Is There a Standard Adjuvant Therapy for Resected Pancreatic Cancer?
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ABSTRACT:
SUBMITTER: Fenocchio E
PROVIDER: S-EPMC6826876 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
Publications
Is There a Standard Adjuvant Therapy for Resected Pancreatic Cancer?
Fenocchio Elisabetta E Filippi Roberto R Lombardi Pasquale P Quarà Virginia V Milanesio Michela M Aimar Giacomo G Leone Francesco F Aglietta Massimo M
Cancers 20191012 10
Surgical resection remains the only treatment that offers a potential chance of long-term survival. Unfortunately, about 80% of patients treated with curative intent will develop recurrence. Since 2001, adjuvant therapy with gemcitabine or 5-fluorouracyle was recommended. This approach allows a median overall survival (OS) of around 23 months, and 5-year survival of 22%. In recent years, two phase-3 trials investigating new chemotherapy regimens resulted in considerably improved survival times. ...[more]
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Project description:BackgroundNeoadjuvant therapy (NAT) is increasingly utilized for pancreatic cancer, however the added benefit of adjuvant therapy (AT) in this setting is unknown. We hypothesized that the magnitude of CA19-9 response to NAT can guide the need for further AT in resected pancreatic cancer.MethodsCA19-9 secretors who received NAT for pancreatic cancer during 2008-2016 at a single institution were analyzed and CA19-9 response (difference between pre- and post-NAT values) was measured. Kaplan-Meier estimators and Cox proportional hazard ratio models were used to determine the optimal CA19-9 response at which AT ceases to confer any additional survival benefit after NAT.ResultsA total of 241 patients (mean age 65.4 years, 50% female) with complete CA19-9 data who underwent NAT followed by resection were analyzed. In a cohort of patients (n = 78) in whom CA19-9 normalized with a decrease > 50% after NAT (optimal responders), AT was not associated with additional survival benefit (40.6 vs. 39.0 months, p = 0.815). Conversely, in the cohort of patients (n = 163) in whom NAT was not associated with normalization and a decrease of ≤ 50% in CA19-9 (suboptimal responders), receipt of AT was associated with a survival benefit (34.5 vs. 19.1 months, p < 0.001) following NAT. A Cox proportional hazards model confirmed CA19-9 normalization and decrease > 50% during NAT to predict no additional survival benefit from AT.ConclusionsThe magnitude of CA19-9 response to NAT may predict the need for further AT in resected pancreatic cancer. Prospective studies are needed to elucidate the optimal interplay of NAT and AT in pancreatic cancer.
| S-EPMC7931260 | biostudies-literature
Project description:AIM: Interferons (IFNs) are known to have antiproliferative and immunoregulatory activities that are modulated through specific cell surface ligands, known as IFN-alpha, -beta, and -gamma receptors. The presence of these receptors and their impact on response to adjuvant therapy in patients with pancreatic cancer has not been determined. PATIENTS AND METHODS: Slides were prepared from 46 patients with pancreatic adenocarcinoma. Immunohistochemistry (IHC) was subsequently used to determine the expression of IFN- alpha/beta receptor-chain 2 (IFN-alpha/betaR) and IFN-gamma receptor-chain 1 (IFN-gammaR). The correlation between IFN receptor expression, tumor characteristics, and the overall patient response to adjuvant therapy were determined analytically. RESULTS: The IHC performed for pancreatic adenocarcinoma demonstrated a high IFN-alpha/betaR expression in 4% (2/46) of patients, moderate expression in 20% (9/46) of patients, and faint or no expression in 76% (35/46) of patients. IHC confirmed a high expression of IFN-gammaR in 52% (24/46) of patients, moderate expression in 35% (16/46) of patients, and faint or no expression in the remaining 13% (6/46) of patients. Thirty-two (69.7%) patients received adjuvant therapy. Clinicopathological survey did not demonstrate any significant correlation between IFN-alpha/betaR and IFN-gammaR expression with regard to tumor size, vascular invasion, perineural invasion, lymph node metastases, or stage of disease. Use of adjuvant therapy was associated with increased survival in patients with IFN-alpha/betaR-positive tumors compared with patients with IFN-alpha/betaR-negative tumors (24 months versus 14.7 months in log rank test, p=0.012). The expression of IFN-gammaR, however, had no impact on patient survival (20 months vs 17 months; p=0.656, log rank test). CONCLUSION: IFN-alpha/betaR is associated with improved survival for patients with resectable pancreatic cancer who received adjuvant therapy.
