Le Beausset, France

Drug Sensitivity Detection of Micro Tumor (PTC) to Guide Postoperative Adjuvant Treatment Strategy of Colorectal Cancer

The study is a multi agency prospective cohort study in China. The subjects were patients aged 18 ~ 75 years with colorectal cancer diagnosed by histopathology or cytology. They must be colorectal cancer patients who have at least one assessable tumor focus, need adjuvant therapy after radical surgery, and have not received neoadjuvant therapy， ECoG physical condition score ≤ 2 points. And they must be voluntarily participate in and sign informed consent. The patients were randomly divided into PTC drug sensitivity test group and control group. The PTC drug sensitivity test group selected the adjuvant chemotherapy scheme according to the 3D drug sensitivity test results of micro tumor (PTC) in vitro. The control group made adjuvant chemotherapy strategy according to clinical experience. All exon (WES) data collection was used to predict postoperative survival in both groups. The primary endpoint was the non inferiority test, and the 3-year disease-free survival rate was T-C >- Δ

The Efficacy and Safety of Using Intralesional 5-fluorouracil for Basal Cell Carcinoma

Brief Description: The investigatorswant to assess the safety and efficacy of using intralesional 5-FU for the management of different types of BCC (including all the types EXCEPT the infiltrative one), by estimating different outcomes after the intralesional administration of 5-FU to BCC patient. Patients are randomly selected from the outpatient dermatologic clinic in the Aleppo University Hospital (AUH) over a period of 12 months and then these patients are followed up over another 12 months. Detailed Description: Clinicians routinely consider surgical removal as the best and sometimes the only cost-effective treatment of Basal cell carcinoma, but several studies have discussed other promising treatment approaches for BCC including 5% 5-FU cream which is indicated for the treatment of superficial BCC, in addition many studies have investigated the efficacy of the combination of 5-FU with Imiquimode or cryoablation presenting promising results, however when searching the medical literature there was only few studies dealing with types other than superficial BCC, in addition intralesional administration of 5-FU alone was not thoroughly assessed so far even though there are some studies showing positive results suggesting 5-FU to be a cost-effective alternative to surgical excision, but as these papers are asking for further studies and stronger evidence the invistigators decided to conduct this study in accordance with the best recommendations reached by latest medical literature.

5-Fluorouracil and Calcipotriene for Treatment of Low Grade Skin Cancer

Hepatic Arterial Infusion Chemotherapy With Lipiodol Embolization in Advanced Hepatocellular Carcinoma

Hepatic artery infusion chemotherapy (HAIC) is an effective locoregional therapy commonly utilized in hepatocellular carcinoma (HCC). The rationale for the anti-tumor efficacy of HAIC is to deliver high local concentrations of chemotherapeutic agents to the liver tumor. Previous studies on HAIC alone or in combination with other systemic therapies have demonstrated excellent intrahepatic tumor contr rates and survival benefits. The investigators have previously conducted a pilot study of HAIC in National Taiwan University Hospital (NTUH) using cisplatin and 5-fluorouracil and demonstrated a high response rate of 26% in advanced HCC patients. In addition to the observed efficacy, HAIC does not impair liver function significantly over repeated administration and can be safely given to patients with poor or limited liver reserve. Transarterial chemoembolization (TACE) and transarterial embolization (TAE) are the most recognized standard treatment in intermediate-stage HCC and are also commonly utilized in advanced-stage HCC. TACE procedure is based on administering a cytotoxic drug mixed with lipiodol followed by definitive embolization of the tumor-feeding arteries by an embolic agent. However, repeated embolization can impair liver function and jeopardize the chance of patients receiving further salvage treatment. Lipiodol used in TACE/TAE has transient and plastic embolization effects on the tumor in contrast to the long-lasting embolization effect of the embolic agent, such as Gelfoam. Performing embolization with lipiodol alone without an embolic agent may limit detrimental effects on the normal liver and help preserve liver function in patients with HCC. The investigators hypothesize that combining HAIC and transient embolization using lipiodol may have enhanced efficacy compared to HAIC alone. In addition, the unwanted liver function impairment caused by repeated embolization is alleviated by the characteristic transient embolization effect of lipiodol. Thus, The investigators propose this prospective, single-arm, phase 2 pilot study comprising HAIC with cisplatin and 5-fluorouracil in combination with lipiodol embolization to investigate its efficacy and safety in patients with advanced HCC.

