Background
Pancreatic cancer is the fourth most common cause of cancer death in the USA with a dismal 5-year survival of less than 8%. Reference Siegel, Miller and Jemal1 While surgery is considered part of the definitive management, only 10–15% of pancreatic cancers present with resectable disease. Reference McGuigan, Kelly, Turkington, Jones, Coleman and McCain2,Reference Weledji, Enoworock, Mokake and Sinju3 Treatment for unresectable locally advanced pancreatic cancer (LAPC) typically involves chemotherapy with or without radiation therapy. However, nearly half of all patients experience disease progression following conventional chemoradiation. Reference Willett, Czito, Bendell and Ryan4 The optimal combination of these modalities remains unclear, though recent literature suggests a role for induction chemotherapy (iC) and stereotactic body radiation therapy (SBRT).
The use of chemoradiation following iC for LAPC has been controversial due to conflicting reports. Reference Torgeson, Lloyd and Boothe5–Reference Huguet, Andre and Hammel8 The LAP-07 trial randomised patients with non-progressing LAPC to chemoradiation or chemotherapy after a 4-month period of iC and found no overall survival (OS) benefit with the addition of radiation. Despite this, the study did find significant improvement in rates of local progression (43 versus 36%, p = 0·03). Reference Hammel, Huguet and van Laethem6 Contrasting these results are two large retrospective reports from MD Anderson and the Groupe Coopérateur Multidisciplinaire en Oncologie that suggest OS is improved by chemoradiation following iC compared to chemotherapy alone. Reference Krishnan, Rana and Janjan7,Reference Huguet, Andre and Hammel8 A recent National Cancer Database (NCDB) study similarly showed that chemoradiation following iC improved OS. Reference Torgeson, Lloyd and Boothe5
The rising utilisation of SBRT has also shown promise in improving outcomes for LAPC. First reported as feasible in patients with LAPC by Koong et al., Reference Koong, Le and Ho9 SBRT has the advantage over conventionally fractionated radiation therapy (CFRT) of quicker treatment time while still achieving favourable OS and locoregional control. Reference Petrelli, Comito, Ghidini, Torri, Scorsetti and Barni10 A recent meta-analysis suggested the survival benefit and favourable toxicity profile when treated with SBRT compared to CFRT. Reference Tchelebi, Lehrer and Trifiletti11 Several single-institutional experiences have demonstrated iC followed by SBRT to be well tolerated and exhibit favourable efficacy in LAPC. Reference Ch’ang, Lin and Wang12–Reference Moningi, Dholakia and Raman19 Two recent NCDB analyses have compared outcomes between SBRT and CFRT for LAPC and found improved OS was associated with SBRT. Reference Zhong, Patel and Switchenko20,Reference Dohopolski, Glaser, Vargo, Balasubramani and Beriwal21 However, the survival benefit of SBRT in the setting of iC remains unclear.
This study compares the outcomes of patients who have received CFRT versus SBRT for stage III LAPC treated with iC.
Methods
Patient population
The NCDB was used to select for LAPC cases diagnosed between 2004 and 2015. It is a national cancer registry database with data gathered from over 1,500 hospitals. Reference Bilimoria, Stewart, Winchester and Ko22 This study was exempt from institutional review board review.
Patient selection criteria are shown in Figure 1. Our initial query selected for patients with unresected stage III, clinical T4N0-1M0 pancreatic adenocarcinoma who had been treated with curative-intent iC followed by concurrent chemoradiation with SBRT or CFRT. Stage III disease in 2004–15 was based on American Joint Committee on Cancer 7th editions.
Patient selection diagram. iC, induction chemotherapy; CFRT, conventionally fractionated radiation therapy; SBRT, stereotactic body radiation therapy.
To take into account variability of dose fractionation schedules among hospitals for LAPC, CFRT was defined as 1·8–2·5 Gy/fraction up to a total dose of 45–70 Gy, while SBRT was defined as ≥4 Gy/fraction up to a total dose of 20–60 Gy. Reference Moningi, Dholakia and Raman19,Reference Colbert, Rebueno and Moningi23–Reference Hall, Colbert and Nickleach26 The definition of iC was based on chemotherapy delivered within 31–180 days prior to the radiation therapy. Reference Torgeson, Lloyd and Boothe5 Patients who received chemotherapy more than 180 days prior to the radiation therapy and those who received chemotherapy or radiation therapy within 30 days of each other were excluded from our analysis.
Other patients were also excluded if they had surgery, incomplete follow-up data, missing data regarding radiation dose or fractionation, incomplete data on the number of days between diagnosis and treatments, palliative-intent treatments and any other dose fractionation besides the defined CFRT and SBRT regimens. Those who survived less than 3 months after their diagnosis were excluded.
