Nadia Haj Mohammad

Systematic Review of Resection Rates and Clinical Outcomes After FOLFIRINOX-Based Treatment in Patients with Locally Advanced Pancreatic Cancer

BackgroundFOLFIRINOX prolongs survival in patients with metastatic pancreatic cancer and may also benefit patients with locally advanced pancreatic cancer (LAPC). Furthermore, it may downstage a proportion of LAPC into (borderline) resectable disease, however data are lacking. This review assessed outcomes after FOLFIRINOX-based therapy in LAPC.MethodsThe PubMed, EMBASE and Cochrane library databases were systematically searched for studies published to 31 August 2015. Primary outcome was the (R0) resection rate.ResultsFourteen studies involving 365 patients with LAPC were included; three studies administered a modified FOLFIRINOX regimen. Of all patients, 57xa0% (nxa0=xa0208) received radiotherapy. The pooled resection rate was 28xa0% (nxa0=xa0103, 77xa0% R0), with a perioperative mortality of 3xa0% (nxa0=xa02), and median overall survival ranged from 8.9 to 25.0xa0months. Survival data after resection were scarce, with only one study reporting a median overall survival of 24.9xa0months in 28 patients. A complete pathologic response was found in 6 of 85 (7xa0%) resected specimens. Dose reductions were described in up to 65xa0% of patients, grade 3–4 toxicity occurred in 23xa0% (nxa0=xa051) of patients, and 2xa0% (nxa0=xa05) had to discontinue treatment. Data of patients treated solely with FOLFIRINOX, without additional radiotherapy, were available from 292 patients: resection rate was 12xa0% (nxa0=xa029, 70xa0% R0), with 15.7xa0months median overall survival and 19xa0% (nxa0=xa034) grade 3–4 toxicity.ConclusionsOutcomes after FOLFIRINOX-based therapy in patients with LAPC seem very promising but further prospective studies are needed, especially with regard to survival after resection.

The Efficacy and Safety of First-line Chemotherapy in Advanced Esophagogastric Cancer: A Network Meta-analysis.

BACKGROUNDnA globally accepted standard first-line chemotherapy regimen in advanced esophagogastric cancer (AEGC) is not clearly established. We conducted a systematic review to investigate the efficacy and safety of first-line chemotherapy using Network meta-analysis (NMA).nnnMETHODSnMedline, EMBASE, CENTRAL, and conferences were searched until June 2015 for randomized controlled trials that compared regimens containing: fluoropyrimidine (F), platinum (cisplatin [C] and oxaliplatin [Ox]), taxane (T), anthracycline (A), irinotecan (I), or methotrexate (M). Direct and indirect evidence for overall survival (OS) and progression-free-survival (PFS) were combined using random-effects NMA on the hazard ratio (HR) scale and calculated as combined hazard ratios and 95% credible intervals (CrIs).nnnRESULTSnThe NMA incorporated 17 chemotherapy regimens with 37 direct comparisons between regimens for OS (50 studies, nu2009=u200910 249) and 29 direct comparisons for PFS (34 studies, nu2009=u20097795). Combining direct and indirect effects showed increased efficacy for fluoropyrimidine noncisplatin doublets (F-doublets) over cisplatin doublets (C-doublets): FI vs CF (combined HRu2009=u20090.85, 95% CrI = 0.71 to 0.99), FOx vs CF (combined HRu2009=u20090.83, 95% CrI = 0.71 to 0.98) in OS and FOx vs CF (combined HRu2009=u20090.82, 95% CrI = 0.66 to 0.99) in PFS. Anthracycline-containing triplets (A-triplets: ACF, AFOx, AFM) and TCF triplet showed no benefit over F-doublets in OS and PFS. The triplet FOxT showed increased PFS vs F-doublets FT (combined HRu2009=u20090.61, 95% CrI = 0.38 to 0.99), FI (combined HRu2009=u20090.62, 95% CrI = 0.38 to 0.99), and FOx (combined HRu2009=u20090.67, 95% CrI = 0.44 to 0.99). Increased grade 3 to 4 toxicity was found for CF vs F-doublets, for ACF vs FI for TCF vs CF, and for FOxT vs FOx.nnnCONCLUSIONSnBased on efficacy and toxicity, F-doublets FOx, FI, and FT are preferred as first-line treatment for AEGC compared with C-doublets, A-triplets, and TCF. FOxT is the most promising triplet.

