A randomized trial of induction docetaxel-cisplatin-5FU followed by concomitant cisplatin-RT versus concomitant cisplatin-RT in nasopharyngeal carcinoma (GORTEC 2006-02).

Background: Concomitant chemotherapy (CT)-radiotherapy (RT) is a standard of care in locally advanced nasopharyngeal carcinoma (NPC) and a role for induction CT is not established. Methods: Patients with locally advanced NPC, WHO type 2 or 3, were randomized to induction TPF plus concomitant cisplatin-RT or concomitant cisplatin-RT alone. The TPF regimen consisted of three cycles of Docetaxel 75 mg/m2 day 1; cisplatin 75 mg/m2 day 1; 5FU 750 mg/m2/day days 1-5. RT consisted of 70 Gy in 7 weeks plus concomitant cisplatin 40 mg/m2 weekly. Results: A total of 83 patients were included in the study. Demographics and tumour characteristics were well balanced between both arms. Most of the patients (95%) in the TPF arm received three cycles of induction CT. The rate of grade 3-4 toxicity and the compliance (NCI-CTCAE v3) during cisplatin-RT were not different between both arms. With a median follow-up of 43.1 months, the 3-year PFS rate was 73.9% in the TPF arm versus 57.2% in the reference arm [hazard ratio (HR) = 0.44; 95% confidence interval (CI): 0.20-0.97, P = 0.042]. Similarly the 3 years overall survival rate was 86.3% in the TPF arm versus 68.9% in the reference arm (HR = 0.40; 95% CI: 0.15-1.04, P = 0.05). Conclusion: In conclusion, several important aspects can be emphasized: the compliance to induction TPF was good and TPF did not compromise the tolerance of the concomitant RT-cisplatin phase. The improved PFS and overall survival rates needs to be confirmed by further trials.

[Recurrence sites following definitive intensity-modulated conformational radiotherapy of squamous-cell carcinomas of the upper aerodigestive tract]. / Sites de récidive après radiothérapie conformationnelle avec modulation d'intensité des carcinomes épidermoïdes des voies aérodigestives supérieures.

PURPOSE: The implementation of intensity-modulated radiotherapy (IMRT) in a centre requires regular critical review of medical practices and feedback to optimize the subsequent management of patients. PATIENTS AND METHODS: We reviewed and determined through a retrospective single-centre study recurrence sites of 167 consecutive patients treated for head and neck squamous cell carcinoma excluding skin or sinuses. Patients had mostly stage III or IV locally advanced cancer (n=123). RESULTS: Locoregional control rates at 1 and 2 years were respectively 87.9% (95% confidence interval [95%CI]: 81.6%-92.1%) and 77.6% (95%CI: 70.1%-83.5). Among 55 relapses, 20 patients (36.4%) had treatment failures. Patients treated with 70 Gy relapsed mainly in high risk volume (78%). Those treated with 66 Gy recurred regionally outside the irradiated volume (n=4) or in the irradiated high risk volume (n=3) or had isolated metastatic failure (n=3). Those irradiated with 50 Gy had regional relapse outside the irradiated volume (n=2) or isolated metastatic relapse (n=2). We noticed respectively 5.4%, 10.2% and 4.2% isolated metastatic, local, cervical lymph node relapse. CONCLUSION: Our results are consistent with data from the literature. Corrective actions were performed to enhance our practices.

Fracture incidence after 3 years of aromatase inhibitor therapy.

BACKGROUND: The purpose of this study was to describe the fracture incidence and bone mineral density (BMD) evolution in a large cohort of post-menopausal women with breast cancer after 3 years of aromatase inhibitor (AI) therapy. PATIENTS AND METHODS: A prospective, longitudinal study in real-life setting. Each woman had an extensive medical assessment, a biological evaluation, a BMD measurement, and systematic spinal X-rays at baseline and after 3 years of AI therapy. Women with osteoporosis at baseline (T-score < -2.5 and/or non-traumatic fracture history) were treated by oral weekly bisphosphonates. RESULTS: Among 497 women (mean age 63.8 ± 9.6 years) included in this study, 389 had a bone evaluation both at baseline and after 3 years of AI therapy: 267 women (mean age 61.2 ± 8.6) with no osteoporosis at baseline and 122 women (mean age 67.2 ± 9.1) with osteoporosis at baseline justifying a weekly oral bisphosphonate treatment. Women without bisphosphonates had a significant decrease in spine BMD (-3.5%, P < 0.01), neck BMD (-2.0%, P < 0.01), and total hip BMD (-2.1%, P < 0.01) over the 3 years but only 15 of them (5.6%) presented an incident vertebral or non-vertebral fracture. In osteoporotic women treated with bisphosphonates, spine and hip BMD were maintained at 3 years but 12 of them (9.8%) had an incident fracture. These fractured women were significantly older (74.1 ± 9.8 versus 66.5 ± 8.8) but also presented BMD loss during treatment suggesting poor adherence to bisphosphonate treatment. CONCLUSION: This real-life study confirmed that AIs induced moderate bone loss and low fracture incidence in post-menopausal women without initial osteoporosis. In women with baseline osteoporosis and AI therapy, oral bisphosphonates maintain BMD but were associated with a persistent fracture risk, particularly in older women.

