Association of time-to-surgery with outcomes in clinical stage I-II pancreatic adenocarcinoma treated with upfront surgery

doi:10.1016/j.surg.2017.10.054

Surgery

Volume 163, Issue 4, April 2018, Pages 753-760

https://doi.org/10.1016/j.surg.2017.10.054 Get rights and content

Abstract

Background

Time-to-surgery from cancer diagnosis has increased in the United States. We aimed to determine the association between time-to-surgery and oncologic outcomes in patients with resectable pancreatic ductal adenocarcinoma undergoing upfront surgery.

Methods

The 2004–2012 National Cancer Database was reviewed for patients undergoing curative-intent surgery without neoadjuvant therapy for clinical stage I–II pancreatic ductal adenocarcinoma. A multivariable Cox model with restricted cubic splines was used to define time-to-surgery as short (1–14 days), medium (15–42), and long (43–120). Overall survival was examined using Cox shared frailty models. Secondary outcomes were examined using mixed-effects logistic regression models.

Results

Of 16,763 patients, time-to-surgery was short in 34.4%, medium in 51.6%, and long in 14.0%. More short time-to-surgery patients were young, privately insured, healthy, and treated at low-volume hospitals. Adjusted hazards of mortality were lower for medium (hazard ratio 0.94, 95% confidence interval, .90, 0.97) and long time-to-surgery (hazard ratio 0.91, 95% confidence interval, 0.86, 0.96) than short. There were no differences in adjusted odds of node positivity, clinical to pathologic upstaging, being unresectable or stage IV at exploration, and positive margins. Medium time-to-surgery patients had higher adjusted odds (odds ratio 1.11, 95% confidence interval, 1.03, 1.20) of receiving an adequate lymphadenectomy than short. Ninety-day mortality was lower in medium (odds ratio 0.75, 95% confidence interval, 0.65, 0.85) and long time-to-surgery (odds ratio 0.72, 95% confidence interval, 0.60, 0.88) than short.

Conclusion

In this observational analysis, short time-to-surgery was associated with slightly shorter OS and higher perioperative mortality. These results may suggest that delays for medical optimization and referral to high volume surgeons are safe.

Section snippets

Methods

The data source for this study is the NCDB, a hospital-based registry jointly managed by the Commission on Cancer (CoC) and the American Cancer Society. The NCDB includes >1,500 CoC-accredited hospitals, and it captures >70% of new cancer diagnoses in the United States.¹⁵ The University of Utah Institutional Review Board considered this study exempt from review.

The study population was adults with clinical stage I to II PDAC that underwent curative-intent surgery without neoadjuvant therapy.

Sensitivity Analyses

Sensitivity analyses were conducted to verify the robustness of the assumptions and findings of the primary analysis. Covariates of patients excluded for diagnosis at surgery (TTS 0 days) were compared to the primary analysis cohort (TTS 1–120 days) because values of 0 days of TTS were handled as a form of missing data. Multivariable models for primary and secondary outcomes were repeated including patients diagnosed at surgery. Multivariable survival analyses were repeated with OS defined as

Results

Of 16,763 patients, 5,774 (34.4%) had short TTS, 8,650 (51.6%) had medium TTS, and 2,339 (14.0%) had long TTS. Covariates stratified by TTS groups are shown in Table 1. More patients in the short TTS group were young, privately insured, without comorbidities or cancer history, had undocumented clinical stage, had pancreatic head tumors, were seen at only one CoC hospital, and traveled a short distance compared to medium TTS. More long TTS patients were elderly, Medicare insured, had

Discussion

Patients and physicians often assume that time is of the essence with regard to surgical wait times in PDAC because it is such an aggressive disease. In this observational analysis of patients with clinical stage I to II PDAC that underwent upfront curative-intent surgery, TTS ≤2 weeks was associated with slightly shorter OS and higher perioperative mortality. Furthermore, patients with medium and long TTS did not have higher odds of secondary outcomes selected to act as surrogates for tumor

