Combination Of Oxaliplatin Research Articles

Cell-Free Tumor DNA Dominant Clone Allele Frequency Is Associated With Poor Outcomes in Advanced Biliary Cancers Treated With Platinum-Based Chemotherapy.

This investigation sought to evaluate the prognostic value of pretreatment of circulating tumor DNA (ctDNA) in metastatic biliary tract cancers (BTCs) treated with platinum-based first-line chemotherapy treatment. We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis, we considered the detected gene with highest variant allele frequency as the dominant clone allele frequency (DCAF). Results of ctDNA analysis were correlated with patients' demographics, progression-free survival (PFS), and overall survival (OS). The median age of patients was 67 (27-90) years. Fifty-four (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma, and six gallbladder cancers. Forty-six (68.6%) of the patients were treated with cisplatin plus gemcitabine, and 16.4% of patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations, whereas 15% of patients were treated on a clinical trial with gemcitabine and cisplatin plus additional agents (CX4945, PEGPH20, or nab-paclitaxel). TP53, KRAS, FGFR2, ARID1A, STK11, and IDH1 were the genes with highest frequency as DCAF. The median DCAF was 3% (0%-97%). DCAF > 3% was associated with worse OS (median OS: 10.8 v 18.8 months, P = .032). Stratifying DCAF in quartiles, DCAF > 10% was significantly related to worse PFS (median PFS: 3 months, P = .014) and worse OS (median OS: 7.0 months, P = .001). Each 1% increase in ctDNA was associated with a hazard ratio of 13.1 in OS when adjusting for subtypes, metastatic sites, size of largest tumor, age, sex, and CA19-9. DCAF at diagnosis of advanced BTC can stratify patients who have worse outcomes when treated with upfront platinum-based chemotherapy. Each increase in %ctDNA decreases survival probabilities.

Clinical efficacy of combination of oxaliplatin and vascular intervention in treatment of advanced cervical cancer and related prognostic factors

Purpose: To investigate the therapeutic effect of combination of oxaliplatin and vascular intervention in patients with advanced cervical cancer (ACC), and its influence on the prognosis of patients.Methods: One hundred ACC patients were selected and equally assigned to control (oxaliplatin) and combination or study (oxaliplatin plus vascular intervention) groups. The patients in control group received oxaliplatin, while those in study group were treated with oxaliplatin combined with vascular intervention. Clinical efficacy, levels of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2), fibroblast growth factor-2 (FGF-2), BFGF and platelet-derived growth factor (PDGF) before and after therapy, and survival rate at 3, 6, 12 and 18 months after therapy were determined compared between the two groups. The prognostic factors were analyzed with logistic factor analysis.Results: The clinical efficacy and survival rate at 3, 6, 12 and 18 months after therapy in the combination group were higher when compared with those of the control group (p < 0.05). After therapy, the levels of VEGF, VEGFR-2, FGF-2, BFGF and PDGF were lower in the combination group than in control group. Age, short-term efficacy and basic diseases were identified as the influencing factors for the prognosis of patients with advanced cervical cancer (p < 0.05).Conclusion: The combination of oxaliplatin and vascular intervention significantly improved clinical treatment efficacy and survival rate in ACC patients. Age, short-term efficacy and basic diseases affected the prognosis of patients.

Blockade LAT1 Mediates Methionine Metabolism to Overcome Oxaliplatin Resistance under Hypoxia in Renal Cell Carcinoma.

Simple SummaryThe transformation and mechanism of methionine metabolism of renal cell carcinoma (RCC) under a hypoxic microenvironment is not well understood as yet. This study illustrated that the reprogramming of methionine metabolism and the subsequent glutathione (GSH) synthesis were mediated by amino acid transporter 1 (LAT1). Correspondingly, we proposed a combination strategy of LAT1 inhibitor JPH203 and oxaliplatin, which presented an enhanced therapeutic efficacy for RCC both in vivo and in vitro.Hypoxic microenvironment and metabolic dysregulation of tumor impairs the therapeutic efficacy of chemotherapeutic drugs, resulting in drug resistance and tumor metastasis, which has always been a challenge for the treatment of solid tumors, including renal cell carcinoma (RCC). Herein, starting from the evaluation of methionine metabolism in RCC cells, we demonstrated that the increased methionine accumulation in RCC cells was mediated by L-type amino acid transporter 1 (LAT1) under hypoxia. Glutathione (GSH), as a methionine metabolite, would attenuate the therapeutic efficacy of oxaliplatin through chemical chelation. Reducing methionine uptake by LAT1 inhibitor JPH203 significantly enhanced the sensitivity of RCC cells to oxaliplatin by reducing GSH production in vitro and in vivo. Therefore, we proposed an effective and stable therapeutic strategy based on the combination of oxaliplatin and LAT1 inhibitor, which is expected to solve the resistance of RCC to platinum-based drugs under hypoxia to a certain extent, providing a meaningful insight into the development of new therapeutic strategies and RCC treatment

