Learning curve for robotic-assisted total mesorectal excision: a multicentre, prospective study.

AIM: Robotic-assisted surgery (RAS) is becoming increasingly important in colorectal surgery. Recognition of the short, safe learning curve (LC) could potentially improve implementation. We evaluated the extent and safety of the LC in robotic resection for rectal cancer. METHOD: Consecutive rectal cancer resections (January 2018 to February 2021) were prospectively included from three French centres, involving nine surgeons. LC analyses only included surgeons who had performed more than 25 robotic rectal cancer surgeries. The primary endpoint was operating time LC and the secondary endpoint conversion rate LC. Interphase comparisons included demographic and intraoperative data, operating time, conversion rate, pathological specimen features and postoperative morbidity. RESULTS: In 174 patients (69% men; mean age 62.6 years) the mean operating time was 334.5 ± 92.1 min. Operative procedures included low anterior resection (n = 143) and intersphincteric resection (n = 31). For operating time, there were two or three (centre-dependent) LC phases. After 12-21 cases (learning phase), there was a significant decrease in total operating time (all centres) and an increase in the number of harvested lymph nodes (two centres). For conversion rate, there were two or four LC phases. After 9-14 cases (learning phase), the conversion rate decreased significantly in two centres; in one centre, there was a nonsignificant decrease despite the treatment of significantly more obese patients and patients with previous abdominal surgery. There were no significant differences in interphase comparisons. CONCLUSION: The LC for RAS in rectal cancer was achieved after 12-21 cases for the operating time and 9-14 cases for the conversion rate. RAS for rectal cancer was safe during this time, with no interphase differences in postoperative complications and circumferential resection margin.

[Clinical trials in Radiation Oncology: Methodologic approach]. / Essais cliniques en Oncologie Radiothérapie : réflexion méthodologique.

In the context of the clinical development of radiation oncology, the specificities of curative treatments and the necessary follow-ups for the acute and late tolerance evaluation require rigourous and up-dated methodological approaches given the limited feasibility of some studies to demonstrate their effectiveness. Indeed, the diversity of treatments in terms of delivery, type of radiation and multiple technologies render difficult the medical assessment. Although the randomized controlled trial is the gold standard for demonstrating the causal link of the treatment effect size, a state of the art of current limits is presented and proposals for new methodological approaches are discussed as alternative or complementary possibilities. Co-primary endpoints or pragmatic composite endpoints are to be used with adequate statistical analyses, the use of Bayesian methods, the re-use of observational data for the external control arms identification and the development of Real World Data registers is to be preferred to respond to this colossal challenge.

Tumour and normal tissue radiosensitivity.

The place of personalized treatments is highly increasing in medical and radiation oncology. During the last decades, a huge number of assays have been developed to predict responses of normal tissues and tumours. These tests have not yet been included into daily clinical practice but the recent developments of radiation oncology are paving the way of personalized strategies including the risk of tumour recurrence and normal tissue reactions. Concerning tumor radiosensitivity prediction, no test are currently used, even if the radiosensitivity index and the genome-based model for adjusting radiotherapy dose assays seem the most promising with level II of evidence. Commercial developments are under progress. Concerning normal tissue radiosensitivity prediction, single nucleotide polymorphims of prostate cancer patients and radiation-induced CD8 T-lymphocyte apoptosis breast and prostate assays are of level I of evidence. They can be proposed before the beginning of radiotherapy in order to propose personalized treatments according to both risks of tumour and normal tissue radiosensitivity. Commercial developments are also under way.

GUIP1: a R package for dose escalation strategies in phase I cancer clinical trials.

