Point/Counter

Should stereotactic body radiation therapy be adopted as a standard of care for patients with locally advanced pancreatic cancer?

Click here to read the Cover Story, “Greater collaboration, understanding of disease biology may improve outcomes in pancreatic cancer.”

POINT

Yes.

Based on phase 1 and phase 2 data, hypofractionated stereotactic body radiation therapy (SBRT) should be a standard-of-care option for patients with locally advanced pancreatic cancer (LAPC).

Joseph M. Herman, MD, MSc
Joseph M. Herman

However, not all patients with LAPC are good candidates for SBRT. Treatment options should be discussed in a multidisciplinary setting, taking into account patient preference, anatomy, location of the tumor (head, body or tail) and tumor biology (genetics and tumor microenvironment). For patients with LAPC, historical treatments with single-agent chemotherapy and chemoradiation largely have been ineffective, cause gastrointestinal toxicity and have resulted in a median survival of only 12 to 14 months. For example, the LAP07 trial enrolled patients with LAPC to gemcitabine with or without erlotinib (Tarceva, Genentech), followed by randomization to standard chemoradiation with concurrent capecitabine. The addition of chemoradiation increased toxicity without a survival benefit. Chemoradiation did, however, result in a significant benefit in local control, suggesting a persistent role for radiation but with the need to reduce side effects.

SBRT allows for accurate delivery of high doses of radiation to the pancreatic tumor in less than a week with limited acute toxicity. SBRT given in one to five fractions has been shown to be superior to chemoradiation in several malignancies, including lung and brain cancers; however, it took several years to develop the most effective dose and fractionation regimens. In patients with LAPC, initial results of SBRT (25 Gy in one fraction) showed favorable local control but high rates of late grade 2 to grade 4 gastrointestinal toxicity. In a multicenter study, we demonstrated that one week of SBRT (6.6 Gy in five fractions) decreased late gastrointestinal toxicity compared with 25 Gy in one fraction, with survival equivalent to chemoradiation (13.9 months). In this study, SBRT actually resulted in an improvement in pain and no change in quality of life, at roughly half the cost of chemoradiation.

To realize the true benefit of SBRT in pancreatic cancer, it needs to be coupled with more aggressive multiagent systemic therapy. At Johns Hopkins University, a prospective study offered pancreas SBRT after completion of 4 to 6 months of FOLFIRINOX or nab-paclitaxel plus gemcitabine. Given the potential overlapping gastrointestinal toxicities of SBRT with these multiagent chemotherapy regimens, the dose of SBRT was conservative in this study (33 Gy in five fractions). However, dose escalation (more than 33 Gy) was allowed if normal tissue-dose constraints were met. Despite these lower doses of SBRT, a large proportion of patients on this trial have undergone a margin- and node-negative resection with several pathologic complete responses and OS approaching 3 years. Efforts to evaluate efficacy and safely escalate the dose (up to 9 Gy in five fractions) of SBRT are underway and will be formally evaluated in the Alliance 021501 borderline resectable pancreatic cancer trial.

Now that SBRT can be considered a standard option for LAPC, the next steps to further improve patient outcomes include: Determine the optimal dose and fractionation necessary for tumor eradication; identify how to combine SBRT with targeted therapies and immunotherapy; and utilize imaging, tissue and liquid biomarkers to personalize treatment.

References:

Brunner TB, et al. Radiother Oncol. 2015;doi:10.1016/j.radonc.2014.10.015.

Chuong MD, et al. Int J Radiat Oncol Biol Phys. 2013;doi:10.1016/j.ijrobp.2013.02.022.

Finkelstein SE, et al. Clin Dev Immunol. 2011;doi:10.1155/2011/439752.

Gurka MK, et al. Radiat Oncol. 2013;doi:10.1186/1748-717X-8-44.

Hammel P, et al. JAMA. 2016;doi:10.1001jama.2016.4324.

Herman JM, et al. Cancer. 2015;doi:10.1002/cncr.29161.

Katz MH, et al. JAMA Surg. 2016;doi:10.1001/jamasurg.2016.1137.

