PIPAC in patients with peritoneal metastases from gastrointestinal tract (PIPOX01): An open label, non-comparative phase 1/2 dose escalation and expansion trial.

BACKGROUND: Despite modern systemic chemotherapy, survival remains poor for patients with advanced isolated peritoneal metastases from the gastrointestinal tract. We aimed to assess the safety and efficacy of pressurized intraperitoneal aerosol chemotherapy (PIPAC) with oxaliplatin. PATIENTS AND METHODS: We conducted a phase 1/2, open label, non-comparative, dose escalation and expansion trial of PIPAC with oxaliplatin in patients with a peritoneal cancer index (PCI) of more than 5, 13 and 15 for respectively a gastric, small bowel and colorectal primary cancer, and who had received at least three months of systemic chemotherapy. PIPAC cycle lengths were 4-6 weeks with systemic chemotherapy allowed 15 days after each PIPAC. PCI and oxaliplatin tumor concentration were assessed every PIPAC cycle. The main endpoints were tolerability, tumor response, and survival. RESULTS: Between 2017 and 2020, 34 patients were enrolled in three centers, in this phase 1/2 study, of whom 25 were evaluable at the recommended dose determined in the phase I trial (90 mg/m2 plus systemic 5-FU). Before inclusion, patients received a median of 2 [1-4] chemotherapy lines and had a median PCI of 22.5 [7-29]. At this dose, the safety profile showed acceptable tolerability. Eight patients (32 %) had grade 3/4 treatment-related adverse events. Minor (grade 1/2) adverse events were mainly abdominal pain (n = 19, 76 %) and nausea (n = 16, 64 %). Median PFS was 6.1 months and median OS was 13 months. CONCLUSION: In patients with advanced and refractory peritoneal metastasis, PFS of 6.1 months is encouraging. A prospective randomized phase II study is required.

Smoking and Cannabis Use among Childhood Cancer Survivors: Results of the French Childhood Cancer Survivor Study.

BACKGROUND: Unhealthy behaviors among childhood cancer survivors increase the risks for cancer treatment adverse effects. We aimed to assess tobacco and cannabis use prevalence in this population and to identify factors associated with these consumptions. METHODS: This study involved 2,887 5-year survivors from the French childhood cancer survivor study (FCCSS) cohort. Data on health behaviors were compared with those of controls from the general population. Associations of current smoking and cannabis use with clinical features, sociodemographic characteristics, and health-related quality of life (QOL) were investigated using multivariable logistic regressions. RESULTS: Prevalence for tobacco use was lower in survivors (26%) than in controls (41%, P < 0.001). Among current smokers, survivors smoked more cigarettes per day and started at a younger age than controls. Women, college graduates, older, married, and CNS tumor survivors, as well as those who received chemotherapy and thoracic radiation therapy, were less likely to be smokers and/or cannabis consumers than others. Participants with a poor mental QOL were more likely to smoke. CONCLUSIONS: Preventive interventions and cessation programs must be carried out as early as possible in survivors' life, especially among young males with low educational level and poor mental health. IMPACT: This study brings new insights to health behaviors among childhood cancer survivors from a population with high rates of smoking and cannabis use.

A phase I dose-escalation study of oxaliplatin delivered via a laparoscopic approach using pressurised intraperitoneal aerosol chemotherapy for advanced peritoneal metastases of gastrointestinal tract cancers.

