Palliative radiotherapy for pancreatic cancer
Pancreatic cancer is a devastating disease, with 5-year survival rates of 12.5% (1). In the adjuvant setting for resectable tumors, radiation may be utilized in the case of positive margins or other pathologic risk factors for local recurrence; in borderline resectable disease, neoadjuvant radiation can be offered to sterilize surgical resection borders and increase the probability of a margin-negative resection (2,3). Unfortunately, most patients present with unresectable locally advanced or metastatic disease (1). In the locally advanced population, radiation has not consistently prolonged survival (4-6), but can improve local control (7,8). In the metastatic setting, systemic therapy remains the mainstay of treatment (9), but pancreas-directed radiotherapy remains a powerful tool for both palliation and primary tumor control.
Pancreatic cancer may lead to a myriad of symptoms due to its anatomic location. Patients may have pain related to local effects of the tumor, celiac plexus involvement with neuropathic symptoms, mild to life-threatening bleeding from tumor erosion, post-prandial intestinal angina from vasculature encasement, altered stool and urine function from biliary blockage, or abdominal bloating and early satiety from gastric outlet obstruction. This introduces questions to the radiation oncologist in each unique scenario: What is the optimal dose and fractionation? What is the target? What technique of radiation should be used? And how quickly can we return the patient to optimal systemic treatment without causing harm?
In this issue, Liu and Lefresne offer insight to these considerations (10). The authors retrospectively review the provincial cancer database across five regional centers in British Columbia between 2006–2013 for patients receiving palliative radiotherapy to the pancreas. The authors report the largest series to date, including 100 patients with metastatic, recurrent, or locally advanced disease in the study. Patients received a wide variety of radiotherapy prescriptions ranging from 20 Gy in 5 fractions to 45–55 Gy in 20–30 fractions, most often delivered with simple radiotherapy techniques [i.e., two-dimensional (2D) complex and three-dimensional (3D) conformal radiation]. The most common regimens were 30 Gy in 10 fractions (22%) and 20 Gy in 5 fractions (19%). Patients receiving stereotactic body radiotherapy (SBRT) were excluded.
Importantly, the authors list response to palliation for pain in addition to early satiety and bleeding, the latter of which are underrepresented or rarely reported in the literature. Responses to treatment were excellent: 73% of patients had a complete response to palliation for bleeding, 69% had improvement in pain, and 59% had improvement of early satiety. Palliation was safe without significant toxicity; only one patient had a grade 3 event of diarrhea. A significant finding was that symptom response was not correlated with radiotherapy dose.
The study is not without limitations. Most patients were treated over 10 years ago and 50% of the cohort received non-contemporary systemic therapy (i.e., gemcitabine). Pain and symptom response was dependent on physician interpretation of the medical record, which may result in bias. Finally, pancreatic cancer symptoms are temporally dynamic; the single timepoint of assessment in the study may underreport data regarding the evolving nature of pain in this disease. Regardless, this remains the most robust report to date and the data will help guide physicians faced with the task of palliating pancreatic tumors.
In line with the findings of this study, the utility of a short-course hypofractionated regimen in this population was also validated in the phase II PAINPANC trial that demonstrated three single fractions of 8 Gy (once weekly) rapidly reduced pain within three weeks and improved global quality of life (11). Patients underwent computed tomography (CT) simulation without contrast or motion management with generous clinical planning margins. Further literature for palliative radiation in pancreatic cancer is summarized in Table 1 and are in general agreement with the present article at hand. American Society for Radiation Oncology (ASTRO) guidelines for pancreatic cancer additionally suggest standard regimens of 20 Gy in 5 fractions or 30 Gy in 10 fractions as reasonable approaches for palliation (19).
