Failure to Undergo Resection Following Neoadjuvant Therapy for Resectable Pancreatic Cancer: A Secondary Analysis of SWOG S1505

Authors:
Jordan M. Cloyd Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH

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Sarah Colby SWOG Statistical and Data Management Center, Fred Hutchinson Cancer Center, Seattle, WA

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Katherine A. Guthrie SWOG Statistical and Data Management Center, Fred Hutchinson Cancer Center, Seattle, WA

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Andy M. Lowy Department of Surgery, University of California, San Diego, CA

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E. Gabrielle Chiorean University of Washington School of Medicine, Fred Hutchinson Cancer Center, Seattle, WA

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Phillip Philip Henry Ford Health, Detroit, Michigan

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Davendra Sohal Division of Hematology and Oncology, University of Cincinnati, Cincinnati, OH

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Syed Ahmad Department of Surgery, University of Cincinnati, Cincinnati, OH

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Background: Neoadjuvant therapy (NT) is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC), and yet reasons for not undergoing subsequent pancreatectomy are poorly understood. Given the importance of completing multimodality therapy, we investigated factors associated with failure to undergo surgical resection following NT for PDAC. Methods: SWOG S1505 was a multicenter phase II randomized trial of preoperative mFOLFIRINOX or gemcitabine/nab-paclitaxel prior to planned pancreatectomy for patients with potentially resectable PDAC. Associations between clinical, demographic, and hospital-level characteristics and receipt of surgical resection were estimated via multiple logistic regression. Differences in overall survival from 18 weeks postrandomization (scheduled time of surgery) according to resection status were assessed via Cox regression models. Results: Among 102 eligible patients, 73 (71.6%) underwent successful pancreatectomy, whereas 29 (28.4%) did not, primarily because of progression (n=11; 10.8%) or toxicity during NT (n=9; 8.8%). Weight loss during NT (odds ratio [OR], 0.34; 95% CI, 0.11–0.93) and the hospital’s city size (small: OR, 0.24 [95% CI, 0.07–0.80] and large: OR, 0.28 [95% CI, 0.10–0.79] compared with midsize) were significantly associated with a lower probability of surgical resection in adjusted models, whereas age, sex, race, body mass index, performance status, insurance type, geographic region, treatment arm, tumor location, chemotherapy delays/modifications, and hospital characteristics were not. Surgical resection following NT was associated with improved overall survival (median, 23.8 vs 10.8 months; P<.01) even after adjusting for grade 3–5 adverse events during NT, performance status, and body mass index (hazard ratio, 0.55; 95% CI, 0.32–0.95). Conclusions: Failure to undergo resection following NT was relatively common among patients with potentially resectable PDAC and associated with worse survival. Although few predictive factors were identified in this secondary analysis of the SWOG S1505 randomized trial, further research must focus on risk factors for severe toxicities during NT that preclude surgical resection so that patient-centered interventions can be delivered or alternate treatment sequencing can be recommended.

Background

Surgical resection followed by adjuvant therapy has historically been the recommended approach for patients with localized pancreatic ductal adenocarcinoma (PDAC).1,2 Nevertheless, given the challenges in administering adjuvant therapy following major pancreatectomy3 as well as the advantages of improved patient selection and margin-negative resection rates,4 chemotherapy and/or radiation therapy is increasingly being administered prior to surgery.5,6 In addition, increasing evidence suggests that neoadjuvant therapy (NT) may have survival benefits compared with up-front resection.7

Regardless of indication, surgical resection is the primary goal following NT given its influence on long-term survival and importance to patients.8 However, a significant proportion of patients who initiate NT will ultimately not undergo resection.9 Common reasons for not undergoing resection after NT include disease progression, inadequate performance status (PS) for surgery due to underlying comorbidities or toxicity from treatment, persistent unresectability, or patient preference. Yet, little research has been conducted on risk factors for attrition during NT. Such research might elucidate specific patient populations that could benefit from patient-centered interventions during therapy or alternative treatment sequencing.10

In SWOG S1505, patients with resectable PDAC were randomized to 1 of 2 preoperative chemotherapy regimens.11 Despite resectable disease at baseline, only 71.6% of patients were able to undergo successful surgical resection, with no difference observed based on preoperative chemotherapy regimen.12 Given the importance of completing multimodality therapy, the purpose of this secondary analysis of SWOG S1505 was to investigate factors associated with failure to undergo surgical resection following NT for PDAC.

