In a prospective, randomized trial involving patients with resected pancreatic cancer, adjuvant combination chemotherapy with FOLFIRINOX resulted in a median disease-free survival of 21.6 months, as ...compared with 12.8 months with gemcitabine therapy. Overall survival was also longer with FOLFIRINOX.
Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether ...administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences.
We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18–75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0–1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 intravenously every 14 days for 6 cycles), chemoradiotherapy (50 Gy during 5 weeks and 800 mg/m2 concurrent oral capecitabine twice daily for 5 days per week), total mesorectal excision, and adjuvant chemotherapy (3 months of modified FOLFOX6 intravenous oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2, followed by intravenous 400 mg/m2 fluorouracil bolus and then continuous infusion at a dose of 2400 mg/m2 over 46 h every 14 days for six cycles or capecitabine 1250 mg/m2 orally twice daily on days 1–14 every 21 days). The standard-of-care group received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Safety analyses were done on treated patients. This trial was registered with EudraCT (2011-004406-25) and ClinicalTrials.gov (NCT01804790) and is now complete.
Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46·5 months (IQR 35·4–61·6), 3-year disease-free survival rates were 76% (95% CI 69–81) in the neoadjuvant chemotherapy group and 69% (62–74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49–0·97; p=0·034). During neoadjuvant chemotherapy, the most common grade 3–4 adverse events were neutropenia (38 17% of 225 patients) and diarrhoea (25 11% of 226). During chemoradiotherapy, the most common grade 3–4 adverse event was lymphopenia (59 28% of 212 in the neoadjuvant chemotherapy group vs 67 30% of 226 patients in the standard-of-care group). During adjuvant chemotherapy, the most common grade 3–4 adverse events were lymphopenia (18 11% of 161 in the neoadjuvant chemotherapy group vs 42 27% of 155 in the standard-of-care group), neutropenia (nine 6% of 161 vs 28 18% of 155), and peripheral sensory neuropathy (19 12% of 162 vs 32 21% of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0·167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0·0049). Treatment-related deaths occurred in one (<1%) of 226 patients in the neoadjuvant chemotherapy group (sudden death) and two (1%) of 227 patients in the standard-of-care group (one sudden death and one myocardial infarction).
Intensification of chemotherapy using FOLFIRINOX before preoperative chemoradiotherapy significantly improved outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer. The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the decreased neurotoxicity indicates that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, the PRODIGE 23 results might change clinical practice.
Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer.
Genomic studies have revealed subtypes of pancreatic ductal adenocarcinoma (PDA) based on their molecular features, but different studies have reported different classification systems. It is a ...challenge to obtain high-quality, freshly frozen tissue for clinical analysis and determination of PDA subtypes. We aimed to redefine subtypes of PDA using a large number of formalin-fixed and paraffin-embedded PDA samples, which are more amenable to routine clinical evaluation.
We collected PDA samples from 309 consecutive patients who underwent surgery from September 1996 through December 2010 at 4 academic hospitals in Europe; nontumor tissue samples were not included. Samples were formalin fixed and paraffin embedded. DNA and RNA were isolated; gene expression, targeted DNA sequencing, and immunohistochemical analyses were performed. We used independent component analysis to deconvolute normal, tumor, and microenvironment transcriptome patterns in samples. We devised classification systems from an unsupervised analysis using a consensus clustering approach of our data set after removing normal contamination components. We associated subtypes with overall survival and disease-free survival of patients using Cox proportional hazards regression with estimation of hazard ratios and 95% confidence interval. We used The Cancer Genome Consortium and International Cancer Genome Consortium PDA data sets as validation cohorts.