Esophageal Cancer in Epiphrenic Diverticulum With Fistulization to the Lung.

CASE REPORT A 56-year-old man with a history of smoking and alcohol dependence presented to the emergency department with a 3-day history of epigastric pain and fever. The laboratory results were consistent with infection (white blood cell count: 27.8 × 103/mm3; C-reactive protein: 287 mg/L). Computed tomography showed an esophageal perforation in continuity with a right lower lobe abscess (Figure 1). Esophagogastroduodenoscopy demonstrated an ulcerative mass originating from a large epiphrenic diverticulum concealing a fistula at the inferior aspect (Figure 2).Figure 1.: Axial section of computed tomography showing the epiphrenic diverticulum with perforation (*) and pulmonary abscessation of the right lower lobe (arrow).Figure 2.: (A) Endoscopic view on the epiphrenic diverticulum (*) with an ulcerative wall and (B) endoscopic view inside the diverticulum showing the fistula (arrow) on an ulcerative base.Pathological examination confirmed the presence of a squamous cell carcinoma (Figure 3). After a 10-day antibiotic treatment (penicillin 4 × 1 g), an esophagectomy and segment-6-sparing lower lobectomy through right thoracotomy were performed. Owing to inflammation, the reconstruction was postponed, and a cervical esophagostomy was created. Twelve days later, a retrosternal laparoscopic-assisted esophagogastric reconstruction was performed.Figure 3.: Histopathological image (H&E coloring, ×25) on the edge of the diverticulum showing the origin of the squamous cell carcinoma (arrow).Pathological examination demonstrated transmural invasion into the right lower lobe and 3 positive lymph nodes (pT4b N2). The patient was discharged after 10 days after an uneventful postoperative course. Adjuvant chemotherapy (6 courses of a combination of Oxaliplatin, 5- Fluorouracil and Leucovorin (FOLFOX)) was administered for 3 months, followed by paclitaxel for local lymph node recurrence. A follow-up positron emission tomography with computed tomography, 9 months after surgery, revealed disease progression in mediastinal lymph nodes and metastases in the kidney and liver. Despite salvage immunotherapy with nivolumab, the patient died 3 months later. Epiphrenic diverticula are very rare and account for only 10% of all esophageal diverticula.1 The incidence of the latter is estimated between 0.06% and 3.6% and is the result of the herniation of mucosa and submucosa through the muscular wall of the esophagus.2,3 The development of cancer in an esophageal diverticulum is seen in only 0.3%–3% and believed to be the consequence of chronic irritation of retained food and its subsequent inflammation.4 Most tumors are detected in an advanced stage given the absence of the muscularis propria. In a literature overview of Yoshida et al, 1 in 3 patients (7/19) was diagnosed with invasion in the surrounding organs and had a 1-year mortality rate of 66% (4/6).5 Therefore, early detection is paramount and could be realized with regular endoscopic and radiologic follow-up and subsequent treatment. DISCLOSURES Author contributions: LJ Ceulemans, MD, PhD is the article guarantor. All authors of this article have substantially contributed to the conception and design, drafting and revision of its content, and approval of the final version. All authors agree to the correctness and are accountable for all the content of this article. Financial disclosure: None to report. Informed consent was obtained for this case report.

Class III β-Tubulin Expression Is of Value in Selecting nab -Paclitaxel and Gemcitabine as First-Line Therapy in Unresectable Pancreatic Cancer.