BACKGROUND: The main objective of phase I cancer clinical trials is to identify the maximum tolerated dose, usually defined as the highest dose associated with an acceptable level of severe toxicity during the first cycle of treatment. Several dose-escalation designs based on mathematical modeling of the dose-toxicity relationship have been developed. The main ones are: the continual reassessment method (CRM), the escalation with overdose control (EWOC) method and, for late-onset and cumulative toxicities, the time-to-event continual reassessment method (TITE-CRM) and the time-to-event escalation with overdose control (TITE-EWOC) methods. The objective of this work was to perform a user-friendly R package that combines the latter model-guided adaptive designs. RESULTS: GUIP1 is an R Graphical User Interface for dose escalation strategies in Phase 1 cancer clinical trials. It implements the CRM (based on Bayesian or maximum likelihood estimation), EWOC and TITE-CRM methods using the dfcrm and bcrm R packages, while the TITE-EWOC method has been specifically developed. The program is built using the TCL/TK programming language, which can be compiled via R software libraries (tcltk, tkrplot, tcltk2). GUIP1 offers the possibility of simulating and/or conducting and managing phase I clinical trials in real-time using file management options with automatic backup of study and/or simulation results. CONCLUSIONS: GUIP1 is implemented using the software R, which is widely used by statisticians in oncology. This package simplifies the use of the main model-based dose escalation methods and is designed to be fairly simple for beginners in R. Furthermore, it offers multiple possibilities such as a full traceability of the study. By including multiple innovative adaptive methods in a free and user-friendly program, we hope that GUIP1 will promote and facilitate their use in designing future phase I cancer clinical trials.

[Predictive assays for responses of tumors and normal tissues in radiation oncology]. / Outils pour la prédiction de la réponse tumorale et des tissus sains en oncologie radiothérapie.

The impact of curative radiotherapy depends mainly on the total dose delivered homogenously in the target volume. Tumor sensitivity to radiotherapy may be particularly inconstant depending on location, histology, somatic genetic parameters and the capacity of the immune system to infiltrate the tumor. In addition, the dose delivered to the surrounding healthy tissues may reduce the therapeutic ratio of many radiation treatments. In a same population treated in one center with the same technique, it appears that individual radiosensitivity clearly exists, namely in terms of late side effects that are in principle non-reversible. This review details the different radiobiological approaches that have been developed to better predict the tumor response but also the radiation-induced late effects.

[Individual modification of the dose, volume and fractionation of breast radiotherapy]. / Personnalisation de la dose, du volume et du fractionnement de la radiothérapie du sein.

Randomized trials demonstrated similar overall survival between mastectomy and breast-conservative surgery followed by adjuvant radiation therapy. Breast-conservative surgery, with adjuvant radiation therapy, with or without neoadjuvant systemic therapy has become the standard of care for women with early or locally advanced breast cancer. Nevertheless, certain cardiac, lung or cutaneous toxicities may alter the long-term body image and the quality of life of a limited number of patients who consider having had "overtreatment" or treatment outside the best knowledge of science. In case of low-risk breast cancer, several trials have evaluated the carcinologic outcome in absence of radiation therapy after breast-conservative surgery. Local recurrences increased in case of breast-conservative surgery alone but without impact on overall survival. Multiple debates have emerged in order to select the most appropriate evaluation criteria. Finally, a large consensus has considered that reducing local recurrences is important but with modern technologies and after identifying patients of individual radiosensitivity. Indeed, in case of a low absolute risk of local recurrence, radiation therapy techniques have been developed to allow a focal treatment especially for patients with high risk of developing late effects. This kind of compromise takes into account the reduction risk of local recurrences but also the probability of developing radiation-induced cutaneous sequelae. In the same way, for patients considered at high risk of recurrence, the huge volumes need specific techniques to better cover the targets while protecting the surrounding critic organs such as heart and lung. Intensity-modulated radiation therapy and the local high boost may help to decrease local recurrences of these more extended and aggressive diseases while considering the individual radiosensitivity that paves the way of long-term sequelae. In this article, we detail a personalized approach of breast radiation therapy considering the absolute risk of local recurrences and the probability of radiation-induced toxicity appearance.

Early MRI predictors of disease-free survival in locally advanced rectal cancer from the GRECCAR 4 trial.

