While tumor-tissue remains the ‘gold standard’ for genetic analysis in cancer patients, it is challenged with the advent of circulating cell-free tumor DNA (ctDNA) analysis from blood samples. Here, ...we broaden our previous study on the clinical validation of plasma DNA in metastatic colorectal cancer patients, by evaluating its clinical utility under standard management care.
Concordance and data turnaround-time of ctDNA when compared with tumor-tissue analysis were studied in a real-time blinded prospective multicenter clinical study (n = 140 metastatic colorectal patients). Results are presented according to STARD criteria and were discussed in regard with clinical outcomes of patients.
Much more mutations were found by ctDNA analysis: 59%, 11.8% and 14.4% of the patients were found KRAS, NRAS and BRAF mutant by ctDNA analysis instead of 44%, 8.8% and 7.2% by tumor-tissue analysis. Median tumor-tissue data turnaround-time was 16 days while 2 days for ctDNA analysis. Discordant samples analysis revealed that use of biopsy, long delay between tumor-tissue and blood collection and resection of the tumor at time of blood draw, tumor site, or type of tissue analyzed seem to affect concordance. Altogether, the clinical data with respect to the anti-epidermal growth factor receptor response (RAS status) and the prognosis (BRAF status) of those discordant patients do not appear contradictory to the mutational status as determined by plasma analysis. Lastly, we present the first distribution profile of the RAS and BRAF hotspot mutations as determined by ctDNA analysis (n = 119), revealing a high proportion of patients with multiple mutations (45% of the population and up to 5 mutations) and only 24% of WT scored patients for both genes. Mutation profile as determined from ctDNA analysis with using various detection thresholds highlights the importance of the test sensitivity.
Our study showed that ctDNA could replace tumor-tissue analysis, and also clinical utility of ctDNA analysis by considerably reducing data turnaround time.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The past 5 years have seen the clear recognition that the administration of chemotherapy to patients with initially unresectable colorectal liver metastases can increase the number of patients who ...can undergo potentially curative secondary liver resection. Coupled with this, recent data have emerged that show that perioperative chemotherapy confers a disease-free survival advantage over surgery alone in colorectal cancer (CRC) patients with initially resectable liver disease. The purpose of this paper is to build on the existing knowledge and review the issues surrounding the use of chemotherapy ± targeted agents combined with surgery in the treatment of CRC patients with liver metastases, with a view to providing clinical recommendations. An international panel of 21 experts in colorectal oncology comprising liver surgeons and medical oncologists reviewed the available evidence. In a major change to clinical practice, the panel's recommendation was that the majority of patients with CRC liver metastases should be treated up front with chemotherapy, irrespective of the initial resectability status of their metastases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Studies indicate that adjuvant 5-fluorouracil (5-FU) with folinic acid (FA) in colorectal cancer patients with completely resectable liver-limited metastases (LMCRC) offers clinical benefit over ...surgery alone. This phase III trial compared FOLFIRI with simplified 5-FU/FA in this setting.
LMCRC patients were randomized to receive every 14 days, FA, 400 mg/m2 infused over 2 h, followed by 5-FU as a 400 mg/m2 i.v. bolus, followed by continuous 5-FU infusion, 2400 mg/m2 over 46 h (LV5FUs) with or without irinotecan: 180 mg/m2 infusion (FOLFIRI). The primary end point was disease-free survival (DFS); secondary end points included overall survival (OS) and safety.
Treated patients (n = 306) were balanced for critical prognostic factors in each arm. Median DFS in patients receiving LV5FUs was 21.6 versus 24.7 months for FOLFIRI hazard ratio (HR) 0.89, log-rank P = 0.44. No significant differences were found in OS. A trend was observed for improved DFS in patients receiving FOLFIRI within 42 days of surgery (HR 0.75, P = 0.17). Grade 3/4 toxic effects were more common in patients treated with FOLFIRI versus LV5FUs (47% versus 30%) with neutropenia being most common (23% versus 7%).
