Adel Courdi

Mean Inactivation Dose: A Useful Concept for Intercomparison of Human Cell Survival Curves

The mean inactivation dose (D) is calculated for published in vitro survival curves obtained from cell lines of both normal and neoplastic human tissues. Cells belonging to different histological categories (melanomas, carcinomas, etc.) are shown to be characterized by distinct values of D which are related to the clinical radiosensitivity of tumors from these categories. Compared to other ways of representing in vitro radiosensitivity, e.g., by the multitarget parameters D0 and n, the parameter D has several specific advantages: (i) D is representative for the whole cell population rather than for a fraction of it; (ii) it minimizes the fluctuations of the survival curves of a given cell line investigated by different authors; (iii) there is low variability of D within each histological category; (iv) significant differences in radiosensitivity between the categories emerge when using D. D appears to be a useful concept for specifying intrinsic radiosensitivity of human cell lines.

Cell proliferation kinetics in human solid tumors: relation to probability of metastatic dissemination and long-term survival

A large number of studies have investigated the relationship between the long-term survival and the percentage of tumor cells in S phase assessed by autoradiography after tritiated thymidine labelling, image cytometry, flow cytometry or labelling with an halogenated analog of thymidine, in various types of human solid tumors. The survey of the results clearly shows that the S-phase fraction (SPF) is of high prognostic significance in several types of cancers, in particular in breast cancers, non-Hodgkin lymphomas, ovarian cancers, neuroblastoma, bladder cancers and lung cancers. SPF was found of high independent significance in 10 of the 11 studies in which multivariate analyses of prognostic factors had been carried out. Proliferation appears generally to be of higher prognostic significance than ploidy. In view of the wide differences in the biological characteristics of the tumors studied, it is likely that the association between a high proliferation rate and the degree of tumor aggressiveness is a general feature of human solid tumors. However, high proliferative rate of tumor cells is probably not the cause of tumor biological aggressiveness but a variable associated with it. The extent to which cells escape from the regulatory systems which control their proliferation appears to be a good index of tumor progression.

Results of proton therapy of uveal melanomas treated in Nice

PURPOSE To present the first results of uveal melanomas treated with the Medicyc Cyclotron 65 MeV proton beam facility in Nice, analyzing the factors that affect the cause-specific survival (CSS), metastatic rate, and reporting the visual outcome. METHODS AND MATERIALS This study concerns 538 patients referred by French institutions between June 1991 and December 1996. The eye and tumor parameters were measured using ultrasonography and angiography. Since 1994, CT scans were performed in most patients to help determine the axial length and the shape of the ocular globe. Tantalum clips were inserted around the tumor by the referring ophthalmologist. There were 349 posterior pole tumors (64.9%), 130 equatorial tumors (24.1%), and 59 ciliary body tumors (11%). Two hundred four patients (37.9%) had T1 or T2 tumors, and 334 patients (62.1%) had T3 or T4 tumors. The median tumor diameter was 14.6 mm, and the median tumor height was 5.1 mm. All patients received 52 Gy (57.20 Gy Co-equivalent dose) on 4 consecutive days. The data were analyzed by December 1997. RESULTS The CSS was 77.4% at 78 months, the overall survival was 73.8% and the local control was 89.0%. The CSS was not influenced by the patient age or the site of the tumor. It was 81.5% for T1 and T2 tumors, versus 75% for T3 and T4 tumors (P = 0.035). It was found that the tumor diameter, rather than the height, was the most important parameter affecting outcome. The metastatic rate was 8%. It depended on the T stage, tumor diameter and thickness, but not the tumor site. Thirty-eight enucleations were performed, most of them due to tumor progression and/or glaucoma. One-third of the patients in whom visual acuity was adequately scored before and after treatment had a stable, if not improved vision, and half the patients retained useful vision after treatment. CONCLUSION The outcome of patients suffering from uveal melanoma and treated with high-energy protons compares favorably with other techniques of treatment. The tumor dimensions affected CSS and metastatic rate. Even though two-thirds of patients had posterior pole tumors, half of them retained useful vision.