Intralesional 5-Fluorouracil (5FU), Topical Imiquimod Treatment for SCC

Squamous cell carcinoma (SCC) of the lower extremity is a distinct subset of cutaneous squamous cell carcinomas which tend to occur multiply in elderly women. In contrast, the majority of cutaneous SCCs occur on the head and neck, and in men more than women. Histopathological studies of lower extremity SCCs revealed that they tend to be well differentiated and have low incidence of perineural and lymphovascular invasion. SCCs of the lower extremity are also less prone to metastasis. Surgical excision has been the mainstay in the treatment of SCC, including lower extremity SCC. However, the lower extremity, as a site, is prone poor wound healing and postoperative complications such as infections. Furthermore, a phenomenon called eruptive postoperative SCC can occur, in which cytokines released during wound healing trigger secondary tumor formation in genetically predisposed cells surrounding the original SCC. Given that lower extremity SCCs are less aggressive but more prone to surgical complications when excised, the investigators believe these types of lesions may be good candidates for non-surgical treatment. 5-fluorouracil (5FU) is a chemotherapeutic agent that has been used systemically for various malignancies, but it has also been used topically or intralesionally for a variety of dermatological conditions. But reports of its use in invasive cutaneous SCC, other than in keratoacanthomas, are very limited. The investigators are aware of 3 such reports in the literature. In the largest study to date, 6 weekly intralesional injections of 5FU-epinephrine gel were performed on 23 patients with cutaneous SCC on various body sites, 22 (96%) of whom demonstrated histologically confirmed tumor clearance. This study, however, used a proprietary gel formulation which is not widely available. There are two other case reports of successful treatment of SCC with 6-8 intralesional injections of 5FU at weekly intervals. The three published studies injected 0.6ml to 2.4ml of 5FU, per each weekly session, at concentrations of 30mg/ml to 50mg/ml. Imiquimod is a topical immune response modulator which acts through the toll-like-receptor 7 pathway. It is FDA approved for the treatment actinic keratosis, genital warts, and superficial basal cell carcinomas. It has also been used off-label for the treatment of squamous cell carcinomas in situ and invasive cutaneous squamous cell carcinomas. A review of published studies to date found 50-88% clearance rate for squamous cell carcinomas in situ treated with daily application of topical imiquimod. There is only one study, other than case reports of treating invasive squamous cell carcinomas with topical imiquimod. In that study, 7 out of 12 (71%) invasive squamous cell carcinomas cleared with topical imiquimod 5 days per week for 12 weeks. Common reported adverse reactions are erythema, pruritus, weeping, erosions, crusting at the application site. The aim of the proposed study is to evaluate a relatively unexplored approach to treatment of SCC on the lower extremities. The strategy is to directly and specifically deliver a drug to the tumor through an injection weekly for three weeks. For the proposed phase I clinical trial, the investigators will perform intralesional injections of a well-characterized, potent chemotherapeutic agent (5-fluorouracil) to kill topically accessible SCC cells. Importantly, 5-fluorouracil is currently in clinical use with a well-established safety profile. It is anticipated that intralesional injections of 5-fluorouracil (5FU) will enable direct and specific delivery of chemotherapy to the tumor, thereby reducing the potential for systemic toxicity. Further, intralesional injections of 5FU enable tumoral delivery of locally effective concentrations of 5FU using doses that are orders of magnitude below those used currently for the intravenous (IV) treatment of multiple malignancies. In addition to the 5FU injections, a subset of study participants will also have their lesions treated with a topical application of 5% imiquimod, another well-characterized chemotherapeutic agent with some demonstrated efficacy in treating cutaneous squamous cell carcinomas. The investigators hope that the concomitant use of topical 5% imiquimod will work synergistically with intralesional 5FU. No study published to date has been found on the concomitant use of intralesional 5FU and topical imiquimod. Participants will have at least 1 SCC lesion greater 1cm and less than 2 cm in largest diameter, on their lower extremities. The clinical diagnosis of SCC will be confirmed histologically by a deep shave biopsy of less than half of the lesion. The remainder of the lesion will be used for intralesional injections of 5FU or intralesional 5FU/topical imiquimod according to the following schema: In this study, a total of 30 participants will be randomly assigned into 3 groups. Randomization will be conducted using the University of Pittsburgh Cancer Institute (UPCI) randomizer, which is maintained by the Biostatistics Facility of UPCI (https://randomize.upci.pitt.edu/randomizer/home.seam).10 participants will serve as a control group, and will receive neither 5FU injection nor topical imiquimod. In another 10 participants, intralesional injections of 50mg of 5FU in 1ml aqueous injectable solution will be administered weekly for 3 weeks. In yet another 10 participants, intralesional 5FU will be administered as in the previous group, additionally participants will also receive three-times-weekly topical application of 5% imiquimod to the same lesion. At the end of week two, a 2mm punch biopsy of the lesion will be obtained for mid-point analysis, and will be stored for tissue banking and future study. A week after the last injection (week 4), the lesion will be surgical resected in all participants including the control group, to render the patients disease free. Resection is the current standard of care for these tumors. A part of, or all of, the resected tumor and surrounding skin will be stored for tissue banking and future studies to characterize and compare the tumor microenvironment before, during, and after therapy. All lesions will be photographed and treatment response will be evaluated 4 weeks after the first 5FU injection prior to excision.