Baseline characteristics about patients, tumours and treatments were extracted. Based on their median values, age and tumour size were stratified by <65 or ≥65 years and <3·8 or ≥3·8 cm. Relevant prognostic factors and outcomes such as performance status, the number of cycles and type of chemotherapy given, toxicities, and local and distant failure are unavailable in the NCDB. CA 19-9 factor was excluded from analysis, since 340 patients (39·0%) had missing information and another 312 patients (35·8%) had an unknown value above 98·0 U/mL. Tumour grade was also excluded, since 690 patients (79·1%) had missing data. The primary endpoint was OS, defined as the time between the diagnosis and the last follow-up or death.
Statistical analysis
OS was assessed using Kaplan–Meier method and log-rank tests. Categorical and continuous variables between the CFRT and SBRT groups were compared using Fisher’s exact and Mann–Whitney U tests, respectively. Logistic regression univariable (UVA) and multivariable analyses (MVA) were used to evaluate potential predictors for the receipt of SBRT and were shown as odds ratio (OR). Cox proportional hazard UVA and MVA were used to examine potential predictors for the OS and were shown as hazards ratio (HR). MVA models were initially constructed with all statistically significant variables from UVA and were finalised based on a backward stepwise elimination. Potential treatment interactions with other variables were examined using Cox MVA with interaction terms. Reference Barraclough and Govindan27
To minimise selection bias, propensity score matching was used. All matching was performed in a 1:1 ratio without any replacement and was based on nearest neighbour method with a caliper distance of 0·2 of the standard deviation of the logit of the propensity score. Reference Austin28 After matching, matched-sample Cox UVA was used to evaluate the effect of SBRT on OS. R software (version 3.4.3; R Foundation for Statistical Computing, Vienna, Austria) was used to perform all statistical analyses. p Values were all two-sided and were considered statistically significant if p values were less than 0.·05.
Results
A total of 872 patients with unresected clinical stage III, T4N0-1M0 pancreatic adenocarcinoma treated with iC followed by concurrent chemoradiation with SBRT or CFRT were identified. Of those, 738 patients received CFRT and 134 patients underwent SBRT. The majority of patients had clinical T4N0M0 adenocarcinoma of the pancreatic head (Table 1). The SBRT group included more patients treated at academic facilities, of older age, above median household income and diagnosed between 2012 and 2015. Other variables were well balanced.
Baseline characteristics before matching
CFRT, conventionally fractionated radiation therapy; SBRT, stereotactic body radiation therapy; CCP, Community Cancer Program; CCCP, Comprehensive Community Cancer Program; INCP, Integrated Network Cancer Program; NA, not available; IQR, interquartile range.
On logistic MVA, patients with lower income (OR 0·65, p = 0·045) were less likely to receive SBRT, while those aged 65 or older (OR 1·52, p = 0·031) and diagnosed between 2012 and 2015 (OR 2·87, p = 0·048) were more likely to be treated with SBRT.
On Cox MVA (Table 2), a larger tumour (HR 1·20, p = 0·023) was associated with worse mortality. In contrast, being diagnosed between 2012 and 2015 (HR 0·61, p = 0·002) and having received multi-agent chemotherapy (HR 0·72, p < 0·001) and SBRT (HR 0·78, p = 0·025) were associated with improved OS. After Cox MVA, there was no treatment interaction with age ≥65 versus <65 (p = 0·47), Charlson–Deyo Score (CDS) ≥2 versus 0–1 (p = 0·46), year of diagnosis (2008–11, p = 0·17; 2012–15, p = 0·44), tumour size ≥3·8 cm versus <3·8 cm (p = 0·39), clinical N1 versus N0 stage (p = 0·99) or pancreatic tumour site (body and tail, p = 0·78).
Cox UVA and MVA
UVA, univariate analysis; MVA, multivariate analysis; HR, hazards ratio; CI, confidence interval; CFRT, conventionally fractionated radiation therapy; SBRT, stereotactic body radiation therapy; CCP, Community Cancer Program; CCCP, Comprehensive Community Cancer Program; INCP, Integrated Network Cancer Program; Ref, reference.
The overall median follow-up for all patients was 24·1 months [interquartile range (IQR) 16·1–38·1]. The CFRT and SBRT groups had a median follow-up of 24·3 months (IQR 16·2–38·0) and 22·9 months (IQR 17·2–35·5), respectively. The median OS was 16·0 months (IQR 11·1–23·2) for the CFRT group and 18·3 months (IQR 12·3–25·5) for the SBRT group (log-rank p = 0·035). OS at 2 years was 27·0% for the CFRT group and 34·8% for the SBRT group (Figure 2).
Overall survival before matching. CFRT, conventionally fractionated radiation therapy; SBRT, stereotactic body radiation therapy.