| S-EPMC2215399 | biostudies-other
Project description:Pancreatic cancer remains one of the leading causes of cancer related death worldwide with an overall five-year survival of less than 5%. Potentially curative surgery, which alone can improve 5-year survival to 10%, is an option for only 10%-20% of patients at presentation owing to local invasion of the tumour or metastatic disease. Adjuvant chemotherapy has been shown to improve 5-year survival to 20%-25% but conflicting evidence remains with regards to chemoradiation. In this article we review the current evidence available from published randomised trials and discuss ongoing phase III trials in relation to adjuvant therapy in pancreatic cancer.
| S-EPMC4209539 | biostudies-literature
Project description:ImportanceSurgery followed by adjuvant chemotherapy or chemoradiation is widely used to treat resectable pancreatic cancer. Although studies suggest initiation of adjuvant therapy within 12 weeks of surgery, there is no clear time interval associated with better survival.ObjectiveTo evaluate the ideal timing of adjuvant therapy for patients with stage I to II resected pancreatic cancer.Design, setting, and participantsThis cohort study included 7548 patients with stage I to II resected pancreatic cancer (5453 with adjuvant therapy; 2095 without adjuvant therapy) from the National Cancer Database from 2004 to 2015. Data were collected from January 2014 to December 2015 and analyzed from December 2018 to May 2019.ExposuresAdjuvant chemotherapy or chemoradiation at various time intervals.Main outcomes and measuresOverall survival (OS).ResultsA total of 7548 patients (3770 male [49.9%]; median [interquartile range] age, 67 [59-74] years) were identified from the National Cancer Database. Among 5453 patients with adjuvant therapy, a Cox model with restricted cubic splines identified the lowest mortality risk when adjuvant therapy was started 28 to 59 days after surgery. Patients were divided into early (n = 269, adjuvant therapy initiated within <28 days), reference (n = 3048, adjuvant therapy initiated within 28-59 days), and late (n = 2136, adjuvant therapy initiated after >59 days) interval cohorts. Median (interquartile range) overall follow-up was 38.6 (24.6-62.0) months. Compared with the reference interval cohort on multivariable analysis, both the early cohort (hazard ratio, 1.17; 95% CI, 1.02-1.35; P = .03) and the late cohort (hazard ratio, 1.09; 95% CI, 1.02-1.17; P = .008) were associated with worse mortality. Similarly, the reference interval cohort had improved OS compared with the early cohort in 268 propensity-matched pairs (2-year OS, 52.5% [95% CI, 46.7%-59.0%] vs 45.1% [95% CI, 39.5%-51.6%]; P = .02) and compared with the late cohort in 2042 propensity-matched pairs (2-year OS, 51.3% [95% CI, 49.1%-53.6%] vs 45.4% [95% CI, 43.3%-47.7%]; P = .01). Patients who received adjuvant therapy more than 12 weeks after surgery (n = 683) had improved OS compared with surgery alone in both multivariable analysis (hazard ratio, 0.75; 95% CI, 0.66-0.85; P < .001) and 655 propensity-matched pairs (2-year OS, 47.2% [95% CI, 43.5%-51.3%] vs 38.0% [95% CI, 34.4%-42.0%]; P < .001).Conclusions and relevancePatients with stage I to II pancreatic cancer who commenced adjuvant therapy within 28 to 59 days after primary surgical resection had improved survival outcomes compared with those with adjuvant therapy before 28 days or after 59 days. Patients who recovered slowly from surgery still benefited from delayed adjuvant therapy initiated more than 12 weeks after surgery compared with patients who underwent surgery only.