Methods

S1505 was a phase II randomized trial coordinated by SWOG Cancer Research Network, a member of the NCI’s National Clinical Trials Network, comparing 2 neoadjuvant chemotherapy regimens among patients with resectable PDAC. Patients were eligible if they had histologic or cytologic confirmed disease, no evidence of metastatic disease, Zubrod PS of 0 or 1, between ≥18 and ≤75 years of age, and measurable disease that was deemed resectable by local surgeon evaluation and central radiographic review. Resectability was defined as no arterial interface and <180° interface between tumor and portal or superior mesenteric veins.

Eligible participants were then randomized in nonblinded 1:1 fashion with stratification for PS (0 vs 1) to 3 months preoperative and 3 months postoperative therapy using either mFOLFIRINOX (oxaliplatin, 85 mg/m2 followed by irinotecan, 180 mg/m2 and 5-fluorouracil, 2,400 mg/m2, infused over 46 hours and administered every 2 weeks, for a total of 6 neoadjuvant doses and 6 adjuvant doses) or GA (nab-paclitaxel, 125 mg/m2 followed by gemcitabine, 1,000 mg/m2, administered every week, 3 weeks on and 1 week off, for a total of 9 neoadjuvant doses and 9 adjuvant doses). In the absence of disease progression and acceptable PS, surgery was recommended 4 to 8 weeks after the final cycle of NT. Adjuvant therapy resumed 4 to 12 weeks after surgery. Protocol treatment was stopped at the time participants were deemed ineligible for surgical resection. Complete information on eligibility criteria, study design, and treatment arms, including a prescribed dose modification schema, response assessment, and follow-up, have been previously published.11,12

The primary outcome of SWOG S1505 was 2-year overall survival (OS) rate; overall resection rate was a prospectively assessed secondary outcome. In this secondary analysis, factors were evaluated for association with undergoing successful (ie R0/R1) surgical resection. Potential predictors included factors measured at study entry and during NT: demographic (age, sex, race, body mass index), clinical (treatment arm; PS; insurance type; tumor location; preoperative laboratory values; incidence of treatment delays or modifications; incidence of grade 3, 4, or 5 adverse events [AEs]; weight change during NT), and hospital-level (institutional SWOG membership type, city size, pancreatic surgery volume, hospital bed capacity, American College of Surgeons Commission on Cancer accreditation). Hospital-specific data were captured from the results of the 2020 American Hospital Association annual survey. Annual pancreatic cancer resection volume was estimated using 100% Medicare Standard Analytic Files and categorized as low (<5), medium (5–18), or high (>18).13 City size was categorized as small (population <5,000), midsize (5,000 to <500,000), or large (≥500,000). CA 19-9 and RECIST response were not available for analysis.

Univariate analysis was applied to compare characteristics of participants who did and did not undergo surgical resection using Student t tests for continuous variables and Fisher exact for categorical variables. Laboratory values were log transformed to approximate normal distributions. Adjusted associations, expressed as odds ratios (ORs), of potential predictors of undergoing surgical resection were estimated via multiple logistic regression. The final multiple logistic regression model was built with the purposeful selection method. Variables with P<.20 in the univariate analysis were included in the first model. Variables with P>.15 in multiple regression were then removed from the model. Removed variables were then entered back in the model one at a time and assessed for significance (P≤.10) using a likelihood ratio test or confounding of any of the remaining variables (change of beta coefficient ≥20%). Then, all of the insignificant variables were re-entered and assessed for significance. No additional variables were significant or identified as confounders. Although not included in the model, dose density, defined as the proportion of neoadjuvant chemotherapy actually received relative to the amount prescribed, was compared between the cohorts.

OS from 18 weeks postrandomization (scheduled time of surgery) according to resection status was described using the Kaplan-Meier method, with statistical significance estimated via log-rank test. Adjusted models of factors associated with OS, including receipt of surgical resection, were assessed via Cox regression models. Variables that were significant (P<.20) in a univariate cox model were included in the selection process. The final multivariable model was chosen using a backward selection process based on Akaike information criterion. A subset analysis of factors associated with inability to undergo surgical resection due to toxicity from NT was performed using similar methods. Finally, AEs were compared between patients who did not undergo surgical resection due to toxicity versus other reasons.

