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Neoadjuvant Radiotherapy is Associated With Improved Pathologic Outcomes and Survival in Resected Stage II-III Pancreatic Adenocarcinoma Treated With Multiagent Neoadjuvant Chemotherapy in the Modern Era
Abstract
Background
Neoadjuvant chemotherapy (CT) is being utilized more frequently in patients diagnosed with localized pancreatic cancer. The role of additional neoadjuvant radiotherapy (RT) remains undefined. We explored outcomes associated with neoadjuvant RT in the modern era.
Methods
The National Cancer Database (2010-2017) was queried for patients with clinical stage II-III pancreatic adenocarcinoma who received neoadjuvant multiagent systemic CT +/− RT. Demographics, pathologic outcomes, postoperative outcomes, and overall survival were compared.
Results
A total of 5245 patients were included, of whom 3123 received CT and 1941 received CT + RT. Use of RT decreased over the 8-year study period. On multivariable analysis, treatment at academic facilities (odds ratio (OR) = 1.52, P < .001) and clinical T4 tumors (OR = 1.68, P < .001) were independently associated with receipt of RT. Patients treated with CT + RT had a higher frequency of ypT0-T2 tumors (35.8% vs. 22.7%) and a lower rate of ypT3-T4 tumors (57.3% vs. 72.8%; P < .001), lower rate of node-positive disease (36.6% vs. 59.8%, P < .001), and margin-positive resections (13.8% vs. 20.2%, P < .001), but slightly higher 90-day postoperative mortality (4.9% vs. 3.6%, P = .04). Neoadjuvant chemotherapy+ RT was associated with longer overall survival (32.7 vs. 29.8 months, P = .008), and remained independently associated with survival on multivariable analysis (HR = .85, P < .001).
Discussion
In patients with stage II-III pancreatic adenocarcinoma, the addition of neoadjuvant RT to multiagent neoadjuvant CT may be associated with increased rates of node-negative and margin-negative resection, as well as improved overall survival.
... The purpose of NAT relies on negative and positive selection principles: identifying patients likely to not benefit from resection, treatment of occult metastases, and potential downstaging to achieve margin-negative resection. [1][2][3][4] If we anticipate that NAT will improve outcomes over up-front resection, then we need to objectively show therapeutic responses. ...
Background:
Neoadjuvant therapy (NAT) is used in borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). Anatomic imaging (CT/MRI) poorly predicts response, and biochemical (CA 19-9) markers are not useful (nonsecretors/nonelevated) in many patients. Pathologic response highly predicts survival post-NAT, but is only known postoperatively. Because metabolic imaging (FDG-PET) reveals primary tumor viability, this study aimed to evaluate our experience with preoperative FDG-PET in patients with BR/LA PDAC in predicting NAT response and survival.
Methods:
We reviewed all patients with resected BR/LA PDAC who underwent NAT with FDG-PET within 60 days of resection. Pre- and post-NAT metabolic (FDG-PET) and biochemical (CA 19-9) responses were dichotomized in addition to pathologic responses. We compared post-NAT metabolic and biochemical responses as preoperative predictors of pathologic responses and recurrence-free survival (RFS) and overall survival (OS).
Results:
We identified 202 eligible patients. Post-NAT, 58% of patients had optimization of CA 19-9 levels. Major metabolic and pathologic responses were present in 51% and 38% of patients, respectively. Median RFS and OS times were 21 and 48.7 months, respectively. Metabolic response was superior to biochemical response in predicting pathologic response (area under the curve, 0.86 vs 0.75; P<.001). Metabolic response was the only univariate preoperative predictor of OS (odds ratio, 0.25; 95% CI, 0.13-0.40), and was highly correlated (P=.001) with pathologic response as opposed to biochemical response alone. After multivariate adjustment, metabolic response was the single largest independent preoperative predictor (P<.001) for pathologic response (odds ratio, 43.2; 95% CI, 16.9-153.2), RFS (hazard ratio, 0.37; 95% CI, 0.2-0.6), and OS (hazard ratio, 0.21; 95% CI, 0.1-0.4).
Conclusions:
Among patients with post-NAT resected BR/LA PDAC, FDG-PET highly predicts pathologic response and survival, superior to biochemical responses alone. Given the poor ability of anatomic imaging or biochemical markers to assess NAT responses in these patients, FDG-PET is a preoperative metric of NAT efficacy, thereby allowing potential therapeutic alterations and surgical treatment decisions. We suggest that FDG-PET should be an adjunct and recommended modality during the NAT phase of care for these patients.
... In a meta-analysis including 512 patients with BR or PR PDAC from 15 small single-arm studies, neoadjuvant RT after (m)FOLFIRINOX was not associated with a difference in OS. 28 Retrospective series evaluating neoadjuvant chemotherapy regimens other than (m)FOLFIRINOX 5-8 and the randomized LAP-07 trial for patients with locally advanced PDAC 29 also found no difference in OS with and without RT. Four studies found better survival with neoadjuvant RT after multiagent chemotherapy regimens 16,[30][31][32] ; 3 of these studies, however, only included the selected subgroup of patients who underwent a resection, thereby introducing selection bias. In the no RT group, a patient who undergoes a resection might be diagnosed with liver metastases 3 months after surgery; in the RT group, the same patient would be diagnosed with liver metastases at restaging after RT and would therefore not end up in the resection cohort. ...
Background:
The value of neoadjuvant radiotherapy (RT) after 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan, with or without dose modifications [(m)FOLFIRINOX], for patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is uncertain.
Methods:
We conducted an international retrospective cohort study including consecutive patients with BR PDAC who received (m)FOLFIRINOX as initial treatment (2012-2019) from the Trans-Atlantic Pancreatic Surgery Consortium. Because the decision to administer RT is made after chemotherapy, patients with metastases or deterioration after (m)FOLFIRINOX or a performance score ≥2 were excluded. Patients who received RT after (m)FOLFIRINOX were matched 1:1 by nearest neighbor propensity scores with patients who did not receive RT. Propensity scores were calculated using sex, age (≤70 vs >70 years), WHO performance score (0 vs 1), tumor size (0-20 vs 21-40 vs >40 mm), tumor location (head/uncinate vs body/tail), number of cycles (1-4 vs 5-8 vs >8), and baseline CA 19-9 level (≤500 vs >500 U/mL). Primary outcome was overall survival (OS) from diagnosis.
Results:
Of 531 patients who received neoadjuvant (m)FOLFIRINOX for BR PDAC, 424 met inclusion criteria and 300 (70.8%) were propensity score-matched. After matching, median OS was 26.2 months (95% CI, 24.0-38.4) with RT versus 32.8 months (95% CI, 25.3-42.0) without RT (P=.71). RT was associated with a lower resection rate (55.3% vs 72.7%; P=.002). In patients who underwent a resection, RT was associated with a comparable margin-negative resection rate (>1 mm) (70.6% vs 64.8%; P=.51), more node-negative disease (57.3% vs 37.6%; P=.01), and more major pathologic response with <5% tumor viability (24.7% vs 8.3%; P=.006). The OS associated with conventional and stereotactic body RT approaches was similar (median OS, 25.7 vs 26.0 months; P=.92).
Conclusions:
In patients with BR PDAC, neoadjuvant RT following (m)FOLFIRINOX was associated with more node-negative disease and better pathologic response in patients who underwent resection, yet no difference in OS was found. Routine use of RT cannot be recommended based on these data.
