Stereotactic Body Radiation Therapy: A New Standard Option for Pancreatic Cancer?

Keywords:

For many patients, a pancreatic cancer diagnosis involves a dismal (<6%) chance of survival beyond 5 years, and little progress has been made in terms of prevention and early detection of this disease. As a result, most patients present with advanced disease and a poor performance status that often precludes them from receiving aggressive therapy or surgery.

Advances in imaging technology, such as multidetector CT, high-field MRI, and PET, have improved staging for patients with pancreatic cancer. In addition, multiagent chemotherapy regimens such as FOLFIRINOX (leucovorin, 5-FU, irinotecan, and oxaliplatin) and gemcitabine with nab-paclitaxel have resulted in significant improvements in survival when compared to gemcitabine monotherapy. Nonetheless, these multiagent regimens can cause more toxicity than single-agent chemotherapy, including nausea, vomiting, infection, and severe neuropathy. These toxicities can be debilitating, particularly with chronic administration. Efforts to include targeted therapies have not been very effective and, unfortunately, often increase rates of treatment-related toxicity.

Radiation therapy has been shown to improve local control, stability of disease progression, and pain control in many stages of pancreatic cancer. However, these clinical benefits have historically been limited by (1) the relatively long courses of therapy, which often exceed 5 to 6 weeks; (2) the associated toxicity resulting from a lack of dose conformality; and (3) the fact that concurrent chemoradiation often decreases the ability to give patients full-dose systemic therapy. Recently, however, advances in radiation therapy techniques, including image guidance, target delineation (ie, fiducial markers, dose constraints), and motion management (ie, active breathing control, respiratory gating, respiratory tracking) now allow for very precise irradiation of pancreatic tumors, with an accuracy of 1 mm.

This form of therapy, otherwise known as stereotactic body radiation therapy (SBRT) or stereotactic ablative radiation therapy (SABR), has now been used in several malignancies, including those of the lung, liver, brain, spine, and prostate. However, its integration into the treatment paradigm of pancreatic cancer has been limited thus far. This slow integration primarily stems from the requirement for increased physical support and findings of several early studies in which SBRT resulted in increased rates of late gastrointestinal toxicity (ie, ulcers, gastrointestinal bleeding).1-3 More recently, however, single-institution studies and a multi-institution prospective study with SBRT4-7 have shown acceptable levels of late toxicity with minimal acute toxicity when treatment is delivered over 3 to 5 days as opposed to 1 day. Additionally, SBRT is typically delivered without the need for concurrent chemotherapy, resulting in improved quality of life, less delay in the administration of full-dose systemic therapy, and enhanced integration with other cancer treatment modalities. To date, more than 600 patients with pancreatic cancer have been treated with SBRT, and reports suggest an improvement in pain scores and quality of life. Furthermore, the efficacy and toxicity data compare favorably with those on conventional chemoradiotherapy.

Nonetheless, evaluation of SBRT in a prospective randomized trial is necessary to define its role in the management of pancreatic cancer and to ensure its safe implementation for treating patients. Precise delivery of SBRT is particularly important because errors involving any dimension of the planning and treatment process (ie, contouring, target delineation, breathing motion) can significantly increase the risk of toxicity due to the close proximity of adjacent radiosensitive organs (ie, bowel and stomach).

SBRT has most often been studied in the setting of locally advanced, unresectable cancer. Although early studies evaluating single-fraction (25 Gy x 1 fraction) SBRT showed excellent local control (>90%), high rates of late grade 2 to 4 gastrointestinal toxicity were reported.1-3 Limiting toxicity in this patient population is especially important because this group of patients may not recover from any gastrointestinal toxicity that requires an invasive intervention. However, when appropriate strict dose constraints are met,8 significant gastrointestinal toxicity from SBRT can be avoided. Furthermore, when compared with single-fraction SBRT, 5-fraction SBRT also results in decreased long-term gastrointestinal toxicity (J.M.H. et al, unpublished data, 2014).4 These data indicate that SBRT is an ideal option to complement any systemic regimen with the goal of maximizing local control, preserving quality of life, and potentially enhancing overall survival.