OBJECTIVE: The objectives were to define the maximum tolerated dose (MTD), safety profile and pharmacokinetics (PKs) of intraperitoneal oxaliplatin delivered by pressurised intraperitoneal aerosol chemotherapy (PIPAC) in patients with advanced peritoneal carcinomatosis from gastrointestinal tract cancers. METHODS: PIPAC was applied every 4-6 weeks, for 5 cycles, in a phase I dose-escalation study using a 3 + 3 design. The first dose level was 90 mg/m2 with planned increases of 50 mg/m2 per level. Platinum concentration was measured in plasma, tissues and intraperitoneal fluid samples. The trial was registered at ClinicalTrials.gov (NCT03294252). RESULTS: Ten patients with 33 PIPAC sessions were included. No dose limiting toxicity (DLT) occurred at 90 mg/m2 and two at 140 mg/m2. The MTD was therefore set at 90 mg/m2. Overall treatment included a median number of three PIPAC sessions (range: 1-5) and secondary complete cytoreductive surgery for two patients. Overall safety showed 67 grade I-II and 11 grade III-IV toxicities, usually haematologic, digestive (nausea/vomiting, abdominal pain), and fatigue. Oxaliplatin concentrations were three- to four-fold higher in tissue in contact with aerosol than in muscle without contact. At 140 mg/m2, the plasma oxaliplatin concentration was high with Cmax and area under the curve (AUC)0-48h of 1035 µg/l and 9028 µg h/L, respectively. CONCLUSIONS: The MTD of oxaliplatin during PIPAC is 90 mg/m2. PK data demonstrate a high tumour concentration and a significant systemic absorption.

Identifying clusters of health risk behaviors and their predictors in adult survivors of childhood cancer: A report from the French Childhood Cancer Survivor Study.

OBJECTIVE: Health risk behaviors (HRB) of childhood cancer survivors (CCS) are generally studied separately, despite the evidence suggesting that HRB are not independent. To our knowledge, few studies have examined HRB profiles in the former pediatric cancer patients. In this study, we identified HRB profiles and examined predictors engaging in unhealthy behaviors in CCS. METHODS: We used data from a French cohort of CCS that includes five-year survivors diagnosed between 1945 and 2000 and treated before reaching age 18, in five centers in France. A total of 2961 adult CCS answered a self-reported questionnaire pertaining to HRB. Latent class analysis was used to identify HRB profiles combining physical activity, smoking, cannabis use, and alcohol drinking. Multinomial logistic analyses examined predictors for engaging in unhealthy behaviors. RESULTS: Three HRB patterns emerged: "Low-risk" (n = 1846, 62.3%) included CCS who exhibited the highest frequency for usual physical activity and the lowest probabilities for current smoking or cannabis use, but most drank at least moderately; "Moderate-risk behaviors" (n = 291, 9.8%), and "High-risk behaviors" (n = 824, 27.8%) for CCS who exhibited the highest frequencies for current smoking, cannabis use, and heavy drinking. The multivariable regression revealed that male CCS, less educated or not married were significantly more likely to be in the high-risk behaviors group than the low-risk group. CONCLUSIONS: As CCS remain a vulnerable population, screening for HRB should be routinized in long-term follow-up care and interventions targeting multiple HRB simultaneously among survivors should be developed.

The fully synthetic glycopeptide MAG-Tn3 therapeutic vaccine induces tumor-specific cytotoxic antibodies in breast cancer patients.

Cancer is one of the main causes of mortality worldwide and a major public health concern. Among various strategies, therapeutic vaccines have been developed to stimulate anti-tumoral immune responses. However, in spite of extensive studies, this approach suffers from a lack of efficacy. Recently, we designed the MAG-Tn3 vaccine, aiming to induce antibody responses against Tn, a tumor-associated carbohydrate antigen. The Tn antigen is of interest because it is expressed by several adenocarcinomas, but not normal cells. The fully synthetic glycopeptide vaccine MAG-Tn3 is composed of four arms built on three adjacent Tn moieties associated with the tetanus toxin-derived peptide TT830-844 CD4+ T-cell epitope. This promiscuous CD4+ T-cell epitope can bind to a wide range of HLA-DRB molecules and is thus expected to activate CD4+ T-cell responses in a large part of the human population. The MAG-Tn3 vaccine was formulated with the GSK-proprietary immunostimulant AS15, composed of CpG7909, MPL, and QS21, which has been shown to stimulate both innate and humoral responses, in addition to being well tolerated. Here, seven patients with localized breast cancer with a high-risk of relapse were immunized with the MAG-Tn3 vaccine formulated with AS15. The first results of phase I clinical trial demonstrated that all vaccinated patients developed high levels of Tn-specific antibodies. Moreover, these antibodies specifically recognized Tn-expressing human tumor cells and killed them through a complement-dependent cytotoxicity mechanism. Overall, this study establishes, for the first time, the capacity of a fully synthetic glycopeptide cancer vaccine to induce specific immune responses in humans.