A total of 240 patients were matched, with 120 patients in each group. All variables were well balanced (Table 3). The median follow-up of the CFRT group was 21·0 months (IQR 11·6–26·5) and that of the SBRT group was 24·2 months (IQR 19·0–36·9). The median OS was 15·9 months (IQR 10·9–22·9) for the CFRT group and 18·1 months (IQR 12·3–26·3) for the SBRT group (log-rank p = 0·004). OS at 2 years was 25·5% for the CFRT group and 37·3% for the SBRT group (Figure 3).
Baseline characteristics, after matching
CFRT, conventionally fractionated radiation therapy; SBRT, stereotactic body radiation therapy.
Overall survival after matching. CFRT, conventionally fractionated radiation therapy; SBRT, stereotactic body radiation therapy.
Discussion
To the best of our knowledge, this is the first study using a multi-institutional national registry to evaluate outcomes of concurrent chemotherapy with SBRT compared to CFRT, following iC for patients with LAPC. Our results show that the use of SBRT improved OS after multivariate analysis compared to CFRT (HR 0·78, p = 0·025). This is consistent with two prior reports by Doholposki et al. (HR 0·79, p = 0·010) and Zhong et al. (HR 0·84, p < 0·001) which examined the NCDB, though neither of these reports specifically examined the effects of chemoradiation following iC (20, 21). Upon 1:1 propensity score matching, our results demonstrate significantly improved OS with the use of SBRT compared to the CFRT (p = 0·004), with median OS (18·1 months versus 15·9 months) and 2-year OS (37·3% versus 25·5%). These results are comparable to other single-institutional studies investigating SBRT after iC for LAPC (median OS range 11·8–20·0 months). Reference Ch’ang, Lin and Wang12–Reference Moningi, Dholakia and Raman19
On MVA, patients with lower income were less likely to receive SBRT, while those with age ≥65 and diagnosed in 2012–15 were more likely to be treated with SBRT. Increased SBRT usage in the elderly can be attributed to its favourable toxicity profile, which makes it a reasonable choice for those patients who have multiple comorbidities, poor performance status or for whom a longer course of treatment may not be feasible. Reference Rosati and Herman29 Shorter treatment time also permits for easier concurrent chemotherapy management with fewer interruptions, which may contribute to the survival advantage seen in this study. The general trend towards expanded usage of SBRT is likely related to increasing provider comfort level with the technique, the lack of clear benefits with use of CFRT and its favourable toxicity profile. Reference Dohopolski, Glaser, Vargo, Balasubramani and Beriwal21
Worse mortality was associated with larger tumour size (HR 1·20, p = 0·023) on Cox MVA, as may be expected, as increased tumour burden likely makes local control more difficult to achieve and poses a greater risk of distant metastasis. In contrast, being diagnosed between 2012 and 2015 (HR 0·61, p = 0·002) and having received multi-agent chemotherapy (HR 0·72, p < 0·001) were associated with improved OS. These factors suggest recent improvements in chemotherapy regimens and greater utilisation of multi-agent combinations contribute to increased survival. The ESPAC-4 trial and a large meta-analysis both demonstrated that gemcitabine combinations improve survival over gemcitabine alone in advanced disease. Reference Neoptolemos, Palmer and Ghaneh30,Reference Sultana, Smith, Cunningham, Starling, Neoptolemos and Ghaneh31
As a national registry-based study, our study is limited by missing patient information and documentation error. Relevant prognostic factors such as performance status, the number of cycles of chemotherapy and type of chemotherapy received are unavailable in the NCDB. Although CDS for comorbidity burden and single- versus multi-agent chemotherapy were well balanced in our cohorts both prior to and after matching, there may be unmeasured confounding factors that affected survival outcomes. Important outcomes, including toxicity, local and distant failure rates are also not reported in the NCDB. Despite these factors, the NCDB provides data on large numbers of patients not otherwise available through single-institutional studies.
Conclusions
We believe this is the first study using the NCDB to evaluate outcomes of concurrent chemotherapy with SBRT compared to CFRT, in the setting of definitive management for LAPC following iC. This analysis shows a significant survival benefit with the use of SBRT, though further prospective studies evaluating the use of SBRT in the definitive treatment of this challenging population are warranted.
Acknowledgements
The National Cancer Database is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. 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 employed, or the conclusions drawn from these data by the investigator.
Financial Support
Dr. Singh is currently supported by the National Cancer Institute (grant number 5P30CA016056-42) Cancer Center Support Grant.
Conflicts of Interest
The authors declare none.
Ethical Standards
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008, and have been approved by Clinical Research Services and Office and Office of Research Subject Protection at Roswell Park Cancer Institute. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guides on the care and have been approved by Clinical Research Services and Office and Office of Research Subject Protection at Roswell Park Cancer Institute under the study number STUDY00000621/BDR 099918.
Availability of Data and Materials
The data that support the findings of this study are available from the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The data are publicly accessible by any investigator affiliated with the Fellow of the American College of Surgeons applying to gain access. More information can be found at: http://ncdbpuf.facs.org