[Advances in head and neck cancers on behalf of the French Intergroup ORL and GORTEC]. / Évolution des concepts dans les cancers des voies aérodigestives supérieures, sous l'égide de l'Intergroupe ORL (GORTEC, GETTEC, GERCOR).

Head and neck cancers are the fifth among the most common cancers in France. Two thirds of cases occur at an advanced stage. For advanced disease, progression-free survival, despite undeniable progress, remains below 50% at three years. The last 20 years have been marked by the necessity to identify situations where less intense surgery and/or radiotherapy and/or chemotherapy is possible without jeopardizing the prognosis, and situations where a therapeutic intensification is necessary and results in a gain in survival while better preserving function with less toxicity. French cooperative groups gathering radiation oncologists (GORTEC), surgeons (GETTEC) and medical oncologists or physicians involved in the management of systemic treatments in head and neck cancers (GERCOR) are now belonging to the INCa-labelled Intergroup ORL to deal with the challenges of head and neck cancers.

[Adjuvant treatment of keloid scars: electrons or brachytherapy?]. / Traitement postopératoire des cicatrices chéloïdes : électrons ou irradiation interstitielle ?

PURPOSE: Evaluation of perioperative treatment of keloid scars with electron beam therapy or iridium 192 low dose rate brachytherapy. PATIENTS AND METHODS: From 1994 to 2010, 95 patients with 142 keloid scars have been treated by immediate perioperative irradiation and retrospectively reviewed in our institute: 116 scars were treated by electrontherapy and 26 by brachytherapy. RESULTS: In the electrontherapy group treated locations were: earlobe (n=88, 76%), thorax (n=14, 12%), neck (n=9, 8%), limbs (n=5, 4%). The median size of lesions was 3cm (range [R]: 0.5-18cm). In 95.6% of cases, a dose of 15Gy was delivered in five fractions of 3Gy. The median follow-up was 70 months (R: 7-161 months). The 2-year and 5-year local control were respectively 69% (95% confidence interval [95% CI]: 59-76%) and 55% (95% CI: 45-64%). In the brachytherapy group treated locations were: neck (n=3, 11%), earlobe (n=8, 32%), abdomen (n=3, 11%), thorax (n=2, 8%), limbs (n=10, 38%). The median size of lesions was 6.6cm (R: 1.7-28cm). The median dose delivered at 5mm from the source was 20Gy (R: 15-20.69). The median follow-up was 113 months (R: 21-219 months). The 2-year and 5-year local control were respectively 84.6% (95% CI: 64-94%) and 73.5% (95% CI: 49-87%). So far, no radiation-induced cancer has occurred. A trend to a better local control with brachytherapy was noted (compared to electrontherapy, 2-year relapse is halved with brachytherapy) though this difference did not reach the significance (P=0.0991), probably due to the reduced number of patients in the brachytherapy group. CONCLUSION: Brachytherapy seems to provide better local control compared to electrontherapy, and should be proposed as first line treatment. However, electrontherapy is an interesting alternative in case of difficulty to realize brachytherapy. There is probably a dose effect: according to published data, 25 to 30Gy should at least be proposed.

[Dosimetric study of the different techniques to deal with respiratory motion for lung stereotactic radiotherapy]. / Étude dosimétrique des différentes techniques de gestion du mouvement respiratoire pour l'irradiation thoracique en conditions stéréotaxiques.