Patients with resectable or borderline resectable pancreatic cancer are more likely than those with locally advanced cancer to undergo successful surgical resection. Therefore, this clinical scenario provides an ideal opportunity to use SBRT to treat the pancreas tumor and the interface adjacent to or involving blood vessels, with the ultimate goal of achieving a margin-negative (R0) resection. SBRT has been studied in the neoadjuvant and borderline settings.9,10 One study evaluated neoadjuvant capecitabine and SBRT with protons (5 Gy x 5) in patients with resectable pancreatic cancer. The regimen was tolerable (grade ≥3 toxicity, 4.1%); however, local recurrences still occurred (16.2%). The relatively high rate of local recurrence may be attributed to insufficient radiation dose to sterilize all microscopic disease. Another study reported the combination of gemcitabine, docetaxel, and capecitabine (GTX) and SBRT in 57 patients with borderline resectable pancreatic cancer.11 Of these patients, 32 (56.1%) underwent successful surgical resection, with a 96.9% rate of R0 resection, a 9.4% rate of pathologic complete response, and a median overall survival (OS) of 19.3 months. Median OS for all patients with borderline resectable disease who received GTX and SBRT was 16.4 months.

Although the data are limited, SBRT can also offer potential advantages in the adjuvant setting. In a study by Rwigema et al,12 12 patients underwent adjuvant SBRT after resection with a close (0.5-1.5 mm) or positive margin after surgery. Rates of freedom from local progression and OS at 1 year were 70.7% and 81.8%, respectively, whereas the mean OS was reported to be 20.6 months. The same group also published a follow-up study of 24 patients with close (1.0-2.5 mm) or positive margins who received adjuvant SBRT.13 Freedom from local progression at 1 year was 66%, and 1-year OS was 80.4%, with a median OS of 26.7 months. The small sample size of these cohorts merits further investigation. SBRT targeting of the tumor bed outlined by surgical clips is being explored in a prospective single-arm trial in combination with a pancreatic tumor cell vaccine (GVAX) and FOLFIRINOX in the adjuvant setting (ClinicalTrials.gov identifier: NCT01595321, Table 1).14

SBRT may also offer significant clinical benefit in patients with pancreatic cancer with a poor performance status, advanced age, or existing comorbidities. Approximately 20% to 30% of patients diagnosed with pancreatic cancer never receive any therapy because of these precluding factors.15 Data suggest that these patients are not optimal surgical candidates,16 and standard or multiagent systemic therapy or long-course chemoradiation (5-6 weeks) is often not well tolerated. Recently, Von Hoff et al17 showed that the addition of nab-paclitaxel to gemcitabine monotherapy provided a survival benefit in patients with metastatic pancreatic cancer with a poor performance status. Because the median survival of this population is typically about 6 months, adding SBRT (3-5 fractions) to chemotherapy may minimize local progression, decrease pain, and possibly prolong survival.

Given the current health care environment characterized by limited resources and cost containment, another potential benefit of SBRT is the reduced costs when compared with standard chemoradiation.18 In general, SBRT treatment is approximately half the cost of a standard pancreas regimen of 28 fractions with intensity-modulated radiation therapy. Furthermore, fewer routine laboratory tests and clinic visits are necessary to monitor symptoms, thereby decreasing the costs and burden for the patient and family.18

Table 1

Ongoing Clinical Trials Exploring the Role of Fractionated SBRT in Pancreatic Cancer

Table 1

At the 2014 ASCO Annual Meeting, a preliminary report of the LAP 07 trial reported no significant improvement in survival of patients with locally advanced pancreatic cancer who received standard chemoradiation after induction chemotherapy.19 However, chemoradiation did result in improved local control (65% vs 34%; P<.0001). Since patients with unresectable disease have an expected survival of approximately 1 year after diagnosis, undergoing conventional chemoradiation essentially commits patients to spending a significant portion of their remaining life receiving and recovering from radiation treatment. If SBRT can be shown to be equivalent to or better than with regard to local control and tumor response, it seems reasonable that it should be evaluated as a possible standard option for these patients.

