Key Points
Question
What is the optimal neoadjuvant treatment regimen for patients with borderline resectable pancreatic cancer?
Findings
In this phase 2 clinical trial of 126 patients with borderline resectable pancreatic ductal adenocarcinoma, the 18-month overall survival (OS) rate of patients who received treatment with neoadjuvant mFOLFIRINOX was 66.7% and was favorable compared with historical data, whereas the 18-month OS rate of patients who received treatment with neoadjuvant mFOLFIRINOX and hypofractionated radiotherapy was 47.3%. The 18-month OS rates of patients who underwent pancreatectomy following treatment with mFOLFIRINOX or mFOLFIRINOX and radiotherapy were 87.5% and 78.9%, respectively.
Meaning
The results of this randomized clinical trial suggest that mFOLFIRINOX represents a reference neoadjuvant treatment regimen for borderline resectable pancreatic cancer; however, the role of radiotherapy in this setting remains undefined.
Abstract
Importance
National guidelines endorse treatment with neoadjuvant therapy for borderline resectable pancreatic ductal adenocarcinoma (PDAC), but the optimal strategy remains unclear.
Objective
To compare treatment with neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) with or without hypofractionated radiation therapy with historical data and establish standards for therapy in borderline resectable PDAC.
Design, Setting, and Participants
This prospective, multicenter, randomized phase 2 clinical trial conducted from February 2017 to January 2019 among member institutions of National Clinical Trials Network cooperative groups used standardized quality control measures and included 126 patients, of whom 70 (55.6%) were registered to arm 1 (systemic therapy; 54 randomized, 16 following closure of arm 2 at interim analysis) and 56 (44.4%) to arm 2 (systemic therapy and sequential hypofractionated radiotherapy; all randomized before closure). Data were analyzed by the Alliance Statistics and Data Management Center during September 2021.
Interventions
Arm 1: 8 treatment cycles of mFOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2) over 46 hours, administered every 2 weeks. Arm 2: 7 treatment cycles of mFOLFIRINOX followed by stereotactic body radiotherapy (33-40 Gy in 5 fractions) or hypofractionated image-guided radiotherapy (25 Gy in 5 fractions). Patients without disease progression underwent pancreatectomy, which was followed by 4 cycles of treatment with postoperative FOLFOX6 (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; bolus fluorouracil, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2 over 46 hours).
Main Outcomes and Measures
Each treatment arm’s 18-month overall survival (OS) rate was compared with a historical control rate of 50%. A planned interim analysis mandated closure of either arm for which 11 or fewer of the first 30 accrued patients underwent margin-negative (R0) resection.
Results
Of 126 patients, 62 (49%) were women, and the median (range) age was 64 (37-83) years. Among the first 30 evaluable patients enrolled to each arm, 17 patients in arm 1 (57%) and 10 patients in arm 2 (33%) had undergone R0 resection, leading to closure of arm 2 but continuation to full enrollment in arm 1. The 18-month OS rate of evaluable patients was 66.7% (95% CI, 56.1%-79.4%) in arm 1 and 47.3% (95% CI 35.8%-62.5%) in arm 2. The median OS of evaluable patients in arm 1 and arm 2 was 29.8 (95% CI, 21.1-36.6) months and 17.1 (95% CI, 12.8-24.4) months, respectively.
Conclusions and Relevance
This randomized clinical trial found that treatment with neoadjuvant mFOLFIRINOX alone was associated with favorable OS in patients with borderline resectable PDAC compared with mFOLFIRINOX treatment plus hypofractionated radiotherapy; thus, mFOLFIRINOX represents a reference regimen in this setting.
Trial Registration
ClinicalTrials.gov Identifier: NCT02839343
This randomized clinical trial compares treatment with neoadjuvant modified FOLFIRINOX with or without hypofractionated radiation therapy with historical data and establishes standards for therapy in borderline resectable pancreatic ductal adenocarcinoma.