PURPOSE: To evaluate the different respiratory movement management techniques during irradiation of lung tumours. PATIENTS AND METHODS: Seven patients with one or more primary or secondary lung lesions less than 5 cm (11 tumours in total) had three computed tomographies (CT): free-breathing, deep-inspiration breath-hold using a spirometer, and 4-dimensional (4D). From these three acquisitions, five treatment plans were performed: free-breathing (reference method), deep-inspiration breath-hold, and three from the 4D CT: two breathing synchronized treatments (inspiration and expiration) and one treatment taking into account all the tumour motions (definition of the internal target volume [ITV]). Planning target volume (PTV) size and dose delivered to the lungs were compared. RESULTS: Mean PTV with the free-breathing modality was 83 ± 28 cm(3), which was significantly greater than any of the other techniques (P<0.0001). Compared to the free-breathing PTV, PTV defined with the ITV was reduced by one quarter (63 ± 31 cm(3)), and PTV with the deep-inspiration breath-hold, breathing synchronized inspiration and breathing synchronized expiration techniques were reduced by one third (50 to 54 ± 24 to 26 cm(3)). Deep-inspiration led to significantly increase the healthy lung volume compared to other methods (mean volume of 5500 ± 1500 cm(3) versus 3540 to 3920 cm(3), respectively, P<0.0001). The volume of healthy lungs receiving at least 5 and 20 Gy (V5 and V5) were significantly higher with the free-breathing method than any of the other methods (P<0.0001). The deep-inspiration breath-hold modality led to the lowest lung V5 and V20. CONCLUSION: Deep-inspiration breath-hold technique provides the most significant dosimetric advantages: small PTV and large lung volume. However, patients must be able to hold 20 seconds of apnea. Respiratory gating also reduces the PTV, but its application often requires the implantation of fiducial, which limit its use. A 4-dimensional CT allows for a personalized and reduced PTV compared to free-breathing CT.

Radiation recall dermatitis with pemetrexed.

Pemetrexed has recently been approved for use in combination with cisplatin as first-line chemotherapy for malignant pleural mesothelioma (MPM). Radiation therapy is frequently administered to the thoracic orifices and no data are available about the interactions between radiotherapy and pemetrexed. We report the first case of radiation recall dermatitis occurring after pemetrexed chemotherapy in a patient with MPM previously treated with radiation therapy to the thoracoscopy and drainage orifices. The patient received chemotherapy with pemetrexed and cisplatin 19 days after completion of chest wall radiation therapy delivering 21 gray in 3 days. Conventional premedication by folic acid and intramuscular administration of Vitamin B12 and prednisolone was correctly performed. Twelve days later, confluent erythematous and pruritus rash of the irradiated skin was observed. The toxicity grade of this lesion was evaluated at 2 according to the Acute Radiation Morbidity Scoring Criteria proposed by the Radiation Therapy Oncology Group. Pemetrexed challenge was performed without worsening of skin lesions. Three weeks later, skin cicatrisation was observed after a desquamative phase. Persistent hyperpigmentation was seen in the irradiated skin. Pemetrexed could also act as a radiosensitizing agent that should be used with care for several weeks after radiotherapy.

Triangular test and randomized trials: practical problems in a small cell lung cancer trial.

The triangular test has been used to monitor survival data from a randomized trial in patients with small cell lung cancer. The results of consecutive interim analyses and the problems met by the data monitoring committee and the co-ordinators are described. The methods as well as the consequences of the early stopping on the analysis and the results of this trial are discussed. From this experience, we believe that statistical stopping rules--only one of the factors to be taken into account when deciding to stop a trial--should be used with caution. Independent data monitoring committees may be useful in helping to review the ongoing results and advise the participants in the trial.

Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer.

BACKGROUND: Moderate increases in the initial doses of certain chemotherapeutic drugs, such as cisplatin and cyclophosphamide, may prolong overall survival in patients with limited small-cell lung cancer. METHODS: We conducted a prospective study of 105 patients with limited small-cell lung cancer. The patients were randomly assigned to receive higher or lower initial doses of cisplatin (100 or 80 mg per square meter of body-surface area) and cyclophosphamide (300 or 225 mg per square meter daily for four days); all patients received the same doses of doxorubicin and etoposide. The first course of chemotherapy was followed by five additional courses and by three courses of radiotherapy. All patients received the lower doses of cisplatin and cyclophosphamide and the same doses of doxorubicin and etoposide from the second through the sixth cycle of chemotherapy. RESULTS: The median follow-up was 33 months. The two-year survival rate for the 55 patients who received the higher doses of chemotherapy was 43 percent, as compared with 26 percent for the 50 patients who received the lower doses (P = 0.02). The rates of complete response at six months were 67 percent in the higher-dose group and 54 percent in the lower-dose group (P = 0.16). Disease-free survival at two years was 28 percent in the higher-dose group, as compared with 8 percent in the lower-dose group (P = 0.02). Side effects from treatment were not increased in the higher-dose group. CONCLUSIONS: Higher initial doses of cyclophosphamide and cisplatin improve disease-free and overall survival in patients with limited small-cell lung cancer.