Current trials evaluating fractionated SBRT in pancreatic cancer are outlined in Table 1. Given the potential benefits described previously and the number of trials evaluating SBRT, why has SBRT not been more widely accepted? The most likely reason is that linear accelerators capable of SBRT have only recently become widely available. Further, early publications suggested that significant toxicity may be encountered if technical considerations related to dose and gating are not met.1-3,8,20 However, since the early SBRT studies, dose constraints have been defined, and 3 to 5-fraction SBRT regimens have been shown to result in less toxicity than single-fraction SBRT. As the technology and physician education regarding SBRT become more widespread, radiation oncologists will become more adept at using this method of radiation delivery. This will inevitably lead to higher-quality SBRT and well-defined indications for its use in pancreatic cancer.

Future SBRT studies in localized (resectable, borderline resectable, and locally advanced) pancreatic cancer should determine the optimal dose needed to maximize tumor response while limiting associated toxicity. Subsequent steps include integration of novel radiosensitizers (eg, poly[ADP-ribose] polymerase inhibitors) and radioprotectors (to enhance recovery of duodenum/stomach after radiation). Finally, unpublished data on patients with pancreatic cancer receiving radiotherapy at Johns Hopkins demonstrate that patients who received SBRT tended to have less immunosuppression, as indicated by lymphopenia levels 2 months after radiation therapy, than patients who underwent conventional chemoradiation therapy. This suggests that SBRT may be better integrated with immunotherapy than conventional approaches. In summary, we believe that SBRT shows considerable potential as a standard option in the treatment paradigm of pancreatic cancer. However, additional prospective studies with well-selected clinical end points are needed to advance this modality into the standard of care.

We would like to acknowledge Lauren Rosati, BS, for her assistance in the editing and review of this manuscript.

References

  • 1.

    HoyerMRoedHSengelovL. Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma. Radiother Oncol2005;76:4853.

    • Search Google Scholar
    • Export Citation
  • 2.

    SchellenbergDGoodmanKALeeF. Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys2008;72:678686.

    • Search Google Scholar
    • Export Citation
  • 3.

    SchellenbergDKimJChristman-SkiellerC. Single-fraction stereotactic body radiation therapy and sequential gemcitabine for the treatment of locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys2011;81:181188.

    • Search Google Scholar
    • Export Citation
  • 4.

    HermanJChangDGoodmanK. A phase II multi-institutional study to evaluate gemcitabine and fractionated stereotactic body radiotherapy for unresectable, locally advanced pancreatic adenocarcinoma [abstract]. J Clin Oncol2012;30(Suppl):Abstract 4045.

    • Search Google Scholar
    • Export Citation
  • 5.

    MahadevanAJainSGoldsteinM. Stereotactic body radiotherapy and gemcitabine for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys2010;78:735742.

    • Search Google Scholar
    • Export Citation
  • 6.

    TozziAComitoTAlongiF. SBRT in unresectable advanced pancreatic cancer: preliminary results of a mono-institutional experience. Radiat Oncol2013;8:148.

    • Search Google Scholar
    • Export Citation
  • 7.

    TimmermanRDHermanJChoLC. Emergence of stereotactic body radiation therapy and its impact on current and future clinical practice. J Clin Oncol2014;32:28472854.

    • Search Google Scholar
    • Export Citation
  • 8.

    MurphyJDChristman-SkiellerCKimJ. A dosimetric model of duodenal toxicity after stereotactic body radiotherapy for pancreatic cancer. Int J Radiat Oncol Biol Phys2010;78:14201426.

    • Search Google Scholar
    • Export Citation
  • 9.

    HongTSRyanDPBlaszkowskyLS. Phase I study of preoperative short-course chemoradiation with proton beam therapy and capecitabine for resectable pancreatic ductal adenocarcinoma of the head. Int J Radiat Oncol Biol Phys2011;79:151157.

    • Search Google Scholar
    • Export Citation
  • 10.

    HongTSRyanDPBorgerDR. A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. Int J Radiat Oncol Biol Phys2014;89:830838.

    • Search Google Scholar
    • Export Citation
  • 11.

    ChuongMDSpringettGMFreilichJM. Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is effective and well tolerated. Int J Radiat Oncol Biol Phys2013;86:516522.

    • Search Google Scholar
    • Export Citation
  • 12.

    RwigemaJCParikhSDHeronDE. Stereotactic body radiotherapy in the treatment of advanced adenocarcinoma of the pancreas. Am J Clin Oncol2011;34:6369.