BACKGROUND: Tailored neoadjuvant treatment of locally advanced rectal cancer (LARC) may improve outcomes. The aim of this study was to determine early MRI prognostic parameters with which to stratify neoadjuvant treatment in patients with LARC. METHODS: All patients from a prospective, phase II, multicentre randomized study (GRECCAR4; NCT01333709) were included, and underwent rectal MRI before treatment, 4 weeks after induction chemotherapy and after completion of chemoradiotherapy (CRT). Tumour volumetry, MRI tumour regression grade (mrTRG), T and N categories, circumferential resection margin (CRM) status and extramural vascular invasion identified by MRI (mrEMVI) were evaluated. RESULTS: A total of 133 randomized patients were analysed. Median follow-up was 41·4 (95 per cent c.i. 36·6 to 45·2) months. Thirty-one patients (23·3 per cent) developed tumour recurrence. In univariable analysis, mrEMVI at baseline was the only prognostic factor associated with poorer outcome (P = 0·015). After induction chemotherapy, a larger tumour volume on MRI (P = 0·019), tumour volume regression of 60 per cent or less (P = 0·002), involvement of the CRM (P = 0·037), mrEMVI (P = 0·026) and a poor mrTRG (P = 0·023) were associated with poor outcome. After completion of CRT, the absence of complete response on MRI (P = 0·004), mrEMVI (P = 0·038) and a poor mrTRG (P = 0·005) were associated with shorter disease-free survival. A final multivariable model including all significant variables (baseline, after induction, after CRT) revealed that Eastern Cooperative Oncology Group performance status (P = 0·011), sphincter involvement (P = 0·009), mrEMVI at baseline (P = 0·002) and early tumour volume regression of 60 per cent or less after induction (P = 0·007) were associated with relapse. CONCLUSION: Baseline and early post-treatment MRI parameters are associated with prognosis in LARC. Future preoperative treatment should stratify treatment according to baseline mrEMVI status and early tumour volume regression.

ANTECEDENTES: El tratamiento neoadyuvante personalizado del cáncer de recto localmente avanzado (locally advanced rectal cancer, LARC) puede mejorar los resultados. El objetivo de este estudio fue determinar factores pronósticos precoces mediante RMN para estratificar el tratamiento neoadyuvante en pacientes con LARC. MÉTODOS: Todos los pacientes de un eensayo prospectivo de fase II, multicéntrico y aleatorizado (GRECCAR4-NCT01333709) se incluyeron en este estudio y se les realizó una RMN antes del tratamiento, 4 semanas después de la quimioterapia de inducción y después de completar la quimiorradioterapia (chemoradiation, CRT). Se evaluó la volumetría tumoral, el grado de regresión tumoral mediante RMN (MRI Tumor Regression Grade, mrTRG), la estadificación T, la estadificación N, el estado del margen de resección circunferencial (circumferential resection margin, CRM) y la presencia de invasión extramural vascular en la RMN (extramural vascular invasion, mrEMVI). RESULTADOS: Se analizaron 133 pacientes aleatorizados. La mediana de seguimiento fue de 41,4 meses (i.c. del 95%: 36,6-45,2). En 31 pacientes (23%) se diagnosticó una recidiva. En el análisis univariado de la situación basal, mrEMVI fue el único factor pronóstico asociado con un peor resultado (P = 0,0152). Después de la quimioterapia de inducción, un volumen tumoral más alto en la RMN (P = 0,019), una regresión del volumen tumoral ≤ 60% (P = 0,002), la afectación del CRM (P = 0,037), mrEMVI (P = 0,026) y un grado escaso mrTRG (P = 0,023) se asociaron con un mal resultado. Después de completar la CRT, la ausencia de respuesta completa en la RMN (P = 0,004), la presencia de mrEMVI (P = 0,04) y una insuficiente mrTRG (P = 0,005) se asociaron con una supervivencia libre de enfermedad más corta. En el modelo multivariable final en el que se incluyeron todas las variables significativas (basales, postinducción, post-CRT), el estado de ECOG (P = 0,011), la afectación esfinteriana (P = 0,009), la presencia de EMVI al inicio (P = 0,002) y una regresión precoz del volumen tumoral ≤ 60% después de la inducción (P = 0,007) se asociaron con una recidiva. CONCLUSIÓN: Los parámetros basales y post-tratamiento precoces de la RMN se asocian con el pronóstico en el LARC. La estrategia terapéutica preoperatoria futura deberá estratificar el tratamiento de acuerdo con la presencia de EMVI al inicio y la regresión precoz del volumen tumoral.