Nab -paclitaxel and gemcitabine (GnP) or FOLFIRINOX (a combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin [FFX]) is currently recognized as the standard first-line regimen for unresectable pancreatic ductal adenocarcinoma (PDAC). Class III β-tubulin (TUBB3) has the potential to predict resistance to taxane in various tumors; therefore, this study aimed to clarify whether TUBB3 is a predictive marker for GnP response. We retrospectively reviewed 113 patients with PDAC who received GnP or FFX as first-line chemotherapy and examined immunohistochemically the TUBB3 expression in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration. High TUBB3 expression was associated with a significantly lower disease control rate ( P = 0.017) and shorter progression-free survival (PFS) ( P = 0.019), and multivariate analysis revealed that TUBB3 expression was an independent variable for PFS in the GnP first-line group ( P = 0.045). In addition, in the FFX first-line group, TUBB3 expression was not correlated with PFS or overall survival (OS). In all 113 patients, TUBB3 expression was not also associated with OS. Class III β-tubulin might be a predictive factor for the response of GnP, but not a prognostic factor for OS, helping the selection of an optimized first-line chemotherapy regimen for unresectable PDAC.

Downregulation of MEIS1 mediated by ELFN1-AS1/EZH2/DNMT3a axis promotes tumorigenesis and oxaliplatin resistance in colorectal cancer

Oxaliplatin is widely used in the frontline treatment of colorectal cancer (CRC), but an estimated 50% of patients will eventually stop responding to treatment due to acquired resistance. This study revealed that diminished MEIS1 expression was detected in CRC and harmed the survival of CRC patients. MEIS1 impaired CRC cell viabilities and tumor growth in mice and enhanced CRC cell sensitivity to oxaliplatin by preventing DNA damage repair. Mechanistically, oxaliplatin resistance following MEIS1 suppression was critically dependent on enhanced FEN1 expression. Subsequently, we confirmed that EZH2-DNMT3a was assisted by lncRNA ELFN1-AS1 in locating the promoter of MEIS1 to suppress MEIS1 transcription epigenetically. Based on the above, therapeutics targeting the role of MEIS1 in oxaliplatin resistance were developed and our results suggested that the combination of oxaliplatin with either ELFN1-AS1 ASO or EZH2 inhibitor GSK126 could largely suppress tumor growth and reverse oxaliplatin resistance. This study highlights the potential of therapeutics targeting ELFN1-AS1 and EZH2 in cell survival and oxaliplatin resistance, based on their controlling of MEIS1 expression, which deserve further verification as a prospective therapeutic strategy.

Determination of Oxaliplatin and Curcumin in Combination via Micellar HPLC and Its Method Validation.

A micellar-HPLC method was developed for the determination of oxaliplatin (OHP) and curcumin (CUR) employing a C18 column [4.6 × 250 mm, particle size (dp) = 5 µm] and diode array detector. A rapid, cost-effective, environmentally friendly, time-efficient, easy-to-handle, and safe method was developed. The conditions were optimized for the estimation of OHP and CUR: 0.15 M sodium dodecyl sulfate (SDS) in 6% (v/v) pentanol buffered to pH 5.0 with a flow rate of 1.0 mL/min, injection volume of 20 µL, and detection at 325 nm. Different analytical parameters, including linearity, accuracy, precision, robustness, specificity, LOD, and LOQ, were determined in compliance with the International Council on Harmonisation (ICH) guidelines. The LOD (S/N = 3) of OHP was 0.004 µg/mL and for CUR it was 0.005 µg/mL. The calibration curves for OHP and CUR were linear over the range 0.015-10 µg/mL (determination coefficient r2 = 0.9999) and 0.015-10 µg/mL (r2 = 0.9994), respectively. The drugs were eluted in <12 min and the developed method was applicable for analyzing multiple samples per day. Moreover, it was determined to be robust and was used to quantify OHP and CUR in mice serum/blood. The method could pave the way for quantitative analysis of these drugs during the development of a pharmaceutical preparation for the treatment of colorectal cancer. A simple, cost-effective, eco-friendly HPLC method was developed to simultaneously estimate oxaliplatin and curcumin. The developed method was validated as per the ICH guidelines.

Functionalized LbL Film for Localized Delivery of STAT3 siRNA and Oxaliplatin Combination to Treat Colon Cancer.