Background
Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients.
Methods
This nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤ 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤ 270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3 years and 1.5 years follow-up.
Discussion
The PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer.
Trial registration
Primary registry and trial identifying number: EudraCT: 2017–002036-17 .
Date of registration: March 6, 2018.
Secondary identifying numbers: The Netherlands National Trial Register – NL7094 , NL61961.078.17, MEC-2018-004.
PURPOSE
Preoperative chemoradiotherapy may improve the radical resection rate for resectable or borderline resectable pancreatic cancer, but the overall benefit is unproven.
PATIENTS AND METHODS
In this randomized phase III trial in 16 centers, patients with resectable or borderline resectable pancreatic cancer were randomly assigned to receive preoperative chemoradiotherapy, which consisted of 3 courses of gemcitabine, the second combined with 15 × 2.4 Gy radiotherapy, followed by surgery and 4 courses of adjuvant gemcitabine or to immediate surgery and 6 courses of adjuvant gemcitabine. The primary end point was overall survival by intention to treat.
RESULTS
Between April 2013 and July 2017, 246 eligible patients were randomly assigned; 119 were assigned to preoperative chemoradiotherapy and 127 to immediate surgery. Median overall survival by intention to treat was 16.0 months with preoperative chemoradiotherapy and 14.3 months with immediate surgery (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P = .096). The resection rate was 61% and 72% ( P = .058). The R0 resection rate was 71% (51 of 72) in patients who received preoperative chemoradiotherapy and 40% (37 of 92) in patients assigned to immediate surgery ( P < .001). Preoperative chemoradiotherapy was associated with significantly better disease-free survival and locoregional failure-free interval as well as with significantly lower rates of pathologic lymph nodes, perineural invasion, and venous invasion. Survival analysis of patients who underwent tumor resection and started adjuvant chemotherapy showed improved survival with preoperative chemoradiotherapy (35.2 v 19.8 months; P = .029). The proportion of patients who suffered serious adverse events was 52% versus 41% ( P = .096).
CONCLUSION
Preoperative chemoradiotherapy for resectable or borderline resectable pancreatic cancer did not show a significant overall survival benefit. Although the outcomes of the secondary end points and predefined subgroup analyses suggest an advantage of the neoadjuvant approach, additional evidence is required.
Pancreatic cancer remains a devastating disease with dismal outcomes despite the development of novel chemotherapeutic regimens and radiation techniques. Stereotactic body radiation therapy (SBRT) offers an advantage both in image guidance and radiation dose delivery to direct ablative doses to tumors with acceptable toxicity compared to conventional techniques. Recent literature is clustered with data pertaining to SBRT in patients with resectable, borderline resectable and locally advanced pancreatic tumors. We here present a summary of the current data and highlight the limitations and potential for future growth. Further clinical study in the form of multi-institutional trials is warranted to establish the role of SBRT in combination with new chemo- therapeutic agents as well as a non-invasive alternative to surgery.
Objective:
To identify predictive factors associated with operative morbidity, mortality, and survival outcomes in patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) undergoing total neoadjuvant therapy (TNT).
Background:
The optimal preoperative treatment sequencing for BR/LA PDA is unknown. TNT, or systemic chemotherapy followed by chemoradiation (CRT), addresses both occult metastases and positive margin risks and thus is a potentially optimal strategy; however, factors predictive of perioperative and survival outcomes are currently undefined.
Methods:
We reviewed our experience in BR/LA patients undergoing resection from 2010 to 2017 following TNT assessing operative morbidity, mortality, and survival in order to define outcome predictors and response endpoints.
Results:
One hundred ninety-four patients underwent resection after TNT, including 123 (63%) BR and 71 (37%) LA PDAC. FOLFIRINOX or gemcitabine along with nab-paclitaxel were used in 165 (85%) and 65 (34%) patients, with 36 (19%) requiring chemotherapeutic switch before long-course CRT and subsequent resection. Radiologic anatomical downstaging was uncommon (28%). En bloc venous and/or arterial resection was required in 125 (65%) patients with 94% of patients achieving R0 margins. The 90-day major morbidity and mortality was 36% and 6.7%, respectively. Excluding operative mortalities, the median, 1-year, 2-year, and 3-year recurrence-free survival (RFS) [overall survival (OS)] rates were 23.5 (58.8) months, 65 (96)%, 48 (78)%, and 32 (62)%, respectively. Radiologic downstaging, vascular resection, and chemotherapy regimen/switch were not associated with survival. Only 3 factors independently associated with prolonged survival, including extended duration (≥6 cycles) chemotherapy, optimal post-chemotherapy CA19-9 response, and major pathologic response. Patients achieving all 3 factors had superior survival outcomes with a survival detriment for each failing factor. In a subset of patients with interval metabolic (PET) imaging after initial chemotherapy, complete metabolic response highly correlated with major pathologic response.
Conclusion:
Our TNT experience in resected BR/LA PDAC revealed high negative margin rates despite low radiologic downstaging. Extended duration chemotherapy with associated biochemical and pathologic responses highly predicted postoperative survival. Potential modifications of initial chemotherapy treatment include extending cycle duration to normalize CA19-9 or achieve complete metabolic response, or consideration of chemotherapeutic switch in order to achieve these factors may improve survival before moving forward with CRT and subsequent resection.
Background
Studies comparing upfront surgery with neoadjuvant treatment in pancreatic cancer may report only patients who underwent resection and so survival will be skewed. The aim of this study was to report survival by intention to treat in a comparison of upfront surgery versus neoadjuvant treatment in resectable or borderline resectable pancreatic cancer.
Methods
MEDLINE, Embase and the Cochrane Library were searched for studies reporting median overall survival by intention to treat in patients with resectable or borderline resectable pancreatic cancer treated with or without neoadjuvant treatment. Secondary outcomes included overall and R0 resection rate, pathological lymph node rate, reasons for unresectability and toxicity of neoadjuvant treatment.
Results
In total, 38 studies were included with 3484 patients, of whom 1738 (49·9 per cent) had neoadjuvant treatment. The weighted median overall survival by intention to treat was 18·8 months for neoadjuvant treatment and 14·8 months for upfront surgery; the difference was larger among patients whose tumours were resected (26·1 versus 15·0 months respectively). The overall resection rate was lower with neoadjuvant treatment than with upfront surgery (66·0 versus 81·3 per cent; P < 0·001), but the R0 rate was higher (86·8 (95 per cent c.i. 84·6 to 88·7) versus 66·9 (64·2 to 69·6) per cent; P < 0·001). Reported by intention to treat, the R0 rates were 58·0 and 54·9 per cent respectively (P = 0·088). The pathological lymph node rate was 43·8 per cent after neoadjuvant therapy and 64·8 per cent in the upfront surgery group (P < 0·001). Toxicity of at least grade III was reported in up to 64 per cent of the patients.
Conclusion
Neoadjuvant treatment appears to improve overall survival by intention to treat, despite lower overall resection rates for resectable or borderline resectable pancreatic cancer.
PROSPERO registration number: CRD42016049374.
Objectives:
To describe the survival outcome of patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) who have a pathologic complete response (pCR) following neoadjuvant chemoradiation.
Background:
Patients with BR/LA-PDAC are often treated with neoadjuvant chemoradiation in an attempt to downstage the tumor. Uncommonly, a pCR may result.