Results of a randomized clinical trial comparing two radiation schedules in the palliative treatment of brain metastases.

In 216 patients with brain metastases two schedules of brain irradiation were compared in a randomized trial: one course of 18 Gy/3 fractions/3 days versus the same fractionation followed by a second course of radiotherapy with a one-month time interval. The second course was identical to the first one or delivered 25 Gy/10 fractions/14 days. No difference in overall survival, nor in the neurologic response or in the incidence of complications was demonstrated. Two clinical factors appeared to be prognostic of the overall survival: the presence of multiple brain metastases and the presence of extracerebral metastases.

Localized adenocarcinoma of the lung: a retrospective study of 186 non-metastatic patients from the French Federation of Cancer Institutes--the Radiotherapy Cooperative Group.

From January 1980 to December 1984, 186 patients with non-metastatic primary adenocarcinoma of the lung were treated in 10 different French Cancer Institutes. All patients have a minimal 5-year follow-up. There were 19 Stage I, 58 Stage II, and 109 Stage III. Survival was correlated with treatment modality. Survival rates for patients treated with surgery (36 pts), surgery and radiotherapy (65 pts), or radiotherapy with or without chemotherapy (80 pts) were 44.7%, 28.5%, and 6%, respectively. In the group of patients who were operated on, local control rate was improved by adjunctive radiotherapy delivering more than 50 Gy in 5 weeks. The cumulative risk of developing distant metastasis was 37% at the end of the first year following diagnosis and 68% at 5 years. Stage of the disease, nodal involvement, and location of the primary were the main factors of prognosis.

Computed tomography in radiotherapy of prostatic carcinoma.

Hundred forty-four correlations are reported between radiological simulation and CT-scan in cases of prostate adenocarcinoma without metastases treated from 1980 to 1986 exclusively by transcutaneous radiotherapy using the box technique with 25 MV photons. Forty-eight percent of the cases were intracapsular forms. On the basis of correlation criteria defined, the prostatic boost volume was shifted in the sagittal plan in 18% of the cases. Suspect seminal vesicles were found in 60% of the cases. Our treatment plans were considered "correct" in 65% of the cases, "acceptable" in 26% of the cases and "unsatisfactory" in 29% of the cases. The corrections applied to the treatment plan do not vary according to grade but according to stage and concern mainly the posterior limit of the boost volume and to a lesser extent the superior and anterior limits. The boost volume should be determined specifically for each case. CT-scans thus seem indispensable in establishing treatment plans in prostate cancer.

Flow DNA analysis in human lung cancer: potentiality and limitations due to sampling methods.

Flow DNA analysis was performed on samples from 71 surgically removed lung cancers and from 145 patients undergoing bronchoscopy. Abnormal DNA stem lines, characterized by their DNA index (DI), were frequently observed in operated lung carcinomas (87%). Two or three abnormal DNA stem lines were discovered simultaneously in 10% of the samples. The mean DI of all abnormal tumor stem lines was lowest for rare tumor cell types and highest for adenocarcinomas. Intermediate mean DI values were found for epidermoid and small cell carcinomas, which were among the most proliferative tumors. The high rate of false negative results suggests poor diagnostic reliability of flow DNA analysis on bronchoscopic samples. However, the method appears to provide a promising objective tool capable of evaluating tumor behavior and prognosis.

[beta2-Microglobulin in cancer patients (author's transl)]. / La beta2-Microglobulineen pathologie cancéreuse.

Cancerembryonic antigen (CEA) and beta2-microglobulin (beta2m) have been measured in cancer patients and patients with benign diseases. Of 168 patients with intestinal cancer, almost 90% had increasing concentrations of either CEA or beta2m or both. In 29 patients at different stages of pancreatic cancer there was a high incidence of increased values in the more severe cases. In 60 patients with histologically classified colorectal cancer the TNomegaMomega group of 19 patients had 47% and 42% of elevated beta2m and CEA respectively. A significant correlation of beta2m or CEA to extension of disease was noted. In benign intestinal disease like cirrhosis and pancreatitis both beta2m and CEA is commonly elevated. Of 26 breast cancer patients, seven had elevated CEA and five had elevated beta2m values before treatment. In the patients with extraganglionary metastasis almost 90% had high beta2m or CEA or both. Of 40 patients with uterine cancer, 26 were found to have increased values of beta2m or CEA or both. Finally, 140 colorectal cancer patients, 62 patients with breast cancer and 10 patients with uterine cancer have been followed longitudinally.