There are few data to guide the management of nonmetastatic pancreatic ductal adenocarcinoma in patients who are elderly or have a poor performance status. Although most such patients are offered supportive care or gemcitabine alone, the addition of stereotactic body radiotherapy may improve outcomes. In a recent article in the Journal of Oncology Practice,1 Joseph M. Herman, MD, MSc, Professor of Radiation Oncology at The University of Texas MD Anderson Cancer Center, Houston, described treatments that incorporate stereotactic body radiotherapy and provided some thoughts on this topic in an interview with The ASCO Post.
Neglected Group of Patients
Why is a discussion of stereotactic body radiotherapy in the elderly and in patients with a poor performance status a timely topic?
Pancreatic cancer is the third-leading cause of cancer-related deaths in the United States and is projected to become the second-leading cause of cancer death by 2020. The median age at diagnosis is 71 years, and over 40% of patients are diagnosed after the age of 75. Nearly 40% of patients present with nonmetastatic “localized” disease (ie, resectable, borderline resectable, and locally advanced), and surgery is the only potentially curative option.
A particularly neglected group of patients with nonmetastatic pancreatic cancer are those who are ineligible for clinical trials due to a poor performance status (including advanced age). This represents at least 20% of our patients, and without a poor performance status, they would have qualified for curative therapy (surgery or neoadjuvant chemotherapy followed by surgery).
Joseph M. Herman, MD, MSc
We are learning that with better supportive care, some patients will be in a better position to receive more aggressive treatments, which we hope will correlate with better long-term outcomes. The problem is that this hasn’t been addressed in clinical trials. Since no clinical trials exist for this patient population, nonmetastatic patients with a poor performance status are often offered gemcitabine alone or supportive care. As a result, their overall survival is poor, and many patients die of painful local and systemic disease progression. We think we can do better.
How does the use of stereotactic body radiotherapy address this problem?
Stereotactic body radiotherapy is a treatment modality with limited toxicity. It may not always correlate clearly with a survival benefit, but it can offer many patients a few extra months of life. This technique may improve outcomes over supportive care alone. It’s a shorter course than we give with standard radiation, and it is better tolerated. The rationale for giving stereotactic body radiotherapy is that it may allow us to debulk the disease so patients can tolerate a little more chemotherapy. By receiving more chemotherapy, their survival may improve.
Generally speaking, just giving chemotherapy alone to elderly patients or those with a poor performance status results in an overall survival of about 6 to 12 months.
Longevity of Chemotherapy
How do you incorporate stereotactic body radiotherapy into your treatment approach?
Historically, in healthier patients, we maximize the chemotherapy and then select patients for local therapy (ie, radiation and surgery). But in this population, where we know patients cannot tolerate maximum chemotherapy, as an alternative we can give a few doses of chemotherapy, then integrate radiation earlier (ie, during the chemotherapy course, not after it) to debulk the tumor, reduce the extent of disease, and eliminate the pain and obstructive symptoms. The hope is that we can improve the patient’s status and treatment tolerability and allow for more longevity of chemotherapy. We can also give stereotactic body radiotherapy after 4 to 6 months of standard chemotherapy.
Preferred Regimen
In patients who can tolerate chemotherapy, what is the preferred regimen in this population?
For patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, gemcitabine plus albumin-bound paclitaxel (Abraxane) is preferred, based on a median improvement in overall survival of 1.8 months in the phase III MPACT trial.2 An intriguing finding from this study was that patients with a poorer performance status were among those who had the greatest reduction in the risk of death, benefiting more than those with a better performance status. However, this was in a metastatic setting, and the same has not been elucidated in patients with nonmetastatic pancreatic cancer who have a poor performance status. With this in mind, we hope to conduct studies evaluating chemotherapy and stereotactic body radiotherapy in this patient population.
Overall Survival
To what degree does the use of stereotactic body radiotherapy in this population improve overall survival?
To substantially contribute to extended overall survival, radiation therapy should ideally be coupled with effective systemic therapies. Unforunately, most studies fail to adequately report performance status or comordities, so outcomes in this population of interest are unclear. Some studies have begun to speak to the potential of novel therapies, but none have investigated them in patients with a poor performance status who have nonmetastatic disease.
Our own group recently reported the first prospective phase II multicenter trial of gemcitabine plus stereotactic body radiotherapy in locally advanced pancreatic cancer, which resulted in a median overall survival of 13.9 months.3 This outcome was accompanied by a reduction in pain, no decrease in global quality of life, and < 5% acute grade 3–4 toxicity. A subgroup of patients even had margin-negative resections and a complete pathologic response. It would be good to see a study evaluting early palliative care (shown to improve outcomes in other cancers) combined with gemcitabine, albumin-bound paclitaxel, and stereotactic body radiotherapy in this unique patient population.
MD Anderson Regimen
What is your stereotactic body radiotherapy regimen at MD Anderson?
We usually give stereotactic body radiotherapy over 5 days. A systematic review of all pancreatic stereotactic body radiotherapy trials concluded that 30 to 40 Gy of stereotactic body radiotherapy administered over 3 to 5 days results in an optimal local control rate (about 80%) and acceptable acute and chronic toxicity risk. It is given in daily fractions of 5 to 15 Gy. In the elderly, we tend to err on the side of caution and give 5 to 8 Gy a day over 5 days.
There are a few situations where we don’t give stereotactic body radiotherapy—mainly when there is direct invasion of tumor into the duodenum, small bowel, or stomach, because response to the radiation can produce ulcers in a high percentage of these patients.
Moving Toward More Widespread Use
Is the use of stereotactic body radiotherapy in the pancreatic cancer population restricted to cancer centers, or is it being done in the community?
Currently, it’s mainly being done in academic centers, although the technology does exist in the community. There is a steep learning curve for administering it carefully, however, and we are hoping that the Alliance A021501 trial will help move us down that path. Although the study is in nonelderly patients with a good performance status, randomized to FOLFIRINOX [fluorouracil, leucovorin, irinotecan, oxaliplatin] alone, or FOLFIRINOX plus stereotactic body radiotherapy, we think it will be very informative. It’s the first to evaluate the use of this modality by community physicians, and the results should help move us toward more widespread adoption of this approach.
Closing Thoughts
Would you like to share some closing thoughts?
More studies are needed to better define poor performance status patients with nonmetastatic pancreatic cancer and their optimal treatment outside of clinical trials. Although these therapies have never been tested in this population, both stereotactic body radiotherapy and albumin-bound paclitaxel are hypothesized to be tolerable and effective in this group. In addition, the extent of benefits for early palliative care (which involves pain control, nutrition, and ideally exercise) in this group needs to be better described. We are hopeful that the proposed regimens with integrated palliative care will result in an improvement in survival as well as quality of life and cancer-related symptoms. ■
DISCLOSURE: Dr. Herman reported no conflicts of interest.
REFERENCES
1. Rosati LM, Herman JM: Role of stereotactic body radiotherapy in the treatment of elderly and poor performance status patients with pancreatic cancer. J Oncol Pract 13:157-166, 2017.
2. Von Hoff DD, Ervin T, Arena FP, et al: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691-1703, 2013.
3. Herman JM, Chang DT, Goodman KA, et al: Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. Cancer 121:1128-1137, 2015.