Table 1
| Author and study year | Study design | Radiotherapy intervention | Number of patients | Primary outcome of interest | Efficacy | Toxicity | Target volumes and simulation details |
|---|---|---|---|---|---|---|---|
| Morganti, 2003, (12) | Prospective, single-arm | 30 Gy in 10 fractions | 12 | Pain | 50% of patients did not require analgesics at 4 weeks; mean reduction in consumption of analgesics was 63.1% | 33% G1–2 nausea/vomiting, 8% G2 diarrhea, no G3 events | 3-field technique, 9–10 MV photons, CTV = tumor volume with 1.5 cm margin |
| Wolny-Rokicka, 2016, (13) | Retrospective | 6–30 Gy in 1–10 fractions | 31 | Pain | 55% achieved good pain control without need for further analgesics at 4 weeks | 19% G2 nausea, 10% G2 vomiting, 10% G1 diarrhea | 3DCRT, 20 MV photons, 2- or 3-field technique, CTV = whole pancreas with 1.0 cm margin |
| Ebrahimi, 2018, (14) | Retrospective | 8 Gy in 1 fraction, repeated over 1, 2, or 3 weeks | 61 | Pain | 66% with any pain resolution, 7% with complete response, median 2.5 months relief | 51% G1–2 nausea, 21% G1–2 vomiting, 33% pain flare | 14% AP/PA, 56% 3DCRT, 30% IMRT. No details regarding targets |
| Tian, 2018, (15) | Single-arm, prospective | 40–42 Gy in 7–10 fractions | 31 | Pain (BPI) and QoL (FACT-G) | 57% with pain improvement at 1 month, 89% with improvement in QoL | 52% G2 anorexia, 29% G2 nausea, 1 patient with G3 ileus | SBRT (CyberKnife), GTV = tumor causing symptoms = PTV, Rx to 70–80% IDL |
| Wang, 2018, (16) | Retrospective | 25 Gy in 5 fractions | 24 | Pain | 79% with decreased pain at 2 weeks | 29% nausea and vomiting, 13% diarrhea, 21% pain flare | No immobilization, 17% SBRT (CyberKnife), 58% IMRT, 25% 3-field 3DCRT. No details regarding targets |
| Hammer, 2022, (17) | Prospective, single-arm phase II | 25 Gy in 1 fraction | 18 | Severe, celiac plexus-associated pain | 84% with decreased pain at 3 weeks and 22% with complete relief at 6 weeks, significant reduction in MME | 11% G1–2 diarrhea, 39% G1–2 fatigue, 22% G1–2 vomiting. No G3+ events | 4DCT with abdominal compression and IV contrast, 100% SBRT with 6 MV photons, GTV = anterior-medial aspect aorta at T12–L2 |
| Tello Valverde, 2023, (11) | Prospective, single-arm phase II | 8 Gy in 1 fraction, repeated over 1, 2, or 3 weeks | 30 | Severe pain (BPI), QoL (EORTC-QLQ-C15) | 80% with pain reduction ≥2 points, significant improvement in global QoL, significant reduction in MME | 34% G1–2 nausea, 23% G1–2 vomiting, 7% G3 nausea, 3% G3 vomiting, 10% G3 pain flare | 100% IMRT/VMAT with 6–10 MV photons, no motion management, GTV = tumor with fat infiltration, CTV = GTV + 5 mm, PTV = CTV + 2.0 cm CC and 1.0 AP |
Data from Palliative Radiation Oncology 1st Edition (18). G1, grade 1; G2, grade 2; G3, grade 3; CTV, clinical target volume; 3DCRT, three-dimensional conformal radiotherapy; AP, anterior/posterior; PA, posterior/anterior; IMRT, intensity-modulated radiotherapy; BPI, brief pain inventory; QoL, quality of life; FACT-G, Functional Assessment of Cancer Therapy-General; SBRT, stereotactic body radiotherapy; GTV, gross tumor volume; PTV, planning target volume; Rx, prescription; IDL, isodose line; MME, morphine milligram equivalents; 4DCT, four-dimensional computed tomography; IV, intravenous; EORTC-QLQ-C15, European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Quality of Life Questionnaire-Core 15; VMAT, volumetric-modulated arc therapy; CC, craniocaudal.
In this context, when the goals of treatment are purely palliative in a patient with limited life expectancy, our practice is to offer short course hypofractionated regimens that relieve symptoms, assuage patient and family logistical burdens, and minimize time off systemic therapy. Given the vulnerable patient population and guarded median survival (5.1 months in this study), we maximize comfort during simulation and premedicate with low dose anti-emetics or dexamethasone to quell any unanticipated side effects during treatment. Protracted or dose-escalated courses of radiation with or without systemic therapy are reserved for patients with controlled disease and more favorable prognoses where durable local control may significantly impact survival or quality of life (8,20,21).
Unfortunately, despite this promising data, pancreatic cancer does not universally respond to palliation, as evidenced in the approximately 30% of patients without pain response in the study at hand. Further work involving advanced forms of radiotherapy remains to optimize pain response. For example, celiac plexus radiosurgery was recently piloted in a proof-of-concept phase II trial where a single fraction of SBRT resulted in a significant reduction in severe pain for 84% of patients with complete resolution of pain in 22% (17).