Introduction
Patients with pancreatic ductal adenocarcinoma (PDAC) who have a localized primary tumor that has a substantial radiographic interface with the major mesenteric blood vessels are at risk for early disease recurrence when pancreatectomy is performed without prior treatment.1 Practice guidelines recommend that neoadjuvant chemotherapy and/or radiotherapy be administered to these patients with borderline resectable PDAC to facilitate margin-negative (R0) resection, eradicate occult disease, prolong overall survival (OS), and avoid unnecessary surgery in those with evolving metastases.2,3
The optimal neoadjuvant treatment regimen has not been defined. In one common strategy, treatment with systemic chemotherapy is administered for 2 to 6 months, followed by conventionally fractionated radiotherapy over 5 to 6 weeks.4 The standard chemotherapy when this approach was developed was gemcitabine, an agent with a response rate of less than 10% in PDAC, and radiotherapy was thought necessary to facilitate R0 pancreatectomy.5,6 However, the effects of preoperative radiotherapy, particularly following treatment with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX), have been incompletely characterized.7,8 Additionally, alternatives to conventionally fractionated radiotherapy, such as stereotactic body radiation therapy (SBRT) and hypofractionated image-guided radiation therapy (HIGRT), now enable precise delivery of high doses of radiation in 5 days.9,10 In this article, we describe the primary results of A021501, a randomized phase 2 National Cancer Institute National Clinical Trials Network trial that was designed to evaluate the efficacy of 2 neoadjuvant regimens in patients with borderline resectable PDAC, 1 using only systemic chemotherapy and 1 incorporating sequential hypofractionated radiotherapy.
Methods
Eligibility
The A021501 trial was led by the Alliance for Clinical Trials in Oncology with participation from the SWOG Cancer Research Network, NRG Oncology, and Eastern Cooperative Oncology Group (ECOG)–American College of Radiology Imaging Network institutions (Supplement 1). Registration was accomplished in 2 steps. Final registration required confirmation of disease stage by a central review of all radiologic images.11 Complete eligibility criteria are presented in eFigure 1 in Supplement 2.
All patients signed a protocol-specific informed consent document. The institutional review board for each participating institution approved the trial.
Treatment Plan
Patients continued to participate in the study until disease progression, an unacceptable adverse event or inability to tolerate treatment with all permitted dose reductions, or completion of the treatment program. Following participation, patients were treated per their multidisciplinary oncology team.
Preoperative Chemotherapy (Arms 1 and 2)
Patients who were registered to arm 1 and arm 2 were treated with modified FOLFIRINOX (mFOLFIRINOX; oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; and leucovorin, 400 mg/m2, all intravenous, then a 46-hour to 48-hour intravenous infusion of fluorouracil, 2400 mg/m2) for 4 cycles, which was administered every 2 weeks. White blood cell support was required within 24 hours of infusion. Following restaging computed tomography (CT) or magnetic resonance imaging (MRI), patients in arms 1 and 2 without clinical or radiographic evidence of disease progression were treated with 4 or 3 additional cycles of mFOLFIRINOX, respectively.
Preoperative Radiotherapy (Arm 2 Only)
Following completion of the seventh treatment cycle of mFOLFIRINOX, patients in arm 2 received radiotherapy. Treatment with SBRT was strongly preferred, when appropriate. Credentialing was required of all centers delivering SBRT. Treatment with HIGRT was allowed in centers that were not credentialed for SBRT and for patients who met prespecified criteria (eFigure 2 in Supplement 2). Fiducial marker placement was required. Each dosimetric plan was centrally reviewed before treatment. The maximum dose within the planning target volume (PTV) was mandated to be within 93% and 115% of the prescribed dose.