| S-EPMC6694394 | biostudies-literature
Project description:The 5-year survival of pancreatic adenocarcinoma with surgery and adjuvant chemotherapy is below 25%. The original Gastrointestinal Tumor Study Group (GITSG) adjuvant study demonstrated a survival benefit attributed to weekly intravenous boluses of 5-fluorouracil (5-FU) for 2 years in addition to chemoradiation compared to surgery alone. In theory, the prolonged exposure to therapy could maintain pressure on dormant cancer cells that remain in G0 arrest and kill them as they infrequently enter the G1/S phase. We retrospectively evaluated outcomes in patients who were treated with adjuvant chemotherapy and maintenance capecitabine compared with those who received only adjuvant chemotherapy.Patients who had undergone surgical resection with curative intent and received adjuvant chemotherapy were analyzed. Those who subsequently received maintenance capecitabine therapy were compared to those who received adjuvant chemotherapy only. The primary end points were disease recurrence and all-cause mortality.The median overall survival (OS) of patients receiving maintenance capecitabine was greater than 48.4 months (the exact estimate was not available, since the survival probability curve does not cross 0.5). It was 22.0 months (95% confidence interval [CI], 16.6-29.2) in patients who received adjuvant chemotherapy only (P < .001 by log-rank test). The median recurrence-free survival (RFS) was also longer in the maintenance capecitabine group: 54.3 (95% CI, 22.2-Inf) compared to 14.1 (95% CI, 11.6-16.7) months (P < .001, by log-rank test).In this retrospective study, patients with resected pancreatic adenocarcinoma who received adjuvant chemotherapy had improved OS and RFS with additional maintenance therapy with capecitabine. These findings should be confirmed with a randomized, controlled trial.
| S-EPMC4171974 | biostudies-other
Project description:ImportanceThe benefit of adjuvant chemotherapy after resection of pancreatic cancer following neoadjuvant combination treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is unclear.ObjectiveTo assess the association of adjuvant chemotherapy with overall survival (OS) in patients after pancreatic cancer resection and neoadjuvant FOLFIRINOX treatment.Design, setting, and participantsThis international, multicenter, retrospective cohort study was conducted from January 1, 2012, to December 31, 2018. An existing cohort of patients undergoing resection of pancreatic cancer after FOLFIRINOX was updated and expanded for the purpose of this study. All consecutive patients who underwent pancreatic surgery after at least 2 cycles of neoadjuvant FOLFIRINOX chemotherapy for nonmetastatic pancreatic cancer were retrospectively identified from institutional databases. Patients with resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer were eligible for this study. Patients with in-hospital mortality or who died within 3 months after surgery were excluded.ExposuresThe association of adjuvant chemotherapy with OS was evaluated in different subgroups including interaction terms for clinicopathological parameters with adjuvant treatment in a multivariable Cox model. Overall survival was defined as the time starting from surgery plus 3 months (moment eligible for adjuvant therapy), unless mentioned otherwise.ResultsWe included 520 patients (median [interquartile range] age, 61 [53-66] years; 279 [53.7%] men) from 31 centers in 19 countries. The median number of neoadjuvant cycles of FOLFIRINOX was 6 (interquartile range, 5-8). Overall, 343 patients (66.0%) received adjuvant chemotherapy, of whom 68 (19.8%) received FOLFIRINOX, 201 (58.6%) received gemcitabine-based chemotherapy, 14 (4.1%) received capecitabine, 45 (13.1%) received a combination or other agents, and 15 (4.4%) received an unknown type of adjuvant chemotherapy. Median OS was 38 months (95% CI, 36-46 months) after diagnosis and 31 months (95% CI, 29-37 months) after surgery. No survival difference was found for patients who received adjuvant chemotherapy vs those who did not (median OS, 29 vs 29 months, univariable hazard ratio [HR], 0.99; 95% CI, 0.77-1.28; P = .93). In multivariable analysis, only the interaction term for lymph node stage with adjuvant therapy was statistically significant: In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved survival (median OS, 26 vs 13 months; multivariable HR, 0.41 [95% CI, 0.22-0.75]; P = .004). In patients with node-negative disease, adjuvant chemotherapy was not associated with improved survival (median OS, 38 vs 54 months; multivariable HR, 0.85; 95% CI, 0.35-2.10; P = .73).Conclusions and relevanceThese results suggest that adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease. Future randomized studies should be conducted to confirm this finding.