Ten weeks to live : a population-based study on treatment and survival of patients with metastatic pancreatic cancer in the south of the Netherlands

Abstract Background. A large proportion of patients with pancreatic cancer presents with metastatic disease. We conducted a population-based study to evaluate trends in treatment and survival of patients with metastatic pancreatic cancer. Methods. We included all patients diagnosed with pancreatic cancer between 1993 and 2010 in the South of the Netherlands (N = 3099). Multivariable logistic regression analysis was conducted to evaluate trends in treatment with chemotherapy. Crude overall survival according to period of diagnosis was analyzed, and independent risk factors for death were identified. Results. Forty-eight percent of the patients (N = 1494) were diagnosed with metastatic disease. The percentage of patients being diagnosed with metastatic disease increased during the study period from 35% in 1993–1996 to 59% in 2009–2010 (p < 0.0001). Overall, 18% of these patients received chemotherapy. The prescription of palliative chemotherapy almost tripled from 10% to 27% (p < 0.0001). Treatment largely depended on age, ranging from 38% among patients aged < 50 years [compared to 60–69 years: adjusted odds ratio (ORadj) 2.5 (95% CI 1.4–4.2)] to 1% among patients aged ≥ 80 years [compared to 60–69 years: ORadj 0.04 (95% CI 0.0–0.2)]. Patients were more likely to receive chemotherapy if they had a high socioeconomic status [ORadj 2.0 (95% CI 1.3–3.1)], and if diagnosis was pathologically verified [no verification vs. verification: ORadj 0.3 (95% CI 0.2–0.5)]. The administration of chemotherapy varied widely between 10 hospitals (5–34%, p < 0.0001). The median overall survival of patients with metastatic pancreatic cancer remained 9–11 weeks. Conclusion. A growing proportion of pancreatic cancer patients presented with metastatic disease. Usage of palliative chemotherapy increased over time, but median survival remained 9–11 weeks. In the near future, it should be evaluated if the recently introduced regimens have an impact on population-based survival.

The efficacy and safety of S-1-based regimens in the first-line treatment of advanced gastric cancer: a systematic review and meta-analysis

BackgroundS-1 is first-line therapy for advanced gastric cancer in Asia and is used with increased frequency in Western counties. We conducted a meta-analysis to investigate the efficacy and toxicity of S-1-based therapy compared with 5-fluorouracil (5-FU)/capecitabine-based therapy and S-1-based combination therapy compared with S-1 monotherapy.MethodsMEDLINE, Embase, the Cochrane Central Register of Controlled Trials, American Society of Clinical Oncology meeting abstracts, European Society for Medical Oncology meeting abstracts and ClinicalTrials.gov were searched for randomized clinical trials until May 2015. Data were extracted for overall survival (OS), progression-free-survival (PFS), objective response rate (ORR) and grade 1–2 and grade 3–4 adverse events. Stratified OS data for subgroups were extracted.ResultsS-1 was not different from 5-FU (eight studies, nxa0=xa02788) in terms of OS [hazard ratio (HR) 0.93, 95xa0% confidence interval (CI) 0.85–1.01] and PFS (HR 0.87, 95xa0% CI 0.73–1.04), whereas ORR was higher (risk ratio 1.43, 95xa0% CI 1.05–1.96). There was no subgroup difference in efficacy among Asian and Western patients, but in Western patients S-1 was associated with a lower rate of febrile neutropenia, toxicity-related deaths and grade 3–4 stomatitis and mucositis compared with 5-FU. S-1 showed no difference in efficacy compared with capecitabine (three studies, nxa0=xa0329), but was associated with a lower rate of grade 3–4 neutropenia and grade 1–2 hand–foot syndrome. S-1-combination therapy was superior to S-1 monotherapy (eight studies, nxa0=xa01808) in terms of OS (HR 0.76, 95xa0% CI 0.65–0.90), PFS (HR 0.68, 95xa0% CI 0.56–0.82) and ORR (risk ratio 1.20, 95xa0% CI 1.04–1.38) but was more toxic. Survival benefit of S-1 combination therapy over S-1 monotherapy was most pronounced in patients with non-measurable disease, diffuse-type histological features and peritoneal metastasis.ConclusionsS-1 is effective and tolerable as first-line therapy for advanced gastric cancer in both Asian and Western countries.