Rectal Surgery Evaluation Trial: protocol for a parallel cohort trial of outcomes using surgical techniques for total mesorectal excision with low anterior resection in high-risk rectal cancer patients.

AIM: Total mesorectal excision (TME) is the standard of care for rectal cancer, which can be combined with low anterior resection (LAR) in patients with mid-to-low rectal cancer. The narrow pelvic space and difficulties in obtaining adequate exposure make surgery technically challenging. Four techniques are used to perform the surgery: open laparotomy, laparoscopy, robot-assisted surgery and transanal surgery. Comparative data for these techniques are required to provide clinical data on the surgical management of rectal cancers. METHODS: The Rectal Surgery Evaluation Trial will be a prospective, observational, case-matched, four-cohort, multicentre trial designed to study TME with LAR using open laparotomy, laparoscopy, robot-assisted surgery or transanal surgery in high-surgical-risk patients with mid-to-low non-metastatic rectal cancer. All surgeries will be performed by surgeons experienced in at least one of the techniques. Oncological, morbidity and functional outcomes will be assessed in a composite primary outcome, with success defined as circumferential resection margin ≥ 1 mm, TME Grade III and minimal postoperative morbidity (absence of Clavien-Dindo Grade III-IV complications within 30 days after surgery). Secondary end-points will include the co-primary end-points over the long term (2 years), quality of surgery, quality of life, length of hospital stay, operative time and rate of unplanned conversions. DISCUSSION: This will be the first trial to study all four surgical techniques currently used for TME with LAR in a specific group of high-risk patients. The knowledge obtained will contribute towards helping physicians determine the advantages of each technique and which may be the most appropriate for their patients.

Prospective medical analysis of radiation therapist image repositioning during image-guided radiotherapy.

PURPOSE: Radiation oncologists are responsible for deciding which day-to-day variations are acceptable or not in the treatment setup. However, properly qualified and trained radiation therapists might be capable to perform image registration. We evaluated in our centre the capability and accuracy of radiation therapists to validate positioning images in a prospective study. METHODS AND PATIENTS: A total of 84 patients treated for prostate, head and neck, lung or breast cancer was prospectively and randomly included from July 2011 to July 2013 in radiotherapy unit of our institution. For each patient, three positioning images were randomly analysed. Two radiation oncologists analysed all positioning images and shifts decided by the radiation therapists in an independent and blinded way. The radiation oncologists had to decide whether to validate or not this shift and give a corresponding additional shift, if any. A theoretical disagreement rate less than 5% between radiation therapists and radiation oncologists was planned. RESULTS: A total of 240 images were analysed (head and neck: 15.0%; prostate: 14.2%; breast: 55.0%; lung: 15.8%). The global disagreement between radiation oncologists and radiation therapists for all the images analysed was 2.5% 95% confidence interval (95% CI) [1.0-5.0], corresponding to six images out of 240. A 100% agreement was reached for prostate and lung images, a 97.2% agreement for head and neck images and a 96.2% agreement for breast images. CONCLUSIONS: The radiation therapist validation for repositioning images seemed accurate for image-guided radiotherapy in our institution. Periodic evaluation and in-house training are warranted when routine delegation of image registration to radiation therapists is considered.

Health-related quality of life results from the PRODIGE 5/ACCORD 17 randomised trial of FOLFOX versus fluorouracil-cisplatin regimen in oesophageal cancer.