Phage II Trial of Stathmin as Predictive Biomarker for TPF Induction Chemotherapy in OSCC

Induction chemotherapy is regarded as an effective way to reduce or downgrade the locally advanced or aggressive cancers, and to improve the chance of eradication of the locoregional lesions by radical surgery and/or radiotherapy. However, there are still debates on the clinical value of induction chemotherapy for patients with advanced and resectable oral squamous cell carcinoma(OSCC). A prospective, open label, parallel, interventional, randomized control trial on TPF induction chemotherapy indicate there is no difference in overall survival, disease free survival, local regional recurrence free survival and metastasis free survival between experimental group and control group (Zhong et al, Randomized Phase III Trial of Induction Chemotherapy With Docetaxel, Cisplatin, and Fluorouracil Followed by Surgery Versus Up-Front Surgery in Locally Advanced Resectable Oral Squamous Cell Carcinoma, J Clin Oncol 2013); however, the subgroup analysis proves that the induction chemotherapy of TPF protocol could benefit the patients with low stathmin expression.The previous study was registered at ClinicalTrials.gov website with NCT01542931 identification number. This prospective, interventional, randomized control trial was to evaluate the TPF induction chemotherapy have a better effects in the OSCC patients with low stathmin expression. The patients would receive TPF induction chemotherapy followed by radical surgery and post-operative radiotherapy (the experimental group) or radical surgery and post-operative radiotherapy (the control group). The study had a power of 80% on the basis of an assumed 5-year survival rate of 93% in the experiment group and 52% in the control group, with use of a two-sided log-rank test at a level of significance of 0.05. The recruitment period would be 2 years, and the follow-up period would be 5 years, and 10% of patients would drop out early or be lost to follow-up. A total number of 60 patients were to be recruited with stplan 4.5 software calculation. （Department of Biostatics, MD Anderson Cancer Center, University of Texas，USA） The patients in the experimental group received the TPF induction chemotherapy for 2 cycles followed by radical surgery and post-operative radiotherapy/chemoradiotherapy. The palpable edges of the primary lesion (both the longest and shortest axis) were marked before induction chemotherapy by at least four points, which were 0.5cm away. The patients in the control group received the radical surgery and post-operative radiotherapy. Induction chemotherapy: For the patients who were randomly assigned to receive TPF induction chemotherapy, peripherally inserted central catheter was firstly inserted before intravenous infusion, docetaxel(at a dose of 75mg/m2 of body surface area) was administered as a 2-hour intravenous infusion, followed by intravenous cisplatin(75 mg/m2), administered during a period of 2 to 3 hours. Then, 5-Fu(750 mg/m2/day) was administered as a 120-hour continuous intravenous infusion for 5 days. Induction chemotherapy was given every 3 weeks for 2 cycles, unless there was disease progression, unacceptable toxic effects, or withdrawal of consent by the patients. Dexamethasone was given before docetaxel infusion to prevent docetaxel-related hypersensitivity reactions, skin toxic effects, and fluid retention; prophylactic antibiotics were also given starting on day 5 of each cycle for 3 days. Hydration with diuretic and antiemetic treatment was also performed. Primary prophylaxis with recombinant granulocyte colony-stimulating factor was not suggested. Chemotherapy dose reductions were allowed for grade 3/4 toxicities occurring after cycle 1: 25% and 50% dose reductions of the three chemotherapy agents were suggested for grade 3 and grade 4 hematologic toxicities or gastrointestinal toxicities, respectively; 25% and 50% cisplatin dose reductions were suggested for grade 3 and grade 4 renal toxicities, respectively. Surgery was performed at least 2 weeks after completion of induction chemotherapy. Surgery: Radical resection of the primary lesion and full neck dissection(functional or radical) with proper reconstruction(pedicle or free flap) were performed. The safety margins of the primary lesion were 1.0-1.5cm far away from the palpable margins of the lesion; for patients who received induction chemotherapy, the safety margins were 1.0cm away from the marks that were placed before induction chemotherapy, to ensure the same extent surgery in both arms. Frozen sections during surgery were performed to confirm adequate margins. Post-operative radiotherapy: Radiotherapy was arranged 4 to 6 weeks after surgery. Routine external beam radiotherapy, such as conformal or intensity modulated radiotherapy was performed, and the dose was 1.8-2 Gy/day, 5 days/week for 6 weeks, and totally 54-60 Gy, in the patient with high risk features, such as positive surgical margin, extra capsular nodal spread, vascular embolism, concurrent chemotherapy with cisplatin of 80mg/m2 was suggested. A complete medical history was obtained and tumor assessment was performed at baseline. Clinical tumor response was assessed by clinical evaluation and imaging study and was characterized according to the criteria of response evaluation criteria in solid tumors (version 1.1) before surgery. Post-operative pathologic response was assessed by post-operative pathologic examination as good and bad response. A good response was defined as absence of any tumor cells (pathologic complete response) or presence of scattered foci of a few tumor cells (minimal residual disease with <10% viable tumor cells); otherwise, a bad pathologic response was defined. Toxic effects were assessed weekly during and after completion of induction chemotherapy and radiotherapy according to the common terminology criteria for adverse events (version 3.0). Overall survival was calculated from the date of randomization to the date of death; disease free survival was calculated from the date of randomization to tumor recurrence or distant metastasis or death from any cause; locoregional recurrence/distant metastasis free survival was calculated from the date of randomization to locoregional recurrence/distant metastasis of tumor or death from any cause. Time to locoregional recurrence/distant metastasis was calculated from the date of finishing treatment to tumor locoregional recurrence/distant metastasis. Patients were monitored by every three months in the first two years, every six months in the next 2 years, and once a year thereafter until death or data censoring