The role of irradiated heart and left ventricular volumes in heart failure occurrence after childhood cancer.

BACKGROUND: Paediatric cancer survivors have a high risk of developing cardiac diseases, and the most frequent cardiac disease is heart failure (HF). The radiation dose-volume effects in the heart and cardiac substructures have not been explored in childhood cancer survivors (CCS). Therefore, the role of irradiated heart volume in the occurrence of HF among this population remains unclear. The aims of this study were to determine the doses and irradiated volumes of the heart and left ventricle (LV) related to the risk of HF in CCS and to investigate the impact of anthracycline exposure on this risk. METHODS AND RESULTS: A case-control study nested in the French Childhood Cancer Survivors Study cohort. The mean heart and left ventricular doses and volumes indicators were estimated by reconstruction of individual treatments. A total of 239 HF cases and 1042 matched controls were included. The median age of HF diagnosis was 25.1 years. The median volume of the heart that received ≥ 30 Gy was 61.1% for cases and 16.9% for controls. In patients who did not receive anthracycline, the risk of HF was increased 3.6-fold when less than 10% of the LV received ≥ 30 Gy when compared to patients who were not exposed to any cardiac radiation and anthracycline. CONCLUSIONS: Small irradiated volumes of the heart or LV were significantly associated with HF risk. To the author's knowledge, this is the first study to report a dose-response relationship based on dose-volume indicators in CCS, which can be translated efficiently into current clinical practice.

Phase I/II study of oxaliplatin dose escalation via a laparoscopic approach using pressurized aerosol intraperitoneal chemotherapy (PIPOX trial) for nonresectable peritoneal metastases of digestive cancers (stomach, small bowel and colorectal): Rationale and design.

BACKGROUND: The annual incidence of gastrointestinal carcinomas (stomach, small bowel, colon and rectum) is increasing in Western countries, reaching 50,000 new cases each year in France. Peritoneal carcinomatosis (PC) is diagnosed in 15% of these patients. Complete cytoreductive surgery (CCS) plus Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) is the only therapy that can offer patients with PC a chance for long-term survival with a 5 year overall survival (OS) rate of 30-60% versus 0-5% with systemic chemotherapy alone. However, CCS plus HIPEC still presents serious limitations and very few patients (10%) are candidates for these radical treatments. PC remains a palliative setting for 90% of patients with a median survival ranging from 15 to 25 months. Innovative surgical therapies such as Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) therefore need to be developed to improve the prognosis. Potential benefits were obtained after intraperitoneal nebulization of oxaliplatin in patients with advanced PC from colorectal cancer. Innovative surgical therapies such as pressurized intraperitoneal aerosol chemotherapy (PIPAC) have been proposed as palliative locoregional treatment with some promising results. The dose of oxaliplatin currently established by nebulization (PIPAC) is really low at 92 mg/m2. However, the peritoneum acts as a barrier limiting the systemic passage of intraperitoneal drug. Oxaliplatin used at higher doses during PIPAC procedures could be a safe option and allow better intratumoral penetration of chemotherapy. METHOD AND DESIGN: The proposed study is a multicenter phase I/II trial of oxaliplatin dose escalation during PIPAC. The aim is to determine the maximum tolerated dose of pressurized oxaliplatin administered by the intraperitoneal route (PIPAC) during two consecutive procedures at a 4-6 week interval for patients with extended peritoneal carcinomatosis from the gastrointestinal tract. Dose started at 90 mg/m2 and escalation was in 50 mg/m2 steps up to a maximum of 300 mg/m2. DISCUSSION: Oxaliplatin is an effective drug in gastrointestinal cancer and high doses given by the intraperitoneal route during HIPEC are well tolerated. In this phase I trial, we hypothesized that high-dose oxaliplatin during PIPAC is feasible and safe. The repeated local administration of high doses of oxaliplatin could improve tumor response and prognosis. TRIAL REGISTRATION: Prospective study. ClinicalTrials.gov: NCT03294252. EudraCT: 2016-003666-49.

Cardiac Diseases Following Childhood Cancer Treatment: Cohort Study.