BACKGROUND: A recent prospective randomised trial did not reveal significant differences in median progression-free survival between two chemoradiotherapy (CRT) regimens for inoperable non-metastatic oesophageal cancer patients. This secondary analysis aimed to describe the impact of CRT on health-related quality of life (HRQOL), physical functioning, dysphagia, fatigue and pain and to evaluate whether baseline HRQOL domains can predict overall survival. PATIENTS AND METHODS: A total of 267 patients were randomly assigned to receive with 50 Gy of radiotherapy in 25 fractions six cycles of FOLFOX or four cycles of fluorouracil and cisplatin on day 1. HRQOL was prospectively assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire version 3.0 with the oesophageal cancer module (QLQ-OES18). RESULTS: Both groups showed high baseline compliance. Subsequently, compliance reduced to 41% at the 6-month follow-up. Baseline HRQOL scores showed no statistical differences between treatment arms. During treatment, both groups exhibited lower physical and social functioning and increased fatigue and dyspnoea, although dysphagia moderately improved in the fluorouracil-cisplatin arm only (p = 0.047). During follow-up, HRQOL scores revealed no significant differences between chemotherapy regimens. Linear mixed model exhibited a treatment-by-time interaction effect for dysphagia (p = 0.017) with a greater decrease in dysphagia in the fluorouracil-cisplatin group. Time until definitive deterioration analysis showed no significant differences in global HRQOL, functional or main symptom domains. However, time until definitive deterioration was significantly longer for the fluorouracil and cisplatin arm compared with FOLFOX for appetite loss (p = 0.002), QLQ-OES-18 pain (p = 0.008), trouble swallowing saliva (p = 0.011) and trouble talking (p = 0.020). CONCLUSION: Analyses of HRQOL scores revealed no statistically significant differences between patients with inoperable non-metastatic oesophageal cancer treated by FOLFOX versus those treated with a fluorouracil-cisplatin regimen as part of definitive CRT.

Concurrent or sequential letrozole with adjuvant breast radiotherapy: final results of the CO-HO-RT phase II randomized trial.

BACKGROUND: We present here final clinical results of the COHORT trial and both translational sub-studies aiming at identifying patients at risk of radiation-induced subcutaneous fibrosis (RISF): (i) radiation-induced lymphocyte apoptosis (RILA) and (ii) candidates of certain single-nucleotide polymorphisms (SNPs). PATIENTS AND METHODS: Post-menopausal patients with stage I-II breast cancer (n = 150) were enrolled and assigned to either concurrent (arm A) or sequential radiotherapy (RT)-letrozole (arm B). Among them, 121 were eligible for RILA and SNP assays. Grade ≥2 RISF were the primary end point. Secondary end points were lung and heart events and carcinologic outcome. RILA was performed to predict differences in RISF between individuals. A genome-wide association study was performed to identify SNPs associated with RILA and RISF. Analyses were done by intention to treat. RESULTS: After a median follow-up of 74 months, 5 patients developed a grade ≥2 RISF. No significant difference was observed between arms A and B. Neither grade ≥2 lung nor symptomatic cardiac toxicity was observed. Median RILA value of the five patients who had grade ≥2 RISF was significantly lower compared with those who developed grade ≤1 RISF (6.9% versus 13%, P = 0.02). Two SNPs were identified as being significantly associated with RILA: rs1182531 (P = 4.2 × 10(-9)) and rs1182532 (P = 3.6 × 10(-8)); both located within the PHACTR3 gene on chromosome 20q13.33. CONCLUSIONS: With long-term follow-up, letrozole can safely be delivered concomitantly with adjuvant breast RT. Translational sub-studies showed that high RILA values were correlated with patients who did not develop RISF. REGISTERED CLINICAL TRIAL: NCT00208273.

Total laparoscopic radical hysterectomy for locally advanced cervical carcinoma (stages IIB, IIA and bulky stages IB) after concurrent chemoradiation therapy: surgical morbidity and oncological results.

OBJECTIVES: To evaluate the surgical outcome and the oncologic results of total laparoscopic radical hysterectomy (TLRH) after neoadjuvant chemoradiation therapy (CRT) for locally advanced cervical carcinoma. METHODS: All patients who underwent TLRH after CRT for stages IIB-IIA and bulky IB diseases were reviewed. The control group for this analysis was a cohort of patients treated with abdominal radical hysterectomy (ARH) after CRT for the same stage cancers. RESULTS: We reviewed 102 patients operated on between 2000 and 2008 (46 TLRH and 56 ARH). Mean age at diagnosis was 44 years, and mean B.M.I was 22.1. There was no difference in tumor characteristics between the two groups. Seven patients in the laparoscopic group required conversion to laparotomy (15%). Mean estimated blood loss (200 vs. 400 mL, p<0.01) and the median duration of hospital stay (5 vs. 8 days, p<0.01) were significantly lower in the laparoscopic group. Morbidity rates and urinary complications were reduced in the laparoscopic group (p=0.04). Local recurrence rates, disease-free and overall survival were comparable in the two groups. Best survival was observed for patients with pathological complete response or microscopic residual disease compared to patients with macroscopic residues (p<0.01). CONCLUSIONS: Radical hysterectomy after CRT is known to be difficult with significant morbidity rates and remains controversial in comparison to exclusive CRT. TLRH after preoperative CRT is feasible for patients with locally advanced cervical cancer in 85% of the cases. For these patients, TLRH compared with ARH was associated with favorable surgical outcome with comparable oncological results.

