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  Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 3  |  Page : 530-534
 

Nontrial, real-world outcomes in unresectable locally advanced pancreatic cancer: Chemotherapy and chemoradiation is the standard while surgery is uncommon


1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication24-May-2018

Correspondence Address:
Dr. Vikas Ostwal
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_377_17

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 » Abstract 


BACKGROUND: Outcomes and survival of truly unresectable locally advanced pancreatic cancers (LAPC) is often reported along with borderline resectable pancreatic cancers especially from a real world cohort. METHODS: The audit of LAPC patients, diagnosed based on the NCCN criteria between February 2013 and January 2016 was used to identify patients starting and continuing treatment in our institution. Practice patterns, outcomes and prognostic factors for overall survival were evaluated. RESULTS: Of the 83 patients, 52 were available for inclusion in the analysis. Median age was 56 years (range 30- 77), with males constituting 75% of patients. Baseline comorbidities seen were diabetes mellitus, hypertension and cardiac dysfunction in 46.1%, 69.1% and 52% of patients respectively. 84.6% of patients had arterial vascular involvement as criteria for unresectable LAPC. 50% of patients received chemotherapy only, while the remainder received chemotherapy and concurrent chemoradiation. One patient was able to undergo curative R0 resection. FOLFIRINOX was the most commonly used chemotherapy regimen (53.8%). With a median follow up of 15.9 months, median progression free survival (mPFS) was 7.26 months (95% CI: 5.75-8.76) and median OS was 11.8 months (95% CI: 9.96 – 13.61). None of the potential prognostic factors evaluated, i.e., age, gender, nodal status, pre-treatment CA 19.9 levels, showed correlation with OS. CONCLUSION: This analysis shows outcomes in unresectable LAPC comparable to existing literature. Surgery in unresectable LAPC patients is less common than seen in previously published studies, more likely due to this cohort being truly 'unresectable' in terms of major arterial involvement.


Keywords: Chemotherapy–radiation therapy, chemotherapy, locally advanced pancreatic cancers


How to cite this article:
Ramaswamy A, Jandyal S, Ostwal V, Engineer R, Lewis S, Bose S, Pande N, Shrikhande SV. Nontrial, real-world outcomes in unresectable locally advanced pancreatic cancer: Chemotherapy and chemoradiation is the standard while surgery is uncommon. Indian J Cancer 2017;54:530-4

How to cite this URL:
Ramaswamy A, Jandyal S, Ostwal V, Engineer R, Lewis S, Bose S, Pande N, Shrikhande SV. Nontrial, real-world outcomes in unresectable locally advanced pancreatic cancer: Chemotherapy and chemoradiation is the standard while surgery is uncommon. Indian J Cancer [serial online] 2017 [cited 2019 Oct 18];54:530-4. Available from: http://www.indianjcancer.com/text.asp?2017/54/3/530/233154





 » Introduction Top


A majority of pancreatic cancers present at an unresectable stage (70%–80%), whether locally advanced pancreatic cancer (LAPC) or metastatic.[1],[2] Patients with unresectable LAPC are treated by a multitude of management strategies, which is because of the varying criteria used in classifying LAPC and contrasting data regarding optimal treatment. Although surgery is the only curative option in pancreatic cancers, chemotherapy and radiation therapy (CT-RT) have enabled improvement in survival for the LAPC subgroup.[3],[4],[5],[6] The use of potentially superior chemotherapeutic regimens such as FOLFIRINOX has improved overall survival (OS) in LAPC to approximately 24 months in a recent meta-analysis.[7] Recent data have also suggested resection rates of up to 60% in LAPC, although the actual nature of LAPC in such studies is heterogeneous.[8]

However, the role of CT-RT is yet to be conclusively defined. Although the recently published results of the LAP-07 trial argue against CT-RT vis-a-vis continuing palliative intent chemotherapy, previous studies, including ECOG 4201, showed a marginal, albeit statistically significant benefit, in median OS (mOS) in patients receiving CT-RT.[6],[9] However, a majority of larger studies in LAPC have used gemcitabine-based regimens as neoadjuvant, and whether this is a valid standard arm when superior regimens such as FOLFIRINOX or gemcitabine–abraxane exist is debatable.

There is a paucity of data regarding the clinical outcomes of patients with truly unresectable LAPC, as opposed to outcomes reported for combined borderline resectable and unresectable cohorts. With this in mind, we evaluated the practice patterns and outcomes in patients with unresectable LAPC treated at our center.


 » Methods Top


A retrospective analysis from a prospectively maintained database of LAPC patients who were started on treatment in Tata Memorial Hospital (TMH) between February 2013 and January 2016 was conducted. Data collection was as per the ethical guidelines of the Declaration of Helsinki.

