Abstract Ovarian carcinoma is the most lethal gynaecologic malignancy. Despite wide initial sensibility to chemotherapy especially to platinum-based regimens, the vast majority of patients with ...advanced stages of the disease develop recurrences and subsequent resistance to treatments. Ovarian cancer is actually considered as a heterogeneous disease at the clinical, histological and molecular level. In this review, the mechanisms of intrinsic sensitivity or resistance to treatment, especially to platinum-based chemotherapy are considered with particular reference to the significance of tumour heterogeneity. The molecular features involved in acquired resistance are reviewed and the current hypotheses are discussed. In particular, potential disruptions of the DNA reparation pathways are highlighted.
Purpose A pathologic complete response (pCR; ypT0N0) of a rectal tumor after neoadjuvant radiochemotherapy (RCT) is associated with an excellent prognosis. Several retrospective studies have ...investigated the effect of increasing the delay after RCT. The aim of this study was to evaluate the effect of increasing the interval between the end of RCT and surgery on the pCR rate. Methods GRECCAR6 was a phase III, multicenter, randomized, open-label, parallel-group controlled trial. Patients with cT3/T4 or Tx N+ tumors of the mid or lower rectum who had received RCT (45 to 50 Gy with fluorouracil or capecitabine) were included. Patients were randomly included in the 7-week or the 11-week (11w) group. Primary end point was the pCR rate defined as a ypT0N0 specimen (NCT01648894). Results A total of 265 patients from 24 centers were enrolled between October 2012 and February 2015. The majority of the tumors were cT3 (82%). After RCT, surgery was not performed in nine patients (3.4%) because of the occurrence of distant metastasis (n = 5) or other reasons. Two patients underwent local resection of the tumor scar. A total of 47 (18.6%) specimens were classified as ypT0 (four had invaded lymph nodes 8.5%). The primary end point (ypT0N0) was not different (7 weeks: 20 of 133, 15.0% v 11w: 23 of 132, 17.4%; P = .5983). Morbidity was significantly increased in the 11w group (44.5% v 32%; P = .0404) as a result of increased medical complications (32.8% v 19.2%; P = .0137). The 11w group had a worse quality of mesorectal resection (complete mesorectum I 78.7% v 90%; P = .0156). Conclusion Waiting 11 weeks after RCT did not increase the rate of pCR after surgical resection. A longer waiting period may be associated with higher morbidity and more difficult surgical resection.
Summary Background Organ preservation is a concept proposed for patients with rectal cancer after a good clinical response to neoadjuvant chemotherapy, to potentially avoid morbidity and side-effects ...of rectal excision. The objective of this study was to compare local excision and total mesorectal excision in patients with a good response after chemoradiotherapy for lower rectal cancer. Methods We did a prospective, randomised, open-label, multicentre, phase 3 trial at 15 tertiary centres in France that were experts in the treatment of rectal cancer. Patients aged 18 years and older with stage T2T3 lower rectal carcinoma, of maximum size 4 cm, who had a good clinical response to neoadjuvant chemoradiotherapy (residual tumour ≤2 cm) were centrally randomly assigned by the surgeon before surgery to either local excision or total mesorectal excision surgery. Randomisation, which was done via the internet, was not stratified and used permuted blocks of size eight. In the local excision group, a completion total mesorectal excision was required if tumour stage was ypT2–3. The primary endpoint was a composite outcome of death, recurrence, morbidity, and side-effects at 2 years after surgery, to show superiority of local excision over total mesorectal excision in the modified intention-to-treat (ITT) population (expected proportions of patients having at least one event were 25% vs 60% for superiority). This trial was registered with ClinicalTrials.gov , number NCT00427375. Findings From March 1, 2007, to Sept 24, 2012, 186 patients received chemoradiotherapy and were enrolled in the study. 148 good clinical responders were randomly assigned to treatment, three were excluded (because they had metastatic disease, tumour >8 cm from anal verge, and withdrew consent), and 145 were analysed: 74 in the local excision group and 71 in the total mesorectal excision group. In the local excision group, 26 patients had a completion total mesorectal excision. At 2 years in the modified ITT population, one or more events from the composite primary outcome occurred in 41 (56%) of 73 patients in the local excision group and 33 (48%) of 69 in the total mesorectal excision group (odds ratio 1·33, 95% CI 0·62–2·86; p=0·43). In the modified ITT analysis, there was no difference between the groups in all components of the composite outcome, and superiority was not shown for local excision over total mesorectal excision. Interpretation We failed to show superiority of local excision over total mesorectal excision, because many patients in the local excision group received a completion total mesorectal excision that probably increased morbidity and side-effects, and compromised the potential advantages of local excision. Better patient selection to avoid unnecessary completion total mesorectal excision could improve the strategy. Funding National Cancer Institute of France, Sanofi, Roche Pharma.