Study of NALIRIFOX in Advanced Unresectable Small Bowel Tumors

Neoadjuvant Treatment of Tislelizumab Combined Chemotherapy for Locally Advanced Oral Squamous Cell Carcinoma ：A Single-arm, Prospective, Phase II Trial

Neoadjuvant Therapy for Stage II-IVA Resectable Esophageal Squamous Cell

The aim of this study was to investigate the efficacy and safety of pembrolizumab combined with albumin paclitaxel and cisplatin versus albumin paclitaxel and cisplatin or 5-fluorouracil and cisplatin in neoadjuvant therapy for stage II-IVa resectable esophageal squamous cell carcinoma. The study plans to enroll 114 eligible patients who will be randomly assigned in a 1:1:1 ratio to receive 3 cycles of neoadjuvant immunochemotherapy (pembrolizumab plus albumin paclitaxel and cisplatin;Pembrolizumab plus 5-fluorouracil and cisplatin) or chemotherapy alone (5-fluorouracil and cisplatin), followed by surgery 3 weeks later, followed by 16 cycles of adjuvant immunotherapy (pembrolizumab).Patients were followed up for efficacy and safety during treatment.Tumor evaluation will be performed at screening, after neoadjuvant therapy, before surgery, and after adjuvant therapy until objective disease progression is confirmed. Study Endpoints Primary Endpoints PCR: This was assessed by examining the postoperative pathological tissue for the absence of tumor cells in the primary tumor and lymph nodes. Safety: Adverse reactions during neoadjuvant therapy were recorded following CTCAE version 5.0 guidelines. Perioperative complications were assessed using the Clavien-Dindo classification. Grade I complications included any deviation from the normal postoperative recovery process without requiring medical, surgical, endoscopic, or radiological intervention. Acceptable medical management included antiemetics, antipyretics, analgesics, diuretics, electrolytes, and physical therapy. Bedside open incisional infections were included under this category. Grade II complications were those that required medications beyond those used for treating Grade 1 complications, including blood transfusions and total parenteral nutrition. Grade III complications were those that required surgical, endoscopic, or radiological intervention. Grade IV complications were those considered life-threatening and requiring mid-term care or admission to an intensive care unit (including central nervous system complications, such as cerebral hemorrhage, ischemic stroke, and subarachnoid hemorrhage, and excluding transient ischemic attacks). Grade V complications included patient deaths. Secondary Endpoints 1) Major pathological response (MPR) refers to the proportion of residual tumor cells in the primary tumor and lymph nodes in the postoperative pathological tissue being <10%, or the primary tumor completely disappearing, and the number of positive lymph nodes being ≤1. 2) R0 resection rate: R0 resection was defined as achieving negative upper and lower resection margins. 3) RECIST Criteria Assessment: Complete response (CR): complete response of target lesions; PR: >30% regression of target lesions; Non-CR/Non-PD: target lesions did not completely disappear and did not increase by >20%, or other new lesions appeared in the body; Stable disease (SD): target lesions were reduced or increased by <20%; Progressive disease (PD): target lesions had increased by >20%. Statistical Methods The sample size was determined using Simon's two-stage design. With a minimum expected pCR of 20% and an expected pCR of 40%, a Type I error (α) of 0.05, and a Type II error of 80%, a sample size of 34 was calculated. In the first stage, 17 patients were enrolled. The study was carefully monitored to limit the number of pCR cases to three or below, and any increase in the risk of surgery and mortality due to the treatment regimen would have led to its discontinuation. All continuous variables were presented as frequencies. Statistical significance was set at P <0.05.