The criteria for inclusion in the audit were as follows:

  1. Diagnosed as initially unresectable LAPC, as per NCCN criteria [10]
  2. Histological diagnosis of adenocarcinoma, inclusive of adenocarcinoma with squamous component
  3. Planned for chemotherapy and RT in TMH
  4. Treatment started in TMH.


The diagnosis of LAPC was made by a gastrointestinal (GI) multidisciplinary joint clinic (MDJC), comprising a dedicated pancreatic surgical oncologist, medical oncologist, radiation oncologist, pathologist, gastroenterologist, and radiologist based on the NCCN criteria. All patients were considered initially unresectable LAPC based on agreement between a dedicated pancreatic surgeon and GI radiologist.

Baseline patient and tumor characteristics including age, gender, Eastern Cooperative Oncology Group Performance Status (ECOG PS), tumor location, T-stage, nodal status, vessel involvement histologic grade, and nonobstructive pretreatment CA19-9 levels were retrieved through electronic medical records.

Treatment

All patients received chemotherapy based on the assessment by treating medical oncologist. Regimens were heterogeneous in nature, based on the evaluation of potential tolerance, ECOG PS, and comorbidities. Patients who received radiation (at some point during their treatment) underwent computed tomography (CT) simulation for treatment planning and received intensity-modulated RT (IMRT) or three-dimensional-conformal external beam radiation therapy (3D-CRT) concurrently with capecitabine or gemcitabine. Toxicity from treatment was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Patients were planned for reassessment (RECIST 1.01) of disease status after —two to three cycles of chemotherapy, with further management strategy being re-discussed in MDJC. Patients who had poor tolerance to chemotherapy and/or clinical progression of disease before planned response assessment and continued further supportive care did not have response assessment scans. Patients were planned for chemoradiation in the following scenarios:

  1. Pain predominant symptoms which would benefit from radiotherapy
  2. Postchemotherapy, disease nonprogression.


Endpoints

The primary endpoint of this analysis was mOS, whereas the secondary endpoint was median progression-free survival (mPFS) of the entire cohort. PFS was calculated from the date of starting of treatment to date of progression or death (in case disease had not progressed). OS was calculated from the date of starting of treatment to date of death.

Statistical analysis

The values for categorical data were specified as frequencies. The Kaplan–Meier method was used to obtain PFS and OS estimates. Prognostic factors evaluated were age, gender, nodal stage (negative vs. positive), and pretreatment CA 19.9 levels (raised vs. not raised). OS and PFS of entire cohort as well as OS and PFS of patients who received radiotherapy and those who did not receive radiotherapy were computed separately by Kaplan–Meier method. Statistical analysis was performed using SPSS version 20 (IBM).


 » Results Top


Baseline and treatment characteristics

A total of 83 patients were diagnosed with LAPC in the specified period, of which 52 patients satisfied the prespecified criteria for inclusion into the audit. In all, 39 patients were male (75%) and 13 patients were female (25%), with a median age of 56 years (range: 30–77 years). About 48 patients (92.31%) had an ECOG PS of 0/1. Baseline comorbidities noted were hypertension in 36 patients (69.1%), diabetes mellitus in 24 patients (46.1%), and cardiac comorbidities in 27 patients (52%). Vascular involvement was arterial in 44 patients (84.6%). Other baseline characteristics, including vascular involvement, are listed in [Table 1].
Table 1: Baseline characteristics and treatment details

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Of the 52 patients, 26 patients (50%) received only chemotherapy, whereas the remaining 26 patients (50%) received chemotherapy and concurrent CT-RT.

Details of chemotherapy

The most common chemotherapy regimen used was FOLFIRINOX, in 28 patients (53.8%), followed by gemcitabine-based chemotherapy (i.e., gemcitabine–erlotinib, gemcitabine–abraxane, etc.) in the remaining 24 patients (46.2%).

The median number of cycles of chemotherapy received was four. About 20 patients (38.5%) required dose modification during chemotherapy. The incidence of Grade 3 and Grade 4 toxicities during chemotherapy is listed in [Table 2].
Table 2: Details of treatment and adverse events (Grade 3 and Grade 4) during chemotherapy

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In patients receiving concurrent CT-RT (n = 26), capecitabine was used concurrently in 20 patients (76.9%) and gemcitabine in the remaining 6 patients (23.1%). The median number of cycles of concurrent chemotherapy delivered was four.

Response rates and outcomes

Of the 26 patients who received only chemotherapy, 4 patients achieved a partial response (PR; 7.1%), 7 patients had stable disease (SD; 26.9%), and 8 patients had progressive disease (PD; 30.8%) as best response to chemotherapy. Seven patients did not have a response assessment scan because of chemotherapy-related side effects and cessation of chemotherapy.