The aim of the study was to develop and evaluate the efficacy of a functionalized layer-by-layer (LbL) assembled film entrapped with oxaliplatin (OX) and signal transducer and activator of transcription 3 (STAT3) siRNA in the localized treatment of colon cancer. The LbL film was prepared by the sequential layering of chitosan (CS) and alginate to attain desired physical and mechanical properties. The film was functionalized by coating folic acid-conjugated CS on one side. On the other side, polycaprolactone was coated as a backing layer to provide directional drug release. OX was entrapped within the layers of the film, while STAT3 siRNA was complexed with CS to form nanoparticles before entrapment in the LbL film. The CS-siRNA nanoparticles were taken up by the colon carcinoma, Caco-2 cells within 3 h and provided concentration-dependent reduction in STAT3 protein expression. The functionalized LbL film (F-LbL film) selectively adhered to the colon cancer tissue in the mice model, whereas the nonfunctionalized film adhered to the normal colon tissue. The combination of OX and STAT3 siRNA provided significantly greater tumor regression, survival rate, and STAT3 protein suppression after localized delivery through oral administration compared with intravenous administration. Taken together, the F-LbL film can selectively bind to colon tumors for localized delivery of drugs to treat colon cancer.

Causes of mortality in elderly UICC stage III colon cancer (CC) patients--Tumor-related death and competing risks from the German AIO colorectal study group Colopredict Plus (CPP) registry.

BackgroundColon cancer (CC) is a disease of elderly patients (pts.) with a median age of 73 years (yrs.). Lack of data about the effects of adjuvant chemotherapy (ACT) is caused by underrepresentation of this clinically relevant cohort in interventional trials. We analyzed real‐world data from the German CPP registry with regard to a possible benefit of ACT in elderly (70+ yrs.) versus younger pts. (50 to <70 yrs.) taking cause‐specific deaths into account.MethodsWe analyzed the effect of age and ACT on overall survival (OS) and cause‐specific death of stage III pts. using Cox regression.ResultsIn total, 1558 pts. were analyzed and follow‐up was 24.6 months. 62.6% of the elderly received ACT whereas 91.1% of younger pts. (p < 0.001). Oxaliplatin combinations were significantly less often given to older than younger pts. (38.8% vs. 88.9%; p < 0.001). Mean Charlson comorbidity score was significantly lower in pts. that received ACT (0.61) than in those without ACT (1.16; p < 0.001). ACT was an independent positive prognostic factor for cancer‐related death in elderly pts. even in pts. 75+ yrs. No significant difference in the effect of ACT could be observed between age groups (interaction: cancer‐specific death HR = 1.7948, p = 0.1079; death of other cause HR = 0.7384, p = 0.6705).ConclusionACT was an independent positive prognostic factor for OS. There may be a cohort of elderly with less co‐morbidities who benefit from ACT.

Impact of previous adjuvant oxaliplatin combination therapy on survival in elderly colorectal cancer patients with recurrence.

48 Background: The benefit of adjuvant chemotherapy with oxaliplatin for elderly patients with colorectal cancer (CRC) remains controversial. Our study could not demonstrate the benefit of adding oxaliplatin for elderly CRC patients aged over 70 years as with the previous clinical trials. Here, we evaluated the prognosis after recurrence in the elderly patients who received adjuvant chemotherapy. Methods: This retrospective study included patients aged over 70 years who were diagnosed with high-risk stage II and stage III CRC and received adjuvant chemotherapy in our two hospitals (The Jikei University Hospital and Katsushika Medical Center) between January 2010 and December 2019. The patients were divided into two groups; patients who received fluoropyrimidine monotherapy were included in Fp group and those who received fluoropyrimidine plus oxaliplatin were included in Fp+OX group. Moreover, we evaluated patient characteristics, treatment, and survival in the patients with recurrence and compared them between two groups. Results: A total of 127 patients received adjuvant chemotherapy; 75 patients in Fp group and 52 patients in Fp+OX group. With a median follow-up time of 64.5 months, the 5-years disease-free survival and 5-years overall survival in Fp group/Fp+OX group were 70.6/67.1% (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.61–1.98) and 89.0/71.8% (HR 1.48, 95% CI 0.76–2.88), respectively. The benefit of adding oxaliplatin was not observed. Among them, 15 patients in Fp group and 14 patients in Fp+OX group were relapsed; median age was 78 (range: 72-83) and 78 (range: 72-86) years, male was 67% and 64%, PS of 0/1 was 67/33% and 86/14%, primary tumor site of right/left was 47/53% and 57/43%, and RAS mutation was 20% and 29%, respectively. Median relapse-free survival was 17.7 and 14.3 months (p = 0.453). There were no significant differences in treatment after recurrence; aggressive treatment (surgery/chemotherapy) was 73% (33/40%) and 86% (21/65%), best supportive care was 7% each, and unknown was 20% and 7%, respectively. However, the median overall survival from the date of relapse was significantly worse in Fp+OX group than Fp group (45.0 and 14.4 months, p = 0.011). Conclusions: Recurrence after receiving adjuvant oxaliplatin combination therapy was considered as one of the poor prognostic factors. It might attenuate the benefit of adding oxaliplatin in adjuvant setting in elderly patients.