Acute toxicity of definitive chemoradiation in patients with inoperable or irresectable esophageal carcinoma

BackgroundDefinitive chemoradiation (dCRT) is considered curative intent treatment for patients with inoperable or irresectable esophageal cancer. Acute toxicity data focussing on dCRT are lacking.MethodsA retrospective analysis of patients treated with dCRT consisting of 6xa0cycles of paclitaxel 50xa0mg/m2 and carboplatin AUC2 concomitant with radiotherapy (50.4xa0Gy1.8Gy) from 2006 through 2011 at a single tertiary center was performed. Toxicity, hospital admissions and survival were analysed.Results127 patients were treated with definitive chemoradiation. 33 patients were medically inoperable, 94 patients were irresectable, Despite of a significantly smaller tumor length in inoperable patients grade ≥3 toxicity was significantly recorded more often in the inoperable patients (44%) than in irresectable patients (20%) (pu2009<u20090.05) Hospital admission occurred more often in the inoperable patients (39%) than in the irresectable patients (22%) (pu2009<u20090.05) Median number of cycles of chemotherapy was five for inoperable patients (pu2009=u20090.01), while six cycles could be administered to patients with irresectable disease. Recurrence and survival were not significantly different. The odds ratio for developing toxicityu2009≥u2009grade 3 was 2.6 (95% CI 1.0-6.4 pu2009<u20090.05) for being an inoperable patient and 1.2 (95% CI 1.0-1.4 pu2009=u20090.02) per 10 extra micromol/l creatinine.ConclusionsOur data show that acute toxicity of definitive chemoradiation is worse in patients with medically inoperable esophageal carcinoma compared to patients with irresectable esophageal cancer and mainly occurs in the 5th cycle of treatment. Improvement of supportive care should be undertaken in this more fragile group.

Reduction of heart volume during neoadjuvant chemoradiation in patients with resectable esophageal cancer

BACKGROUND AND PURPOSEnNeoadjuvant chemoradiation (nCRT) followed by surgery is considered curative intent treatment for patients with resectable esophageal cancer. The aim was to establish hemodynamic aspects of changes in heart volume and to explore whether changes in heart volume resulted in clinically relevant changes in the dose distribution of radiotherapy.nnnMETHODSnA prospective study was conducted in patients who were treated with nCRT consisting of carboplatin and paclitaxel concomitant with radiotherapy (41.4 Gy/1.8 Gy per fraction). Physical parameters, cardiac volume on CT and Cone beam CT, cardiac blood markers and cardiac ultrasound were obtained.nnnRESULTSnIn 23 patients a significant decrease of 55.3 ml in heart volume was detected (95% CI 36.7-73.8 ml, p<0.001). There was a decrease in both systolic (mean decrease 18 mmHg, 95% CI 11-26 mmHg, p<0.001) and diastolic blood pressure (mean decrease 8 mmHg, 95% CI 2-14 mmHg, p=0.008) and an increase in heart rate with 6 beats/min (95% CI 1-11 beats/min, p=0.021). Except for Troponin T, no change in other cardiac markers and echocardiography parameters were observed. The change in heart volume did not result in a clinically relevant change in radiation dose distribution.nnnCONCLUSIONnHeart volume was significantly reduced, but was not accompanied by overt cardiac dysfunction. All observed changes in hemodynamic parameters are consistent with volume depletion. Adaptation of the treatment plan during the course of radiotherapy is not advocated.

Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (preSANO): a prospective multicentre, diagnostic cohort study

BACKGROUNDnAfter neoadjuvant chemoradiotherapy for oesophageal cancer, roughly half of the patients with squamous cell carcinoma and a quarter of those with adenocarcinoma have a pathological complete response of the primary tumour before surgery. Thus, the necessity of standard oesophagectomy after neoadjuvant chemoradiotherapy should be reconsidered for patients who respond sufficiently to neoadjuvant treatment. In this study, we aimed to establish the accuracy of detection of residual disease after neoadjuvant chemoradiotherapy with different diagnostic approaches, and the optimal combination of diagnostic techniques for clinical response evaluations.nnnMETHODSnThe preSANO trial was a prospective, multicentre, diagnostic cohort study at six centres in the Netherlands. Eligible patients were aged 18 years or older, had histologically proven, resectable, squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction, and were eligible for potential curative therapy with neoadjuvant chemoradiotherapy (five weekly cycles of carboplatin [area under the curve 2 mg/mL per min] plus paclitaxel [50 mg/m2 of body-surface area] combined with 41·4 Gy radiotherapy in 23 fractions) followed by oesophagectomy. 4-6 weeks after completion of neoadjuvant chemoradiotherapy, patients had oesophagogastroduodenoscopy with biopsies and endoscopic ultrasonography with measurement of maximum tumour thickness. Patients with histologically proven locoregional residual disease or no-pass during endoscopy and without distant metastases underwent immediate surgical resection. In the remaining patients a second clinical response evaluation was done (PET-CT, oesophagogastroduodenoscopy with biopsies, endoscopic ultrasonography with measurement of maximum tumour thickness, and fine-needle aspiration of suspicious lymph nodes), followed by surgery 12-14 weeks after completion of neoadjuvant chemoradiotherapy. The primary endpoint was the correlation between clinical response during clinical response evaluations and the final pathological response in resection specimens, as shown by the proportion of tumour regression grade (TRG) 3 or 4 (>10% residual carcinoma in the resection specimen) residual tumours that was missed during clinical response evaluations. This study was registered with the Netherlands Trial Register (NTR4834), and has been completed.nnnFINDINGSnBetween July 22, 2013, and Dec 28, 2016, 219 patients were included, 207 of whom were included in the analyses. Eight of 26 TRG3 or TRG4 tumours (31% [95% CI 17-50]) were missed by endoscopy with regular biopsies and fine-needle aspiration. Four of 41 TRG3 or TRG4 tumours (10% [95% CI 4-23]) were missed with bite-on-bite biopsies and fine-needle aspiration. Endoscopic ultrasonography with maximum tumour thickness measurement missed TRG3 or TRG4 residual tumours in 11 of 39 patients (28% [95% CI 17-44]). PET-CT missed six of 41 TRG3 or TRG4 tumours (15% [95% CI 7-28]). PET-CT detected interval distant histologically proven metastases in 18 (9%) of 190 patients (one squamous cell carcinoma, 17 adenocarcinomas).nnnINTERPRETATIONnAfter neoadjuvant chemoradiotherapy for oesophageal cancer, clinical response evaluation with endoscopic ultrasonography, bite-on-bite biopsies, and fine-needle aspiration of suspicious lymph nodes was adequate for detection of locoregional residual disease, with PET-CT for detection of interval metastases. Active surveillance with this combination of diagnostic modalities is now being assessed in a phase 3 randomised controlled trial (SANO trial; Netherlands Trial Register NTR6803).nnnFUNDINGnDutch Cancer Society.