We validated the previously reported basal-like and classical tumor-specific subtypes of PDAs. We identified features of the PDA, including microenvironment gene expression patterns, that allowed tumors to be categorized into 5 subtypes, called pure basal like, stroma activated, desmoplastic, pure classical, and immune classical. These PDA subtypes have features of cancer cells and immune cells that could be targeted by pharmacologic agents. Tumor subtypes were associated with patient outcomes, based on analysis of our data set and the International Cancer Genome Consortium and The Cancer Genome Consortium PDA data sets. We also observed an exocrine signal associated with acinar cell contamination (from pancreatic tissue).
We identified a classification system based on gene expression analysis of formalin-fixed PDA samples. We identified 5 PDA subtypes, based on features of cancer cells and the tumor microenvironment. This system might be used to select therapies and predict patient outcomes. We found evidence that the previously reported exocrine-like (called ADEX) tumor subtype resulted from contamination with pancreatic acinar cells.
ArrayExpress accession number: E-MTAB-6134.
Panitumumab is approved for RAS wild‐type metastatic colorectal cancer and was evaluated in Phase III (PRIME, NCT00364013) and Phase II (PEAK, NCT00819780) first‐line randomised studies. This ...retrospective analysis of these trials investigated efficacy and toxicity of panitumumab‐based maintenance after oxaliplatin discontinuation in RAS wild‐type patients. First‐line regimens were FOLFOX4 ± panitumumab in PRIME and mFOLFOX6 plus panitumumab or mFOLFOX6 plus bevacizumab in PEAK. Outcomes included median progression‐free survival (PFS) and overall survival (OS), from randomisation and oxaliplatin discontinuation, and toxicity. Overall, median duration of panitumumab plus 5‐fluorouracil/leucovorin (5‐FU/LV) maintenance was 21 (interquartile range: 11–41) weeks; that of 5‐FU/LV ± bevacizumab maintenance was 16 (6–31) weeks. Median OS from randomisation was 40.2 (95% confidence interval: 30.3–50.4) and 39.1 (34.2–63.0) months for panitumumab plus 5‐FU/LV maintenance and 24.1 (17.7–33.0) and 28.9 (21.0–32.0) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. Median PFS from randomisation was 16.6 (11.3–23.6) and 15.4 (11.6–18.4) months for panitumumab plus 5‐FU/LV maintenance and 12.6 (9.4–16.2) and 13.1 (9.5–16.6) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. From oxaliplatin discontinuation, median OS was 33.9 (24.7–42.8) and 33.5 (24.5–54.9) months for panitumumab plus 5‐FU/LV maintenance and 16.4 (12.4–24.1) and 23.3 (15.7–26.3) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively; PFS was 11.7 (7.8–19.2) and 9.7 (5.8–14.8) months and 7.1 (5.6–10.2) and 7.0 (3.9–10.6) months, respectively. The most frequently reported adverse events were rash, fatigue and diarrhoea. Maintenance of panitumumab plus 5‐FU/LV after oxaliplatin discontinuation was well tolerated and may be an acceptable treatment paradigm for patients demonstrating a good response to first‐line treatment. Prospective studies are warranted.
What's new?
Panitumumab is an anti‐EGFR antibody used in the treatment of RAS wild‐type metastatic colorectal cancer. But is it useful for long‐term therapy in these patients, especially after more toxic therapies like oxaliplatin are discontinued? In this retrospective analysis, the authors found that a maintenance regimen including panitumumab was well tolerated and may be associated with better outcomes than non‐panitumumab strategies. Patients who received panitumumab‐based maintenance therapy were also more likely to have had a good response to first‐line treatment. The results from this study indicate that further, prospective studies are warranted.