FOLFIRI in the adjuvant treatment of LMCRC showed no significant improvement in DFS compared with LV5FUs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Most patients with pancreatic cancer present with advanced/metastatic disease and have a dismal prognosis. Despite the proven albeit modest benefits of gemcitabine demonstrated over a decade ...ago, subsequent advances have been slow, suggesting it may be time to take a different approach. It is thought that some key characteristics of pancreatic cancer, such as the desmoplasia, restricted vasculature and hypoxic environment, may prevent the delivery of chemotherapy to the tumour thereby explaining the limited benefits observed to-date. Moreover, there is evidence to suggest that the stroma is not only a mechanical barrier but also constitutes a dynamic compartment of pancreatic tumours that is critically involved in tumour formation, progression and metastasis. Thus, targeting the stroma and the tumour represents a promising therapeutic strategy. Currently, several stroma-targeting agents are entering clinical development. Among these, nab-paclitaxel appears promising since it combines cytotoxic therapy with targeted delivery via its proposed ability to bind SPARC on tumour and stromal cells. Preclinical data indicate that co-treatment with nab-paclitaxel and gemcitabine results in stromal depletion, increased tumour vascularization and intratumoural gemcitabine concentration, and increased tumour regression compared with either agent alone. Phase I/II study data also suggest that a high level of antitumor activity can be achieved with this combination in pancreatic cancer. This was recently confirmed in a Phase III study which showed that nab-paclitaxel plus gemcitabine significantly improved overall survival (HR 0.72) and progression-free survival (HR 0.69) versus gemcitabine alone for the first-line treatment of patients with metastatic pancreatic cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Background Currently, metastatic colorectal cancer is treated as a homogeneous disease and only RAS mutational status has been approved as a negative predictive factor in patients treated ...with cetuximab. The aim of this study was to evaluate if recently identified molecular subtypes of colon cancer are associated with response of metastatic patients to first-line therapy. Patients and methods We collected and analysed 143 samples of human colorectal tumours with complete clinical annotations, including the response to treatment. Gene expression profiling was used to classify patients in three to six classes using four different molecular classifications. Correlations between molecular subtypes, response to treatment, progression-free and overall survival were analysed. Results We first demonstrated that the four previously described molecular classifications of colorectal cancer defined in non-metastatic patients also correctly classify stage IV patients. One of the classifications is strongly associated with response to FOLFIRI ( P = 0.003), but not to FOLFOX ( P = 0.911) and FOLFIRI + Bevacizumab ( P = 0.190). In particular, we identify a molecular subtype representing 28% of the patients that shows an exceptionally high response rate to FOLFIRI (87.5%). These patients have a two-fold longer overall survival (40.1 months) when treated with FOLFIRI, as first-line regimen, instead of FOLFOX (18.6 months). Conclusions Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer and a strong impact of the first-line regimen on the overall survival of some patients. This however remains to be confirmed in a large prospective clinical trial.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Metastatic colorectal cancer (mCRC) is one of the major causes of cancer-related death. Despite the substantial progress in mCRC management, it remains important to identify new therapeutic options ...and biological markers for personalized medicine. Here, we investigated the expression of claudin-1 (CLDN1), a major tight junction transmembrane protein, in the different colorectal cancer (CRC) molecular subtypes and then assessed the anti-tumor effect of a new anti-CLDN1 monoclonal antibody (mAb).
Gene expression profiling and immunochemistry analysis of normal and tumor tissue samples from patients with stage IV CRC were used to determine CLDN1 gene expression. Then, the 6F6 mAb against CLDN1 extracellular part was generated. Its effect on CRC cell cycle, proliferation, survival and migration was assessed in vitro, using a 3D cell culture system, flow cytometry, clonogenic and migration assays. In vivo, 6 F6 mAb efficacy was evaluated in nude mice after subcutaneous xenografts or intrasplenic injection of CRC cells.
Compared with normal mucosa where it was almost exclusively cytoplasmic, in CRC samples CLDN1 was overexpressed (p < 0.001) and mainly localized at the membrane. Moreover, it was differentially expressed in the various CRC molecular subtypes. The strongest expressions were found in the consensus molecular subtype CMS2 (p < 0.001), the transit-ampliflying (p < 0.001) and the C5 subtypes (p < 0.001). Lower CLDN1 expression predicted a better outcome in the molecular subtypes C3 and C5 (p = 0.012 and p = 0.004, respectively). CLDN1 targeting with the 6 F6 mAb led to reduction of survival, growth and migration of CLDN1-positive cells. In preclinical mouse models, the 6F6 mAb decreased tumor growth and liver metastasis formation.
Our data indicate that CLDN1 targeting with an anti-CLDN1 mAb results in decreased growth and survival of CRC cells. This suggests that CLDN1 could be a new potential therapeutic target.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background: This multicenter adjuvant phase III trial evaluated the addition of irinotecan to LV5FU2 in colon cancer patients at high risk of relapse. Patients and methods: A total of 400 patients ...with histologically proven primary colon cancer with postoperative N1 detected by occlusion/perforation or N2 were randomised to: A—LV5FU2 leucovorin 200 mg/m2, 2-h infusion, 5-fluorouracil (5-FU) 400 mg/m2 bolus, 600 mg/m2 22-h continuous infusion, days 1 and 2 or B—LV5FU2 + IRI (irinotecan 180 mg/m2 90-min infusion day 1 + LV5FU2) fortnightly for 12 cycles. Primary end point was disease-free survival (DFS). Results: Median follow-up was 63 months. Significantly more T4 tumours and 15 or more positive lymph nodes were observed in arm B. 5-FU relative dose intensity (RDI) was >0.80 for 94% and 77% in arms A and B, respectively (P < 0.001). Irinotecan RDI was >0.80 for 70% patients. There were more grades 3 and 4 neutropenia in arm B (4% versus 28%, P < 0.001). The 3-year DFS was 60% 95% confidence interval (CI) 53% to 66% and 51% (95% CI 44% to 58) in arms A and B, respectively. No difference was observed hazard ratio (HR) = 1.12, 95% CI 0.85–1.47, P = 0.42 even when adjusted for prognostic factors (adjusted HR = 0.98, 95% CI 0.74–1.31, P = 0.92). The 5-year overall survival (OS) was 67% (95% CI 59% to 73%) and 61% (95% CI 53% to 67%) in arms A and B, respectively. Conclusion: Adjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Plusieurs études de phase II ont montré la faisabilité des protocoles de chimioradiothérapie néoadjuvante dans la prise en charge des adénocarcinomes du pancréas considérés comme résécables d’emblée. ...Cependant, en l’absence d’essai de phase III validant cette approche thérapeutique, l’évaluation de son efficacité est toujours d’actualité. À partir des résultats matures de l’essai de phase II de la Société française de radiothérapie oncologique (SFRO) et de la Fédération francophone de cancérologie digestive (FFCD) 9704, nous avons analysé l’efficacité thérapeutique d’une chimioradiothérapie préopératoire à base de 5-fluoro-uracile et de cisplatine, avec un accent tout particulier sur la réponse anatomopathologique, et avons mené une revue de la littérature.