| S-EPMC7489392 | biostudies-literature
Project description:BackgroundPancreatic cancer is a highly malignant tumor with a poor prognosis. Chemotherapy such as gemcitabine is still an important treatment. Gemcitabine (Gem) may prolong survival time and delay the development of recurrent disease after complete resection of pancreatic cancer. Currently, some control studies have been performed between certain drugs and gemcitabine monotherapy after pancreatic cancer surgery, but the outcomes were uncertain. Here, we implemented meta-analysis to compare the efficacy between adjuvant treatments and gemcitabine monotherapy in patients with resected pancreatic cancer.MethodsPubMed, Embase and the Central Registry of Controlled Trials of the Cochrane Library searches were undertaken to identify randomized controlled trials (RCTs). Date of search ranged from January 1997 to December 2017. The meta-analysis included six RCTs. The major endpoints involved overall survival (OS), disease-free survival/progress free survival/relapse-free survival (DFS/PFS/RFS) and grade 3-4 toxicity.ResultsPooled meta-analytic estimates were derived using random-effects model. Subgroup analysis used fixed-effects model. The outcome showed that there was no difference in OS (hazard ratio (HR), 0.87; 95% CI, 0.70-1.07; P = 0.19) and DFS (HR, 0.85; 95% CI, 0.71-1.02; P = 0.08) between the adjuvant treatments group (fluorouracil+folinic acid, S-1, gemcitabine+capecitabine, gemcitabine+erlotinib and gemcitabine+uracil/tegafur) and Gem monotherapy group. However, the subgroup analysis showed that only S-1 chemotherapy, which is an oral fluoropyrimidine agent containing tegafur, gimeracil and oteracil, was significant in OS (HR, 0.59; 95% CI, 0.46-0.74; P < 0.0001) and DFS (HR, 0.63; 95% CI, 0.52-0.75; P < 0.00001) compared with Gem alone. Toxicity analysis showed there was an increased incidence of grade 3/4 diarrhea (risk ratio (RR), 5.11; 95%CI, 3.24-8.05; P < 0.00001) and decreased incidence of grade 3/4 leucopenia (RR, 0.55; 95%CI, 0.31-0.98; P = 0.04), thrombocytopenia (RR, 0.61; 95%CI, 0.39-0.97; P = 0.04) in adjuvant treatments group. Neutropenia (RR, 0.69; 95%CI, 0.36-1.29; P = 0.24) and fatigue (RR, 1.29; 95%CI, 0.95-1.77; P = 0.11) for patients between the two groups were not significantly different.ConclusionsIn our meta-analysis, a significant survival benefit is only observed in the S-1 regimen, but the results are yet to be determined. Optimal cytotoxicity or targeted drug regimens need further validation in clinical trials in the future.
| S-EPMC6199735 | biostudies-literature
Project description:BackgroundData on efficacy of adjuvant therapy for surgically resected small cell lung cancer are scant. This study was determined to reveal the survival benefits of different adjuvant treatment modalities for limited-stage small cell lung cancer patients following surgical resection.MethodsData of patients with histologically confirmed small cell lung cancer after surgical resection were collected from November 2006 to June 2019. Survival analyses were calculated by Kaplan-Meier method, with log-rank test to evaluate statistical significance. Prognostic factors were identified by multivariate analysis using cox proportional hazards model. Further survival analysis and cox regression analysis stratified by clinicopathologic features were conducted to evaluate the survival benefits of different adjuvant treatment modalities.ResultsIn total, 153 out of 157 patients were analyzed. Multivariate analysis showed male sex, lymph node metastasis, residual tumor, VPI and non-adjuvant therapy were independently associated with poor prognosis. Subgroup analyses revealed both adjuvant chemotherapy and adjuvant chemoradiotherapy were significantly associated with superior survival for stage pT2-4 (HR=0.176, 95%CI:0.053-0.578, p=0.004; and HR=0.115, 95%CI:0.033-0.405, p=0.001) and pure SCLC patients (HR=0.182, 95%CI:0.067-0.494, p=0.001; and HR=0.181, 95%CI:0.071-0.465, p<0.001). For pN0 patients, adjuvant chemotherapy was associated with better survival (HR=0.219, 95%CI:0.054-0.891, p=0.034), while adjuvant chemoradiotherapy was associated with improved survival for pN+ patients (HR=0.324, 95%CI:0.138-0.760, p=0.010).ConclusionsFor patients without pathologic lymph node metastasis, there is a survival benefit with adjuvant chemotherapy. However, for patients with pathologic lymph node metastasis, adjuvant chemoradiotherapy might achieve a significant survival benefit. Further prospective studies are needed to validate the results.