Koong AC, et al. Int J Radiat Oncol Biol Phys. 2004;58:1017-1021.

Mellon EA, et al. Acta Oncol. 2015;doi:10.3109/0284186X.2015.1004367.

Moningi S, et al. Ann Surg Oncol. 2015;doi:10.1245/s10434-014-4274-5.

Schellenberg D, et al. Int J Radiat Oncol Biol Phys. 2011;doi:10.1016/j.ijrobp.2010.05.006.

Valero V 3rd, et al. Ann Surg. 2016;doi:10.1097/SLA.0000000000001156.

Vincent A, et al. Lancet. 2011;doi:10.1016/S0140-6736(10)62307-0.

Joseph M. Herman, MD, MSc, is professor and director of clinical research in the division of radiation oncology at The University of Texas MD Anderson Cancer Center. He wished to acknowledge Lauren M. Rosati, BS, for her contribution in revising this manuscript. Herman can be reached at jmherman@mdanderson.org. Disclosure: Herman reports no relevant financial disclosures.

COUNTER

No.

There is great enthusiasm among radiation oncologists to use stereotactic body radiation therapy (SBRT) for patients with locally advanced pancreatic cancer. SBRT can deliver highly precise radiotherapy in one to five outpatient treatments, and patients typically tolerate the treatment very well.

Jason W. Chan, MD
Jason W. Chan
Mary Feng, MD
Mary Feng

So what is the problem? Although SBRT deserves further investigation, sufficient questions remain about its clinical benefit and safety that it should not yet be adopted as a standard of care in locally advanced pancreatic cancer.

There is little doubt that we need to improve local control for patients with pancreatic cancer. However, there is only emerging data suggesting that tumor control and survival after SBRT are even comparable with fractionated radiotherapy, let alone better.

The fundamental reason may be rooted in biology rather than technology. Tumors and normal tissues perceive high doses of radiation differently. For the same dose, normal tissues are more sensitive. Thus, for pancreatic cancer — which is surrounded by the duodenum and stomach — inherently we are limited in the amount of radiation we can safely deliver, even with the most advanced technologies. The consequence of overdosing normal tissues is ulceration and the consequence of underdosing the tumor is progression, and there often is just a millimeter in between due to patient anatomy.

Both the tumor and nearby internal organs move during breathing, further complicating the picture. In patients who do not undergo pancreaticoduodenectomy, duodenal toxicity can be a significant problem following SBRT. An early SBRT trial that used 45 Gy in three fractions without chemotherapy resulted in unacceptable toxicity, with 42% of patients experiencing severe mucositis or ulceration of the stomach or duodenum. A more contemporary phase 2 multi-institutional trial by Herman and colleagues delivered 33 Gy in five fractions with gemcitabine. Gastrointestinal toxicity was more acceptable, with 11% of patients experiencing late grade 2 or higher gastritis, fistula, enteritis or ulcers.

Although now promising, this illustrates the learning curve for pancreas SBRT. Simply put, if executed poorly, SBRT could be harmful rather than helpful. The devil really is in the details. It is no trivial feat to treat a pancreatic tumor to doses that exceed the tolerance of normal organs located millimeters away. The pancreas and bowel are constantly moving and — in inexperienced hands — may be difficult to see and avoid, even with the most modern radiation treatment machines. SBRT for locally advanced pancreatic cancer requires varsity-level care coordination. Educational efforts are ongoing to train the team of physicians, dosimetrists, physicists and therapists required to plan and deliver this precise treatment.

Therefore, SBRT should not be the standard of care until we have more long-term data on its efficacy and safety, and training in this technically challenging treatment type is more widespread. In the meantime, SBRT should be performed at centers of excellence, preferably as part of clinical trials.

References:

Herman JM, et al. Cancer. 2015;doi:10.1002/cncr.29161.

Hoyer M, et al. Radiother Oncol. 2005;76:48-53.

Jason W. Chan, MD, is a radiation oncology resident at University of California, San Francisco. Mary Feng, MD, is associate professor, vice chair for clinical research and interim quality director in the department of radiation oncology at University of California, San Francisco. She can be reached at mary.feng@ucsf.edu. Disclosure: Chan and Feng report no relevant financial disclosures.