Adjuvant radiotherapy (RT) after a local excision (LE) for ductal carcinoma in situ (DCIS) aims at reduction of the incidence of a local recurrence (LR). We analyzed the long-term risk on developing ...LR and its impact on survival after local treatment for DCIS.
Between 1986 and 1996, 1,010 women with complete LE of DCIS less than 5 cm were randomly assigned to no further treatment (LE group, n = 503) or RT (LE+RT group, n = 507). The median follow-up time was 15.8 years.
Radiotherapy reduced the risk of any LR by 48% (hazard ratio HR, 0.52; 95% CI, 0.40 to 0.68; P < .001). The 15-year LR-free rate was 69% in the LE group, which was increased to 82% in the LE+RT group. The 15-year invasive LR-free rate was 84% in the LE group and 90% in the LE+RT group (HR, 0.61; 95% CI, 0.42 to 0.87). The differences in LR in both arms did not lead to differences in breast cancer-specific survival (BCSS; HR, 1.07; 95% CI, 0.60 to 1.91) or overall survival (OS; HR, 1.02; 95% CI, 0.71 to 1.44). Patients with invasive LR had a significantly worse BCSS (HR, 17.66; 95% CI, 8.86 to 35.18) and OS (HR, 5.17; 95% CI, 3.09 to 8.66) compared with those who did not experience recurrence. A lower overall salvage mastectomy rate after LR was observed in the LE+RT group than in the LE group (13% v 19%, respectively).
At 15 years, almost one in three nonirradiated women developed an LR after LE for DCIS. RT reduced this risk by a factor of 2. Although women who developed an invasive recurrence had worse survival, the long-term prognosis was good and independent of the given treatment.
Purpose
To assess technical feasibility, safety, and efficacy of the liver venous deprivation (LVD) technique that combines both portal and hepatic vein embolization during the same procedure for ...liver preparation before major hepatectomy.
Materials and methods
Seven patients (mean age:63.6y42-77y) underwent trans-hepatic LVD for liver metastases (n = 2), hepatocellular carcinoma (n = 1), intrahepatic cholangiocarcinoma (n = 3) and Klatskin tumour (n = 1). Assessment of future remnant liver (FRL) volume, liver enzymes and histology was performed.
Results
Technical success was 100 %. No complication occurred before surgery. Resection was performed in 6/7 patients. CT-scan revealed hepatic congestion in the venous-deprived area (6/7 patients). A mean of 3 days (range: 1–8 days) after LVD, transaminases increased (AST: from 42 ± 24U/L to 103 ± 118U/L, ALT: from 45 ± 25U/L to 163 ± 205U/L). Twenty-three days (range: 13–30 days) after LVD, FRL increased from 28.2 % (range: 22.4–33.3 %) to 40.9 % (range: 33.6–59.3 %). During the first 7 days, venous-deprived liver volume increased (+13.4 %) probably reflecting vascular congestion, whereas it strongly decreased (-21.3 %) at 3-4 weeks. Histology (embolized lobe) revealed sinusoidal dilatation, hepatocyte necrosis and important atrophy in all patients.
Conclusion
Trans-hepatic LVD technique is feasible, well tolerated and provides fast and important hypertrophy of the FRL. This new technique needs to be further evaluated and compared to portal vein embolization.
Key Points
•
Twenty-three days after LVD, FRL increased from 28.2 % (range:22.4-33.3 %) to 40.9 % (range:33.6–59.3 %)
•
During the first 7 days, venous-deprived liver volume increased (+13.4 %)
•
Venous-deprived liver volume strongly decreased (mean atrophy:229 cc; -21.3 %) at 3-4 weeks
•
Histology of venous
-
deprived liver revealed sinusoidal dilatation
,
hepatocyte necrosis and important atrophy
BACKGROUND:Preoperative radiochemotherapy and total mesorectal excision are the standard-of-care for locally advanced rectal carcinoma, but some patients could be over- or undertreated.