Aggressive surgical strategies in advanced ovarian cancer: a monocentric study of 203 stage IIIC and IV patients.

AIMS: The standard treatment for advanced ovarian cancer consists of cytoreductive surgery associated with a platinum/paclitaxel-based chemotherapy. Nevertheless, there is still the question as to the extent and timing of the surgical debulking. The aim of this study was to evaluate the place of surgery in the therapeutic sequence. PATIENTS AND METHODS: We reviewed data from all consecutive patients with stage IIIC and IV epithelial ovarian cancer, operated on at our institution between 1990 and 2005. Patients were divided into 2 groups, according to the position of surgery in the therapeutic sequence. Patients in group 1 received initial debulking surgery. Group 2 consisted of patients having received their first debulking after initial chemotherapy. RESULTS: Two hundred and three patients were identified and frequently underwent aggressive surgery, in particular, digestive surgery with bowel resections. Perioperative mortality and morbidity rates were low (2% and 14%, respectively) and there was no difference between the groups. Overall survival in group 1 for patients with complete cytoreduction (residual disease (RD)=0), optimal surgery (RD<1cm) or sub-optimal surgery (RD>1cm) was 50%, 30% and 14%, respectively. In group 2, overall survival following complete surgery was 30%, and no long-term survival was observed when surgery was not complete at the time of interval surgery. Survival was worse for patients who had received more than 4 cycles of neoadjuvant chemotherapy. CONCLUSION: This study confirms the importance of surgery in the prognosis of advanced ovarian cancer. Only the patient subgroup that underwent complete initial or interval surgery was associated with a prolonged remission. Optimal surgery with a controlled morbidity can be achieved in many cases, even if bowel resection is needed, at the time of primary debulking. In the interval cytoreductive surgery subgroup, the response to initial chemotherapy and surgery was found to be essential for prognosis.

A randomized, prospective study using the LPG technique in treating radiation-induced skin fibrosis: clinical and profilometric analysis.

BACKGROUND/PURPOSE: Cutaneous fibrosis is the quite mandatory sequela after a breast cancer treated by radiotherapy and it induces more or less important functional troubles. The LPG technique is a technique of mechanical massage that allows skin mobilization by folding/unfolding. The aim of this study was to evaluate the changes on irradiated skin before and after LPG treatment by clinical and skin replica analysis. METHODS: Twenty women, 43-55 years old, who had been treated from 6 to 16 months before, for breast cancer with a conservative surgery and radiotherapy, had been enrolled in the trial. They were divided into two groups after randomization: the first group was LPG treated three times a week for 1 month; the second group was only placed under medical supervision. The clinical criteria studied were systematically studied before (T0), at the end of treatment (T1) and 1 month after the end of treatment (T2): pain, itching, skin dryness, erythema, skin infiltration, feeling of tightness and of induration of the skin. Softening of the skin was assessed at T1 and T2. Cutaneous replica was performed on the internal upper 1/4 of each breast with silicone material before, after and 1 month later after the end of the treatment. After polymerization, the replica was stored and then blindly analyzed by image analysis software. The following parameters were systematically measured: average skin roughness, average of wrinkles' depth and residual length, wrinkle number and the space between them. RESULTS: Clinically, the LPG treatment induced a decrease of erythema (10% of the patients vs. 40% before treatment), a decrease of pain and pruritus (10% vs. 20% and 40%, respectively) and a decrease of the feeling of induration of the skin (10% of the patients vs. 70% before treatment). Furthermore, a skin-softening sensation was noted by seven patients vs. one in the control group. Replica shows an increase of roughness and of furrow depth without any change in the residual length and an increase in the space between the wrinkles, whose number decreases. CONCLUSION: This study confirms the impact of the clinical sequelae induced on skin after radiotherapy and shows improvement of the clinical signs after treatment by the LPG technique. The latter induces changes of micro relief, suggesting a softening effect on the skin. These preliminary results have to be confirmed on a more important group of patients.