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Treatment delays have frequently been observed in cancer patients. Whether the treatment delays would impair the survival of patients with nasopharyngeal carcinoma (NPC) is still unclear.
The data were derived from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. Patients were divided into groups of timely treatment (<1 month), intermediate delay (1 and 2 months), and long delay (3–6 months). The influence of different treatment delay intervals on long-term survival was evaluated by multivariate Cox regression analysis.
In total, 2,048 patients with NPC were included in our study. There were 551 patients in the early stage (I, II stage: 26.9 %) and 1,497 patients in the advanced stage (III, IV stage: 73.1 %). No significant difference in overall survival (OS) or cancer-specific survival (CSS) was observed among the groups with various treatment delay intervals (p = 0.48 in OS and p = 0.43 in CSS, respectively). However, upon adjusting for covariates, a significantly improved OS probability emerged in patients with intermediate treatment delays compared to those who received timely interventions in both the entire study population (_adjustedHazard Ratio (_aHR)=0.86, 95 % CI: 0.74–0.99, p = 0.043) and the subgroup with advanced stage (_aHR=0.85, 95 % CI: 0.72–1.00, p = 0.049). Regarding the CSS probability, similar associations were also observed in the entire study population (_aHR=0.84, 95 % CI: 0.71–0.98, p = 0.030) as well as the advanced-stage patients (_aHR=0.83, 95 % CI: 0.70–0.99, p = 0.038).
Our results revealed that treatment delays are not associated with worse survival of NPC patients. Tumor-specific characteristics and subsequent treatment modalities play more pivotal roles in the prognosis of NPC.
The impact of surgery delay on survival of resectable pancreatic cancer: A systematic review of observational studies
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A similar diversity was, also, observed in the terms of the impact of the waiting time interval on survival outcomes (Table 3). In particular, a prolonged waiting time interval was associated with decreased overall survival in 3 studies [24,25,30], whereas it demonstrated a favorable effect on overall survival in 2 studies [28,29] and no impact on survival in 5 studies [21–23,26,27]. However, surgery time delay seemed to be associated with increased unresectability rates [26], increased histopathological disease progression compared to clinical staging [22], increased tumor size [24] and increased vein resections during surgery [21].
Pancreatic cancer is considered a lethal disease and the only potentially curative option is R0 excision. The aim of this study was to investigate whether the waiting time interval from diagnosis to surgical treatment affects overall survival in patients who undergo curative-intent surgery for pancreatic cancer.
Search in Medline, Scopus, Clinicaltrials.gov, EMBASE, Cochrane Central Register of Controlled Trials CENTRAL and Google Scholar databases was conducted from inception until April 2022.
Overall, 10 studies were included that enrolled 181,344 patients. The dominating cut-off time point was 4 weeks in studies which utilized a biphasic waiting time pattern. In addition, prolonged waiting time interval was associated with decreased overall survival in 3 studies, whereas it demonstrated a favorable effect on overall survival in 2 studies and no impact on survival in 5 studies.
The great diversity that was observed regarding the impact of surgery delay on survival underlines the lack of knowledge about biologic pathways of pancreatic cancer. Novel imaging studies and molecular “fingerprints” in combination to time-to-treatment standardization in the design of future randomized trials could lead to the recognition of patients that could benefit from a timely resection.
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The Covid-19 pandemic is changing the organization of healthcare and has a direct impact on digestive surgery. Healthcare priorities and circuits are being modified. Emergency surgery is still a priority. Functional surgery is to be deferred. Laparoscopic surgery must follow strict rules so as not to expose healthcare professionals (HCPs) to added risk. The question looms large in cancer surgery–go ahead or defer? There is probably an added risk due to the pandemic that must be balanced against the risk incurred by deferring surgery. For each type of cancer–colon, pancreas, oesogastric, hepatocellular carcinoma–morbidity and mortality rates are stated and compared with the oncological risk incurred by deferring surgery and/or the tumour doubling time. Strategies can be proposed based on this comparison. For colonic cancers T1-2, N0, it is advisable to defer surgery. For advanced colonic lesions, it seems judicious to undertake neoadjuvant chemotherapy and then wait. For rectal cancers T3-4 and/or N+, chemoradiotherapy is indicated, short radiotherapy must be discussed (followed by a waiting period) to reduce time of exposure in the hospital and to prevent infections. Most complex surgery with high morbidity and mortality–oesogastric, hepatic or pancreatic–is most often best deferred.
Impact of surgical wait times on oncologic outcomes in resectable pancreas adenocarcinoma
2020, HPB
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Similarly, a retrospective study by Rapitis et al. found no significant difference in survival with increased wait time to either systemic therapy for the unresectable disease or surgery for resectable patients.17 The most recently published study by Swords et al. examined the same patient population as our study using a hospital-based registry as a part of a National Cancer Database.18 The authors found that patients had a better survival as wait time increased, concluding that a selection bias of only patients who made it to surgery was likely contributing to their results.
Timely surgical resection in patients with suspected or diagnosed pancreas adenocarcinoma is an essential part of care. We hypothesized that longer surgical wait time was associated with worse oncologic outcomes.
A retrospective cohort of patients (N = 144) with resectable pancreas adenocarcinoma was divided into four wait time groups (<4, 4–8, 8–12, and >12 weeks), defined from the time of diagnosis on cross-sectional imaging. Overall and recurrence-free survival were analyzed using the Kaplan–Meier method and Cox proportional hazards regression. A higher rate of conversion to palliative bypass in patients waiting over 4 weeks was observed and further analyzed using post-hoc multivariate regression.
On multivariable analysis, longer wait time was associated with improved overall (HR 0.49, 95% CI: 0.28–0.85) and recurrence-free survival (HR 0.29, 95% CI: 0.15–0.56) in >12 weeks compared to <4 weeks group. On post-hoc analysis, longer wait time over 8 weeks was positively associated with palliative bypass (OR 5.33, 95% CI: 1.32–27.88).
Wait time over 8 weeks was associated with a higher rate of palliative bypass. There was an improvement in overall and recurrence-free survival in patients who waited over 12 weeks, likely due to selection bias.
ESMO Management and treatment adapted recommendations in the COVID-19 era: Pancreatic Cancer
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Data are lacking, but a registry analysis on 16 673 patients affected by pancreatic cancer in stage I-II showed that a medium time to surgery of 15–42 days does not correlate with worse survival. A delay up to 3 months could select patients with a less aggressive cancer biology and allow a preoperative medical optimisation of patient comorbidities before elective surgery.19 Nevertheless, the immune-depressive but potentially curative pancreatic cancer resection still retains a high priority to be evaluated in a multidisciplinary team consultation, discussing available resources in the pandemic, life expectations, and complications associated with an eventual SARS-CoV-2 infection.
The COVID-19 pandemic is challenging the capacities of health systems in many countries. National healthcare services have to manage unexpected shortages of healthcare resources that have to be re-allocated according to the principles of fair and ethical prioritisation, in order to maintain the highest levels of care to all patients, ensure the safety of patients and healthcare workers, and save as many lives as possible. Also, cancer care services have to pursue restructuring, following the same evidence-based dispositions. In this article, we propose a guidance to the management of pancreatic cancer during the pandemic, prioritised according to a three-tiered framework, and based on expert clinical judgement and magnitude of benefit expected from specific interventions. Since the availability of resources for diagnostic procedures, surgery and postoperative care, systemic therapy and radiotherapy may differ, the authors have separated the prioritisation analyses. The impact of postponing or abrogating cancer interventions on outcomes according to a high, medium or low priority scale is outlined and discussed. The implementation of healthcare services using telemedicine is explored; it reveals itself as functional and effective for limiting patients’ need to travel to centres and thereby has the potential to reduce diffusion of SARS-CoV-2. Pancreatic cancer demands a considerable amount of medical resources. Therefore, the redefinition of its diagnostic and therapeutic algorithms with a rigorous method is crucial in order to ensure the highest quality of continuum of care in the broader context of the pandemic and the challenged healthcare systems.
Commentary: Take your time but quickly! Impact of time to surgery in early esophageal cancer
2020, Journal of Thoracic and Cardiovascular Surgery