La chimioradiothérapie préopératoire consistait en une irradiation de la tumeur pancréatique et des ganglions lymphatiques satellites à la dose de 50
Gy en 25 fractions et cinq semaines, et en une chimiothérapie concomitante par 300
mg/m
2/jour de 5-fluoro-uracile, cinq jours par semaine, cinq semaines consécutives, et 20
mg/m
2/j de cisplatine de j1 à j5 et j29 à j33. L’exérèse chirurgicale était réalisée trois à six semaines plus tard en l’absence de progression locorégionale.
Parmi les 41 patients inclus, 26 (63 %) ont eu une exérèse chirurgicale de la tumeur, dont 21 (80,7 %) microscopiquement complète. Une réponse pathologique majeure (≥
80 % de cellules cancéreuses sévèrement dégénérées) a été observée sur 13 des 26 pièces opératoires (50 %), dont une réponse histologique complète. Les taux de récidive locale et de survie globale à deux ans étaient, respectivement, de 4 et 32 % chez les 26 patients opérés.
Nos résultats suggèrent que la chimioradiothérapie préopératoire aurait une efficacité antitumorale se traduisant par une réponse histopathologique majeure chez 50 % des patients et un taux élevé de résection R0. Une discussion particulière, peu fréquemment disponible dans la littérature, découle des résultats anatomopathologiques relatifs à la réponse au traitement et suggère la mise en place de paramètres prédictifs et pronostiques de la réponse thérapeutique.
Several phase II studies have shown the feasibility of neoadjuvant chemoradiation regimens for resectable localized pancreatic adenocarcinoma. However, there is to date no completed phase III study to validate this approach and treatment effects evaluation still remains an active area of investigation. From the mature results of the SFRO-FFCD 9704 trial, we explored the antitumoral effect of a 5-fluoro-uracil and cisplatin-based preoperative chemoradiation regimen, with a special highlight on the histopathological response and performed a literature review.
Treatment consisted of concurrent radiotherapy (50
Gy within five weeks) and chemotherapy with 5-fluoro-uracil (300
mg/m
2/day, five days/week, weeks 1–5) and cisplatin (20
mg/m
2/day, days 1–5 and 29–33), followed by surgical resection of the pancreatic tumour in patients without progression.
In all, 41 patients were enrolled, 26 patients (63%) underwent surgical resection with curative intent and 21 (80.7%) had R0 resection. A total of 13 of 26 specimens (50%) presented a major pathologic response (≥
80% of severely degenerative cancer cells), with one complete pathologic response. The local recurrence and two-year survival rates were 4 and 32%, respectively, for the 26 operated patients.
Our results suggest that preoperative chemoradiation provides antitumoral effect associated with major histopathological response in 50% of patients and a high R0 resection rate. Evaluation of histopathological response to neoadjuvant chemoradiation may serve as a surrogate marker for treatment efficacy and further research is needed to determine new prognostic and predictive factors of treatment response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We explored the feasibility and the histologic assessment of treatment effect of preoperative chemoradiation in patients presenting with resectable pancreatic adenocarcinoma.
Treatment consisted of ...concurrent radiotherapy (50 Gy within 5 weeks) and chemotherapy with 5-fluorouracil (300 mg/m2/day, 5 days/week, weeks 1–5) and cisplatin (20 mg/m2/day, days 1–5 and 29–33), followed by surgical resection of the pancreatic tumor in patients without progression.
In all, 41 patients were enrolled; 38 (93%) received ≥47 Gy; 30 patients (73%) received ≥75% of the prescribed doses of chemotherapy. Among 40 assessable patients, 27 (67.5%; 95% confidence interval 50.9% to 81.4%) were successfully treated (entire dose of radiation, ≥75% of the chemotherapy dose, no grade 4 non-hematologic toxicity). In all, 26 patients (63%) underwent surgical resection with curative intent and 21 (80.7%) had R0 resection. A total of 13 of 26 specimens (50%) presented a major pathologic response (≥80% of severely degenerative cancer cells), with one complete pathologic response. Operative mortality was 2.8%. The local recurrence and 2-year survival rates were 4% and 32%, respectively, for the 26 operated patients.
This proposed preoperative scheme is feasible, does not prevent successful surgery, and provides antitumoral effect associated with major histopathological response in 50% of patients and a high R0 resection rate.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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