This phase III trial compares the effect of dose-escalated radiation therapy to usual care in patients with locally advanced unresectable pancreatic ductal adenocarcinoma who have received an initial 4-8 months of chemotherapy. Usual care options include additional chemotherapy, observation, or standard lower-dose radiation therapy. These treatments may delay tumor growth but have not been shown to improve survival. Radiation therapy uses high energy X-rays to kill cancer cells and shrink tumors. Dose-escalated radiation therapy involves the precise delivery of higher doses to the tumor, often over a shorter period of time. This trial assesses whether using dose-escalated radiation therapy can prolong survival.
At time of enrollment, the patient must have received 4-8 months of active chemotherapy with FOLFIRINOX or NALIRIFOX or gemcitabine/nab-paclitaxel. Patients are permitted to receive more than 1 type of chemotherapy for reasons other than radiographic progression by Response Evaluation Criteria in Solid Tumors (RECIST) (i.e. chemotherapy regimen switch is allowed for toxicity, and/or switch is allowed for toxicity and/or CA19-9 level not declining). Patients are allowed to receive chemotherapy after restaging scans, as long as 1) restaging scans are performed after at least 4 months of chemotherapy and 2) the total chemotherapy duration does not exceed 8 months
"Active chemotherapy" refers to time on chemotherapy not counting treatment breaks (i.e. if a patient had 1 month of chemotherapy followed by 1 month break, this would count as 1 month chemotherapy). Study registration must occur within 45 days of last day of pre-study entry chemotherapy
Pathologically (histologically or cytologically) proven diagnosis of pancreatic ductal adenocarcinoma
Locally advanced unresectable disease (as defined per the National Comprehensive Cancer Network [NCCN] guidelines and institutional tumor board review)
None
Parallel
Biopsy Procedure
Procedure/SurgeryUndergo tumor tissue biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Capecitabine
DrugGiven capecitabine
Computed Tomography
Procedure/SurgeryUndergo CT or PET/CT
Dose-escalated Radiation Therapy
RadiationUndergo dose-escalated radiation using intensity-modulated radiation therapy treatment planning
Fluorouracil
DrugGiven fluorouracil
Gemcitabine
DrugGiven gemcitabine
Irinotecan Hydrochloride
DrugGiven irinotecan hydrochloride
Irinotecan Sucrosofate
DrugGiven liposomal irinotecan
Leucovorin Calcium
DrugGiven leucovorin calcium
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Nab-paclitaxel
DrugGiven nab-paclitaxel
Observation Activity
Other interventionUndergo observation
Oxaliplatin
DrugGiven oxaliplatin
Positron Emission Tomography
Procedure/SurgeryUndergo PET/CT
Questionnaire Administration
Other interventionAncillary studies
Radiation Therapy
RadiationUndergo standard radiation therapy
Tumor Treating Fields Therapy
Procedure/SurgeryUndergo TTF
Overall survival (OS)
OS will be estimated by the Kaplan-Meier method (Kaplan 1958). The 3-year OS estimates between the two arms will be compared using a Z-test. A logistic regression model will be used to analyze the effects of factors, in addition to treatment, including, but not limited to the stratification factor, which may be associated with 3-year OS. The primary hypothesis of improved 3-year OS will be tested with a 1-sided significance level of 0.023 (level based on not having stopped at either of the 2 planned interim analyses).
Local progression (LP)
Defined as progression of the primary tumor/nodes as determined by Response Evaluation Criteria in Solid Tumors criteria. LP will be estimated by the cumulative incidence method (Kalbfleish 1980), with death as a competing risk, and compared between treatment arms using Gray's test (Gray 1988). The Fine-Gray regression model will be used to analyze the effects of factors, in addition to treatment, which may be associated with LP (Fine 1999).
Progression-free survival (PFS)
Defined as local progression, distant failure, or death due to any cause. PFS will be estimated by the Kaplan-Meier method (Kaplan 1958) and estimates between treatment arms will be compared using the log-rank test (Mantel 1966). The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, which may be associated with PFS (Cox 1972).
Chemotherapy-free interval (CFI)
Defined as the time in months without chemotherapy for locally advanced pancreatic cancer post the initial chemotherapy treatment. Mean CFI will be compared between treatment arms using a Z-test. Regression modeling will be used to analyze the effects of factors, in addition to treatment, which may be associated with CFI.
Long-term radiation-related ≥ grade 3 adverse events
The percentage of patients on the dose-escalated radiation therapy arm will be reported.
Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) total score at 6 months
Mean FACT-Hep total score at 6 months will be compared between treatment arms using a t-test, if normality is met, or Wilcoxon test if not. Regression modeling will be used to analyze the effects of factors (e.g. stratification factor and other relevant baseline factors), in addition to treatment, that may be associated with 6-month mean FACT-Hep Total Score.
FACT-Hep score nadir
The nadir is defined as the lowest score after baseline assessment. Mean nadir (for each of total score and Hep subscale) will be compared between treatment arms using a t-test, if normality is met, or Wilcoxon test if not, using 2-sided alpha=0.01 to account for multiple comparisons.
FACT-Hep total score over time
Longitudinal analyses incorporating all follow-up time points will be done using longitudinal linear modeling methods to assess FACT-Hep Total Score trends across time. Baseline scores, treatment arm, time, treatment by time interaction (if significant), the stratification factor, and relevant covariates will be included in the model analyses. Other than baseline score, treatment arm, and time, only covariates with a 2-sided p-value \< 0.01, to account for multiple comparisons, will be retained in the model.
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