Methods:
A retrospective review of a prospectively maintained database was performed at a single institution. pCR was defined as no viable tumor identified in the pancreas or lymph nodes by pathology. A near complete response (nCR) was defined as a primary tumor less than 1 cm, without nodal metastasis. Overall survival (OS) and disease-free survival (DFS) were reported.
Results:
One hundred eighty-six patients with BR/LA-PDAC underwent neoadjuvant chemoradiation and subsequent pancreatectomy. Nineteen patients (10%) had a pCR, 29 (16%) had an nCR, and the remaining 138 (74%) had a limited response. Median DFS was 26 months in patients with pCR, which was superior to nCR (12 months, P = 0.019) and limited response (12 months, P < 0.001). The median OS of nCR (27 months, P = 0.003) or limited response (26 months, P = 0.001) was less than that of pCR (more than 60 months). In multivariable analyses pCR was an independent prognostic factor for DFS (HR = 0.45; 0.22-0.93, P = 0.030) and OS (HR=0.41; 0.17-0.97, P = 0.044). Neoadjuvant FOLFIRINOX (HR=0.47; 0.26-0.87, P = 0.015) and negative lymph node status (HR=0.57; 0.36-0.90, P = 0.018) were also associated with improved survival.
Conclusions:
Patients with BR/LA-PDAC who had a pCR after neoadjuvant chemoradiation had a significantly prolonged survival compared with those who had nCR or a limited response.
Background
Borderline resectable pancreatic cancers infiltrate into adjacent vascular structures to an extent that makes an R0 resection unlikely when pancreatectomy is performed de novo. In a pilot study, Alliance for Clinical Trials in Oncology Trial A021101, the median survival of patients who received chemotherapy and radiation prior to anticipated pancreatectomy was 22 months, and 64% of operations achieved an R0 resection. However, the individual contributions of preoperative chemotherapy and radiation therapy to therapeutic outcome remain poorly defined.
Methods
In Alliance for Clinical Oncology Trial A021501, a recently activated randomized phase II trial, patients (N = 134) with a CT or MRI showing a biopsy-confirmed pancreatic ductal adenocarcinoma that meets centrally-reviewed anatomic criteria for borderline resectable disease will be randomized to receive either 8 cycles of modified FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m² and infusional 5-fluorouracil 2400 mg/m² over 2 days for 4 cycles) or to 7 cycles of modified FOLFIRINOX followed by stereotactic body radiation therapy (33–40 Gy in 5 fractions). Patients without evidence of disease progression following preoperative therapy will undergo pancreatectomy and will subsequently receive 4 cycles of postoperative modified FOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², bolus 5-fluorouracil 400 mg/m², and infusional 5-fluorouracil 2400 mg/m² over 2 days for 4 cycles). The primary endpoint is the 18-month overall survival rate of patients enrolled into each of the two treatment arms. An interim analysis of the R0 resection rate within each arm will be conducted to assess treatment futility after accrual of 30 patients. Secondary endpoints include rates of margin-negative resection and event-free survival. The primary analysis will compare the 18-month overall survival rate of each arm to a historical control rate of 50%. The trial is activated nationwide and eligible to be opened for accrual at any National Clinical Trials Network cooperative group member site.
Discussion
This study will help define standard preoperative treatment regimens for borderline resectable pancreatic cancer and position the superior arm for further evaluation in future phase III trials.
Trial registration
ClinicalTrials.gov: NCT02839343, registered July 14, 2016.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-017-3441-z) contains supplementary material, which is available to authorized users.
Background:
Neoadjuvant multi-agent chemotherapy and stereotactic body radiation therapy (SBRT) are utilized to increase margin negative (R0) resection rates in borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) patients. Concerns persist that these neoadjuvant therapies may worsen perioperative morbidities and mortality.
Methods:
Upfront resection patients (n=241) underwent resection without neoadjuvant treatment for resectable disease. They were compared to BRPC or LAPC patients (n=61) who underwent resection after chemotherapy and 5 fraction SBRT. Group comparisons were performed by Mann-Whitney U or Fisher's exact test. Overall Survival (OS) was estimated by Kaplan-Meier and compared by log-rank methods.
Results:
In the neoadjuvant therapy group, there was significantly higher T classification, N classification, and vascular resection/repair rate. Surgical positive margin rate was lower after neoadjuvant therapy (3.3% vs. 16.2%, P=0.006). Post-operative morbidities (39.3% vs. 31.1%, P=0.226) and 90-day mortality (2% vs. 4%, P=0.693) were similar between the groups. Median OS was 33.5 months in the neoadjuvant therapy group compared to 23.1 months in upfront resection patients who received adjuvant treatment (P=0.057).
Conclusions:
Patients with BRPC or LAPC and sufficient response to neoadjuvant multi-agent chemotherapy and SBRT have similar or improved peri-operative and long-term survival outcomes compared to upfront resection patients.
The management of localized pancreatic cancer (PC) remains controversial. Historically, patients with localized disease have been treated with surgery followed by adjuvant therapy (surgery-first approach) under the assumption that surgical resection is necessary, even if not sufficient for cure. However, a surgery-first approach is associated with a median overall survival of only 22-24 months, suggesting that a large proportion of patients with localized PC have clinically occult metastatic disease. As a result, adjuvant therapy has been recommended for all patients with localized PC, but in actuality, it is often not received due to the high rates of perioperative complications associated with pancreatic resections. Recognizing that surgery may be necessary but usually not sufficient for cure, there has been growing interest in neoadjuvant treatment sequencing, which benefits patients with both localized and metastatic PC by ensuring the delivery of oncologic therapies which are commensurate with the stage of disease. For patients who have clinically occult metastatic disease, neoadjuvant therapy allows for the early delivery of systemic therapy and avoids the morbidity and mortality of a surgical resection which would provide no oncologic benefit. For patients with truly localized disease, neoadjuvant therapy ensures the delivery of all components of the multimodality treatment. This review details the rationale for a neoadjuvant approach to localized PC and provides specific recommendations for both pretreatment staging and treatment sequencing for patients with resectable and borderline resectable (BLR) disease.
Background
In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. Methods
We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. ResultsA total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. Conclusions
In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.) In this report, the addition of nab-paclitaxel to standard gemcitabine increased the response rate, progression-free survival, and overall survival among patients with metastatic pancreatic adenocarcinoma. Pancreatic cancer is the fourth leading cause of cancer-related death in Europe and the United States.(1),(2) Since 1997, gemcitabine therapy has been the standard first-line treatment for patients with unresectable locally advanced or metastatic pancreatic cancer.(3) Among patients with metastatic disease, the 5-year survival rate is only 2%,(1) and 1-year survival rates of 17 to 23% have been reported with gemcitabine.(3)-(5) Numerous phase 2 studies involving patients with advanced pancreatic cancer have shown promising results; however, most subsequent large phase 3 studies have not shown significantly improved survival,(6)-(16) with the exception of a study involving patients who ...
The purpose of this trial was to evaluate the role of radiation therapy with concurrent gemcitabine (GEM) compared with GEM alone in patients with localized unresectable pancreatic cancer.
Patients with localized unresectable adenocarcinoma of the pancreas were randomly assigned to receive GEM alone (at 1,000 mg/m(2)/wk for weeks 1 to 6, followed by 1 week rest, then for 3 of 4 weeks) or GEM (600 mg/m(2)/wk for weeks 1 to 5, then 4 weeks later 1,000 mg/m(2) for 3 of 4 weeks) plus radiotherapy (starting on day 1, 1.8 Gy/Fx for total of 50.4 Gy). Measurement of quality of life using the Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire was also performed.