Treatment with SBRT comprised 33 to 40 Gy in 5 fractions, and HIGRT comprised 25 Gy in 5 fractions. The gross tumor volume included the primary tumor. The tumor-vessel interface (TVI) included the segment of any major vessel that was in contact with the gross tumor volume, which was circumferentially contoured and expanded by 3 mm. The gross internal target volume (GITV) was determined by contouring the fiducial markers on the 2 extreme phases of the breathing cycle. For SBRT, the PTV was an expansion of 3 mm from the summed GITV and TVI volumes. For HIGRT, the PTV was created by uniform expansion of 5 to 10 mm from the summed GITV and TVI volumes.
Surgical Resection
Following mFOLFIRINOX (arm 1) or radiotherapy (arm 2), patients were restaged with CT or MRI. Patients without advanced disease on central radiologic review and who had a ECOG performance status (PS) of 0 or 1 underwent surgery within 4 to 8 weeks. Specific operative techniques were mandated.12
Postoperative Treatment
Patients with a PS of 0 or 1 and without evidence of residual or recurrent disease on CT/MRI images were considered for 4 cycles of FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, bolus 5-fluorouracil 400 mg/m2, and infusional 5-fluorouracil 2400 mg/m2 over 46 hours) administered every 2 weeks. Treatment was initiated 4 to 12 weeks from the date of surgery.
Assessment
Radiologic response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, guidelines.13 Analysis of the surgical specimen was performed following recommendations of the College of American Pathologists.14,15 Histopathologic complete response (pCR) was defined as the absence of cancer cells in the specimen; in such cases, the pretreatment biopsy was centrally reviewed to confirm adenocarcinoma. Resection status was characterized as R0, R1 (microscopic tumor at any margin), or R2 (macroscopically incomplete resection).
Adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events, version 4.0.16 Adverse events were recorded from enrollment to 30 days following the end of therapy.
Patients were followed up every 4 months after the end of treatment until they reached 24 months postregistration or until documented progression, whichever occurred first. Thereafter, survival information was required every 6 months for 5 years postregistration. All visits included a history and physical examination, laboratory studies, and CT or MRI of the chest and abdomen. Any lesion with characteristics of local relapse or metastatic disease was considered recurrence.
Statistical Analysis
The primary end point was the 18-month OS rate, defined as the number of patients who were alive at 18 months after randomization divided by the total number of evaluable patients in each arm. A maximum of 124 evaluable patients (62 in each arm) was planned, plus an additional 5 patients to account for lost to follow-up. An evaluable patient was defined as any patient who provided written consent, was deemed eligible by central review, and received any protocol-defined treatment. Eligible patients were randomized 1:1 and stratified by ECOG PS (0 vs 1).
Interim Analysis
One interim analysis was performed to assess treatment futility. For each arm, the R0 resection rate was evaluated when surgical data became available for the first 30 evaluable patients. If 11 or fewer patients among 30 evaluable patients underwent an R0 resection, then the given treatment arm was deemed not promising and accrual to the arm was terminated. Accrual was not halted for the interim analysis.
Final Analysis
We conducted a literature review of studies that were published between 2004 and 2015 of preoperative therapy for patients purported to have borderline resectable PDAC to identify a historical control 18-month OS rate (eTable 1 in Supplement 2).4,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37 We considered an 18-month OS rate of 50% (equivalent to the median OS of 18 months) or less, which was the lower bound of the IQR of literature-reported data, as the null hypothesis. To demonstrate clinically meaningful improvement in OS, we targeted an alternative hypothesis of an 18-month OS rate of 63% (equivalent to a median OS of at least 27 months), a 50% increase in median OS duration. The sample size was based on hypothesis testing on the binary 18-month OS rate for the 2 treatment arms separately. The comparison of OS between arms was to be carried out only if both were deemed promising at the end of the trial by a “pick a winner” strategy to choose 1 treatment regimen for recommendation.
For each arm, if full accrual was reached and at least 36 of the first 62 evaluable patients were alive up to 18 months after randomization, the regimen of the arm was considered beneficial. Otherwise, the regimen was deemed inefficacious. This design would provide 82% power to detect an improvement of 13% in 18-month OS rate at a 1-sided significance level of .07.