...OBJECTIVE:This study aimed to assess the feasibility of radiochemotherapy tailored based on the tumor response to induction chemotherapy (FOLFIRINOX) to obtain a minimum R0 resection rate of 90% in the 4 arms of the study.
DESIGN:This study is a multicenter randomized trial (NCT01333709).
SETTING:This study was conducted at 16 French cancer specialty centers.
PATIENTS:Two hundred six patients with locally advanced rectal carcinoma were enrolled between 2011 and 2014.
INTERVENTIONS:Good responders (≥75% tumor volume reduction) were randomly assigned to immediate surgery (arm A) or standard radiochemotherapy (Cap 5050 Gy irradiation and 1600 mg/m oral capecitabine daily) plus surgery (arm B). Poor responders were randomly assigned to Cap 50 (arm C) or intensive radiochemotherapy (Cap 60, 60 Gy irradiation, arm D) before surgery.
OUTCOME MEASURES:The primary end point was a R0 resection rate (circumferential resection margin >1 mm).
STATISTICAL CONSIDERATIONS:The experimental strategies were to be considered effective if at least 28 successes (R0 resection) among 31 patients in each arm of stratum I and 34 successes among 40 patients in each arm of stratum II were reported (Simon 2-stage design).
RESULTS:After induction treatment (good compliance), 194 patients were classified as good (n = 30, 15%) or poor (n = 164, 85%) responders who were included in arms A and B (16 and 14 patients) and arms C and D (113 and 51 patients). The trial was prematurely stopped because of low accrual in arms A and B and recruitment completion in arms C and D. Data from 133 randomly assigned patients were analyzed11, 19, 52, and 51 patients in arms A, B, C, and D. Good responders had smaller tumors than poor responders (23 cm vs 45 cm; p < 0.001). The surgical procedure was similar among groups. The R0 resection rates 90% CI were 100% 70–100, 100% 85–100, 83% 72–91, and 88% 77–95. Among the first 40 patients, 34 successes were reported in arms C and D (85% R0 resection rate). The circumferential resection margin ≤1 rates were 0%, 0%, 12%, and 5% in arms A, B, C, and D. The rate of transformation from positive to negative circumferential resection margin was 93%.
LIMITATIONS:There was low accrual in arms A and B.
CONCLUSION:Tailoring preoperative radiochemotherapy based on the induction treatment response appears safe for poor responders and promising for good responders. Long-term clinical results are needed to confirm its efficacy. See Video Abstract at http://links.lww.com/DCR/A359.
Background
Resectability of pancreatic carcinoma (PC) is directly linked to vascular extension (Tempero MA et al. in J Natl Compr Canc Netw 15(8):1028–1061, 2017.
...https://doi.org/10.6004/jnccn.2017.0131
; Isaji S et al. in Pancreatology 18(1):2–11, 2018.
https://doi.org/10.1016/j.pan.2017.11.011
). Involvement of the celiac axis (CA) is typically a contraindication to surgery. High postoperative morbidity and subsequent poor prognosis have been observed in this case, especially for contact > 180° requiring arterial resection (Tempero MA et al. 2017). Recent medical advances in PC treatment, such as FOLFIRINOX-based chemotherapy eventually followed by chemoradiation therapy, offer the potential to select tumour for surgery and to obtain a negative-margin resection even in case of unresectable PC at diagnosis (Suker M et al. in Lancet Oncol 17(6):801–10, 2016.
https://doi.org/10.1016/s1470-2045(16)00172-8
; Pietrasz D et al. in Ann Surg Oncol 26(1):109–117, 2019.
https://doi.org/10.1245/s10434-018-6931-6
). A major pathologic response has been observed in more than 20% of patients after this treatment and is associated with an improved survival (Suker M et al. 2016; Pietrasz D et al. 2019). This evolution allows aggressive surgical strategies with the possibility of long-term disease control for patients showing a good response to induction treatment.
Patient
This video presents the case of a 66-year-old man diagnosed with a locally advanced ductal adenocarcinoma of the pancreatic body with a 360° involvement of the CA and the hepatic artery. After eight courses of FOLFIRINOX chemotherapy and a capecitabin-based chemoradiation, a surgical exploration was planned for potential resection.
