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.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by poor response to chemotherapy and radiotherapy due to the lack of efficient therapeutic tools and early diagnostic ...markers. We previously generated the nonligand competing anti‐HER3 antibody 9F7–F11 that binds to pancreatic tumor cells and induces tumor regression in vivo in experimental models. Here, we asked whether coupling 9F7–F11 with a radiosensitizer, such as monomethylauristatin E (MMAE), by using the antibody‐drug conjugate (ADC) technology could improve radiation therapy efficacy in PDAC. We found that the MMAE‐based HER3 antibody‐drug conjugate (HER3‐ADC) was efficiently internalized in tumor cells, increased the fraction of cells arrested in G2/M, which is the most radiosensitive phase of the cell cycle, and promoted programmed cell death of irradiated HER3‐positive pancreatic cancer cells (BxPC3 and HPAC cell lines). HER3‐ADC decreased the clonogenic survival of irradiated cells by increasing DNA double‐strand break formation (based on γH2AX level), and by modulating DNA damage repair. Tumor radiosensitization with HER3‐ADC favored the inhibition of the AKT‐induced survival pathway, together with more efficient caspase 3/PARP‐mediated apoptosis. Incubation with HER3‐ADC before irradiation synergistically reduced the phosphorylation of STAT3, which is involved in chemoradiation resistance. In vivo, the combination of HER3‐ADC with radiation therapy increased the overall survival of mice harboring BxPC3, HPAC cell xenografts or patient‐derived xenografts, and reduced proliferation (KI67‐positive cells). Combining auristatin radiosensitizer delivery via an HER3‐ADC with radiotherapy is a new promising therapeutic strategy in PDAC.
What's new?
In pancreatic ductal adenocarcinoma (PDAC), chemoradiation is prescribed to patients with borderline resectable lesions to make surgery possible. The HER3 receptor is a key signaling hub in PDAC. Here, the authors developed a novel antibody‐drug conjugate targeting HER3 (HER3‐ADC) that enhanced radiosensitivity of PDAC by arresting cells in G2/M. HER3‐ADC increased radiation response in mice xenografted with PDAC cells, through inhibition of cell survival and induction of DNA break formation and apoptosis. Combining auristatin radiosensitizer delivery via an HER3‐ADC with radiotherapy could help increase the rate of resection for patients with borderline resectable pancreatic cancer.
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 spite of tremendous advances in advanced ovarian cancer management through the past decade, notably owing to surgical expertise and novel combination molecules (including bevacizumab and PARP ...inhibitors), the optimal initial sequential strategy remains a major concern. Indeed, following seminal clinical trials, primary cytoreductive surgery (PCS) followed by adjuvant systemic therapy and interval cytoreductive surgery (ICS) following neoadjuvant chemotherapy (NACT) have been positioned as validated alternatives with distinct pros and cons, although a definite response is still unassessed. In clinical practice, decisions between PCS and ICS rely on multilayer parameters: the tumor itself, the patient, and the health structure. In this state-of-the-art review, we will discuss the current evidence based on clinical trials and real-world data and highlight the remaining questions, including the fittest positioning of PCS vs. ICS and the optimal number of NACT cycles; subsequently, we will discuss current axes of research such as dedicated clinical trials and more global perspectives. These ongoing strategies and perspectives could contribute to improving the patient journey through personalized medicine.
Abstract Aim To investigate whether adding bevacizumab to neoadjuvant carboplatin-paclitaxel (CP) helps achieve optimal debulking, measured by complete resection rate (CRR) at interval debulking ...surgery (IDS), in patients with initially unresectable International Federation of Gynecology and Obstetrics stage IIIC/IV ovarian, tubal or peritoneal adenocarcinoma. Methods Multicentre, open-label, non-comparative phase II study. Ninety-five patients randomised (2:1) to receive four cycles of neoadjuvant CP ±3 concomitant cycles of bevacizumab 15 mg/kg (BCP) followed by IDS. Primary objective is to evaluate the CRR at IDS in the BCP group (reference CRR rate defined as 45% CRR). A stopping rule based on bevacizumab-related adverse events (AEs) of special interest was implemented. Results In the BCP group (N = 58), IDS was performed in 40 (69%) patients, of whom 85% had a complete resection. The CRR of this group was therefore 58.6% (34 patients), statistically over pre-defined 45%. The CRR in the CP group was 51.4%: 22 (60%) patients underwent IDS (85% had a complete resection). Grade ≥3 adverse events occurred in 62% of the BCP-treated patients and 63% of the CP-treated patients: mainly blood and lymphatic, gastrointestinal and vascular disorders, without more toxicity with BCP. Postoperative complications (mainly wound, infectious and gastrointestinal complications) occurred in 28% and 36% of the patients, respectively. The pre-specified safety stopping rule was not reached. Conclusion The primary objective was met as the CRR with BCP was significantly higher than the reference rate. Bevacizumab may be safely added to a preoperative program in patients deemed non-optimally resectable, whatever the final surgical decision. Bevacizumab's role in this setting should be further investigated.
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