Estimations of median OS and the 18-month OS rate were also computed based on the Kaplan-Meier method38 for all evaluable patients while accounting for censoring. The Alliance data safety monitoring board reviewed accrual and safety data for this trial twice annually until November 2, 2018. At that point, the study became a single-arm trial; safety was monitored by the study team.
Secondary End Points
Secondary end points included event-free survival (EFS), defined as time from randomization to the first documentation of (1) disease progression per RECIST, (2) surgery with R2 resection, (3) recurrent disease following surgery, or (4) death of any cause; R0 resection rate; pathologic complete response rate; and rate of adverse events. Point estimates and confidence intervals were computed for binary end points. The Fisher exact test was use to compare binary end points.39 The Kaplan-Meier method was used to estimate the distributions of time-to-event end points.38 For analyses based on treated patients, the registration date was the start date of the time-to-event end points; for analyses based on resected patients, the surgery date was the start date. The log-rank test was used to compare time-to-event end points between subgroups. Data collection and statistical analyses were conducted by the Alliance Statistics and Data Center. Data quality was ensured by review of data by the Alliance Statistics and Data Center and the study chairperson following Alliance policies. All analyses were based on the study database as frozen on September 1, 2021. All analyses were conducted using SAS, version 9 (SAS Institute).
Results
The study opened for accrual on December 1, 2016. The interim analysis was completed on August 1, 2018, at which time 54 patients had been registered and randomized to arm 1 and 56 to arm 2. Among the first 30 patients in each arm, 17 patients (57%) in arm 1 and 10 patients (33%) in arm 2 had undergone R0 resection. Arm 2 was thus closed to further enrollment. An additional 16 patients were sequentially registered to arm 1 to complete accrual to that arm before the study was closed on May 31, 2019. In all, 155 patients were preregistered to yield the 126 registered patients. Fifty sites registered at least 1 patient. The CONSORT diagram is presented in Figure 1. A description of each patient’s flow through the study is presented in eTable 2 in Supplement 2. The baseline characteristics of the 120 evaluable patients who initiated treatment and were included in the analyses are summarized in Table 1.
Figure 1. CONSORT Diagram of All Patients Who Were Assessed for Eligibility for the Study.
aThe final 16 patients receiving treatment with modified FOLFIRINOX (mFOLFIRINOX) were not randomized owing to the mFOLFIRINOX plus radiotherapy arm closing.
bThe patients’ nutrition and performance scores deteriorated.
Table 1. Baseline Clinicopathologic Profile of All Evaluable Patients.
| Characteristic | No. (%) | P value | |
|---|---|---|---|
| Arm 1 mFOLFIRINOX (n = 65) | Arm 2 mFOLFIRINOX to RT (n = 55) | ||
| Age, median (range), y | 62 (37-83) | 66 (40-80) | .09a |
| Female gender | 32 (49) | 28 (51) | .85b |
| Race | |||
| American Indian/Alaska Native | 3 (5) | 0 | .39b |
| Asian | 0 | 1 (2) | |
| Black | 3 (5) | 2 (4) | |
| Native Hawaiian/Pacific Islander | 1 (2) | 0 | |
| Unknown | 4 (6) | 2 (4) | |
| White | 54 (83) | 50 (91) | |
| ECOG PS 0c | 33 (51) | 32 (58) | .42b |
| Albumin levels less than LLN | 7 (11) | 11 (20) | .16b |
| CA 19-9, median (range), U/mL | 167 (1-13 221) | 260 (0-14 010) | .31a |
Abbreviations: CA, cancer antigen; ECOG PS, Eastern Cooperative Oncology Group performance status; LLN, lower limit of normal; RT, radiotherapy.
Kruskal-Wallis P value.
χ2 P value.
PS 0 = fully active; PS 1 = restricted in physically strenuous activity but ambulatory and able to carry out light work; PS 2 = ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours.