HIPEC + FLOT vs. FLOT Alone in Patients With Gastric Cancer and GEJ (PREVENT)

This is a multicenter, randomized, controlled, open-label study including patients with localized and locally advanced diffuse and mixed type adenocarcinoma of the stomach and Type II/III GEJ scheduled to receive perioperative chemotherapy combined with intraoperative HIPEC procedure. The scope of the trial is to evaluate the efficacy as well as the safety and tolerability of the combination of perioperative chemotherapy combined with an intraoperative HIPEC for resectable diffuse and mixed type gastric and GEJ (types II/III) adenocarcinoma. Intraoperative hyperthermic chemoperfusion is summarized under the abbreviation HIPEC in the following. Patients with localized and locally advanced diffuse or mixed type adenocarcinoma of the stomach and Type II/III GEJ (i.e. ≥cT3 any N or any T N-positive) with exclusion of distant metastases and after receiving neoadjuvant FLOT- therapy will be included in this trial after a central review. All enrolled patients will have received 3-6 pre-operative cycles (de-escalation or dose modification allowed) of biweekly FLOT (Docetaxel 50 mg/m² in 250 ml NaCl 0.9%, iv over 1 h; Oxaliplatin 85 mg/m² in 500 ml G5%, iv over 2h; Leucovorin 200 mg/m² in 250 ml NaCl 0.9%, iv over 30 min; 5-FU 2600 mg/m², iv over 24 h, q2wk) in the preoperative treatment phase. After completion of neoadjuvant FLOT- therapy followed by pre-operative tumor assessment, (also including diagnostic laparoscopy prior to start of FLOT), patients without disease progression (expected to be approximately 90% of the patients) will be included into the trial, stratified by initial clinical stage (N- vs. N+), histological type of tumor (Lauren classification diffuse vs. mixed) and study site. Patients will be randomized 1:1 to receive either postoperative FLOT (Arm A) or postoperative FLOT + intraoperative HIPEC (Arm B). Arm A (FLOT) Surgery in Arm A is planned to occur 4 to 6 weeks after d1 of last FLOT. Surgery is carried out in kind of gastrectomy, transhiatal extended gastrectomy. Following surgery, patients will receive four further 2-week treatment cycles FLOT in the post-operative treatment phase. Post-operative treatment should start 6 to 8 weeks, but at maximum 12 weeks after surgery. Arm B (FLOT/ HIPEC) Surgery in Arm B is planned to occur 4 to 6 weeks after d1 of last FLOT. Surgery is carried out in kind of gastrectomy, transhiatal extended gastrectomy. Surgery will be combined with an intraoperative Hyperthermic IntraPEritoneal Chemoperfusion (HIPEC) including cisplatin solution administered at a temperature of 42°C for 90 minutes. Following surgery, patients will receive four further 2-week treatment cycles FLOT in the post-operative treatment phase. Post-operative treatment should start 6 to 8 weeks, but at maximum 12 weeks after surgery. In both of the arms, tumor assessments (CT or MRI) are performed before randomization prior to surgery, and then every 3 months (radiological tumor assessment) thereafter until progression/relapse, death or end of follow-up. A change from CT into MRI in the follow up period is possible at any time. During treatment, clinical visits (blood cell counts, detection of toxicity) occur prior to every treatment dose. Safety of FLOT/ HIPEC will be monitored continuously by careful monitoring of all adverse events (AEs) and serious adverse events (SAEs) reported. The phase III design starts with a safety run-in phase. After 20 patients had curatively intended resection in Arm B, an interim safety analysis is performed that shows feasibility, safety, and tolerability of Arm B planned at the time 8 weeks after the 20th patient in Arm B had curatively intended resection. It is not planned to discontinue recruitment for the interim safety analysis.