Comparative Outcomes of First-Line Chemotherapy for Metastatic Pancreatic Cancer Among the Regimens Used in Japan

Various first-line chemotherapy treatment regimens for patients with metastatic pancreatic cancer have been approved in Japan, including gemcitabine (GEM); fluorouracil, leucovorin, irinotecan, and oxaliplatin combination (FOLFIRINOX); GEM plus albumin-bound paclitaxel (GEM+NPTX), and S-1 (tegafur + gimeracil + oteracil). However, direct comparisons of these chemotherapy regimens are limited. To assess the short-term and long-term outcomes associated with first-line chemotherapy regimens for metastatic pancreatic cancer compared with chemotherapy regimens recommended in Japanese guidelines. In this systematic review and network meta-analysis, the bibliographic databases PubMed, Cochrane Library, and Web of Science, as well as medical journals published between January 1, 2002, and December 31, 2018, were searched for clinical trials comparing chemotherapy regimens. Randomized 2-arm clinical trials evaluating first-line chemotherapy for advanced or metastatic pancreatic cancer were included. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions was followed for data abstractions. Data were pooled using a random-effects model. The SIGN 50 Quality Assessment Instrument was used to assess the risk of bias and overall study quality of the selected trials. The primary end point was overall survival (OS), and the secondary end point was progression-free survival (PFS) compared with GEM for first-line chemotherapy for metastatic pancreatic cancer. The Kaplan-Meier curve of GEM from the literature and the estimated hazard ratios (HRs) were used to model the long-term associations to calculate the area under the curve (AUC) (person-months) for OS and PFS of each chemotherapy. Sensitivity analyses with multiple functional models were conducted to confirm the long-term estimations. A total of 22 regimens (25 studies) for OS and a total of 18 regimens (21 studies) for PFS were identified from literature. The total number of participants was 10 186, with 5856 male (57.5%) and 4330 female (42.5%). The FOLFIRINOX and GEM+NPTX regimens were associated with reduction in the risk of death, with an HR of 0.57 (95% CI, 0.41-0.79) and 0.72 (95% CI, 0.55-0.95) compared with GEM, respectively. The curve estimation also showed that FOLFIRINOX had the largest AUC for survival at 15.49 person-months (range, 13.84-15.51 person-months), followed by GEM+NPTX with 12.36 person-months (range, 10.98-12.59 person-months), GEM+ERLO with 10.84 person-months (range, 9.66-11.23 person-months), S-1 with 8.44 person-months (range, 8.26-9.74 person-months), and GEM with 8.10 person-months (range, 7.93-9.38 person-months). The results of this network meta-analysis support the relative short-term and long-term outcomes associated with first-line chemotherapy for metastatic pancreatic cancer used clinically in Japan.

Oxaliplatin Induced Severe Hypoxemia, Chills and Hypersensitivity Reaction

Hypersensitivity reactions to platinum containing compounds are well described and potentially life threatening. The hypersensitivity reactions can occur either during, or shortly after the infusion of drug. The incidence increases with increase in the number of chemotherapy cycles. Hypersensitivity reactions can vary from mild reactions like rashes to severe reactions, which include laryngospasm, tachycardia, hypotension or hypertension. The combination of 5-flurouracil, leucovarin and oxaliplatin has been used in several studies to increase survival rates and reduce the risk of disease progression in patients with metastatic colorectal cancer (CRC) and stage III colon cancer. We report a case of patient treated with oxaliplatin who developed Severe Grade-III Toxicity including Hypoxemia, Chills and hypersensitivity reaction like rashes all over the body with itching sensation about few hrs after the oxaliplatin infusion. Patient tolerated 7 cycles of FLOT chemotherapy well. During cycle 8 chemotherapy after 50% infusion of oxaliplatin patient developed severe reaction to oxaliplatin such as breathlessness, shivering, hypersensitivity reaction like rashes all over the body and itching sensation. The drug infusion was stopped immediately, vitals were checked which shows BP: 170/110mmhg, Temperature 100⁰F, Spo2 85% RA. It was confirmed as grade 3 toxicity of oxaliplatin. The adverse drug reaction assessment was done using Naranjo’s causality assessment scale which showed ‘definite’ type of adverse drug reaction with oxaliplatin. Prompt recognition of this event and symptomatic treatment with supplemental oxygen and corticosteroids and prolonging the infusion time of oxaliplatin can lead to better patient compliance and lesser hypersensitivity reactions to these regimens.&#x0D; Keywords: Oxaliplatin, Colorectal cancer (CRC), Dyspnoea, Hypersensitivity reactions, Chemotherapy.