In patients who received concurrent chemoradiation, 3 patients achieved a PR (11.5%), 13 had SD (50%), 9 patients had PD (34.6%), and 1 patient's response assessment scan was not available.

With a median follow-up of 15.9 months for the entire cohort, the mOS is 11.80 months (95% confidence interval [CI]: 9.96–13.61 months) and mPFS was 7.26 months (95% CI: 5.75–8.76 months) [Figure 1] and [Figure 2]. At the time of analysis, all the patients had progressed locally and/or distally, with 34 patients dead and 18 patients alive.
Figure 1: Locally advanced pancreatic cancer overall survival

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Figure 2: Locally advanced pancreatic cancer event-free survival

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Patients who received concurrent CT-RT as part of their treatment at any point of the treatment process had an mPFS of 7.92 months (95% CI: 6.48–9.35 months) and mOS of 17.91 months (95% CI: 9.77–26.0 months). Patients receiving chemotherapy alone had an mPFS of 5.62 months (95% CI: 3.40–7.83 months) and a mOS of 8.71 months (95% CI: 7.36–10.2 months).

In patients receiving at least three cycles of chemotherapy and then CT-RT or continuation of chemotherapy, there was no statistical difference in PFS between patients receiving chemotherapy alone (6.77 months, 95% CI: 4.18–9.36 months) and CT-RT with chemotherapy (8.25 months, 95% CI: 6.12–10.37 months; P = 0.099). Variables evaluated as prognostic factors did not show significance with respect to mOS [Table 3].
Table 3: Prognostic factors evaluated for median overall survival

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 » Discussion Top


The outcomes of unresectable LAPC have improved marginally following the introduction of multimodality management of this subset, specifically with the introduction of more effective chemotherapeutic regimens such as FOLFIRINOX and the emerging role of stereotactic body RT (SBRT). Although the role of CT-RT continues to elicit debate in the wake of LAP-07 study, a more important question is whether current radiological response assessment criteria are an actual representation of resectability/unresectability. Ferrone et al.'s report on 40 patients (locally advanced and borderline resectable) suggests that radiological criteria for resectability post-FOLFIRINOX have poor correlation with actual intraoperative findings and potential for R0 resection rates.[11] The presence of a preexisting dense desmoplastic reaction characteristic of pancreatic adenocarcinoma, with the added fibrosis because of neoadjuvant therapy, prevents an accurate quantification of response radiologically, resulting in a potentially lesser number of patients being surgically evaluated. The consensus statement by the International Study Group of Pancreatic Surgery, albeit for borderline resectable cancers, also questions the limited specificity of CT scans in differentiating fibrosis, adhesions, and actual cancer involvement of arteries and suggests a surgical exploration for confirmation of arterial involvement. Another major limitation of published studies is the reporting of outcomes with BRPC and LAPC together after neoadjuvant therapy.[12] A 15-year study examining patients undergoing resection for LAPC after neoadjuvant chemotherapy quoted resection rates of up to 50.8%, with patients receiving FOLFIRINOX having an even higher resection rate. Closer inspection of this study reveals that this was not a purely unresectable LAPC cohort – the cohort receiving FOLFIRINOX included more metastatic patients, but those undergoing surgery had a markedly lower incidence of arterial involvement when compared with the non-FOLFIRINOX cohort.[8] The studies by Ferrone et al. and a more recent one by Khushman et al. also reported results for a combined BRPC and LAPC cohort.[11],[13]

With such heterogeneity seen across treatment strategies, it is expected that nontrial clinical practice data will reflect the same. The cohort seen in this audit is heterogeneous in terms of treatment strategy, chemotherapy administered, and regimens used concurrently with external beam RT (EBRT). A majority of patients (42/52; 80.8%) received initial chemotherapy, with FOLFIRINOX being the most common regimen used. This is reflective of the increasing use of FOLFIRINOX worldwide when compared with gemcitabine-based regimens as an attempt to translate the superior outcomes seen in the metastatic setting to neoadjuvant intent therapy.[14] EBRT being delivered to 50% of patients and not in all patients who achieved SD after NACT is also indicative of its as yet undefined role in LAPC and decision being based on a case-to-case scenario.