Concomitant use of tamoxifen with radiotherapy enhances subcutaneous breast fibrosis in hypersensitive patients.

Concomitant use of adjuvant tamoxifen (TAM) and radiation therapy (RT) is not widely accepted. We aim to assess whether this treatment is associated with an increased risk of developing subcutaneous fibrosis after conservative or radical surgery in breast cancer patients. We analysed 147 women with breast cancer treated with adjuvant RT, and who were included in the KFS 00539-9-1997/SKL 00778-2-1999 prospective study aimed at evaluating the predictive value of CD4 and CD8 T-lymphocyte apoptosis for the development of radiation-induced late effects. TAM (20 mg day(-1)) with concomitant RT was prescribed in 90 hormone receptor-positive patients. There was a statistically significant difference in terms of complication-relapse-free survival (CRFS) rates at 3 years, 48% (95% CI 37.2-57.6%) vs 66% (95% CI 49.9-78.6%) and complication-free survival (CFS) rates at 2 years, 51% (95% CI 40-61%) vs 80% (95% CI 67-89%) in the TAM and no-TAM groups, respectively. In each of these groups, the CRFS rates were significantly lower for patients with low levels of CD8 radiation-induced apoptosis, 20% (95% CI 10-31.9%), 66% (95% CI 51.1-77.6%), and 79% (95% CI 55-90.9%) for CD8 24%, respectively. Similar results were observed for the CFS rates. The concomitant use of TAM with RT is significantly associated with an increased incidence of grade 2 or greater subcutaneous fibrosis; therefore, caution is needed for radiosensitive patients.

[Secondary debulking surgery and intraperitoneal chemotherapy in advanced or recurrent epithelial ovarian cancer]. / Chirurgie de fermeture et chimiothérapie intra-péritonéale dans les cancers de l'ovaire de stade avancé ou en récidive.

OBJECTIVE: The aim of this study was to evaluate the indications and the results of secondary cytoreduction surgery with intraperitoneal (i.p.) paclitaxel chemotherapy in advanced or recurrent epithelial ovarian cancer. PATIENTS AND METHODS: In a retrospective study, records were reviewed for 13 patients who received i.p. paclitaxel therapy (175 mg/m2) during secondary cytoreductive surgery or surgery for recurrent disease. All these patients were initially treated with optimal debulking surgery (macroscopic persistent residual disease) and systemic chemotherapy. RESULTS: Nine patients were operated for secondary cytoreductive surgery (group I) and four patients operated for recurrent disease (group II). Postoperative residual disease was absent or microscopic in 69% (n = 9). Median hospital stay was 16 days. Hematologic toxicity grade III-IV was reported by 12 patients (92%). Operative mortality was 7.7% (n = 1). Median follow-up was 22.7 months. The median overall survival was 25.5 months. The median disease-free survival was 8.5 months. The median disease-free survival for group I and II were respectively 11.7 months and 4.2 months (P = 0.3). Progression of disease after completion of treatment was documented in 62% (n = 8): six patients for group I and two patients for group II. DISCUSSION AND CONCLUSION: Secondary cytoreduction surgery associated with intraperitoneal chemotherapy is feasible after adjuvant systemic chemotherapy for patients with recurrent or suboptimally resected ovarian cancer. Results on loco-regional control for recurrent disease are poor. Intraperitoneal chemotherapy should be discussed during a two-step surgical strategy, as secondary cytoreductive surgery.

An open phase I study assessing the feasibility of the triple combination: oxaliplatin plus irinotecan plus leucovorin/ 5-fluorouracil every 2 weeks in patients with advanced solid tumors.