BACKGROUND: Cardiac disease (CD) is one of the major side effects of childhood cancer therapy, but until now little has been known about the relationship between the heart radiation dose (HRD) received during childhood and the risk of CD. METHODS AND RESULTS: The cohort comprised 3162 5-year survivors of childhood cancer. Chemotherapy information was collected and HRD was estimated. There were 347 CDs in 234 patients, 156 of them were rated grade ≥3. Cox and Poisson regression models were used. The cumulative incidence of any type of CD at 40 years of age was 11.0% (95% confidence interval [CI], 9.5-12.7) and 7·4% (95% CI, 6.2-8.9) when only the CDs of grade ≥3 were considered. In comparison with patients who received no anthracycline and either no radiotherapy or an HRD<0·1Gy, the risk was multiplied by 18·4 (95% CI, 7.1-48.0) in patients who had received anthracycline and no radiotherapy or a HRD <0.1Gy, by 60.4 (95% CI, 22.4-163.0) in those who had received no anthracycline and an HRD≥30Gy, and 61.5 (95% CI, 19.6-192.8) in those who had received both anthracycline and an HRD≥30Gy. CONCLUSIONS: Survivors of childhood cancers treated with radiotherapy and anthracycline run a high dose-dependent risk of developing CD. CDs develop earlier in patients treated with anthracycline than in those treated without it.

OLIGOPELVIS - GETUG P07: a multicentre phase II trial of combined salvage radiotherapy and hormone therapy in oligometastatic pelvic node relapses of prostate cancer.

BACKGROUND: Metastatic prostate cancer remains a common cause of death in Europe, and improvements in management of the disease are urgently needed. The advent of positron-emission tomography (PET) imaging enhanced with fluorocholine has led to the identification of a new sub-group of metastatic prostate cancer patients: those with so-called oligometastatic disease. Presenting with a low burden of metastatic disease (≤5 lesions), this new sub-group lies between true metastatic prostate cancer patients for whom androgen- deprivation therapy (ADT) is the mainstay of treatment, and patients with a rising PSA, but no visible lesion on conventional imaging, in whom intermittent ADT has been shown to be no less effective than continuous ADT. One might conclude that intermittent ADT would also be the standard of care for oligometastatic prostate cancer patients, but radical strategies such as extensive lymphadenectomy or high-dose radiotherapy have been suggested as another means to delay the need for ADT, and increase its effectiveness once initiated. This study will explore the role of salvage pelvic image-guided intensity-modulated radiation therapy (IMRT) combined with ADT administered for 6 months in pelvic oligometastatic patients in prolonging the failure-free interval between two consecutive ADT courses, or even to cure selected patients with limited metastatic burden. METHODS/DESIGN: We plan to assess the two year outcome in oligometastatic prostate cancer patients (1-5 pelvic oligometastases) treated concomitantly with high-dose IMRT (54 Gy, 30 fractions to the pelvis and 66 Gy, 30 fractions to the lymph nodes) and ADT for six months. DISCUSSION: This multicenter prospective phase II study will yield new data regarding the safety and efficacy of high-dose radiotherapy combined with ADT and will provide a basis for a larger phase III study to examine the role of radiotherapy in this population currently treated only with hormone therapy. TRIAL REGISTRATION: NCT02274779 , date of registration: 23/10/14.

Characteristics and outcome of stage II and III non-anaplastic Wilms' tumour treated according to the SIOP trial and study 93-01.