Of 74 patients entered on trial and randomly assigned to receive GEM alone (arm A; n = 37) or GEM plus radiation (arm B; n = 34), patients in arm B had greater incidence of grades 4 and 5 toxicities (41% v 9%), but grades 3 and 4 toxicities combined were similar (77% in A v 79% in B). No statistical differences were seen in quality of life measurements at 6, 15 to 16, and 36 weeks. The primary end point was survival, which was 9.2 months (95% CI, 7.9 to 11.4 months) and 11.1 months (95% CI, 7.6 to 15.5 months) for arms A and B, respectively (one-sided P = .017 by stratified log-rank test).
This trial demonstrates improved overall survival with the addition of radiation therapy to GEM in patients with localized unresectable pancreatic cancer, with acceptable toxicity.
Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer.
We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival.
The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001).
As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; ClinicalTrials.gov number, NCT00112658.).
The role of chemoradiation with systemic chemotherapy compared with chemotherapy alone in locally advanced pancreatic cancer (LAPC) is uncertain.
One hundred and nineteen patients with LAPC, World Health Organization performance status of zero to two were randomly assigned to either the induction CHRT group (60 Gy, 2 Gy/fraction; concomitant 5-fluorouracil infusion, 300 mg/m(2)/day, days 1-5 for 6 weeks; cisplatin, 20 mg/m(2)/day, days 1-5 during weeks 1 and 5) or the induction gemcitabine group (GEM: 1000 mg/m(2) weekly for 7 weeks). Maintenance gemcitabine (1000 mg/m(2) weekly, 3/4 weeks) was given in both arms until disease progression or toxicity.
Overall survival was shorter in the CHRT than in GEM arm [median survival 8.6 (99% confidence interval 7.1-11.4) and 13 months (8.7-18.1), P = 0.03]. One-year survival was, respectively, 32% and 53%. These results were confirmed in a per-protocol analysis for patients who received 75% or more of the planned dose of radiotherapy. More overall grades 3-4 toxic effects were recorded in the CHRT arm, both during induction (36 versus 22%) and maintenance (32 versus 18%).
This intensive induction schedule of CHRT was more toxic and less effective than gemcitabine alone.
4016
Background: Preoperative chemoradiotherapy (CRT) may improve overall survival in resectable pancreatic cancer (RPC) and borderline resectable pancreatic cancer (BRPC). Long term results are presented. Methods: In this multicenter phase III trial, patients with RPC or BRPC were randomized between preoperative CRT, (gemcitabine 1000 mg/m ² weekly for 7 of 10 weeks, and 15x2.4 Gy radiotherapy in week 4 to 6), followed by surgery and four cycles of adjuvant gemcitabine (1000 mg/m ² weekly for 3 of 4 weeks), or immediate surgery followed by 6 cycles of adjuvant gemcitabine (1000 mg/m ² weekly for 3 of 4 weeks). Primary endpoint was overall survival by intention-to-treat (ITT). Results: From April 2013 to July 2017, 246 eligible patients were accrued by 16 Dutch centers and randomized, 119 to preoperative CRT and 127 to immediate surgery. After a median follow up of 56 months (35.3-92.0 months), 210 patients have died, 93 (78%) in the preoperative CRT arm and 117 (92%) in the immediate surgery arm. Three- and five-year overall survival ITT was 27.7% and 20.5% after preoperative CRT versus 16.5% and 6.5% after immediate surgery (HR 0.73; 95% CI 0.56 to 0.96; p = 0.025). In addition, disease-free survival (HR 0.70; p = 0.009) locoregional failure-free interval (HR 0.57; p = 0.004) and distant metastases free interval (HR 0.74; p = 0.071) improved after preoperative CRT. Also in the stratified subsets RPC and BRPC, preoperative CRT improved OS: RPC (n = 133, HR 0.79; 95% CI 0.54 to 1.16; P = 0.23). BRPC (n = 113, HR 0.67; 95% CI 0.45 to 0.99; p = 0.045). We could not demonstrate a difference in treatment effect between these subsets (interaction test p = 0.56). Conclusions: Preoperative gemcitabine-based CRT for RPC or BRPC improves long term overall survival compared to immediate surgery with adjuvant gemcitabine. Clinical trial information: NTR3709.
377
Background: Neoadjuvant therapy has been associated with a median overall survival (OS) of 18 – 23 months (mo) in patients (pts) with BR pancreatic ductal adenocarcinoma (PDAC). To establish reference regimens to which novel treatments can be compared in future studies, we evaluated neoadjuvant mFOLFIRINOX with or without RT in BR PDAC in a phase II National Clinical Trials Network (NCTN) trial. Methods: Pts with ECOG PS 0-1 and BR PDAC confirmed by central real-time radiographic review after pre-registration were randomized to either arm A: 8 cycles of neoadjuvant mFOLFIRINOX (oxaliplatin 85 mg/m ² , irinotecan 180 mg/m ² , leucovorin 400 mg/m ² and infusional 5-fluorouracil 2400 mg/m ² over 46 hours), or arm B: 7 cycles of mFOLFIRINOX followed by stereotactic body RT (SBRT, 33-40 Gy in 5 fractions [fx]) or hypofractionated image guided RT (HIGRT, 25 Gy in 5 fx). Pts in either arm without disease progression underwent pancreatectomy, then 4 cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m ² , leucovorin 400 mg/m ² and infusional 5-fluorouracil 2400 mg/m ² over 46 hours). The primary endpoint, 18-mo OS rate, of each arm was compared to a historical control of 50%. Planned interim analysis mandated closure of either arm in which <11 of first 30 accrued pts underwent R0 resection. Results: 155 pts pre-registered and 126 pts were enrolled to arm A (N=70; 54 randomized, 16 following closure of arm B) or arm B (N=56; closed at interim analysis, all pts randomized prior to closure). Median age (A: 63y, B: 67y), median CA 19-9 level (A: 171 U/ml, B: 248 U/ml) and ECOG PS (A: 51% PS 0, B: 57% PS 0) of registered pts were similar between arms (p > 0.05). Treatment detailed in Table. The 18-mo OS rate based on Kaplan Meier estimates was 67.9% (95%CI: 54.6 – 78.0) in arm A and 47.3% (95%CI: 33.7 – 59.7) in arm B. Among pts who underwent pancreatectomy, 18-mo OS rate was 93.1% (95%CI: 84.3 – 100) and 78.9% (95%CI: 62.6 – 99.6) in arm A and B, respectively. With median follow-up of 27 and 31 mo, median OS was 31.0 (95%CI: 22.2 – NE) mo and 17.1 (95%CI: 12.8 – 24.4) mo in arm A and B, respectively. Conclusions: Neoadjuvant mFOLFIRINOX was associated with favorable OS relative to historical data in pts with BL PDAC in this phase II NCTN trial. mFOLFIRINOX with hypofractionated RT did not improve OS compared to historical data. mFOLFIRINOX represents a reference regimen in this setting and a backbone on which to add novel agents. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org Clinical trial information: NCT02839343. [Table: see text]
Background
Neoadjuvant therapy is increasingly utilized in the management of pancreatic adenocarcinoma. The type of neoadjuvant therapy and its effect on pathologic response remains understudied.