Ultimately, our goals as physicians should focus on helping patients live longer, better, or hopefully, both. This study demonstrates that radiation oncologists are armed with a powerful therapeutic tool in the setting of advanced symptomatic pancreatic cancer. Equipped with this knowledge, we can feel confident that we are improving the quality of life and alleviating suffering in a particularly vulnerable population.
Acknowledgments
We thank Karishma Khullar, MD from the Department of Radiation Oncology, Hospital of the University of Pennsylvania, for her review of our article.
Funding: None.
Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Palliative Medicine. The article did not undergo external peer review.
Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-23-560/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17-48. [Crossref] [PubMed]
- Anon. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pancreatic Adenocarcinoma V.2.2023. Available online: https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
- Versteijne E, van Dam JL, Suker M, et al. Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial. J Clin Oncol 2022;40:1220-30. [Crossref] [PubMed]
- Loehrer PJ Sr, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 2011;29:4105-12. [Crossref] [PubMed]
- Klaassen DJ, MacIntyre JM, Catton GE, et al. Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil--an Eastern Cooperative Oncology Group study. J Clin Oncol 1985;3:373-8. [Crossref] [PubMed]
- Chauffert B, Mornex F, Bonnetain F, et al. 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 2008;19:1592-9. [Crossref] [PubMed]
- Hammel P, Huguet F, van Laethem JL, et al. Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial. JAMA 2016;315:1844-53. [Crossref] [PubMed]
- Ben-Josef E, Schipper M, Francis IR, et al. A phase I/II trial of intensity modulated radiation (IMRT) dose escalation with concurrent fixed-dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 2012;84:1166-71. [Crossref] [PubMed]
- Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25. [Crossref] [PubMed]
- Liu AKN, Lefresne S. Palliative radiotherapy in pancreatic cancer: a retrospective study of 100 cases and regional patterns of practice. Ann Palliat Med 2023;12:891-9. [Crossref] [PubMed]
- Tello Valverde CP, Ebrahimi G, Sprangers MA, et al. Impact of Short-Course Palliative Radiation Therapy on Pancreatic Cancer-Related Pain: Prospective Phase 2 Nonrandomized PAINPANC Trial. Int J Radiat Oncol Biol Phys 2023; Epub ahead of print. [Crossref] [PubMed]
- Morganti AG, Trodella L, Valentini V, et al. Pain relief with short-term irradiation in locally advanced carcinoma of the pancreas. J Palliat Care 2003;19:258-62. [Crossref] [PubMed]
- Wolny-Rokicka E, Sutkowski K, Grządziel A, et al. Tolerance and efficacy of palliative radiotherapy for advanced pancreatic cancer: A retrospective analysis of single-institutional experiences. Mol Clin Oncol 2016;4:1088-92. [Crossref] [PubMed]
- Ebrahimi G, Rasch CRN, van Tienhoven G. Pain relief after a short course of palliative radiotherapy in pancreatic cancer, the Academic Medical Center (AMC) experience. Acta Oncol 2018;57:697-700. [Crossref] [PubMed]
- Tian Q, Zhang F, Wang Y. Clinical assessment of palliative radiotherapy for pancreatic cancer. Cancer Radiother 2018;22:778-83. [Crossref] [PubMed]
- Wang Y, Timotin E, Zia W, et al. Pain Palliation Using Hypofractionated Radiotherapy for Unresectable Pancreatic Cancer. J Med Imaging Radiat Sci 2018;49:293-300. [Crossref] [PubMed]
- Hammer L, Hausner D, Ben-Ayun M, et al. Single-Fraction Celiac Plexus Radiosurgery: A Preliminary Proof-of-Concept Phase 2 Clinical Trial. Int J Radiat Oncol Biol Phys 2022;113:588-93. [Crossref] [PubMed]
- Vapiwala N, Jones J, Dharmarajan K. Palliative Radiation Oncology. 1st ed. Elsevier.
- Palta M, Godfrey D, Goodman KA, et al. Radiation Therapy for Pancreatic Cancer: Executive Summary of an ASTRO Clinical Practice Guideline. Pract Radiat Oncol 2019;9:322-32. [Crossref] [PubMed]
- Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 2009;27:1806-13. [Crossref] [PubMed]
- Ben-Josef E, Lawrence TS. Radiotherapy: the importance of local control in pancreatic cancer. Nat Rev Clin Oncol 2011;9:9-10. [Crossref] [PubMed]