FOLFIRINOX as First-line Chemotherapy in Japanese Patients Suffering from Metastatic Pancreatic Cancer (KOBE FOLFIRINOX Study)

Background/Aim: FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin) combination chemotherapy is the gold-standard therapy for advanced pancreatic cancer. In this study, FOLFIRINOX dosages for Japanese patients were established enabling FOLFIRINOX therapy optimization for efficient use. Patients and Methods: Patients with advanced pancreatic cancer were treated with varying doses of FOLFIRINOX to determine the optimum dosage for highest remission outcomes with the least post-chemotherapy toxicities. Results: Patients given 180 mg of irinotecan and a 400 mg bolus of 5-fluorouracil (5-FU) showed a marked difference in outcome when compared to irinotecan 180 mg given without the 5-FU bolus, with the overall response rate being 28%, a survival time of 6.4 months and progression-free survival time of 4.5 months. Conclusion: The optimum dose of FOLFIRINOX was a dosage combination of oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, l-leucovorin 400 mg/m2 and 5-FU 2,400 mg/m2, administered as a continuous 46-h infusion.

Sex hormones and sperm parameters after adjuvant oxaliplatin-based treatment for colorectal cancer

BackgroundThe incidence of colorectal cancer (CRC) in individuals of fertile age is increasing. Oxaliplatin is a cornerstone treatment in the adjuvant setting for stage III and high-risk stage II CRC. Limited data exist on possible side effects of oxaliplatin on fertility and gonadal function. More data is needed to guide possible fertility preservation procedures and aid evidence-based fertility counselling. Patients and methodsThe aim of this study (EudraCT2006-002832-10) was to prospectively investigate sex hormones and sperm parameters after oxaliplatin-based adjuvant chemotherapy to clarify the risk of infertility and hypogonadism. Twenty males aged ≤55 years and 16 females aged ≤40 years were recruited from five hospitals in the Nordic countries. All had undergone radical surgery due to CRC and were given adjuvant oxaliplatin in combination with 5-fluorouracil. Measurement of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, sex hormone binding globulin (SHBG) and semen analysis were done in males, while LH, FSH and oestradiol were measured in females. Measurements were done prior to chemotherapy, after completion of adjuvant treatment and at follow-up 1 and up to 5 years after end of treatment. ResultsFSH and testosterone levels increased in males after chemotherapy treatment but were restored at follow-up. No patients developed hypogonadism. There was a trend towards a decrease in sperm concentration during treatment (p = 0.063). When comparing sperm concentration and rapid progressive motility of sperms prior to chemotherapy and at follow-up, there were no differences, and no patients became permanently azoospermic by treatment. No distinct altering of gonadal function could be observed in females. ConclusionsOxaliplatin in combination with 5-fluorouracil seems to induce transient decrease in sperm concentration with recovery and a minor transient increase in FSH in males. No distinct altering of gonadal function was observed in females. The risk of infertility and hypogonadism in males and females after adjuvant oxaliplatin-based chemotherapy seems low.

Drug treatment for chemotherapy-induced peripheral neuropathy in patients with pancreatic cancer.

Pancreatic cancer (PC) is a lethal disease where most tumors are too advanced at diagnosis for resection, leaving chemotherapy as the mainstay of treatment. Although the prognosis of unresectable PC is poor, it has been dramatically improved by new chemotherapy treatments, such as the combination of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel. However, as oxaliplatin and paclitaxel are common neurotoxic drugs, chemotherapy-induced peripheral neuropathy (CIPN) is a common and severe adverse effect of both treatments. As there are no agents recommended in the ASCO guidelines, we review the methods used to treat CIPN caused by PC treatment. The efficacy of duloxetine was observed in a large randomized controlled trial (RCT). In addition, pregabalin was more effective than duloxetine for CIPN in two RCTs. Although duloxetine and pregabalin can be effective for CIPN, they have several side effects. Therefore, the choice between the two drugs should be determined according to effect and tolerability. Mirogabalin is also used in patients with PC and there is hope it will yield positive outcomes when treating CIPN in the future.