Methods
A retrospective review was performed on patients who underwent neoadjuvant therapy followed by pancreatectomy. Multivariable regressions were used to determine associations between neoadjuvant therapy regimens and pathologic response.
Results
Seventy-five patients with pathologic responses available for review received FOLFIRINOX (61%) or gemcitabine with nab-paclitaxel (39%). Demographics, histologic differentiation, and utilization of chemoradiation were similar between the groups. Multivariable logistic regression demonstrated that chemoradiation was associated with an increased likelihood of a complete or near-complete pathologic response and a decreased rate of lymphovascular invasion and lymph node positivity. Neither chemotherapy regimen nor number of cycles administered were associated with pathologic response.
Conclusions
Neoadjuvant chemoradiation may be associated with complete or near-complete pathologic response regardless of chemotherapy regimen in pancreatic cancer patients.
Background
The authors hypothesized that in resected pancreatic adenocarcinoma (PDAC), pathologic characteristics, oncologic outcomes, prognostic factors, and the accuracy of the American Joint Committee on Cancer (AJCC) staging system might differ based on tumor location.Methods
Patients undergoing pancreatectomy for PDAC at two academic institutions from 2000 to 2015 were retrieved. A comparative analysis between head (H-PDAC) and body–tail (BT-PDAC) tumors was performed using uni- and multivariable models. The accuracy of the eighth AJCC staging system was analyzed using C-statistics.ResultsAmong 1466 patients, 264 (18%) had BT-PDAC, which displayed greater tumor size but significantly lower rates of perineural invasion and G3/4 grading. Furthermore, BT-PDAC was associated with a lower frequency of nodal involvement and a greater representation of earlier stages. The recurrence-free survival and disease-specific survival times were longer for BT-PDAC (16 vs 14 months [p = 0.020] and 33 vs 26 months [p = 0.026], respectively), but tumor location was not an independent predictor of recurrence or survival in the multivariable analyses. The recurrence patterns did not differ. Certain prognostic factors (i.e., CA 19.9, grading, R-status, and adjuvant treatment) were common, whereas others were site-specific (i.e., preoperative pain, diabetes, and multivisceral resection). The performances of the AJCC staging system were similar (C-statistics of 0.573 for H-PDAC and 0.597 for BT-PDAC, respectively).Conclusions
Despite differences in pathologic profile found to be in favor of BT-PDAC, tumor location was not an independent predictor of recurrence or survival after pancreatectomy. An array of site-specific prognostic factors was identified, but the AJCC staging system displayed similar prognostic power regardless of primary tumor location.
Background:
We sought to examine the impact of neoadjuvant chemotherapy (NCT), single agent or multiagent chemotherapy, and neoadjuvant chemoradiation (NCRT) on survival in pancreatic cancer.
Methods:
Utilizing the National Cancer Database, we identified patients who underwent pancreatic resection for adenocarcinoma (2006 to 2013). Overall survival (OS) analysis was performed using the Kaplan-Meier method. Multivariable cox proportional hazard models (MVA) and propensity score matching (PSM) were developed to identify predictors of survival. For upfront surgery (UFS), OS was limited to receipt of adjuvant treatment.
Results:
We identified 26,563 patients who underwent pancreatic resection: UFS =23,877, NCRT =1,482, and NCT =1,204. Multiagent chemotherapy was utilized in 77% of NCT and 42% of NCRT. There was improved R0 resections associated with neoadjuvant therapy compared to UFS, however, there was no difference between NCT and NCRT. In addition, the was improved R0 with MA-NCT (P<0.001) but not for single agent NCT (P=0.26). After PSM, the median OS for UFS, SA-NCT, MA-NCT, SA-NCRT, and MA-NCRT was 21.9, 21.5, 29.8, 25.3, and 25.8 months in all patients (P=0.001), and 23.6, 23.9, 31.6, 25.9, and 26.6 months in R0 patients (P=0.03), respectively. There was no difference in OS in patients with R1/2 resection. MVA after PSM demonstrated that only MA-NCT was associated with decreased mortality while increasing age, higher Charlson-Deyo index, N1, higher grade, tumor size, and positive margins were associated with higher mortality.
Conclusions:
There was improved OS associated with MA-NCT in pancreatic cancer patients compared to UFS with adjuvant therapy.
Background
This study was designed to better define the role of radiation (Neo-Rad) in addition to neoadjuvant multiagent chemotherapy (NAT) for the treatment of locally advanced pancreatic cancer.
Methods
Retrospective cohort study using the NCDB. Individuals with AJCC clinical T3/T4 pancreatic carcinoma who underwent resection and multiagent chemotherapy were included. Kaplan–Meier, logistic-regression, and Cox proportional-hazard models were used for analysis.
Results
A total of 2703 patients were included; 2039 had T3 and 664 had T4 tumors, and 1092 (40.4%) received Neo-Rad. Median follow-up was 22.5 months. During the study period, there was increased use of NAT and a decline in the use of Neo-Rad. Addition of Neo-Rad did not affect 30-day (2.51% vs. 3.24%, p = 0.272) or 90-day mortality (5.23% vs. 6.38%, p = 0.216). Neo-Rad was not associated with improved overall survival on univariable (25.95 vs. 24.7 months, p = 0.202), or multivariable analyses (hazard ratio [HR] 0.94; 95% confidence interval [CI] 0.85–1.05). Time from diagnosis to definitive surgery was increased by Neo-Rad (204 vs. 115 days, p < 0.001). Neo-Rad was associated with increased pathologic downstaging in T3 (32.8% vs. 14.4%) (odds ratio [OR] 2.90; 95% CI 2.30–3.66) and T4 tumors (88.9% vs. 77.8%) (OR 2.29; 95% CI 1.44–3.67); complete pathologic response (5.3% vs. 1.6%) (OR 2.89; 95% CI 1.73–4.83), and increased R0 resection rates (85.7% vs. 76.8%) (OR 1.79; 95% CI 1.44–2.23).
Conclusions
The use of neoadjuvant therapy is increasing for the treatment of locally advanced pancreatic cancer. The addition of radiation to neoadjuvant chemotherapy is associated with improved antineoplastic effectiveness (downstaging, complete pathologic response), surgical resection (R0 rates), but has no effect on overall survival.
Importance
Patients with borderline-resectable pancreatic ductal adenocarcinoma have historically poor outcomes with surgery followed by adjuvant chemotherapy. Evaluation of a total neoadjuvant approach with highly active therapy is warranted.
Objective
To evaluate the margin-negative (R0) resection rate in borderline-resectable pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX (fluorouracil, irinotecan, and oxaliplatin) therapy and individualized chemoradiotherapy.
Design, Setting, and Participants
A single-arm, phase 2 clinical trial was conducted at a large academic hospital with expertise in pancreatic surgery from August 3, 2012, through August 31, 2016, among 48 patients with newly diagnosed, previously untreated, localized pancreatic cancer determined to be borderline resectable by multidisciplinary review, who had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 18.0 months among the 30 patients still alive at study completion.
Interventions
Patients received FOLFIRINOX for 8 cycles. Upon restaging, patients with resolution of vascular involvement received short-course chemoradiotherapy (5 Gy × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy with fluorouracil or capecitabine.
Main Outcomes and Measures
The primary outcome was R0 resection rate; secondary outcomes were median progression-free survival (PFS) and median overall survival (OS).