BACKGROUND: The aim of this study was to determine the maximum-tolerated dose (MTD) and the recommended dose of irinotecan and oxaliplatin with a fixed 5-fluorouracil (5-FU)/leucovorin (LV) regimen in patients with metastatic solid tumors. PATIENTS AND METHODS: The trial was designed to evaluate escalating doses of oxaliplatin and irinotecan, starting at 60 mg/m2 and 90 mg/m2, respectively, given at day 1 with the full-dose LV5FU2 regimen, given on days 1 and 2 as follows: folinic acid 200 mg/m2 followed by 5-FU 400 mg/m2 bolus and 600 mg/m2 22 h continuous infusion, every 2 weeks. The second cohort of patients was treated at the recommended dose for oxaliplatin and irinotecan with the simplified LV5FU regimen: on day 1, a 2-h infusion of folinic acid (400 mg/m2), followed by a 10-min intravenous bolus of 5-FU (400 mg/m2), followed by a continuous infusion of 5-FU (2400 mg/m2) over 46 h. RESULTS: Thirty-four patients were treated at the following dose levels (oxaliplatin/irinotecan mg/m2): 60/90, 60/120, 85/120, 85/150, 85/180, 85/200 and 85/220 and seven patients were treated at the recommended dose with the simplified LV5FU scheme. The MTD was reached at dose level 85/220 mg/m2 but the recommended dose chosen for the second step was 85/180 mg/m2 to keep a better compliance with the biweekly schedule. Main grade 3/4 toxicities per patient included the following: neutropenia in 78% (febrile episodes in 12%), diarrhea in 27%, nausea/vomiting in 24% and peripheral neuropathy in 37% (Lévi's scale). Antitumor activity was observed at almost all dose levels. Most objective responses were observed in digestive malignancies, since 10 out of 11 were obtained in five colorectal cancers, two pancreatic cancers, two cholangiocarcinoma and one gastric cancer. CONCLUSION: The recommended dose for the triple association is 85/180 mg/m2 of oxaliplatin and irinotecan, respectively, with LV5FU2 or simplified LV5FU. The antitumor activity in gastrointestinal malignancies should be evaluated in phase II studies in different tumor types.

Radiation-induced skin fibrosis after treatment of breast cancer: profilometric analysis.

BACKGROUND/AIM: Treatment of breast cancer involves an association of conservative surgery and radiotherapy. This implies various cutaneous complications, well known for their clinical and histological aspects. Little data are available concerning modifications of the cutaneous microrelief after radiotherapy. We have done a profilometric analysis of the skin of breast cancer patients treated with surgery and radiotherapy. The results obtained on the irradiated breast have been compared with the ones of the controlateral normal breast. METHODS: Twenty women, 43-55 year old were enrolled in the study 6-16 months after the end of a treatment associating conservative surgery and radiotherapy for breast cancer. Imprints using a silicone rubber material were performed over symmetrical areas of the treated breast and the controlateral one. All measures were performed over the upper-medial quadrant of each breast. The imprints are then blindly analysed using an image analyser. The following parameters were measured: RA (average roughness of the skin), RZ (average of the furrows depth), RS (residual length), Rn (number of furrows) and AR (space between the furrows). RESULTS: The comparison of the imprints shows important modifications of the microrelief after irradiation. We observe a slight increase of the skin roughness (RA: 26, 39 +/- 2, 58 versus 21, 84 +/- 1, 59), a significantly increase of the furrows depth (RZ: 121, 66 +/- 10, 46 versus 101, 26 +/- 6, 99) along with an increase of the residual length (RS: 580, 60 +/- 60, 60 versus 450, 46 +/- 48, 43). The number of furrows has not significantly decreased but the space between the furrows has increased on the irradiated breast. CONCLUSION: This study shows a breakdown effect of irradiation on the skin in correlation with the fibrosis inducing by ionising radiation. The imprints modifications are clearly different from those usually observed in the ageing process. Our results can be a basis for studying the effects of treatments on cutaneous complications linked to the radiation-induced fibrosis.