Within the confines of a retrospective single-center analysis, the mPFS (7.2 months) and mOS (11.7 months) seen in this study are in concurrence with published data, albeit at the lower end of the spectrum when taking into account more recent studies. A single patient was able to undergo curative resection in this cohort. The outcomes of this analysis regarding outcomes have important caveats when comparing to published literature. The current audit comprises patients who majorly had arterial involvement (44/52; 84.6%) and were truly “unresectable LAPC.” Although extended pancreatic surgeries involving major arterial resections are being considered in some centers, the actual benefit in terms of morbidity and OS is debatable. This audit suggests that resection of patients with truly unresectable LAPC in the real world is not as feasible as worldwide studies suggest and is more an outlier than the norm. Other potential reasons for the lower survival seen in this study are the presence of comorbidities precluding administration of more efficacious, but toxic regimens, and treatment of patients with ECOG PS 2. Patients with significant comorbidities are often excluded from trial populations, and extrapolating trial results directly to such a population may not be an ideal way to manage such patients. Besides the above-mentioned reasons, using current guidelines to assess resectability may also have led to low rates of surgery seen in this series and thereby lower survival.

Patients receiving CT-RT appeared to do better than those not receiving the same (17.9 and 8.6 months, respectively), but a comparison in this cohort may not be appropriate because of multiple factors, including lack of standardized neoadjuvant chemotherapy, potential selection of patients who have not progressed on neoadjuvant chemotherapy, and lack of planned response assessment. When a cohort who are able to complete a reasonable duration of chemotherapy (2–3 months) are compared, there is no difference in PFS between chemotherapy continuation and CT-RT groups. As per LAP-07 results and ASCO 2016 treatment guidelines, chemotherapy remains the standard of care in LAPC, whereas CT-RT should be used only if there is a local progression after chemotherapy or if a patient has an intolerance to chemotherapy.[9],[15] Exciting new data with regard to SBRT have emerged in LAPC, and the introduction of this modality into current treatment management strategies requires further evaluation.[16] However, technical considerations and potentially increased toxicity hamper its widespread usage.

None of the prognostic factors evaluated in this study appeared significant in terms of survival. Peixoto et al., in a study of 244 patients with LAPC, identified easily usable clinical variables such as ECOG PS 2/3, CA 19.9 >1000, female gender, and development of metastases as poor prognostic factors for survival.[17] The authors were unable to validate either ECOG PS or female gender as prognostic factors in this study. The use of FOLFIRINOX did not create an impact in terms of OS, again with the caveat regarding the applicability of this regimen to all comers in a real-world LAPC cohort. Smaller sample size can be one of the reasons for the same.

Although this study has limitations as mentioned previously, it also helps identify lacunae that may help improve outcomes in the authors' institution. Establishment of a standard protocol for the treatment of LAPC, aggressive neoadjuvant chemotherapy (in patients declared fit for the same), selective use of EBRT, a greater evaluation of the role of SBRT, and a lower threshold for surgical evaluation are suggestions that may help improve outcomes in nontrial routine clinical practice.

In conclusion, this audit shows outcomes in unresectable LAPC comparable to the existing literature. It also suggests the need for a standard institutional protocol for treating LAPC, as well as newer criteria for assessment of resectability post neoadjuvant treatment. Surgery in unresectable LAPC patients is rarer than seen in previously published studies, more likely because of this cohort being truly “unresectable” in terms of major arterial involvement.

Acknowledgment

The authors thank Dr. S. D. Banavali for supporting us throughout data collection to writing the article.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Hackert T, Sachsenmaier M, Hinz U, Schneider L, Michalski CW, Springfeld C, et al. Locally advanced pancreatic cancer: Neoadjuvant therapy with folfirinox results in resectability in 60% of the patients. Ann Surg 2016;264:457-63.  Back to cited text no. 8
    
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Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, et al. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA 2016;315:1844-53.  Back to cited text no. 9
    
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NCCN Clinical Practice Guidelines in Oncology. Available from: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. [Last accessed on 2017 Jan 17].  Back to cited text no. 10
    
11.
Ferrone CR, Marchegiani G, Hong TS, Ryan DP, Deshpande V, McDonnell EI, et al. Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. Ann Surg 2015;261:12-7.  Back to cited text no. 11
    
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Bockhorn M, Uzunoglu FG, Adham M, Imrie C, Milicevic M, Sandberg AA, et al. Borderline resectable pancreatic cancer: A consensus statement by the international study group of pancreatic surgery (ISGPS). Surgery 2014;155:977-88.  Back to cited text no. 12
    
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Khushman M, Dempsey N, Maldonado JC, Loaiza-Bonilla A, Velez M, Carcas L, et al. Full dose neoadjuvant FOLFIRINOX is associated with prolonged survival in patients with locally advanced pancreatic adenocarcinoma. Pancreatology 2015;15:667-73.  Back to cited text no. 13
    
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Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25.  Back to cited text no. 14
    
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Peixoto RD, Speers C, McGahan CE, Renouf DJ, Schaeffer DF, Kennecke HF, et al. Prognostic factors and sites of metastasis in unresectable locally advanced pancreatic cancer. Cancer Med 2015;4:1171-7.  Back to cited text no. 17
    


    Figures

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  [Table 1], [Table 2], [Table 3]



 

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