Technique
The key steps of the procedure are presented, i.e. surgical exposition, assessment of resectability with frozen sections of peri-arterial tissues,
en bloc
resection (Strasberg SM et al. in Surgery 133(5):521–527, 2003.
https://doi.org/10.1067/msy.2003.146
), and primary end-to-end arterial reconstruction.
Conclusion
A modified Appleby operation for locally advanced PC is a technically challenging but feasible procedure in experienced teams. It offers the possibility of
en
bloc R0 resection of a locally advanced PC with the potential of long-term disease local control. This video may help surgeons to perform this complex intervention.
Background
Defunctioning stoma (DS) can decrease the rate of symptomatic anastomotic leakage (AL). Since 2010, we have used tailored, highly selective DS management for low colorectal anastomosis ...(LCRA)
.
Methods
In total, 433 rectal cancer patients underwent the same standardized procedure. Non-stoma (NS) management was used in patients with no surgical difficulties as well as good colonic preparation and quality of anastomoses. In all other cases, DS was used. C-reactive protein was measured during postoperative follow-up. Imbalance in the initial population was adjusted using propensity-score matching according to sex, age, body mass index, tumor location, and American Society of Anesthesiologists score. Rate of AL within 30 days, 5-year overall survival, local relapse-free survival, and disease-free survival were recorded.
Results
Anastomosis was mostly ultra-low and was performed equally by laparoscopy or robotic surgery. The overall rate of AL was 13.4%, with no significant differences between groups (DS, 12.2%; NS, 14.6%;
p
= 0.575). Operative time, blood loss, and hospital stay were significantly lower for NS patients. The rate of secondary stoma was 11.4% overall. Pathological results were similar, with a 98% R0 resection rate. With a median follow-up of 5.5 years for the NS and DS groups, the overall survival was 84.9% and 73.4%, respectively (
p
= 0.064), disease-free survival was 67.0% and 55.8%, respectively (
p
= 0.095), and local relapse-free survival was 95.2% and 88.7%, respectively (
p
= 0.084). The long-term, stoma-free rate was 89.1% overall.
Conclusions
Tailoring DS for LCRA seems safe and could provide potential benefits in postoperative morbidity with the same long-term oncological results in NS patients. Prospective, multicentric studies should validate this approach.
In patients treated with cardiotoxic chemotherapies, the presence of cardiovascular risk factors and previous cardiac disease have been strongly correlated to the onset of cardiotoxicity. The ...influence of overweight and obesity as risk factors in the development of treatment-related cardiotoxicity in breast cancer (BC) was recently suggested. However, due to meta-analysis design, it was not possible to take into account associated cardiac risk factors or other classic risk factors for anthracycline (antineoplastic antibiotic) and trastuzumab (monoclonal antibody) cardiotoxicity.
Using prospective data collected from 2012-2014 in the French national multicenter prospective CANTO (CANcer TOxicities) study of 26 French cancer centers, we aimed to examine the association of body mass index (BMI) and cardiotoxicity (defined as a reduction in left ventricular ejection fraction LVEF > 10 percentage points from baseline to LVEF < 50%). In total, 929 patients with stage I-III BC (mean age 52 ± 11 years, mean BMI 25.6 ± 5.1 kg/m2, 42% with 1 or more cardiovascular risk factors) treated with anthracycline (86% epirubicin, 7% doxorubicin) and/or trastuzumab (36%), with LVEF measurement at baseline and at least 1 assessment post-chemotherapy were eligible in this interim analysis. We analyzed associations between BMI and cardiotoxicity using multivariate logistic regression. At baseline, nearly 50% of the study population was overweight or obese. During a mean follow-up of 22 ± 2 months following treatment completion, cardiotoxicity occurred in 29 patients (3.2%). The obese group was more prone to cardiotoxicity than the normal-weight group (9/171 versus 8/466; p = 0.01). In multivariate analysis, obesity (odds ratio OR 3.02; 95% CI 1.10-8.25; p = 0.03) and administration of trastuzumab (OR 12.12; 95% CI 3.6-40.4; p < 0.001) were independently associated with cardiotoxicity. Selection bias and relatively short follow-up are potential limitations of this national multicenter observational cohort.
In BC patients, obesity appears to be associated with an important increase in risk-related cardiotoxicity (CANTO, ClinicalTrials.gov registry ID: NCT01993498).
ClinicalTrials.gov NCT01993498.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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