Results
Of the 48 eligible patients, 27 were men and 21 were women, with a median age of 62 years (range, 46-74 years). Of the 43 patients who planned to receive 8 preoperative cycles of chemotherapy, 34 (79%) were able to complete all cycles. Twenty-seven patients (56%) had short-course chemoradiotherapy, while 17 patients (35%) had long-course chemoradiotherapy. R0 resection was achieved in 31 of the 48 eligible patients (65%; 95% CI, 49%-78%). Among the 32 patients who underwent resection, the R0 resection rate was 97% (n = 31). Median PFS among all eligible patients was 14.7 months (95% CI, 10.5 to not reached), with 2-year PFS of 43%; median OS was 37.7 months (95% CI, 19.4 to not reached), with 2-year OS of 56%. Among patients who underwent resection, median PFS was 48.6 months (95% CI, 14.4 to not reached) and median OS has not been reached, with a 2-year PFS of 55% and a 2-year OS of 72%.
Conclusions and Relevance
Preoperative FOLFIRINOX followed by individualized chemoradiotherapy in borderline resectable pancreatic cancer results in high rates of R0 resection and prolonged median PFS and median OS, supporting ongoing phase 3 trials.
Trial Registration
ClinicalTrials.gov Identifier: NCT01591733
Background:
Unresectable pancreatic cancer remains a challenging disease to treat. Stereotactic body radiotherapy (SBRT) allows for a higher biologically equivalent dose in an abbreviated course more convenient for patients and the integration of systemic therapy. We sought to investigate utilization trends and survival outcomes for patients treated with pancreatic SBRT versus conventionally fractionated radiotherapy (CFRT).
Methods:
We engaged the National Cancer Database (NCDB) from 1998-2012 and identified locally-advanced unresectable patients with histologically confirmed, non-metastatic, pancreatic adenocarcinoma who received radiotherapy. Patients who received CFRT (1.5-4.0 Gy per fraction to a dose of ≥45 Gy, n=11,879) were compared to those who received SBRT (6-15 Gy per fraction to a dose of ≥20 Gy, n=474).
Results:
Median follow-up was 11.0 months (18.4 months for survivors). SBRT utilization increased from 0.2% to 7.4% from 1998 to 2012 (P<0.05). On multivariable analysis, factors predictive for preferential utilization of SBRT over CFRT were later year of diagnosis, age ≥75 years, increased facility volume, and no chemotherapy in the initial treatment plan. Unadjusted median survival was 11.2 months for CFRT vs. 12.6 months for SBRT (P=0.002). Results were consistent in the propensity matched model. Variables predictive for improved survival on multivariable analysis were diagnosis after 2010, younger age, lower comorbidity score, tumor size <3 cm, nodal stage zero, and receipt of chemotherapy (P<0.05).
Conclusions:
SBRT utilization has increased significantly and is associated with a small absolute improvement in overall survival (OS) compared to CFRT. The decreased treatment time, without apparent compromise in survival, makes SBRT an attractive option for patients with unresectable pancreatic cancer warranting further research.
Background:
The role of adjuvant chemoradiotherapy (CRT) following pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PDA) remains controversial. Recent data suggest that increased margin clearance (MC: distance between tumor and cut surface) is associated with improved survival after PD, but the role of adjuvant CRT in patients with known MC is undefined. We sought to delineate the impact of adjuvant CRT on survival based on MC following PD.
Methods:
Patients who underwent PD for PDA between 2002 and 2014 were retrospectively stratified into three groups based on MC: 0 mm, ≤1 mm, and >1 mm. The impact of CRT on survival in each MC group was determined by univariate and multivariate analysis.
Results:
Three hundred and ten patients with known MC were analyzed (0 mm =67, ≤1 mm =113, and >1 mm =130). Increasing MC was independently associated with improved OS (≤1 mm, HR 0.66, 95% CI 0.46-0.96, P=0.03; >1 mm, HR 0.51, 95% CI 0.35-0.75, P=0.001; compared to 0 mm). Adjuvant CRT was administered to 62 patients (20%). On margin-stratified multivariate analysis, adjuvant CRT was independently associated with increased OS in patients with ≤1 mm margins (HR 0.36; 95% CI 0.18-0.69, P=0.002) but not for 0 mm and >1 mm margins.
Conclusions:
This analysis suggests that the benefit of adjuvant CRT may be restricted to patients with ≤1 mm MC after PD for pancreatic cancer.
Background:
Neoadjuvant therapy has theoretical benefits for pancreatic cancer; however, its association with perioperative outcomes remains controversial. This study sought to evaluate variation in use of neoadjuvant therapy and outcomes following pancreatic resection.
Methods:
The National Cancer Data Base (1998-2011) was queried for patients with Stage I or II pancreatic adenocarcinoma who underwent pancreaticoduodenectomy. Subjects were classified by use of neoadjuvant chemotherapy and/or radiation therapy. Factors associated with use of neoadjuvant therapy were evaluated, and outcomes were compared.
Results:
A 18 243 patients were identified; 1375 (7.5%) received neoadjuvant therapy. From 1998 to 2011, use of neoadjuvant therapy increased from 4.3% to 17.0%. Patients receiving neoadjuvant therapy were younger (63.1 vs 66.1 years, P = 0.001) and more likely to receive treatment at an academic facility (64.4% vs 51.4%, P < 0.001). Patients who received neoadjuvant therapy were more likely to have negative margins (77.8% vs 85.5%), negative lymph nodes (42.9% vs 59.3%) and tumors confined to the pancreas (65.8% vs 70.6%, all P < 0.001). Patients receiving neoadjuvant therapy had lower 30-day mortality (2.0% vs 4.6%, P < 0.001) and readmission rates (7.4% vs 9.5%, P = 0.02).
Conclusions:
Neoadjuvant therapy use is increasing and associated with comparable short-term outcomes. Further studies are needed to identify patients who would benefit from neoadjuvant therapy.
Background:
Pancreatic cancer carries a dismal prognosis, with surgical resection and adjuvant therapy offering the only hope for long-term survival. Recently, neoadjuvant therapy (NAT) has been employed to optimize outcomes. This study evaluates the impact of NAT in resected pancreatic cancer.
Methods:
Patients with clinically staged I-III resected carcinoma of the pancreas who underwent at least NAT or surgery first in the 2003-2011 National Cancer Data Base were included. Univariate statistics were used to compare characteristics between treatment groups. Kaplan-Meier and multivariate survival analyses using Cox proportional hazards models were also performed.
Results:
1736 patients who underwent NAT, 6706 patients who underwent surgical resection alone, and 9890 patients who underwent surgical resection followed by adjuvant therapy were studied. In patients with clinical stage I disease, adjuvant therapy was associated with similar median survival to NAT, which was greater than surgery alone (24.9, 24.8, and 18.3 months, respectively, p < 0.0001). However, in stage II, NAT offered improved median survival over adjuvant therapy, which was greater than surgery alone (21.78, 20.63, and 12.1 months, respectively, p < 0.0001). In stage III disease, NAT had better median survival relative to other groups (22.6, 14.6, and 8.7 months, respectively, p < 0.0001). In multivariate survival analysis, patients who received NAT had a 33% lower hazard of mortality up to 5 years as compared to surgical resection alone (p < 0.0001).
Conclusion:
Neoadjuvant therapy in advanced stage pancreatic cancer is associated with a survival benefit, perhaps related to a selection bias. In early stage pancreatic cancer, NAT is associated with similar survival.
