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Brief Report
March 11, 2021

Association of Ablative Radiation Therapy With Survival Among Patients With Inoperable Pancreatic Cancer

Author Affiliations
  • 1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
  • 2David M. Rubenstein Center for Pancreatic Cancer Research, New York, New York
  • 3Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
  • 4Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
  • 5Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
JAMA Oncol. 2021;7(5):735-738. doi:10.1001/jamaoncol.2021.0057
Key Points

Question  Does irradiation dose escalation to doses known to cure other cancers improve local tumor control and survival for patients with localized pancreatic cancer?

Findings  Ablative radiation therapy after induction chemotherapy in 119 patients with locally advanced unresectable pancreatic cancer was associated with a 2-year local tumor progression rate of only 32.8% and a 2-year overall survival rate of 38% from the time of irradiation.

Meaning  Hypofractionated ablative radiation therapy was associated with durable control of the primary tumor leading to favorable survival outcomes.

Abstract

Importance  Surgical resection has been considered the only curative option for patients with pancreatic cancer. Nonoperative local treatment options that can provide a similar benefit are needed. Emerging radiation techniques that address organ motion have enabled curative radiation doses to be given in patients with inoperable disease.

Objective  To determine the association of hypofractionated ablative radiation therapy (A-RT) with survival for patients with locally advanced pancreatic cancer (LAPC) treated with a novel radiation planning and delivery technique.

Design, Setting, and Participants  This cohort study included 119 consecutive patients treated with A-RT between June 2016 and February 2019 and enrolled in a prospectively maintained database. Patients were treated with a standardized technique within a large academic cancer center regional network. All patients with localized, unresectable, or medically inoperable pancreatic cancer with tumors of any size and less than 5 cm luminal abutment with the primary tumor were eligible.

Interventions  Ablative RT (98 Gy biologically effective dose) was delivered using standard equipment. Respiratory gating, soft tissue image guidance, and selective adaptive planning were used to address organ motion and limit the dose to surrounding luminal organs.

Main Outcomes and Measures  The primary outcome was overall survival (OS). Secondary outcomes included incidence of local progression and progression-free survival.

Results  Between 2016 and 2019, 119 patients (59 men, median age 67 years) received A-RT, including 99 with T3/T4 and 53 with node-positive disease, with a median carbohydrate antigen 19-9 (CA19-9) level greater than 167 U/mL. Most (116 [97.5%]) received induction chemotherapy for a median of 4 months (0.5-18.4). Median OS from diagnosis and A-RT were 26.8 and 18.4 months, respectively. Respective 12- and 24-month OS from A-RT were 74% (95% CI, 66%-83%) and 38% (95% CI, 27%-52%). Twelve- and 24-month cumulative incidence of locoregional failure were 17.6% (95% CI, 10.4%-24.9%) and 32.8% (95% CI, 21.6%-44.1%), respectively. Postinduction CA19-9 decline was associated with improved locoregional control and survival. Grade 3 upper gastrointestinal bleeding occurred in 10 patients (8%) with no grade 4 to 5 events.

Conclusions and Relevance  This cohort study of patients with inoperable LAPC found that A-RT following multiagent induction therapy for LAPC was associated with durable locoregional tumor control and favorable survival. Prospective randomized trials in patients with LAPC are warranted.

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    2 Comments for this article
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    Ablative radiation therapy for inoperable pancreatic cancer: promising but more evidence is necessary
    Fu-yu Li, MD, PhD | West China Hospital, Sichuan University
    With great interest, we have read this single-center, retrospective non-randomized study from Reyngold and colleagues entitled “Association of Ablative Radiation Therapy With Survival Among Patients With Inoperable Pancreatic Cancer”.[1] Within their study, ablative radiation therapy (ART) in patients with locally advanced pancreatic cancer (LAPC) was associated with durable locoregional tumor control, improved overall survival (OS), and lower adverse events. The performed study is interesting and so are the results. However, we would like to mention some remarks.

    First, 55.5% of patients in this study received modified FOLFIRINOX induction chemotherapy and have shown better results than the study with conventional
    chemoradiotherapy. In contrast, the patients in the previous studies received conventional radiotherapy after Gemcitabine-based induction chemotherapy.[2, 3] Studies have shown the superiority of FOLFIRINOX based chemotherapy regimen over Gemcitabine.[4] Induction chemotherapy with a modified FOLFIRINOX regimen must have contributed to the favorable outcomes in this study.