Second- and third-line systemic therapy in patients with advanced esophagogastric cancer: a systematic review of the literature

The optimal second- and third-line chemotherapy and targeted therapy for patients with advanced esophagogastric cancer is still a matter of debate. Therefore, a literature search was carried out in Medline, EMBASE, CENTRAL, and oncology conferences until January 2016 for randomized controlled trials that compared second- or third-line therapy. We included 28 studies with 4810 patients. Second-line, single-agent taxane/irinotecan showed increased survival compared to best supportive care (BSC) (hazard ratio 0.65, 95xa0% confidence interval 0.53–0.79). Median survival gain ranged from 1.4 to 2.7xa0months among individual studies. Taxane- and irinotecan-based regimens showed equal survival benefit. Doublet chemotherapy taxane/irinotecan plus platinum and fluoropyrimidine was not different in survival, but showed increased toxicity vs. taxane/irinotecan monotherapy. Compared to BSC, second-line ramucirumab and second- or third-line everolimus and regorafenib showed limited median survival gain ranging from 1.1 to 1.4xa0months, and progression-free survival gain, ranging from 0.3 to 1.6xa0months. Third- or later-line apatinib showed increased survival benefit over BSC (HR 0.50, 0.32–0.79). Median survival gain ranged from 1.8 to 2.3xa0months. Compared to taxane-alone, survival was superior for second-line ramucirumab plus taxane (HR 0.81, 0.68–0.96), and olaparib plus taxane (HR 0.56, 0.35–0.87), with median survival gains of 2.2 and 4.8xa0months respectively. Targeted agents, either in monotherapy or combined with chemotherapy showed increased toxicity compared to BSC and chemotherapy-alone. This review indicates that, given the survival benefit in a phase III study setting, ramucirumab plus taxane is the preferred second-line treatment. Taxane or irinotecan monotherapy are alternatives, although the absolute survival benefit was limited. In third-line setting, apatinib monotherapy is preferred.

Capecitabine, 5-fluorouracil and S-1 based regimens for previously untreated advanced oesophagogastric cancer: A network meta-analysis

As evidence is inconsistent and based on either isolated Asian or Western studies, we conducted a network meta-analysis (NMA) to examine efficacy and safety of 5-FU (5-fluorouracil), capecitabine and S-1-based first-line treatment of advanced esophagogastric cancer in Asian and Western patients. Medline, EMBASE, CENTRAL and conferences ASCO and ESMO were searched up to January 2016 for randomized-controlled-trials comparing 5-FU, capecitabine or S-1-based regimens with equal chemotherapy backbones. Direct and indirect data for overall survival (OS) and progression-free-survival (PFS) were combined on the Hazard Ratio (HR)-scale using random-effects NMA and calculated as combined HRs and 95%credible intervals (95%CrI). Grade 1-2 and grade 3-4 adverse events were compared with pair-wise meta-analysis. Fifteen studies were identified including capecitabine (nu2009=u2009945), 5-FU (nu2009=u20092,132) or S-1 (nu2009=u20091,636). No differences were found in respectively OS and PFS for capecitabine-based versus 5-FU-based regimens (HRu2009=u20090.89, 95%CrIu2009=u20090.76–1.04 and HRu2009=u20090.98, 95%CrIu2009=u20090.75–1.32), S-1-based versus 5-FU-based regimens (HRu2009=u20090.92, 95%CrIu2009=u20090.82–1.04 and HRu2009=u20090.88, 95%CrIu2009=u20090.70–1.11) and S-1-based versus capecitabine-based regimens (HRu2009=u20091.03, 95%CrIu2009=u20090.87–1.22 and HRu2009=u20090.89, 95%CrIu2009=u20090.65–1.20). Effects were similar in Asian and Western subgroups. Toxicity profiles were different but a lower frequency of relevant adverse events was observed with S-1 In conclusion, as efficacy was similar, choosing fluoropyrimidines should be based on their individual toxicity profiles.