The labelling index: a prognostic factor in head and neck carcinoma☆

The thymidine labelling index (LI), representing the percentage of cells in the DNA-synthesis phase, was measured in vitro prior to therapy in 87 patients with squamous cell carcinoma of the head and neck, who were treated between 1977 and 1982. The LI was not related to patient age, site of the tumour, clinical stage or histological grade. Overall survival was 44.5%. Univariate analysis demonstrated that survival was affected by the following factors: (1) age: patients older than 55 had a better outcome (p = 0.03); (2) site of the tumour (p = 0.005): laryngeal tumours had the best survival; (3) clinical stage (p = 0.05). Histological grade did not influence the survival (p = 0.41). Patients having a tumour LI higher than 15.5% (mean + 1 S.D.) had a significantly lower survival than patients with lower tumour LI (p = 0.008). A multivariate analysis using the Cox model showed that clinical stage and LI kept their prognostic impact with regard to survival. Finally, survival after relapse was lower in patients with a high tumour LI. These results demonstrate that a high tumour proliferation rate is an additional factor influencing the disease outcome in head and neck carcinoma. Patients with bad prognosis defined by this parameter could be offered a more energetic treatment.

CONCOMITANT B.I.D. RADIOTHERAPY AND CHEMOTHERAPY WITH CISPLATIN AND 5-FLUOROURACIL IN UNRESECTABLE SQUAMOUS-CELL CARCINOMA OF THE PHARYNX: CLINICAL AND PHARMACOLOGICAL DATA OF A FRENCH MULTICENTER PHASE II STUDY

PURPOSE The aim of this phase II study conducted on unresectable squamous cell carcinoma (USCC) of the oro- and hypopharynx was to associate twice-a-day (b.i.d.) continuous nonaccelerated radiotherapy with concomitant cisplatin (CP)-5-fluorouracil (5-FU) chemotherapy, both given at full dose. Feasibility, efficacy, survival, and pharmacokinetic-pharmacodynamic relationships were analyzed. METHODS AND MATERIALS Fifty-four consecutive patients with strictly USCC of oro- and/or hypopharynx received continuous b.i.d. radiotherapy (RT) (2 daily fractions of 1.2 Gy, 5 days a week, with a 6-h minimal interval between fractions). Total RT dose was 80.4 Gy on the oropharynx and 75.6 Gy on the hypopharynx. Three chemotherapy (CT) courses of CP-5-FU were given during RT at 21-day intervals (third not delivered after the end of RT). CP dose was 100 mg/m2 (day 1) and 5-FU was given as 5-day continuous infusion (day 2-day 6: 750 mg/m2/day cycle 1, 750 mg total dose/day cycle 2 and 3). Pharmacokinetics was performed for 5-FU (105 h follow-up) and CP (single sample at 16 h). Special attention was paid to supportive care. RESULTS Good feasibility of RT was observed (85.2% of patients with total dose > 75 Gy). Five patients received 1 CT cycle, 34: 2 cycles, and 15: 3 cycles. The most frequent and severe acute toxicities were mucositis with grade 3-4 occurring in 28% at cycle 1 and 86% at cycle 2, as well as neutropenia (43% at cycle 2). Locoregional control at 6 months was observed in 66.7% of patients. No late toxicity above grade 2 RTOG was noticed. CP dose and 5-FU AUC(0-105h) were significantly linked to grade 3-4 neutropenia (cycle 2). Cumulative total platinum (Pt) concentration and Karnofsky index were the only independent predictors of locoregional control at 6 months. Finally, total RT dose and total Pt concentration were the only independent predictors of specific survival. CONCLUSION This protocol showed good locoregional response with an acceptable toxicity profile. Pharmacokinetic survey is probably an effective approach to further reduce toxicity and improve efficacy. A multicentric randomized phase III study, now underway, should confirm these encouraging results.