Click here to read the Cover Story, “Greater collaboration, understanding of disease biology may improve outcomes in pancreatic cancer.”

POINT

Yes.

Based on phase 1 and phase 2 data, hypofractionated stereotactic body radiation therapy (SBRT) should be a standard-of-care option for patients with locally advanced pancreatic cancer (LAPC).

Joseph M. Herman, MD, MSc
Joseph M. Herman

However, not all patients with LAPC are good candidates for SBRT. Treatment options should be discussed in a multidisciplinary setting, taking into account patient preference, anatomy, location of the tumor (head, body or tail) and tumor biology (genetics and tumor microenvironment). For patients with LAPC, historical treatments with single-agent chemotherapy and chemoradiation largely have been ineffective, cause gastrointestinal toxicity and have resulted in a median survival of only 12 to 14 months. For example, the LAP07 trial enrolled patients with LAPC to gemcitabine with or without erlotinib (Tarceva, Genentech), followed by randomization to standard chemoradiation with concurrent capecitabine. The addition of chemoradiation increased toxicity without a survival benefit. Chemoradiation did, however, result in a significant benefit in local control, suggesting a persistent role for radiation but with the need to reduce side effects.

SBRT allows for accurate delivery of high doses of radiation to the pancreatic tumor in less than a week with limited acute toxicity. SBRT given in one to five fractions has been shown to be superior to chemoradiation in several malignancies, including lung and brain cancers; however, it took several years to develop the most effective dose and fractionation regimens. In patients with LAPC, initial results of SBRT (25 Gy in one fraction) showed favorable local control but high rates of late grade 2 to grade 4 gastrointestinal toxicity. In a multicenter study, we demonstrated that one week of SBRT (6.6 Gy in five fractions) decreased late gastrointestinal toxicity compared with 25 Gy in one fraction, with survival equivalent to chemoradiation (13.9 months). In this study, SBRT actually resulted in an improvement in pain and no change in quality of life, at roughly half the cost of chemoradiation.

To realize the true benefit of SBRT in pancreatic cancer, it needs to be coupled with more aggressive multiagent systemic therapy. At Johns Hopkins University, a prospective study offered pancreas SBRT after completion of 4 to 6 months of FOLFIRINOX or nab-paclitaxel plus gemcitabine. Given the potential overlapping gastrointestinal toxicities of SBRT with these multiagent chemotherapy regimens, the dose of SBRT was conservative in this study (33 Gy in five fractions). However, dose escalation (more than 33 Gy) was allowed if normal tissue-dose constraints were met. Despite these lower doses of SBRT, a large proportion of patients on this trial have undergone a margin- and node-negative resection with several pathologic complete responses and OS approaching 3 years. Efforts to evaluate efficacy and safely escalate the dose (up to 9 Gy in five fractions) of SBRT are underway and will be formally evaluated in the Alliance 021501 borderline resectable pancreatic cancer trial.

Now that SBRT can be considered a standard option for LAPC, the next steps to further improve patient outcomes include: Determine the optimal dose and fractionation necessary for tumor eradication; identify how to combine SBRT with targeted therapies and immunotherapy; and utilize imaging, tissue and liquid biomarkers to personalize treatment.

References:

Brunner TB, et al. Radiother Oncol. 2015;doi:10.1016/j.radonc.2014.10.015.

Chuong MD, et al. Int J Radiat Oncol Biol Phys. 2013;doi:10.1016/j.ijrobp.2013.02.022.

Finkelstein SE, et al. Clin Dev Immunol. 2011;doi:10.1155/2011/439752.

Gurka MK, et al. Radiat Oncol. 2013;doi:10.1186/1748-717X-8-44.

Hammel P, et al. JAMA. 2016;doi:10.1001jama.2016.4324.

Herman JM, et al. Cancer. 2015;doi:10.1002/cncr.29161.

Katz MH, et al. JAMA Surg. 2016;doi:10.1001/jamasurg.2016.1137.

Koong AC, et al. Int J Radiat Oncol Biol Phys. 2004;58:1017-1021.