| S-EPMC8495161 | biostudies-literature
Project description:BackgroundThe impact of adjuvant chemotherapy and chemo-radiation therapy in the treatment of resectable gastric cancer remains varied. We sought to define the clinical impact of lymph node ratio on the relative benefit of adjuvant chemotherapy or chemo-radiation therapy among patients having undergone curative-intent resection for gastric cancer.MethodsUsing the multi-institutional US Gastric Cancer Collaborative database, 719 patients with gastric adenocarcinoma who underwent curative-intent resection between 2000 and 2013 were identified. Patients with metastasis or an R2 margin were excluded. The impact of lymph node ratio on overall survival among patients who received chemotherapy or chemo-radiation therapy was evaluated.ResultsMedian patient age was 65 years, and the majority of patients were male (56.2%). The majority of patients underwent either subtotal (40.6%) or total gastrectomy (41.0%), with the remainder undergoing distal gastrectomy or wedge resection (18.4%). On pathology, median tumor size was 4 cm; most patients had a T3 (33.0%) or T4 (27.9%) lesion with lymph node metastasis (59.7%). Margin status was R0 in 92.5% of patients. A total of 325 (45.2%) patients underwent resection alone, 253 (35.2%) patients received 5-FU or capecitabine-based chemo-radiation therapy, whereas the remaining 141 (19.6%) received chemotherapy. Median overall survival was 40.9 months, and 5-year overall survival was 40.3%. According to lymph node ratio categories, 5-year overall survival for patients with a lymph node ratio of 0, 0.01-0.10, >0.10-0.25, >0.25 were 54.1%, 53.1 %, 49.1 % and 19.8 %, respectively. Factors associated with worse overall survival included involvement of the gastroesophageal junction (hazard ratio 1.8), T-stage (3-4: hazard ratio 2.1), lymphovascular invasion (hazard ratio 1.4), and lymph node ratio (>0.25: hazard ratio 2.3; all P < .05). In contrast, receipt of adjuvant chemo-radiation therapy was associated with an improved overall survival in the multivariable model (versus resection alone: hazard ratio 0.40; versus chemotherapy: hazard ratio 0.45, both P < .001). The benefit of chemo-radiation therapy for resected gastric cancer was noted only among patients with lymph node ratio >0.25 (versus resection alone: hazard ratio R 0.34; versus chemotherapy: hazard ratio 0.45, both P < .001). In contrast, there was no noted overall survival benefit of chemotherapy or chemo-radiation therapy among patients with lymph node ratio ≤0.25 (all P > .05).ConclusionAdjuvant chemotherapy or chemo-radiation therapy was utilized in more than one-half of patients undergoing curative-intent resection for gastric cancer. Lymph node ratio may be a useful tool to select patients for adjuvant chemo-radiation therapy, because the benefit of chemo-radiation therapy was isolated to patients with greater degrees of lymphatic spread (ie, lymph node ratio >0.25).
| S-EPMC6036903 | biostudies-literature
Project description:PURPOSE:To characterize the patterns of care and potential barriers to access to care for elderly patients with oral cavity cancer in the adjuvant setting. METHODS AND MATERIALS:We performed a retrospective cohort study using the National Cancer Data Base and identified patients with resected oral cavity squamous cell carcinoma diagnosed between 2004 and 2012, who survived for ?3 months after surgery. We used logistic regression models to assess the association between age (<70, 70-79, and ?80 years) and the receipt of adjuvant therapy within 3 months of surgery. We additionally assessed the association between patient and tumor characteristics and the receipt of adjuvant therapy among those aged ?70 years. RESULTS:A total of 25,829 patients were included in the study. Compared with those aged <70 years, older patients were more likely to have no neck dissection or have fewer lymph nodes dissected and were less likely to receive adjuvant therapy than younger patients. Among our cohort, 11,361 patients (44%) had pathologic T3-T4 disease or N2-N3 disease, and 4185 patients (16%) had extracapsular nodal extension or positive surgical margins. In multivariate analyses controlling for comorbidity and demographic characteristics, older age was independently associated with lower odds of receiving adjuvant radiation therapy in the subgroup with T3 or T4 disease or N2 or N3 disease and adjuvant chemoradiation therapy in the positive extracapsular nodal extension or positive surgical margin subgroup. Among elderly patients, both greater patient distance from reporting facility and older age were associated with lower odds of receiving both adjuvant radiation therapy (odds ratio 0.66; 95% confidence interval, 0.55-0.81) and chemoradiation therapy (odds ratio 0.56; 95% confidence interval, 0.40-0.79). CONCLUSIONS:In a national hospital-based cohort of patients with oral cavity cancer, elderly patients were less likely to receive adjuvant radiation or chemoradiation therapy. Greater patient distance from reporting facility, in addition to older age, was associated with lower odds of receiving both adjuvant radiation therapy and adjuvant chemoradiation therapy.
| S-EPMC6240349 | biostudies-literature