At time of diagnosis, less than 10% of patients with pancreatic adenocarcinomas (PDAC) are considered to be immediately operable (i.e. resectable). Considering their poor overall survival (OS), only ...tumours without vascular invasion (NCCN 2017) should be considered for resection, i.e. those for which resection with disease-free margins (R0) is theoretically possible in absence of presurgery treatment. With regard to high R1 rates and undetectable locoregional and/or metastatic spreading prior to surgery explain (at least in part) the observed 1-year relapse and mortality rates of 50 and 25%, respectively. Today, upfront surgery followed by adjuvant chemotherapy is the reference treatment in Europe. The main limitation of the adjuvant approach is the low rate of completion of the full therapeutic sequence. Indeed, only 47 to 60% patients received any adjuvant therapy after resection compared to more than 75% for neoadjuvant therapy. No previous prospective study has compared this approach to a neoadjuvant FOLFIRINOX or FOLFOX chemotherapy for resectable PDAC.
PANACHE01-PRODIGE48 is a prospective multicentre controlled randomized non comparative Phase II trial, evaluating the safety and efficacy of two regimens of neo-adjuvant chemotherapy (4 cycles of mFOLFIRINOX or FOLFOX) relative to the current reference treatment (surgery and then adjuvant chemotherapy) in patients with resectable PDAC. The main co-primary endpoints are OS rate at 12 months and the rate of patients undergoing the full therapeutic sequence.
The "ideal" cancer treatment for resectable PDAC would have the following characteristics: administration to the highest possible proportion of patients, ability to identify fast-progressing patients (i.e. poor candidates for surgery), a low rate of R1 resections (through optimisation of local disease control), and an acceptable toxicity profile. The neoadjuvant approach may meet all these criteria. With respect to published data on the efficacy of FOLFOX and mFOLFIRINOX, these two regimens are potential candidates for neoadjuvant use in the aim to optimising oncological outcomes in resectable PDAC.
ClinicalTrials.gov , NCT02959879 . Trial registration date: November 9, 2016.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Pancreatic adenocarcinoma remains a devastating disease with a 5-year survival rate not exceeding 6%. Treatment of this disease remains a major challenge. This article reviews the ...state-of-the-art in the management of this disease and the new innovative approaches that may help to accelerate progress in treating its victims. After careful pre-therapeutic evaluation, only 15–20% of patients diagnosed with a pancreatic cancer (PC) are eligible for upfront radical surgery. After R0 or R1 resection in such patients, evidence suggests a significantly positive impact on survival of adjuvant chemotherapy comprising 6 months of gemcitabine or fluorouracil/folinic acid. Delayed adjuvant chemoradiation is considered as an option in cases of positive margins. Borderline resectable pancreatic cancer (BRPC) is defined as a tumour involving the mesenteric vasculature to a limited extend. Resection of these tumours is technically feasible, yet runs the high risk of a R1 resection. Neoadjuvant treatment probably offers the best chance of achieving successful R0 resection and long-term survival, but the best treatment options should be determined in prospective randomised studies. Gemcitabine has for 15 years been the only validated therapy for advanced PC. Following decades of negative phase III studies, increasing evidence now suggests that further significant improvements to overall survival can be achieved via either Folfirinox or gemcitabine + nab-paclitaxel regimens. Progress in systemic therapy may improve the chances of resection in borderline resectable pancreatic cancer (BRPC) or locally advanced PC. This requires first enhancing knowledge of the genetic events driving carcinogenesis, which may then be translated into clinical studies.
Oxaliplatin combined with fluoropyrimidine improves survival in patients with stage III colon cancer. However, adjuvant chemotherapy with oxaliplatin is controversial in stage II and elderly ...patients.
We performed subgroup analyses of stage II and elderly patients randomly assigned fluorouracil with leucovorin (FL) ± oxaliplatin (FOLFOX4) in the Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer study. Comorbidities, severe adverse events, second cancers, management of relapse and death as a result of causes than other colon cancer were studied.