Background:
Outcomes of neoadjuvant systemic therapy versus an upfront operation for clinical, stage III pancreatic adenocarcinoma remain poorly defined. Our aim was to compare survival among patients receiving neoadjuvant chemotherapy versus surgery-first with an intention-to-treat analysis.
Methods:
The National Cancer Data Base was reviewed from 2002-2011 for patients with clinical, stage III adenocarcinoma of the head or body of the pancreas. Patients were categorized as neoadjuvant or surgery-first. The intention-to-treat analysis included all neoadjuvant therapy patients in whom a potentially curative operation was planned and all surgery-first patients for whom adjuvant therapy was recommended. Intention-to-treat overall survival was compared by Kaplan-Meier and Cox proportional hazards multivariable regression.
Results:
A total of 593 patients were identified: 377 (63.6%) in the neoadjuvant cohort, wherein 104 (27.6%) experienced preoperative attrition, and 216 (36.4%) in the surgery-first cohort, of whom 30 (13.9%) failed to receive intended adjuvant chemotherapy. Intention-to-treat Kaplan-Meier analysis demonstrated superior survival for neoadjuvant compared to surgery-first (median overall survival 20.7 months vs 13.7 months, log rank P < .001). Intention-to-treat multivariable regression analysis revealed a decreased mortality hazard (hazard ratio = 0.68, 95% confidence interval 0.53-0.86, P = .0012) for neoadjuvant compared to surgery-first.
Conclusion:
Despite preoperative attrition, neoadjuvant therapy in clinical, stage III pancreatic cancer patients is associated with improved overall survival when compared to patients receiving surgery-first.
Importance
In locally advanced pancreatic cancer, the role of chemoradiotherapy is controversial and the efficacy of erlotinib is unknown.
Objectives
To assess whether chemoradiotherapy improves overall survival of patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine-based induction chemotherapy and to assess the effect of erlotinib on survival.
Design, Setting, and Participants
In LAP07, an international, open-label, phase 3 randomized trial, 449 patients were enrolled between 2008 and 2011. Follow-up ended in February 2013.
Interventions
In the first randomization, 223 patients received 1000 mg/m2 weekly of gemcitabine alone and 219 patients received 1000 mg/m2 of gemcitabine plus 100 mg/d of erlotinib. In the second randomization involving patients with progression-free disease after 4 months, 136 patients received 2 months of the same chemotherapy and 133 underwent chemoradiotherapy (54 Gy plus capecitabine).
Main Outcomes and Measures
The primary outcome was overall survival from the date of the first randomization. Secondary outcomes were the effect of erlotinib and quality assurance of radiotherapy on overall survival, progression-free survival of gemcitabine-erlotinib and erlotinib maintenance with gemcitabine alone at the second randomization, and toxic effects.
Results
A total of 442 of the 449 patients (232 men; median age, 63.3 years) enrolled underwent the first randomization. Of these, 269 underwent the second randomization. Interim analysis was performed when 221 patients died (109 in the chemoradiotherapy group and 112 in the chemotherapy group), reaching the early stopping boundaries for futility. With a median follow-up of 36.7 months, the median overall survival from the date of the first randomization was not significantly different between chemotherapy at 16.5 months (95% CI, 14.5-18.5 months) and chemoradiotherapy at 15.2 months (95% CI, 13.9-17.3 months; hazard ratio [HR], 1.03; 95% CI, 0.79-1.34; P = .83). Median overall survival from the date of the first randomization for the 223 patients receiving gemcitabine was 13.6 months (95% CI, 12.3-15.3 months) and was 11.9 months (95% CI, 10.4-13.5 months) for the 219 patients receiving gemcitabine plus erlotinib (HR, 1.19; 95% CI, 0.97-1.45; P = .09; 188 deaths vs 191 deaths). Chemoradiotherapy was associated with decreased local progression (32% vs 46%, P = .03) and no increase in grade 3 to 4 toxicity, except for nausea.
Conclusions and Relevance
In this open-label, randomized trial involving patients with locally advanced pancreatic cancer with disease controlled after 4 months of induction chemotherapy, there was no significant difference in overall survival with chemoradiotherapy compared with chemotherapy alone and there was no significant difference in overall survival with gemcitabine compared with gemcitabine plus erlotinib used as maintenance therapy.
Trial Registration
clinicaltrials.gov Identifier: NCT00634725
BACKGROUND:Several grading schemes for the extent of residual tumor in posttreatment pancreaticoduodenectomy (PD) specimens have been proposed. However, the prognostic significance of these grading schemes is unknown.METHODS:Histopathologic slides of 223 cases who received neoadjuvant chemoradiation and PD were reviewed. The extent of residual tumor was graded using both the College of American Pathologists (CAP) and the Evans grading systems. The grading results were correlated with clinicopathological parameters and survival.RESULTS:Among the 223 patients, 6 patients (2.7%) showed pathologic complete response (pCR; CAP grade 0 or Evans grade IV), 36 cases (16.1%) had minimal residual tumor (CAP grade 1 or Evans grade III), 124 cases (55.6%) had moderate response (CAP grade 2 or Evans grade IIb), and 57 cases (25.6%) had poor response (CAP grade 3, where 18 had Evans grade I and 39 had Evans grade IIa response). Patients with pCR or minimal residual tumor (response group 1) had better survival rates than those with moderate and poor response (response group 2). Response group 1 patients had lower posttherapy tumor and American Joint Committee on Cancer stages and lower rates of lymph node metastasis, positive resection margin, and recurrence and/or metastasis. Grading the extent of residual tumor is an independent prognostic factor for overall survival in multivariate analysis.CONCLUSIONS:pCR or minimal residual tumor in posttreatment PD specimens correlate with better survival in patients with pancreatic ductal adenocarcinoma who received neoadjuvant therapy and PD. Histologic grading of the extent of residual tumor in PD specimen is an important prognostic factor in patients with pancreatic ductal adenocarcinoma who received neoadjuvant therapies. Cancer 2012;118: 3182–90. © 2011 American Cancer Society.
In patients with pancreatic ductal adenocarcinoma (PDA) who received neoadjuvant therapy and pancreatectomy, pathologic complete response (pCR) is rarely observed and the prognostic significance of pCR is not clear. In this study, we identified 11 patients with pCR (2.5%) from 442 patients with PDA who received neoadjuvant treatment and pancreatectomy from 1995 to 2010. There were 6 men and 5 women, with a median age of 61 years. Four patients had either synchronous or history of extrapancreatic cancer. Five patients received neoadjuvant chemotherapy followed by chemoradiation, and 6 received chemoradiation alone. Ten patients had pancreaticoduodenectomy, and 1 had distal pancreatectomy. Scar and chronic pancreatitis consistent with therapy effect were present in all cases (100%). Pancreatic intraepithelial neoplasia (PanIN) 3/carcinoma in situ was present in 5 cases, and PanIN1 and PanIN2 in 5 cases. However, no residual invasive carcinoma or lymph node metastasis was identified in all cases. Follow-up information was available in 10 patients. Follow-up time ranges from 6 to 194 months (median, 63 months). During the follow-up, 3 patients died of other causes, and 1 developed a second primary PDA in the tail of the pancreas at 84 months after the initial pancreaticoduodenectomy and died at 105 months after the initial diagnosis of PDA. The other 6 patients were alive with no evidence of disease. Patients with pCR had a better survival than did those who had posttherapy stage I or IIA disease (P < .001). Patients with PDA who received neoadjuvant therapy and had pCR in pancreatectomy are rare but have a better prognosis.