PURPOSE: To determine the prognosis of children with stage II and III of low or intermediate risk histology (SIOP classification) in unilateral localised Wilms tumour (WT) after neoadjuvant chemotherapy according to the trial and study of the International Society of Paediatric Oncology, SIOP 93-01. PATIENTS AND METHODS: Patients with unilateral localised WT and stage II or III with low (LR) or intermediate risk (IR) histology between 6 months and 18 years of age, were selected from the total sample of patients registered in the SIOP 93-01 study between June 1993 and December 2001. All patients received 4 weeks of actinomycin-D/vincristine before surgery. Postoperative chemotherapy consisted of actinomycin-D, vincristine and epirubicin/doxorubicin for 27 weeks. Flank or whole abdomen irradiation was given for stage III. Event-free survival (EFS) and overall survival (OS) were analysed for various subgroups. RESULTS: Of 1476 registered patients 594 (40%) met the inclusion criteria for this analysis. Four hundred and two (67%) had stage II disease and 563 (95%) had intermediate risk histology. Median tumour volume was 439 ml at diagnosis and 163 ml after preoperative chemotherapy. With a median follow-up of 8 years, 5-year EFS was 90% (95% confidence interval [95% CI]: 87-92%) and OS 95% (95% CI: 93-97%). Patients with stage III, blastemal type histology and a large volume at surgery had a worse outcome. CONCLUSION: Treatment for stage II and III LR or IR WT is successful in a neoadjuvant setting as advised by the SIOP. Stage, tumour volume and blastemal type histology are the most important prognostic factors.

PCA analgesia for children with chemotherapy-related mucositis: a double-blind randomized comparison of morphine and pethidine.

AIMS: This study aimed to compare pethidine and morphine on efficacy and toxicity in children with severe mucositis following chemotherapies. PATIENTS AND METHODS: From March 2000 to November 2003, 35 hospitalized children with chemotherapy-related mucositis were randomly assigned to receive double blindly "patient-controlled analgesia" (PCA) bolus doses of morphine or pethidine. The mucositis pain score was the mean of pain measured four times a day with a Visual Analogue Scale from day 2 to 5 of PCA. RESULTS: Study stops before total accrual for difficulties of recruitment. Out of the 29 patients with more than one day of PCA, the median (range) of the Mean Pain Score was 44 (13-72) and 33 (3-89) in the morphine (n = 14) and pethidine (n = 15) groups, respectively (P = 0.32). PCA was stopped for failure in 10 cases (five in each group). Constipation requiring specific treatment was higher in the morphine group (43% versus 0%). CONCLUSIONS: PCA with pethidine appears not inferior to morphine, with less constipation requiring specific treatment, but a larger study is warranted to confirm this.

Radiation dose and long term risk of cardiac pathology following radiotherapy and anthracyclin for a childhood cancer.

PURPOSE: To determine the cardiac status in children 15 years (yrs) or more after a solid tumour treatment. PATIENTS AND METHODS: Of the 447 patients, 229 were fully studied and 218 were not. The following cardiac evaluation was proposed to all the 447 consecutive patients: (1) cardiac Doppler US by one of two expert cardiologists; (2) cardiac rhythm and conduction abnormalities including 24-h holter ECG; (3) (131)I-mIBG myocardial scintigraphy; (4) serum brain natriuretic peptide levels at rest; (5) an exercise test with VO(2)max measurement. The radiation dose delivered to 7 points in the heart was estimated for all patients who had received radiotherapy. RESULTS: Cardiac disorder was diagnosed in 89 evaluated patients (39%) including 24 heart failures and 65 other asymptomatic cardiac diseases. When adjusting on potential confounders, cardiac disorder and cardiac failure risks were respectively linear (ERR at 1 Gy: 26%) and linear-quadratic (ERR at 1 Gy: 19%) functions of the average radiation dose received to the heart. No interaction between cumulative dose of adriamycin and average radiation dose was evidenced for cardiac disorders, but the ERR/Gy of cardiac failure was higher for patients receiving less than 350 mg/m(2) of Adriamycin. CONCLUSION: Long term heart pathologies are probably one of the major iatrogenic risks encored by patients who survived a childhood cancer. This study strongly emphasizes the need to limit the heart irradiation during radiotherapy, particularly, for patients who also received or were susceptible to later received adriamycin.

[Cardiac toxicity of cancer treatment regimes in children and adolescents: physiopathology, clinical data and the paediatric oncologist's point of view]. / Toxicité cardiaque des traitements du cancer chez l'enfant et l'adolescent: physiopathologie, données cliniques et point de vue de l'oncopédiatre.