    • Search Google Scholar
    • Export Citation
  • 13.

    RwigemaJCHeronDEParikhSD. Adjuvant stereotactic body radiotherapy for resected pancreatic adenocarcinoma with close or positive margins. J Gastrointest Cancer2012;43:7076.

    • Search Google Scholar
    • Export Citation
  • 14.

    DholakiaASKumarRRamanSP. Mapping patterns of local recurrence after pancreaticoduodenectomy for pancreatic adenocarcinoma: a new approach to adjuvant radiation field design. Int J Radiat Oncol Biol Phys2013;87:10071015.

    • Search Google Scholar
    • Export Citation
  • 15.

    VerslypeCVan CutsemEDicatoM. The management of metastatic pancreatic cancer: expert discussion and recommendations from the 14th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2012. Ann Oncol2013;24(Suppl 4):iv510.

    • Search Google Scholar
    • Export Citation
  • 16.

    HsuCCWolfgangCLLaheruDA. Early mortality risk score: identification of poor outcomes following upfront surgery for resectable pancreatic cancer. J Gastrointest Surg2012;16:753761.

    • Search Google Scholar
    • Export Citation
  • 17.

    Von HoffDDErvinTArenaFP. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med2013;369:16911703.

    • Search Google Scholar
    • Export Citation
  • 18.

    MurphyJDChangDTAbelsonJ. Cost-effectiveness of modern radiotherapy techniques in locally advanced pancreatic cancer. Cancer2012;118:11191129.

    • Search Google Scholar
    • Export Citation
  • 19.

    HuguetFHammelPVernereyD. Impact of chemoradiotherapy (CRT) on local control and time without treatment in patients with locally advanced pancreatic cancer (LAPC) included in the international phase III LAP 07 study [abstract]. J Clin Oncol2014;32(Suppl):Abstract 4001.

    • Search Google Scholar
    • Export Citation
  • 20.

    TaniguchiCMMurphyJDEclovN. Dosimetric analysis of organs at risk during expiratory gating in stereotactic body radiation therapy for pancreatic cancer. Int J Radiat Oncol Biol Phys2013;85:10901095.

    • Search Google Scholar
    • Export Citation

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Joseph M. Herman, MD, MSc, is an Associate Professor of Radiation Oncology at The Johns Hopkins University, where he serves as Director of the Gastrointestinal Division. He is the Clinical Research Director of the Department of Radiation Oncology & Molecular Radiation Services and Co-Director of the Pancreatic Multidisciplinary Clinic at Johns Hopkins. He is the site principal investigator on several national and institutional clinical protocols involving pancreatic cancer. He is a writing committee member of the NCCN Pancreatic Adenocarcinoma Panel and American College of Radiology guidelines panels and serves on the National Institute of Health Pancreas Task Force and the medical advisory board for the Pancreatic Cancer Action Network.The ideas and viewpoints expressed in this commentary are those of the author and do not necessarily represent any policy, position, or program of NCCN.Albert C. Koong, MD, PhD, is a Professor of Radiation Oncology at Stanford University School of Medicine. He serves as the Associate Chair and Medical Director of Radiation Oncology Clinical Operations. His area of clinical interest is in the application of advanced radiation techniques for gastrointestinal malignancies. He is Principal Investigator for both institutional and national studies in pancreatic cancer. His current research is funded by the National Cancer Institute and the My Blue Dots Foundation. He is a member of the NCCN Pancreatic Adenocarcinoma and American College of Radiology guidelines panels.
  • 1.

    HoyerMRoedHSengelovL. Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma. Radiother Oncol2005;76:4853.

    • Search Google Scholar
    • Export Citation
  • 2.

    SchellenbergDGoodmanKALeeF. Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys2008;72:678686.

    • Search Google Scholar
    • Export Citation
  • 3.

    SchellenbergDKimJChristman-SkiellerC. Single-fraction stereotactic body radiation therapy and sequential gemcitabine for the treatment of locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys2011;81:181188.

    • Search Google Scholar
    • Export Citation
  • 4.

    HermanJChangDGoodmanK. A phase II multi-institutional study to evaluate gemcitabine and fractionated stereotactic body radiotherapy for unresectable, locally advanced pancreatic adenocarcinoma [abstract]. J Clin Oncol2012;30(Suppl):Abstract 4045.