Results

Among 102 eligible participants, 73 (71.6%) underwent successful pancreatectomy, whereas 29 (28.4%) did not. Reasons for not undergoing resection included distant progression during NT (n=11; 10.8%), toxicity from therapy (n=9; 8.8%), occult metastatic disease (n=3; 2.9%), patient preference (n=2; 2.0%), symptomatic deterioration during treatment (n=1; 0.8%), complications during surgery (n=1; 0.8%), and other (n=2; 2.0%). Table 1 reports the demographic, clinical, and hospital characteristics of participants who did and did not undergo resection. There were no significant differences in age, race, sex, chemotherapy regimen, baseline laboratory values, PS, tumor location, AEs during therapy, insurance type, or hospital characteristics, except that patients residing in midsize cities were more likely to undergo surgery than those in small or large cities (83.3% vs 57.9% and 58.6%, respectively; P<.05). In addition, dose density was significantly higher among patients who underwent surgical resection compared with those who did not (mean [SD], 0.84 [0.19] vs 0.56 [0.31]; P<.001).

Table 1.

Participant Demographic, Clinical, and Hospital-Related Characteristics

Table 1.

On multivariable logistic regression, weight loss during NT (OR, 0.34; 95% CI, 0.11–0.93) and the hospital’s city size (small: OR, 0.24; 95% CI, 0.07–0.80 and large: OR, 0.28; 95% CI, 0.10–0.79 compared with midsize) were associated with lower probability of surgical resection (Table 2). Median OS, after landmark adjustment, was greater among patients who underwent surgical resection compared with those who did not (23.8 vs 10.8 months), as was 2-year OS rate (49.3% vs 24.2%) (Figure 1). On Cox multivariable regression, surgical resection following NT was associated with improved OS (hazard ratio, 0.55; 95% CI, 0.32–0.95), whereas AEs during NT, baseline PS of 1 versus 0, and higher baseline body mass index >25 kg/m2 were associated with worse survival (Table 3).

Table 2.

Univariate and Multivariable Logistic Regression of Factors Associated With Receipt of Surgical Resection Following Neoadjuvant Therapy

Table 2.
Figure 1.
Figure 1.

Kaplan-Meier curve of overall survival from 18 weeks postrandomization among participants with resectable pancreatic cancer who did and did not undergo resection following neoadjuvant therapy.

Citation: Journal of the National Comprehensive Cancer Network 22, 4; 10.6004/jnccn.2023.7099

Table 3.

Factors Associated With Overall Mortality From 18 Weeks Postrandomization

Table 3.

A secondary analysis of factors associated with failure to reach resection due to toxicity from treatment was conducted with overall similar findings (see Table S1 in the supplementary materials, available online with this article). In an adjusted model, weight loss during NT and the hospital’s city size were still associated with lower probability of surgical resection, although not statistically significantly. Specific AEs experienced by patients who were unable to undergo resection due to toxicities versus those who were unable to undergo resection for other reasons are reported in Supplementary Table S2; the proportions of participants who experienced any grade 3–5 AEs did not significantly vary between these groups (66.7% vs 65.0%; P=.99). Given the association between hospital city size and achieving surgical resection, baseline clinical and demographic characteristics as well as postoperative outcomes were compared between patients who were treated at hospitals in midsize versus large or small cities (Supplementary Figure S1 and Table S3).

Discussion

PDAC is an aggressive malignancy with dismal prognosis, yet long-term outcomes are optimized among patients who are able to receive all intended multimodality therapy.14 In fact, one of the strongest rationales for increasing NT use for resectable PDAC is the suboptimal rates of initiating and completing adjuvant therapy following major pancreatic surgery.3,15 Indeed, randomized controlled trials of NT versus up-front surgery demonstrate greater rates of completing all intended multimodality therapy with NT.16,17 Nevertheless, although not necessarily sufficient, surgical resection is generally considered a necessary criterion for long-term survival in patients with localized PDAC. Thus, maximizing the proportion of patients who can complete NT and undergo resection represents an immediate opportunity to improve patient outcomes while better systemic therapies for PDAC are developed. In this secondary analysis of the prospective SWOG S1505 randomized trial, we confirmed that patients who do not undergo surgery after initiating NT experience worse OS, but identified few predictive factors for attrition during NT.

