by 2′, 2′-difluoro-2′-deoxycytidine. Int J Radiat Oncol Biol Phys 34:867–872
7. CJ McGinn et al. (2001) Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. JCO 19:4202–08
8. M Bockbrader and E Kim. (2009) Role of intensity-modulated radiation therapy in gastrointestinal cancer. Expert Rev Anticancer Ther 9:637–647
9. E Ben et al. (2011) Phase I/II radiation dose-escalation trial of intensity-modulated radiotherapy (IMRT) with concurrent fixed dose-rate gemcitabine (FDR-G.) for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 81 (Suppl. 2):127–128 10. JD Murphy et al. (2007) Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 68:801–808
Author affiliations: Edgar Ben-Josef and Theodore S. Lawrence: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA
Practice point:
- Radiation therapy with gemcitabine improves the survival of patients with non-metastatic unresectable pancreatic cancer compared with gemcitabine alone. Therefore, gemcitabine combined with radiation can be considered a standard of care for these patients.
This article was first published in Nature Reviews Clinical Oncology vol. 9 no.1, and is published with permission. © 2012 Nature Publishing Group. doi:10.1038/nrclinonc.2011.182
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