Capecitabine plus oxaliplatin in the treatment of metastatic colorectal cancer at Tygerberg Hospital: a retrospective study.

Introductiona capecitabine and oxaliplatin drug combination regimen has shown a survival benefit in patients with advanced colorectal cancer, yet its administration represents an attractive option for low resource settings. This study aimed to describe the therapeutic utility, efficacy and safety of a capecitabine plus oxaliplatin drug combination in patients with colorectal cancer.Methodsa review of medical records of sixty adult patients with histological diagnosis of colorectal cancer at Tygerberg Hospital between June 2012 and June 2017 was conducted. The overall response rate was assessed after a three cycle regime of capecitabine and oxaliplatin with the progression-free survival (PSF) results estimated using the Kaplan-Meier methods.Resultsamong the 60 participants identified over the study period, the median age was 53 years with 45% being female (n=27). Records showed that 58.33% of patients had the colon as the primary site and 68.33% of patients had synchronous liver metastases at presentation. On average, all patients received 6 cycle regimes of capecitabine and oxaliplatin. Sixty percent of the patients received this treatment regime with palliative intent while in the radical-intent group, equal numbers of patients received the regime as either neoadjuvant or adjuvant. A liver resection was also performed in 20 patients (31.8%). The overall response rate was 69.6% with 13 patients attaining a complete response. Disease progression was reported in 30.4% and the 1-year progression free survival was 44.5% (95% CI: 0.31-0.57) while the 2-year progression free survival was 25.1% (95% CI: 0.14-0.38). Regarding safety, thrombocytopenia was the most frequent adverse event (18.5%) and overall, 15.1% of patients experienced grade 3 and 4 toxicity.Conclusiona drug combination of capecitabine and oxaliplatin showed a good overall response rate and survival particularly in patients with resectable colorectal liver metastases.

Safety and Efficacy of S-IROX (S-1, Irinotecan&amp;nbsp;And Oxaliplatin Combination Therapy) in Patients with Advanced Pancreatic Cancer: A Multicenter Phase 1b Dose-Escalation and Dose-Expansion Clinical Trial

Safety and Efficacy of S-IROX (S-1, Irinotecan&amp;nbsp;And Oxaliplatin Combination Therapy) in Patients with Advanced Pancreatic Cancer: A Multicenter Phase 1b Dose-Escalation and Dose-Expansion Clinical Trial

P-OGC08 Translational Insights from the Dual ErbB Inhibition in Oesophago-gastric Cancer (DEBIOC) Clinical Trial - A Bioinformatic Analysis

Abstract Background Oesophageal Adenocarcinoma (OAC) incidence in the Western-world has increased markedly over 30 years. 5-year survival rates for patients remains below 20% with dismal response to neo-adjuvant or perioperative chemotherapy for operable tumours. The Dual ErbB Inhibition in Oesophago-gastric Cancer (DEBIOC) clinical trial assessed efficacy of combined oxaliplatin and capecitabine (Xelox) with dual ErbB inhibitor AZD8931 in providing additional benefit to operable patients compared to Xelox alone. We utilised a bioinformatic approach combing Almac Clara-T Transcriptional Discovery software with unsupervised machine learning methods to unveil translational clinical potential and biological insights from DEBIOC patient biopsy and resection specimens. Methods Using microarrays of DEBIOC patient specimens with documented clinical observations, we combined unsupervised machine learning techniques with state-of-the-art Almac Clara-T software to assess transcriptional changes between treatment types regarding the 10 hallmarks of cancer, characterised by representative gene-expression signatures and scores. These methods were employed to identify possible mechanisms of treatment resistance, evaluate changes in the tumour-microenvironment and determine clinically significant molecular subgroups in OAC. Differential expression and pathway analytics were used to describe signalling dissimilarities between clusters from unsupervised analysis and phenotypes respective to hallmarks of cancer, with alignment of sensitivities to single-gene drug targets for subgroups of interest. Results Unsupervised clustering analysis of biopsy specimens, resulted in the identification of two robust subgroups pre-treatment in OAC, determined to be significantly associated with the prediction of Mandard Score (Tumour Regression Grade 1-5) post-treatment (fishers exact p &amp;lt; 0.05). Differential expression analysis revealed distinguishing biology between subtypes and noted increased ErbB signalling in non-responding patients in addition to increased PI3K signalling, highlighting a potential mechanism of resistance to dual ErbB inhibition (nominal p-value &amp;lt;0.05, FDR p-value &amp;lt;0.2). Semi-supervised clustering revealed hallmark-specific-phenotypes associated with clinical observations including lymph node involvement, EGFR FISH classification, vascular invasion and progression events at BH adjusted p-values &amp;lt;0.05. Conclusions Our analysis has revealed translational insights into possible mechanisms of drug resistance as well as cancer hallmark-specific phenotypes significantly associated with clinico-pathological factors during the DEBIOC clinical trial. Continued analysis into resulting phenotypes and clusters combined with the alignment of single gene drug target sensitivities is anticipated to reveal novel molecular pathways driving phenotypic differences in an effort to further inform biological understanding and improve treatment response and survival outcomes in OAC patients.