    • Search Google Scholar
    • Export Citation
  • 5.

    MahadevanAJainSGoldsteinM. Stereotactic body radiotherapy and gemcitabine for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys2010;78:735742.

    • Search Google Scholar
    • Export Citation
  • 6.

    TozziAComitoTAlongiF. SBRT in unresectable advanced pancreatic cancer: preliminary results of a mono-institutional experience. Radiat Oncol2013;8:148.

    • Search Google Scholar
    • Export Citation
  • 7.

    TimmermanRDHermanJChoLC. Emergence of stereotactic body radiation therapy and its impact on current and future clinical practice. J Clin Oncol2014;32:28472854.

    • Search Google Scholar
    • Export Citation
  • 8.

    MurphyJDChristman-SkiellerCKimJ. A dosimetric model of duodenal toxicity after stereotactic body radiotherapy for pancreatic cancer. Int J Radiat Oncol Biol Phys2010;78:14201426.

    • Search Google Scholar
    • Export Citation
  • 9.

    HongTSRyanDPBlaszkowskyLS. Phase I study of preoperative short-course chemoradiation with proton beam therapy and capecitabine for resectable pancreatic ductal adenocarcinoma of the head. Int J Radiat Oncol Biol Phys2011;79:151157.

    • Search Google Scholar
    • Export Citation
  • 10.

    HongTSRyanDPBorgerDR. A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. Int J Radiat Oncol Biol Phys2014;89:830838.

    • Search Google Scholar
    • Export Citation
  • 11.

    ChuongMDSpringettGMFreilichJM. Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is effective and well tolerated. Int J Radiat Oncol Biol Phys2013;86:516522.

    • Search Google Scholar
    • Export Citation
  • 12.

    RwigemaJCParikhSDHeronDE. Stereotactic body radiotherapy in the treatment of advanced adenocarcinoma of the pancreas. Am J Clin Oncol2011;34:6369.

    • Search Google Scholar
    • Export Citation
  • 13.

    RwigemaJCHeronDEParikhSD. Adjuvant stereotactic body radiotherapy for resected pancreatic adenocarcinoma with close or positive margins. J Gastrointest Cancer2012;43:7076.

    • Search Google Scholar
    • Export Citation
  • 14.

    DholakiaASKumarRRamanSP. Mapping patterns of local recurrence after pancreaticoduodenectomy for pancreatic adenocarcinoma: a new approach to adjuvant radiation field design. Int J Radiat Oncol Biol Phys2013;87:10071015.

    • Search Google Scholar
    • Export Citation
  • 15.

    VerslypeCVan CutsemEDicatoM. The management of metastatic pancreatic cancer: expert discussion and recommendations from the 14th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2012. Ann Oncol2013;24(Suppl 4):iv510.

    • Search Google Scholar
    • Export Citation
  • 16.

    HsuCCWolfgangCLLaheruDA. Early mortality risk score: identification of poor outcomes following upfront surgery for resectable pancreatic cancer. J Gastrointest Surg2012;16:753761.

    • Search Google Scholar
    • Export Citation
  • 17.

    Von HoffDDErvinTArenaFP. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med2013;369:16911703.

    • Search Google Scholar
    • Export Citation
  • 18.

    MurphyJDChangDTAbelsonJ. Cost-effectiveness of modern radiotherapy techniques in locally advanced pancreatic cancer. Cancer2012;118:11191129.

    • Search Google Scholar
    • Export Citation
  • 19.

    HuguetFHammelPVernereyD. Impact of chemoradiotherapy (CRT) on local control and time without treatment in patients with locally advanced pancreatic cancer (LAPC) included in the international phase III LAP 07 study [abstract]. J Clin Oncol2014;32(Suppl):Abstract 4001.

    • Search Google Scholar
    • Export Citation
  • 20.

    TaniguchiCMMurphyJDEclovN. Dosimetric analysis of organs at risk during expiratory gating in stereotactic body radiation therapy for pancreatic cancer. Int J Radiat Oncol Biol Phys2013;85:10901095.

    • Search Google Scholar
    • Export Citation
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