In our study, weight loss during NT was independently associated with reduced odds of undergoing surgical resection. Previous studies have evaluated changes in body composition during NT for PDAC.1820 Although Cooper et al19 did not find that anthropometric changes during NT predicted inability to undergo resection, Sandini et al20 found that patients who underwent resection had experienced an increase in skeletal muscle area during NT compared with a loss of skeletal muscle in patients who were unable to undergo surgery.

A limitation of the current study was the inclusion of only patients with good baseline PS as well as the absence of follow-up functional testing during NT. Furthermore, we used any weight loss during NT because pretest sensitivity analyses found this threshold was most closely associated with receipt of surgical resection compared with other specific weight loss amounts or percentage weight changes. Future studies may focus on identifying specific nutritional, anthropometric, and/or functional biomarkers that correlate with outcomes of NT. Subsequent prospective trials can use these biomarkers to test the efficacy of nutritional and/or rehabilitation interventions that may prevent attrition and improve outcomes.

The finding of medium city size, compared with small or large city size, as a factor associated with attrition during NT was unexpected and difficult to explain. Although the inverse association between hospital volume and outcomes of pancreas surgery is well established,21 the impact of hospital characteristics on outcomes of NT have not been well studied. Although some studies have identified hospital characteristics predictive of NT utilization,22 hospital surgical volume has not been shown to be a reliable predictor of multimodality therapy completion rates.23 Interestingly, no other hospital characteristics were found to be associated with attrition in our study; therefore, the influence of treatment location (eg, hospital volume, geography, rural vs urban) on outcomes of patients receiving NT requires further evaluation.

Few prior studies have focused on attrition during NT for resectable PDAC. A recent meta-analysis of resection rates following NT for localized PDAC pooled reasons for not undergoing surgery but was unable to explore specific risk factors for attrition.9 A recent single-institution study of patients with localized PDAC (ie, not only resectable) who initiated neoadjuvant FOLFIRINOX found that locally advanced disease, decrease in PS, increase in CA 19-9 level, inability to complete chemotherapy, and single marital status were independently associated with not undergoing surgical exploration.24 Our study also found that patients who did not undergo surgical resection received fewer planned cycles of NT (ie, dose density). On the other hand, Kronenfeld et al25 evaluated factors associated with attrition during NT for gastric cancer and found that only insurance type was predictive. Emerging evidence suggests that some genomic biomarkers may be associated with response to NT and likelihood of attaining surgical resection.26

It is important to recognize that even some patients assigned prospectively to up-front surgery will not undergo resection, most often because of occult metastatic disease. Furthermore, the development of distant progression during NT is typically considered a marker of aggressive tumor biology, one that would likely not benefit significantly from surgical resection. Although the risk of local progression during NT and “losing a window to operate” was initially a major concern of surgeons,27 this occurs infrequently in practice. On the other hand, PS decline or major toxicity from NT that precludes subsequent NT does represent a potentially modifiable risk factor and a possible missed “window to operate.”11 Paniccia et al28 found that among patients with localized PDAC treated with NT, inability to undergo surgery due to PS decline was associated with worse OS. Factors predictive of inability to undergo surgery due to PS decline included older age, diabetes, hospital admission during NT, and lack of CA 19-9 response. Although a subset analysis of only patients who experienced attrition due to toxicity was attempted in our study, it was limited by the small number of patients (n=9). Future studies should focus on identifying risk factors for attrition during NT specifically due to toxicity. These patients may benefit from prehabilitation programs that provide physical, emotional, and nutritional support.4,29 Given the complexity of care coordination in the neoadjuvant setting, especially among those receiving fragmented care,30,31 the use of patient navigators may also be helpful, particularly those with increased physical and social barriers to care.32

One limitation of the study is a lack of longitudinal data on CA 19-9 levels, which has been established as an important prognostic marker and predictor of resectability after initiating NT.33,34 Also missing is dynamic information on imaging response and PS change during treatment. In addition, although the resection rates observed in SWOG S1505 are consistent with similar studies, the patient population enrolled in this prospective clinical trial may not be generalizable to the broader PDAC patient population. Therefore, additional studies are needed using real-life data, preferably with prospective intention-to-treat study designs.