Several grading schemes for the extent of residual tumor in posttreatment pancreaticoduodenectomy (PD) specimens have been proposed. However, the prognostic significance of these grading schemes is unknown.
Histopathologic slides of 223 cases who received neoadjuvant chemoradiation and PD were reviewed. The extent of residual tumor was graded using both the College of American Pathologists (CAP) and the Evans grading systems. The grading results were correlated with clinicopathological parameters and survival.
Among the 223 patients, 6 patients (2.7%) showed pathologic complete response (pCR; CAP grade 0 or Evans grade IV), 36 cases (16.1%) had minimal residual tumor (CAP grade 1 or Evans grade III), 124 cases (55.6%) had moderate response (CAP grade 2 or Evans grade IIb), and 57 cases (25.6%) had poor response (CAP grade 3, where 18 had Evans grade I and 39 had Evans grade IIa response). Patients with pCR or minimal residual tumor (response group 1) had better survival rates than those with moderate and poor response (response group 2). Response group 1 patients had lower posttherapy tumor and American Joint Committee on Cancer stages and lower rates of lymph node metastasis, positive resection margin, and recurrence and/or metastasis. Grading the extent of residual tumor is an independent prognostic factor for overall survival in multivariate analysis.
pCR or minimal residual tumor in posttreatment PD specimens correlate with better survival in patients with pancreatic ductal adenocarcinoma who received neoadjuvant therapy and PD. Histologic grading of the extent of residual tumor in PD specimen is an important prognostic factor in patients with pancreatic ductal adenocarcinoma who received neoadjuvant therapies.
This systematic review and meta-analysis aims to characterize the surgically important benefits and complications associated with the use of neoadjuvant chemoradiotherapy for the treatment of both resectable and initially unresectable pancreatic cancer. Studies were identified through a systematic literature search and analyzed by two independent reviewers. Survival, peri-operative complications, death rate, pancreatic fistula rate, and the incidence of involved surgical margins were analyzed and subject to meta-analysis.
Nineteen studies, involving 2,148 patients were identified. Only cohort studies were included.
The meta-analysis found that patients with unresectable pancreatic cancer who underwent neoadjuvant chemoradiotherapy achieved similar survival outcomes to patients with resectable disease, even though only 40% were ultimately resected. Neoadjuvant chemoradiotherapy was not associated with a statistically significant increase in the rate of pancreatic fistula formation or total complications.
Patients receiving neoadjuvant chemoradiotherapy were less likely to have a positive resection margin, although there was an increase in the risk of peri-operative death.
Randomized trials of the Gastrointestinal Tumor Study Group have previously demonstrated enhanced survival of patients with locally unresectable pancreatic cancer treated with 5-fluorouracil in combination with radiation therapy compared with that of patients treated with radiation therapy alone. The present study compared the survival of patients treated with multidrug chemotherapy [streptozocin, mitomycin, and 5-fluorouracil (SMF)] versus radiation combined with 5-fluorouracil followed by the same three-drug SMF combination. In 43 patients randomly allocated between these two arms, an improved median survival for the combined-modality therapy (42 weeks) compared with chemotherapy alone (32 weeks) was demonstrated. Overall survival following this combined-modality treatment program (41% at 1 year) was significantly superior to that following SMF chemotherapy alone (19% at 1 year), by a two-tailed log rank test (P < .02). Serial studies of the Gastrointestinal Tumor Study Group with patients with locally unresectable pancreatic adenocarcinoma have shown that combined-modality therapy is superior to either optimal radiotherapy or chemotherapy alone. [J Natl Cancer Inst 1988;80:751–755]
One hundred ninety-one patients with pathologically confirmed, locally unresectable adenocarcinoma of the stomach (57 patients) and pancreas (91 patients), were randomly allocated to therapy with 5-fluorouracil (5-FU) alone, 600 mg/m2 intravenously (IV) once weekly, or radiation therapy, 4,000 rad, plus adjuvant 5-FU, 600 mg/m2 IV, the first three days of radiotherapy, then follow-up maintenance 5-FU, 600 mg/m2, weekly. Forty-three patients (22%) could not be analyzed because of ineligibility or cancellation, thus 148 patients were evaluable. The median survival time was similar for both treatment programs and for both types of primary carcinoma, and was as follows: gastric primary carcinoma, 5-FU, 9.3 months; 5-FU plus radiotherapy, 8.2 months; pancreatic primary carcinoma, 5-FU, 8.2 months; 5-FU plus radiotherapy, 8.3 months. Substantially more toxicity was experienced by patients treated with the combined modality arm than by those patients receiving 5-FU alone. Severe or worse toxicity experienced by patients with gastric primary carcinoma treated by 5-FU was 19%, and the combined modality arm was 31%. The toxicity experienced by patients with pancreatic primary carcinoma treated with 5-FU was 27%, and the combined modality arm was 51%. Significant prognostic variables included: weight loss in stomach-cancer patients; and performance status, degree of anaplasia, and reduced appetite in pancreas-cancer patients.
A prospectively randomized trial in advanced gastric and pancreatic carcinoma compared multi-drug chemotherapy, with and without radiotherapy to the local lesion, in terms of median survival and toxicity. Of 29 patients with gastric adenocarcinoma, 14 were randomized to receive 5-FU and Methyl-CCNU, and 15 to receive 5-FU and local radiotherapy to a dose of 4600 rad, and then Methyl-CCNU. Thirty patients with advanced adenocarcinoma of the pancreas were similarly randomized. There was no significant difference between the two arms of the gastric or pancreatic adenocarcinoma groups, with a median survival of 13 months and 11.5 months respectively in gastric carcinoma, and 7.8 months and 7.3 months in pancreatic carcinoma. Complications were minimal in both groups. There was more hematopoietic depression in the radiation-treated patients, but none had radiotherapy discontinued because of toxicity.
It is unknown whether neoadjuvant chemoradiotherapy, compared with adjuvant chemoradiotherapy, decreases the rate of local recurrence after resection of pancreatic adenocarcinoma.
This is a retrospective case review of 102 patients with pancreatic adenocarcinoma who underwent pancreatic resection between 1993 and 2005.
Of 102 patients with pancreatic adenocarcinoma who underwent surgical resection, 19 (19%) had no additional treatment, 41 (40%) underwent adjuvant chemoradiotherapy, and 42 (41%) were treated preoperatively with neoadjuvant chemoradiotherapy. Patients selected to receive neoadjuvant therapy were more likely to have locally advanced tumors. Based on initial CT scan, the percentage of patients with unresectable or borderline resectable tumors in the neoadjuvant group was 67%, compared with 22% in the adjuvant group. Nevertheless, patients receiving neoadjuvant chemoradiotherapy were less likely to have a local recurrence develop than patients receiving adjuvant chemoradiotherapy (5% versus 34%, p = 0.02). For those patients with tumors determined to be resectable on initial CT scan, local recurrences were observed in 31% (10 of 32) of patients in the adjuvant therapy group, compared with only 7% (1 of 14) of the neoadjuvant group. Intraoperative radiation therapy, administered to 51% of patients, was not associated with a lower rate of local recurrence.
Neoadjuvant chemoradiotherapy is associated with improved local tumor control in patients undergoing resection for pancreatic carcinoma.
Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer
- E Versteijne
- J A Vogel
- Besselink
- Mg