Phase 1 Clinical Trial of Stereotactic Body Radiation Therapy Concomitant With Neoadjuvant Chemotherapy for Breast Cancer

PURPOSE Stereotactic body radiation therapy (SBRT) allows stereotactic irradiation of thoracic tumors. It may have a real impact on patients who may not otherwise qualify for breast-conserving surgery. We conducted a phase 1 trial that tested 5 dose levels of SBRT concomitant with neoadjuvant chemotherapy (NACT) before to surgery. The purpose of the current dose escalation study was to determine the maximum tolerable dose of SBRT in the treatment of breast cancer. METHODS AND MATERIALS To define toxicity, we performed dermatologic examinations that included clinical examinations by 2 separate physicians and technical evaluations using colorimetry, dermoscopy, and skin ultrasonography. Dermatologic examinations were performed before NACT, 36 and 56 days after the beginning of NACT, and before surgery. Surgery was performed 4 to 8 weeks after the last chemotherapy session. Efficacy, the primary endpoint, was determined by the pathologic complete response (pCR) rate. RESULTS Maximum tolerable dose was not reached. Only 1 case of dose-limiting toxicity was reported (grade 3 dermatologic toxicity), and SBRT was overall well tolerated. The pCR rate was 36%, with none being observed at the first 2 dose levels, and the highest rate being obtained at dose level 3 (25.5 Gy delivered in 3 fractions). Furthermore, the breast-conserving surgery rate was up to 92% compared with an 8% total mastectomy rate. No surgical complications were reported. CONCLUSIONS This study demonstrates that SBRT can be safely combined with NACT. Regarding the efficacy endpoints, this trial showed promising results in terms of pCR rate (36%) and breast-conserving rate (92%). The findings provide a strong rationale for extending the study into a phase 2 trial. In view of the absence of correlation between dose and pCR, and given that the data from dose level 3 met the statistical requirements, a dose of 25.5 Gy in 3 fractions should be used for the phase 2 trial.

Changes in labeling indices of human tumors after irradiation

Abstract The time courses of the in vitro labeling index (LI) and of the tumor cell density (CD) were studied in 53 patients after one or several sessions of irradiation. Prior to irradiation, a significant positive correlation was observed between LI and CD. In these tumors the depression in LI was greater and of longer duration than in experimental tumors, it increased progressively during the course of fractionated irradiation. The histologic type and the site of the tumor appeared to influence the course of LI and CD. A temporary increase of LI was observed in only 7 of 31 patients irradiated in one or two sessions and in only 2 of 22 patients who were followed during a fractionated course of radiotherapy. In the 9 patients whose LI increased after irradiation, the pretreatment LI and CD were significantly lower than in the other patients. No relationship was observed between pretreatment LI or CD values and either tumor regression with radiotherapy or 5-year survival. However, a significant fall in LI after irradiation was generally observed in patients who had no noticeable tumor regression and in those who did not survive 5 years; no significant or a less significant fall in LI was observed in tumors which regressed after radiotherapy and in patients who survived at 5 years.

Influence of internal mammary node irradiation on long-term outcome and contralateral breast cancer incidence in node-negative breast cancer patients

BACKGROUND AND PURPOSE There is no general consensus concerning irradiation (RT) of internal mammary nodes (IMN) in axillary node-negative breast cancer. Based on a large series of patients treated in a single institute and followed up for a long period of time, we looked at the influence of IMN RT on late outcome of these patients as well as the development of contralateral breast cancer (CBC). PATIENTS AND METHODS The study was based on 1630 node-negative breast cancer patients treated in our institution between 1975 and 2008 with primary conservative surgery and axillary dissection or sentinel node examination. All patients received post-operative breast RT. IMN RT was more frequent in inner or central tumours. Kaplan-Meier (K-M) overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) according to IMN RT were calculated for all patients and for patients with inner/central tumours. The K-M rate of contralateral breast cancer (CBC) was also analysed and correlated with IMN RT. RESULTS Prognostic variables such as tumour size, histological grade, and hormone receptors were not significantly different in the groups having received IMN RT or not. Considering all patients, OS was strictly comparable in the 2 groups: 10-year values were 85% (IMN RT) and 86% (no IMN RT), respective values at 20 years were 66.6% and 61.0% (p=0.95). However, in patients presenting with inner/central tumours, OS was significantly improved in the IMN RT group with respective values of 92.5% and 87.2% at 10 years, and 80.2% and 63.3% at 20 years: Hazard ratio (HR)=0.56 (0.37-0.85); p=0.0052. Again, CSS was improved in patients with inner/central tumours having received IMN RT, with 20-year rates of 89.5% versus 79.1% in patients not receiving IMN RT (p=0.047). No difference in DFS was noticed. The actuarial rate of CBC development was comparable between patients having received IMN RT and other patients. However, considering only patients alive 10 years after primary breast surgery, the K-M rate of CBC at 20 years was 5.3% in patients without IMN RT and 7.2% in patients with such RT; HR=2.47 (1.23-4.95); p=0.008. CONCLUSIONS IMN RT in node-negative tumours was associated with increase in OS and CSS in patients with inner or centrally located lesions. An increase in CBC development was also noticed in long-survivors of IMN RT patients; however, these findings have to be interpreted with caution because of the difference in follow-up between the 2 groups. Further studies are warranted to investigate the potential role of IMN irradiation in the development of CBC.