Conclusions

Failure to undergo resection following NT is relatively common among patients with potentially resectable PDAC and is associated with worse survival. Although few predictive factors were identified in this secondary analysis of the SWOG S1505 randomized controlled, further research must focus on risk factors for PS decline during NT that precludes surgical resection so that patient-centered interventions can be delivered or alternate treatment sequencing can be recommended.

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Submitted May 3, 2023; final revision received September 30, 2023; accepted for publication October 23, 2023. Published online April 29, 2024.

Author contributions: Conceptualization: Cloyd, Lowy, Chiorean, Philip, Sohal, Ahmad. Formal analysis: Colby, Guthrie. Investigation: Cloyd. Methodology: Cloyd, Colby, Guthrie, Ahmad. Project administration: Ahmad. Resources: Ahmad. Supervision: Cloyd, Ahmad. Validation: Ahmad. Visualization: Cloyd. Writing—original draft: Cloyd. Writing—review & editing: All authors.

Disclosures: Dr. Sohal has disclosed participating in research for Aadi Bioscience, Ability Pharma, Amgen, Apexigen, Astellas Pharma, AstraZeneca, Bexion, Bristol Myers Squibb, FibroGen, Genentech, Jiangsu Hengrui Pharmaceuticals, Merck & Co., Mirati Therapeutics, NextCure, PanCAN, Regeneron, Roche, and Triumvira Immunologics; and serving as a consultant for AstraZeneca, Replimune, Cancer Commons, and Totus Medicines. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers U10CA180888 and U10CA180819.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Supplementary material: Supplementary material associated with this article is available online at https://doi.org/10.6004/jnccn.2023.7099. The supplementary material has been supplied by the author(s) and appears in its originally submitted form. It has not been edited or vetted by JNCCN. All contents and opinions are solely those of the author. Any comments or questions related to the supplementary materials should be directed to the corresponding author.

Correspondence: Jordan M. Cloyd, MD, Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, 410 West 10th Avenue, N-907 Doan Hall, Columbus, OH 43210. Email: jordan.cloyd@osumc.edu

Supplementary Materials

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  • Expand
  • Figure 1.

    Kaplan-Meier curve of overall survival from 18 weeks postrandomization among participants with resectable pancreatic cancer who did and did not undergo resection following neoadjuvant therapy.

  • 1.

    Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007;297:267277.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 2018;379:23952406.

  • 3.

    Altman AM, Wirth K, Marmor S, et al. Completion of adjuvant chemotherapy after upfront surgical resection for pancreatic cancer is uncommon yet associated with improved survival. Ann Surg Oncol 2019;26:41084116.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Patel SH, Katz MH, Ahmad SA. The landmark series: preoperative therapy for pancreatic cancer. Ann Surg Oncol 2021;28:41044129.

  • 5.

    Aquina CT, Ejaz A, Tsung A, et al. National trends in the use of neoadjuvant therapy before cancer surgery in the US from 2004 to 2016. JAMA Netw Open 2021;4:e211031.

  • 6.

    Brown ZJ, Cloyd JM. Trends in the utilization of neoadjuvant therapy for pancreatic ductal adenocarcinoma. J Surg Oncol 2021;123:14321440.

  • 7.

    Cloyd JM, Heh V, Pawlik TM, et al. Neoadjuvant therapy for resectable and borderline resectable pancreatic cancer: a meta-analysis of randomized controlled trials. J Clin Med 2020;9:1129.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Hamad A, Crossnohere N, Ejaz A, et al. Patient preferences for neoadjuvant therapy in pancreatic ductal adenocarcinoma. Pancreas 2022;51:657662.

  • 9.

    Brown ZJ, Heh V, Labiner HE, et al. Surgical resection rates after neoadjuvant therapy for localized pancreatic ductal adenocarcinoma: meta-analysis. Br J Surg 2022;110:3442.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Hamad A, Brown ZJ, Ejaz AM, et al. Neoadjuvant therapy for pancreatic ductal adenocarcinoma: opportunities for personalized cancer care. World J Gastroenterol 2021;27:43834394.

    • PubMed
    • Search Google Scholar
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