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: Supported by the University of Utah Study Design and Biostatistics Center, with funding in part from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through grant 5UL1TR001067-02 (formerly 8UL1TR000105 and UL1RR025764).

: Presented as an oral presentation at the 12th Annual Academic Surgical Congress in Las Vegas, NV, February 8, 2017.

: National Cancer Database Acknowledgement: The data used in the study are derived from a de-identified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology used, or the conclusions drawn from these data by the investigator.

: Accepted for publication October 30, 2017.

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PancreasAssociation of time-to-surgery with outcomes in clinical stage I-II pancreatic adenocarcinoma treated with upfront surgery

Abstract

Background

Methods

Results

Conclusion

Section snippets

Methods

Sensitivity Analyses

Results

Discussion

Surgeon

HPB (Oxford)

Surgery

J Am Coll Surg

HPB (Oxford)

Crossing the quality chasm: a new health system for the 21st century

Wait times for cancer surgery in the united states: trends and predictors of delays

Ann Surg

Increasing time to treatment initiation for head and neck cancer: an analysis of the National Cancer Database

Cancer

Time to progression of pancreatic ductal adenocarcinoma from low-to-high tumour stages

Gut

NCCN clinical practice guidelines in oncology: pancreatic adenocarcinoma. Version 3

Morbidity and mortality after pancreaticoduodenectomy in patients with borderline resectable type C clinical classification

J Gastrointest Surg

Impact of delay between imaging and treatment in patients with potentially curable pancreatic cancer

Br J Surg

The effect of wait times on oncological outcomes from periampullary adenocarcinomas

J Surg Oncol

Pancreas
Association of time-to-surgery with outcomes in clinical stage I-II pancreatic adenocarcinoma treated with upfront surgery