Preoperative Therapy
The 65 and 55 patients treated in arms 1 and 2, respectively, received a median of 8 (range, 1-8) and 7 (range, 1-7) treatment cycles of mFOLFIRINOX. Forty patients (73%) in arm 2 received SBRT (35 [87.5%]) or HIGRT (5 [12.5%]).
Delays of mFOLFIRINOX treatment were experienced by 32 patients (49%) in arm 1 and 33 patients (60%) in arm 2. Dose omissions were experienced by 9 (14%) in arm 1 and 8 (15%) in arm 2. Dose reductions were experienced by 39 (60%) in arm 1 and 41 (75%) in arm 2. During treatment with radiotherapy in arm 2, 1 patient (3%) had radiotherapy interrupted.
At least 1 grade 3 or higher AE that was deemed at least possibly related to treatment was experienced by 37 patients (57%) in arm 1 and 35 patients (64%) in arm 2 (Table 2). Most of these occurred during mFOLFIRINOX treatment; only 3 patients (7%) in arm 1 experienced a grade 3 AE that was at least possibly related to treatment during radiotherapy, and no patient experienced a grade 4 or higher AE that was at least possibly related to treatment during radiotherapy. Two patients in arm 1 experienced a grade 5 AE (1 at least possibly related to treatment and 1 unrelated to preoperative therapy).
Table 2. Grade 3 or Higher Adverse Events at Least Possibly Related to Neoadjuvant Therapy.
| AE during treatment | No. (%) | |
|---|---|---|
| Arm 1 mFOLFIRINOX (n = 65) | Arm 2 mFOLFIRINOX to RT (n = 55) | |
| Experienced ≥1 grade ≥3 AE | 37 (57) | 35 (64) |
| During treatment with mFOLFIRINOX | 37 (57) | 35 (64) |
| During RT | NA | 3 (7) |
| Experienced ≥1 grade ≥ 4 AE | 11 (17)a | 5 (9) |
| During treatment with mFOLFIRINOX | 11 (17) | 5 (9) |
| During RT | NA | 0 |
Abbreviations: AE, adverse events; NA, not applicable; RT, radiotherapy.
Two patients in arm 1 experienced a grade 5 AE. One experienced grade 5 sepsis that was probably related to treatment during cycle 1. The other patient experienced a grade 5 death not otherwise specified that was unrelated to treatment during cycle 1. This patient died of disease 2 weeks later owing to disease progression.
The most common grade 3 or higher AEs that were at least possibly related to treatment during mFOLFIRINOX treatment were diarrhea (22 [18%]), hypokalemia (17 [14%]), and neutropenia (14 [12%]). The most common grade 3 or higher AE during radiotherapy was anemia (2 [5%]) (eTable 3 in Supplement 2).
Pancreatectomy
Thirty-eight patients (58%) in arm 1 and 28 patients (51%) in arm 2 underwent surgery on protocol. The median (range) duration between the last treatment with FOLFIRINOX (arm 1) or radiotherapy (arm 2) and surgery was 42 (28-67) days and 44 (26-62) days, respectively.
Pancreatectomy was performed for 32 patients (49%) in arm 1 and 19 patients (35%) in arm 2. Outcomes are reported in Table 3. Among patients who underwent pancreatectomy, R0 resection was achieved in 28 (88%) in arm 1 and 14 (74%) in arm 2. A pCR was identified in 2 patients, both of whom were treated in arm 2. Per protocol, a central rereview of their initial cytopathology samples was required. Adenocarcinoma was confirmed in 1 patient. Unfortunately, the other patient did not have slides available for rereview; the institutional report documented cells that were suspicious for adenocarcinoma.
Table 3. Surgical and Histopathologic Outcomes of Patients Who Underwent Pancreatectomy.
| Characteristic | No. (%) | |
|---|---|---|
| Arm 1 mFOLFIRINOX (n = 32) | Arm 2 mFOLFIRINOX to RT (n = 19) | |
| Pancreatoduodenectomy | 30 (94) | 18 (95) |
| SMV/PV resection | 12 (38) | 6 (32) |
| Hepatic artery resection | 1 (3) | 2 (11) |
| R0 | 28 (88) | 14 (74) |
| N0 | 15 (47) | 9 (47) |
| pCR | 0 | 2 (11)a |
Abbreviations: N0, negative lymph nodes; pCR, pathologic complete response; RT, radiotherapy; R0, resection to macroscopically and microscopically negative surgical margins; SMV/PV, superior mesenteric vein/portal vein.