Mirogabalin vs pregabalin for chemotherapy-induced peripheral neuropathy in pancreatic cancer patients

BackgroundThe prognosis of pancreatic cancer (PC) has been improved by new chemotherapy regimens (combination of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel (GnP)). Unfortunately, chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event of these two regimens. The efficacy of pregabalin for CIPN has been reported in previous studies. However, the efficacy of mirogabalin for CIPN remains unknown. Thus, in this study, we aimed to clarify which drug (mirogabalin or pregabalin) was more valuable for improving CIPN.MethodsA total of 163 PC patients who underwent FOLFIRINOX or GnP between May 2014 and January 2021 were enrolled. Among them, 34 patients were diagnosed with CIPN. Thirteen patients were treated with mirogabalin (mirogabalin group), and twenty-one patients were treated with pregabalin (pregabalin group). Treatment efficacy was compared between the two groups.ResultsIn both the mirogabalin group and the pregabalin group, the grade of patients with CIPN at 2, 4, and 6 weeks after the initiation of treatment showed significant improvement compared to the pretreatment grade. Notably, the rate of CIPN improvement was higher in the mirogabalin group than in the pregabalin group (2 weeks: 84.6% (11/13) vs 33.3% (7/21), P value = 0.005; 4 weeks, 6 weeks: 92.3% (12/13) vs 33.3% (7/21), P value = 0.001).ConclusionsAlthough both mirogabalin and pregabalin were effective at improving CIPN, mirogabalin might be a suitable first choice for CIPN in PC patients.Trial registrationNot applicable

The MK2/Hsp27 axis is a major survival mechanism for pancreatic ductal adenocarcinoma under genotoxic stress.

Combination chemotherapies remain the cornerstone treatment for pancreatic ductal adenocarcinoma (PDAC), but de novo and acquired resistance is common. In this study, we aimed to identify and characterize resistance mechanisms to a FIRINOX chemotherapy regimen (a combination of 5-fluorouracil, irinotecan, and oxaliplatin) because it is the most aggressive regimen currently used clinically for patients with PDAC. Using an unbiased reverse-phase protein array, we detected phospho-activation of heat shock protein 27 (Hsp27) as the most up-regulated event after FIRINOX treatment in PDAC cells. Silencing HSP27 by RNA interference or by a small-molecule inhibitor enhanced apoptosis caused by FIRINOX in vitro. Mechanistically, FIRINOX up-regulated tumor necrosis factor–α (TNFα), causing autocrine phosphorylation and activation of transforming growth factor–β–activated kinase 1 (TAK1), MAPK activated protein kinase 2 (MAPKAPK2 or MK2), and, ultimately, Hsp27. Targeting MK2, the kinase that directly phosphorylates Hsp27, abrogated Hsp27 activation, sensitized PDAC cells to apoptosis, and suppressed SN-38–induced protective autophagy in vitro, in part by blocking phospho-activation of Beclin1. In an autochthonous PDAC mouse model, the MK2 inhibitor ATI-450 decreased PDAC development and progression. When combined with FIRINOX, ATI-450 eliminated most PDAC foci and marked prolonged mouse survival without causing additional toxicity. Last, we found that high phospho-MK2 expression in tumors was associated with poorer survival of patients with PDAC. Our study identified MK2 as a mediator of genotoxic stress–induced activation of prosurvival pathways and provides preclinical support for combining an MK2 inhibitor with FIRINOX-based chemotherapies to treat PDAC.