Over the last 20 years, the increase in the cure rate of childhood cancer and leukemia of almost 80% has facilitated the observation of middle and long-term sequelae, particularly of cardiovascular origin; such after-effects are the consequence of cytotoxic damage to the cells of the cardiovascular system, in particular by anthracyclines and radiotherapy, and all the more so by their combined use. Such destructive lesions to myocytes greatly hinder the capacity of the cardiac muscle to hypertrophy to meet the needs of bodily growth, pregnancy and certain intense sports activities. Endothelial cells also accelerate an early arteriosclerotic process, a potential cause of sudden death in the case of ostial stenosis. All such phenomena build up over time, together with the usual adult cardio-vascular risk factors. Finally, no cardiac tissue, pericardial, valvular endocardium or autonomic nervous tissue escapes these cytotoxic effects, giving rise to pericarditis, calcification, valvular leaks and arrythmias and conduction abnormalities. The resulting excessive cardiac mortality is one of the major concerns of paediatric oncologists, along with secondary tumours and leukaemia. This article analyses physiopathological consequences that are often asymptomatic or clinical, together with diagnostic, screening and follow-up methods for these patients, encouraging lifestyle modifications where appropriate or, when possible, treatment before the appearance of cardiac failure, myocardial infarction or sudden death. Other cytotoxic drugs such as high-dose cyclophosphamide, amsacrin, 5-FU and tubulin acting agents are also mentioned as a result of their cardiac toxicity, but this is not usually dose-cumulative.

A phase I study of irinotecan as a 3-week schedule in children with refractory or recurrent solid tumors.

PURPOSE: A phase I study was performed to determine the maximum-tolerated dose (MTD) and safety profile of irinotecan (CPT-11) administered as a single intravenous infusion every 3 weeks in children with recurrent or refractory solid tumors. PATIENTS AND METHODS: Eighty-one patients were enrolled, including 48 less heavily, and 33 heavily pretreated patients (cranial irradiation and/or high-dose chemotherapy). Children received CPT-11 as a 120-minute infusion at doses ranging from 200 to 720 mg/m2. The dose-limiting toxicities (DLT) on first cycle were determined in both cohorts. RESULTS: One hundred twenty-two cycles and 81 cycles were administered in less heavily, and heavily pretreated patients, respectively. The primary DLT was delayed diarrhea in less heavily pretreated patients, and neutropenia in heavily pretreated patients. MTD was 600 mg/m2 in both cohorts. Grade 3 to 4 neutropenia occurred in 33% and 38% of cycles in less heavily, and heavily pretreated patients, respectively. Grade 3 to 4 nonhematologic toxicities included nausea/vomiting (7% and 4% of cycles in less heavily, and heavily pretreated patients, respectively), asthenia (7% and 4% of cycles, respectively), and delayed diarrhea (6% and 2.5% of cycles, respectively). Four partial responses at 600 mg/m2 (high-grade glioma, neuroblastoma, medulloblastoma, and rhabdomyosarcoma) and 21 minor responses and stable diseases were observed. Pharmacokinetic analysis of CPT-11 and SN-38 was performed in 77 patients. The mean +/- standard deviation (SD) CPT-11 plasma clearance was 20.7 +/- 9.5 L/h/m2 (range, 5 to 54). The mean +/- SD SN-38 metabolic ratio was 1.5% +/- 1.1% (range, 0.15% to 5.55%). CONCLUSION: The recommended phase II dose of CPT-11 in a 3-week schedule is 600 mg/m2 in less heavily, and heavily pretreated children with solid tumors.

Cadherins in Wilms' tumor: E-cadherin expression despite absence of WT1.

Loss of heterozygosity of chromosome 16q occurs in 17-25% of Wilms' tumors. Two cadherin genes mapping to 16q22 were chosen as candidate gens: E-CAD, encoding epithelial cadherin, because it is involved in kidney development and it was recently reported to be a WT1 target; and KSP-CAD because it encodes a kidney-specific cadherin. By RT-PCR analysis in a series of 39 Wilms' tumors, we identified a very low expression of E-CAD and KSP-CAD in 72% and 95% of the tumors, respectively. To ascertain whether down-expression of these genes could be related to WT1 alterations in tumors, we looked for a relationship between WT1 and CAD expression. Our data suggest (i) the existence of alternative mechanisms for regulating E-CAD expression, and (ii) that E-CAD does not belong to the WT1 pathway that is altered in Wilms' tumorigenesis.