Mellon EA, et al. Acta Oncol. 2015;doi:10.3109/0284186X.2015.1004367.

Moningi S, et al. Ann Surg Oncol. 2015;doi:10.1245/s10434-014-4274-5.

Schellenberg D, et al. Int J Radiat Oncol Biol Phys. 2011;doi:10.1016/j.ijrobp.2010.05.006.

Valero V 3rd, et al. Ann Surg. 2016;doi:10.1097/SLA.0000000000001156.

Vincent A, et al. Lancet. 2011;doi:10.1016/S0140-6736(10)62307-0.

Joseph M. Herman, MD, MSc, is professor and director of clinical research in the division of radiation oncology at The University of Texas MD Anderson Cancer Center. He wished to acknowledge Lauren M. Rosati, BS, for her contribution in revising this manuscript. Herman can be reached at jmherman@mdanderson.org. Disclosure: Herman reports no relevant financial disclosures.

PAGE BREAK

COUNTER

No.

There is great enthusiasm among radiation oncologists to use stereotactic body radiation therapy (SBRT) for patients with locally advanced pancreatic cancer. SBRT can deliver highly precise radiotherapy in one to five outpatient treatments, and patients typically tolerate the treatment very well.

Jason W. Chan, MD
Jason W. Chan
Mary Feng, MD
Mary Feng

So what is the problem? Although SBRT deserves further investigation, sufficient questions remain about its clinical benefit and safety that it should not yet be adopted as a standard of care in locally advanced pancreatic cancer.

There is little doubt that we need to improve local control for patients with pancreatic cancer. However, there is only emerging data suggesting that tumor control and survival after SBRT are even comparable with fractionated radiotherapy, let alone better.

The fundamental reason may be rooted in biology rather than technology. Tumors and normal tissues perceive high doses of radiation differently. For the same dose, normal tissues are more sensitive. Thus, for pancreatic cancer — which is surrounded by the duodenum and stomach — inherently we are limited in the amount of radiation we can safely deliver, even with the most advanced technologies. The consequence of overdosing normal tissues is ulceration and the consequence of underdosing the tumor is progression, and there often is just a millimeter in between due to patient anatomy.

Both the tumor and nearby internal organs move during breathing, further complicating the picture. In patients who do not undergo pancreaticoduodenectomy, duodenal toxicity can be a significant problem following SBRT. An early SBRT trial that used 45 Gy in three fractions without chemotherapy resulted in unacceptable toxicity, with 42% of patients experiencing severe mucositis or ulceration of the stomach or duodenum. A more contemporary phase 2 multi-institutional trial by Herman and colleagues delivered 33 Gy in five fractions with gemcitabine. Gastrointestinal toxicity was more acceptable, with 11% of patients experiencing late grade 2 or higher gastritis, fistula, enteritis or ulcers.

Although now promising, this illustrates the learning curve for pancreas SBRT. Simply put, if executed poorly, SBRT could be harmful rather than helpful. The devil really is in the details. It is no trivial feat to treat a pancreatic tumor to doses that exceed the tolerance of normal organs located millimeters away. The pancreas and bowel are constantly moving and — in inexperienced hands — may be difficult to see and avoid, even with the most modern radiation treatment machines. SBRT for locally advanced pancreatic cancer requires varsity-level care coordination. Educational efforts are ongoing to train the team of physicians, dosimetrists, physicists and therapists required to plan and deliver this precise treatment.

Therefore, SBRT should not be the standard of care until we have more long-term data on its efficacy and safety, and training in this technically challenging treatment type is more widespread. In the meantime, SBRT should be performed at centers of excellence, preferably as part of clinical trials.

References:

Herman JM, et al. Cancer. 2015;doi:10.1002/cncr.29161.

Hoyer M, et al. Radiother Oncol. 2005;76:48-53.

Jason W. Chan, MD, is a radiation oncology resident at University of California, San Francisco. Mary Feng, MD, is associate professor, vice chair for clinical research and interim quality director in the department of radiation oncology at University of California, San Francisco. She can be reached at mary.feng@ucsf.edu. Disclosure: Chan and Feng report no relevant financial disclosures.