Two thousand two hundred forty-six patients were enrolled. Overall, 899 patients had stage II disease, including 330 low-risk and 569 high-risk patients. A total of 315 patients were ages 70 to 75 years. For stage II patients, the hazard ratio (HR) for comparing FOLFOX4 with FL was 0.84 (95% CI, 0.62 to 01.14) for disease-free survival (DFS), 0.70 (95% CI, 0.49 to 0.99) for time to recurrence (TTR), and 1.00 (95% CI, 0.70 to 1.41) for overall survival (OS). There was no interaction between treatment and stage or age. Low-risk stage II patients did not benefit from oxaliplatin. In high-risk stage II patients, the HR comparing FOLFOX4 with FL was 0.72 (95% CI, 0.51 to 1.01) for DFS, 0.62 (95% CI, 0.41 to 0.92) for TTR, and 0.91 (95% CI, 0.61 to 1.36) for OS. In elderly patients, the HR comparing FOLFOX4 with FL was 0.93 (95% CI, 0.64 to 1.35) for DFS, 0.72 (95% CI, 0.47 to 1.11) for TTR, and 1.10 (95% CI, 0.73 to 1.65) for OS.
The results of these subset analyses show no statistically significant benefit (OS and DFS) for the addition of oxaliplatin to FL as adjuvant treatment for either stage II and elderly patients.
Background
Neurokinin (NK) 1 receptor antagonists (RAs), administered in combination with a 5‐hydroxytryptamine‐3 (5‐HT3) RA and dexamethasone (DEX), have demonstrated clear improvements in ...chemotherapy‐induced nausea and vomiting (CINV) prevention over a 5‐HT3RA plus DEX. However, studies comparing the NK1RAs in the class are lacking. A fixed combination of a highly selective NK1RA, netupitant, and the 5‐HT3RA, palonosetron (NEPA), simultaneously targets two critical antiemetic pathways, thereby offering a simple convenient antiemetic with long‐lasting protection from CINV. This study is the first head‐to‐head NK1RA comparative study in patients receiving anthracycline cyclophosphamide (AC) and non‐AC moderately emetogenic chemotherapy (MEC).
Materials and Methods
This was a pragmatic, multicenter, randomized, single‐cycle, open‐label, prospective study designed to demonstrate noninferiority of single‐dose NEPA to a 3‐day aprepitant regimen in preventing CINV in chemotherapy‐naive patients receiving AC/non‐AC MEC in a real‐life setting. The primary efficacy endpoint was complete response (no emesis/no rescue) during the overall (0–120 hour) phase. Noninferiority was achieved if the lower limit of the 95% confidence interval (CI) of the difference between NEPA and the aprepitant group was greater than the noninferiority margin set at −10%.
Results
Noninferiority of NEPA versus aprepitant was demonstrated (risk difference 9.2%; 95% CI, −2.3% to 20.7%); the overall complete response rate was numerically higher for NEPA (64.9%) than aprepitant (54.1%). Secondary endpoints also revealed numerically higher rates for NEPA than aprepitant.
Conclusion
This pragmatic study in patients with cancer receiving AC and non‐AC MEC revealed that a single dose of oral NEPA plus DEX was at least as effective as a 3‐day aprepitant regimen, with indication of a potential efficacy benefit for NEPA.
Implications for Practice
In the absence of comparative neurokinin 1 (NK1) receptor antagonist (RA) studies, guideline committees and clinicians consider NK1RA agents to be interchangeable and equivalent. This is the first head‐to‐head study comparing one NK1RA (oral netupitant/palonosetron NEPA) versus another (aprepitant) in patients receiving anthracycline cyclophosphamide (AC) and non‐AC moderately emetogenic chemotherapy. Noninferiority of NEPA versus the aprepitant regimen was demonstrated; the overall complete response (no emesis and no rescue use) rate was numerically higher for NEPA (65%) than aprepitant (54%). As a single‐dose combination antiemetic, NEPA not only simplifies dosing but may offer a potential efficacy benefit over the current standard‐of‐care.
Guidelines suggest that NK1RA agents are interchangeable. This article reports the first study comparing one NK1RA (oral NEPA netupitant/palonosetron) with another (aprepitant) in patients receiving chemotherapy.
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