Central rereview of initial cytopathology samples was required. Adenocarcinoma was confirmed in 1 patient. The other patient did not have slides available for rereview; the institutional report documented cells that were suspicious for adenocarcinoma (Papanicolaou Society of Cytopathology grade 5).
Among patients who underwent pancreatectomy, 1 or more grade 3 or higher AEs that were at least possibly related to treatment was experienced in 9 (28%) in arm 1 and 9 (47%) in arm 2. The most common grade 3 or higher AEs were weight loss (7 [14%]), anemia (4 [8%]), wound infection (3 [6%]), and hypoalbuminemia (3 [6%]).
Postoperative Therapy
Twenty-two patients (34%; 69% of patients who underwent pancreatectomy) in arm 1 and 13 patients (24%; 69% of patients who underwent pancreatectomy) in arm 2 initiated postoperative treatment with FOLFOX. Six (27%) and 1 (5%) patients in arms 1 and 2, respectively, experienced at least 1 grade 3 AE that was at least possibly related to treatment during postoperative therapy. The most commonly occurring of these were neutropenia (4 [11%]), weight loss (3 [9%]), and leukopenia (2 [6%]). In all, 20 patients (31%) in arm 1 and 10 patients (18%) in arm 2 completed all therapy per protocol.
Disease Progression and Recurrence and Survival
The median follow-up of all patients was 42.9 months (95% CI, 39.7-43.4). Arm 1 reached the targeted accrual per protocol. Among the first 62 patients who were evaluable and followed up more than 18 months, 41 patients (66.1%) were alive at 18 months, which was greater than the 36 “successes” needed per the statistical design. The final efficacy decision rule was applied, and the regimen was deemed efficacious. The median OS of patients in arm 1 was 29.8 (95% CI, 21.1-36.6) months, and the Kaplan-Meier–estimated 18-month OS rate was 66.7% (95% CI, 56.1%-79.4%). The median EFS was 15.0 (95% CI, 11.2-21.9) months (Figure 2). Forty-one of the first 62 evaluable patients (66.1%) were alive at 18 months.
Figure 2. Overall and Event-Free Survival of the 120 Evaluable Patients.
OS indicates overall survival; RT, radiotherapy.
As arm 2 closed at the interim futility analysis, statistical requirements to conclude efficacy were not met. The median OS of patients in arm 2 was 17.1 (95% CI, 12.8%-24.4) months, and the Kaplan-Meier–estimated 18-month OS rate was 47.3% (95% CI, 35.8%-62.5%). The median EFS was 10.2 (95% CI, 6.7-17.3) months. The 18-month OS rate of patients who underwent pancreatectomy in arms 1 and 2, respectively, was 87.5% (95% CI, 70.0%-95.1) and 78.9% (95% CI, 53.2%-91.5).
Discussion
In this randomized phase 2 clinical trial conducted within the National Cancer Institute’s National Cancer Treatment Network with inbuilt multimodality measures of quality control, 8 cycles of treatment with mFOLFIRINOX was established as a reference neoadjuvant regimen for patients with borderline resectable PDAC. This regimen was well tolerated and associated with rates of R0 resection and an 18-month OS of 43% and 66.7%, respectively. Although treatment with mFOLFIRINOX followed by hypofractionated radiotherapy was well tolerated, we could not conclude that it was effective.