Second conservative treatment for ipsilateral breast cancer recurrence using high-dose rate interstitial brachytherapy: Preliminary clinical results and evaluation of patient satisfaction

PURPOSE To assess early clinical results and evaluate patient satisfaction in case of second conservative treatment (2nd CT) combining lumpectomy plus high-dose rate (HDR) interstitial brachytherapy for patients (pts) presenting with ipsilateral breast cancer recurrence (IBCR). METHODS AND MATERIALS From June 2005 to July 2009, 42 pts presenting with an IBCR underwent a second lumpectomy with intraoperative implantation of plastic tubes in the tumor bed. After performing the dose distribution analysis on the postimplant CT scan, a total dose of 34 Gy in 10 fractions over 5 consecutive days was delivered. Toxicity evaluation was based on the Common Terminology Criteria for Adverse Events v3.0 criteria. Applying a visual analogic scale (VAS) analysis, patient satisfaction regarding cosmetic result and 2nd CT possibility was performed after the end of brachytherapy. RESULTS Median followup was 21 months (range, 6-50 months) and median age at the time of local recurrence was 65 years (range, 30-85 years). Median delay between primary and recurrence was 11 years (range, 1-35 years). Median recurrence tumor size was 12 mm (range, 2-30 mm). Median number of plastic tubes and planes were nine (range, 5-12) and two (range, 1-3), respectively. Median clinical target volume was 68 cc (range, 31.2-146 cc). Second local control rate was 97%. Twenty-two pts (60%) developed complications. Cutaneous and subcutaneous fibrosis was the most frequent side effect. Median VAS satisfaction score regarding cosmetic result was 7 of 10 (range, 4-9), whereas median VAS satisfaction score for 2nd CT was 10 of 10 (range, 8-10). CONCLUSION A 2nd CT for IBCR using high-dose rate brachytherapy seems feasible with encouraging results in terms of second local control with an acceptable toxicity. Patient satisfaction regarding the possibility of second breast preservation should be considered.

ROBOTIC STEREOTACTIC RADIOABLATION CONCOMITANT WITH NEO-ADJUVANT CHEMOTHERAPY FOR BREAST TUMORS

PURPOSE Robotic stereotactic radioablation (RSR) allows stereotactic irradiation of thoracic tumors; however, it has never been used for breast tumors and may have a real potential. We conducted a Phase I study, including neoadjuvant chemotherapy (NACT), a two-level dose-escalation study (6.5 Gy x 3 fractions and 7.5 Gy x 3 fractions) using RSR and breast-conserving surgery followed by conventional radiotherapy. MATERIALS AND METHODS To define toxicity, we performed a dermatologic exam (DE) including clinical examination by two independent observers and technical examination by colorimetry, dermoscopy, and skin ultrasound. DE was performed before NACT (DE0), at 36 days (DE1), at 56 days (DE2), after the NACT treatment onset, and before surgery (DE3). Surgery was performed 4-8 weeks after the last chemotherapy session. A pathologic examination was also performed. RESULTS There were two clinical complete responses and four clinical partial responses at D56 and D85. Maximum tolerable dose was not reached. All patients tolerated RSR with no fatigue; 2 patients presented with mild pain after the third fraction of the treatment. There was no significant toxicity measured with ultrasound and dermoscopy tests. Postoperative irradiation (50 Gy) has been delivered without toxicity. CONCLUSION The study showed the feasibility of irradiation with RSR combined with chemotherapy and surgery for breast tumors. There was no skin toxicity at a dose of 19.5 Gy or 22.5 Gy delivered in three fractions combined with chemotherapy. Lack of toxicity suggested that the dose could be increased further. Pathologic response was acceptable.