    Second, on comparing the survival outcomes of the current study with a patient-level meta-analysis of FOLFIRINOX chemotherapy, we have identified that median OS, 2-year OS, and progression-free survival were similar to the current study.[5] So we are concerned about the added benefit of ART. Moreover, the author included 83% of patients with radiographic T3/T4 disease, it would be of interest to report the number of patients with major vessel invasion, which is associated with poor outcomes in patients with pancreatic cancer. An in-depth analysis of this group of patients and their survival outcomes after chemoradiotherapy will lead to a better understanding of this therapy.

    It is worth mentioning that the author has identified the postinduction reduction of carbohydrate antigen (CA) 19-9 was associated with improved survival outcomes in both univariate and multivariate analysis. This group of patients may have better outcomes during further investigations. Finally, further multicenter trials with a direct comparison of mFOLFIRINOX induction chemotherapy followed by ART and mFOLFIRINOX chemotherapy without ART are needed to understand the efficacy and safety of this rising alternative therapy for patients with LAPC.

    Authors: Parbatraj Regmi, MD; Fei Liu, MD; Fu-Yu Li, MD, PhD

    References

    1. Reyngold M, O'Reilly EM, Varghese AM et al. Association of Ablative Radiation Therapy With Survival Among Patients With Inoperable Pancreatic Cancer. JAMA Oncol 2021.
    2. 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: 1844-1853.
    3. 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: 1592-1599.
    4. Conroy T, Hammel P, Hebbar M et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med 2018; 379: 2395-2406.
    5. Suker M, Beumer BR, Sadot E et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol 2016; 17: 801-810.
    CONFLICT OF INTEREST: None Reported
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    Ablative radiation therapy for pancreatic cancer is an alternative to surgical treatment
    Gang Ren, MD | Air Force Medical Center of PLA
    Congratulations to Reyngold and colleagues for obtaining the gratifying results of ablative radiation therapy (ART) in the treatment of pancreatic cancer. [1] Although the results of the paper have yet to be confirmed by higher evidence-based medicine, this is indeed a manifestation of the efficacy of ART in the treatment of pancreatic cancer. With the rapid development of radiotherapy equipment and technology in the past ten years, the perception of radiotherapy has been constantly evolving. In the treatment of many solid tumors, the radiotherapy dose mode has been optimized from conventional-dose division to hypofractionated radiotherapy or SBRT mode. While protecting the surrounding tissues, it has the ability to increase the radiation dose of tumors. For example, in lung cancer, ART has been recommended internationally as an alternative therapy for surgical resection.
    Although the pancreas are surrounded by many gastrointestinal tracts, which brings difficulties to the implementation of radiotherapy, the use of advanced radiotherapy equipment and precise radiotherapy procedures, using a reasonable dose mode, pancreatic lesions can also be subject to high Biological Effective Dose (BED). Our team has previously reported that the use of gamma knife or Tomotherapy by high-dose hypofractionated radiotherapy and simultaneous integrated boost mode can achieve a BED of 100Gy for pancreatic lesions,[2] and the 5-year survival rate of patients who are intolerant to surgical resection in the early stage was 18%.[1] Therefore, in the Chinese society of clinical oncology (CSCO) pancreatic cancer diagnosis and treatment guidelines, it is recommended that early stage pancreatic cancer that does not tolerate surgery can receive high-dose hypofractionated radiotherapy. Of course, this needs to be carried out in an experienced radiotherapy center. I look forward to further research results from Reyngold and colleagues in the future to provide stronger evidence for the role of ART in the treatment of pancreatic cancer.

    Authors: Ting-Yi Xia, MD; Ying-Jie Wang, MD; Gang Ren, MD

    References

    1. Reyngold M, O'Reilly EM, Varghese AM, et al. Association of Ablative Radiation Therapy With Survival Among Patients With Inoperable Pancreatic Cancer. JAMA oncology 2021.
    2. Ren G, Xia T, Wang Y. IMRT with capecitabine in advanced pancreatic cancer. In regard to Passoni et al. International journal of radiation oncology, biology, physics 2014; 89(2): 431.
    3. Wang J, Xia T, Wang Y, Guo Y. Long-term results of gamma ray-based stereotactic body radiotherapy in treatment of medically unfit or inoperable non-metastatic pancreatic adenocarcinoma[Abstract 3587]. International journal of radiation oncology, biology, physics 2012; 84(Suppl. 3): S815-816.
    CONFLICT OF INTEREST: None Reported
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