Accumulating evidence supports the administration of neoadjuvant therapy to patients with borderline resectable PDAC. For example, the phase 2 ESPAC 5F study randomized 90 patients with borderline resectable PDAC to undergo pancreatectomy or receive treatment with gemcitabine and capecitabine, FOLFIRINOX, or capecitabine-based chemoradiation before surgery.40 At 1 year, 77% of patients who received preoperative therapy were still alive, compared with 42% of patients who underwent surgery de novo.40 The PREOPANC-1 study randomized patients with either resectable or borderline resectable PDAC to undergo pancreatectomy or receive gemcitabine-based chemoradiation before surgery.41 In the primary analysis, no difference in OS was observed between the 2 treatment arms (14.3 vs 16 months, respectively).41 However, long-term follow-up showed an OS advantage that was associated with preoperative therapy.42
Within the context of these and other trials of neoadjuvant therapy for PDAC, the median OS of approximately 30 months for patients with borderline resectable tumors who were treated with 4 months of preoperative mFOLFIRINOX in the current study is notable. In a similar National Clinical Trials Network trial of patients with resectable PDAC, SWOG Trial S1505, patients who were treated with 3 months of preoperative and postoperative mFOLFIRINOX had a median OS of 23.2 months.43 Although it may be tempting to attribute the difference between these 2 trials to the longer course of preoperative systemic chemotherapy in the present study, additional trials will be required to determine the optimal treatment duration for patients with borderline resectable PDAC.
Strengths and Limitations
Despite nearly meeting full accrual, arm 2 was terminated at interim analysis as required by protocol. Because arm 2 did not meet full accrual, a statistical assessment of the regimen’s efficacy could not be made per protocol. The reasons why an insufficient number of patients in arm 2 met the prespecified threshold for R0 resection are not immediately evident. Although these data suggest that sequential hypofractionated radiotherapy may not benefit all patients with PDAC who are chosen solely on the basis of shared anatomic criteria, they do not eliminate the possibility that preoperative radiotherapy may benefit a subpopulation of patients or that other delivery approaches may be more effective.7,8 Future efforts should focus on identifying criteria to select patients who will benefit from local therapies, including radiotherapy and surgery.
A primary strength of this study was the use of a robust quality control infrastructure that was established in the Alliance clinical trial A021101.4,11 Strict definitions were used to ensure anatomic homogeneity of the treatment group. A 2-stage registration process with central radiographic review was used to ensure accuracy of disease staging. Radiation plans were prospectively centrally reviewed. The indications for surgery and the technical approach to the dissection were mandated. Resected specimens exhibiting pCR mandated review of initial pretreatment cytology. Thus, the data generated from this study are potentially useful for further investigations of novel therapies for patients with PDAC. Additionally, the infrastructure used in this study should represent the standard for these studies.
Conclusions
In this phase 2 randomized clinical trial, 8 treatment cycles of mFOLFIRINOX represented a reference neoadjuvant regimen for patients with borderline resectable PDAC. The role of radiotherapy in this setting remains undefined.
Trial protocol
eTable 1. Literature review of studies, published between 2004 and 2015, of preoperative therapy for patients purported to have “borderline resectable” PDAC
eTable 2. Detailed flow of all patients through the protocol
eTable 3. Detailed commonly occurring grade 3+ AEs at least possibly related to treatment during neoadjuvant therapy
eFigure 1. Complete preregistration and registration criteria. Source: U.S. National Library of Medicine
eFigure 2. Criteria for stereotactic body radiation therapy (SBRT) and hypofractionated image-guided radiation therapy (HIGRT)
Data sharing statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol
eTable 1. Literature review of studies, published between 2004 and 2015, of preoperative therapy for patients purported to have “borderline resectable” PDAC
eTable 2. Detailed flow of all patients through the protocol
eTable 3. Detailed commonly occurring grade 3+ AEs at least possibly related to treatment during neoadjuvant therapy
eFigure 1. Complete preregistration and registration criteria. Source: U.S. National Library of Medicine
eFigure 2. Criteria for stereotactic body radiation therapy (SBRT) and hypofractionated image-guided radiation therapy (HIGRT)
Data sharing statement