[Endobronchial brachytherapy]. / Curiethérapie endobronchique.

Endobronchial brachytherapy was developed following the miniaturization of radio-active sources enabling the use of fiberoptic techniques to deliver treatment at high dose yet substantially reducing the duration of treatment. Endobronchial brachytherapy has been used in patients presenting with symptomatic obstruction of the proximal bronchial tree in association with laser therapy. The level of responses in these palliative indications is around 80 per cent. Currently, other investigations are undergoing evaluation to test the method in association with conventional treatment to determine whether brachytherapy can augment local control. In the treatment of small tumours when other conventional treatments are not possible brachytherapy employed alone has shown undoubted efficacy. However there remain numerous problems to resolve: what is the ideal protocol in terms of total dose, dose per fraction, the order of dosing and fractions? How can secondary complications to endoluminal irradiation be limited in particular for curative therapy. An answer should be found for all these questions before this technique is eventually integrated into the primary treatment regimes for bronchial cancer.

High dose rate endobronchial brachytherapy: results and complications in 189 patients.

The purpose of this study was to determine the benefit of high dose rate endobronchial brachytherapy in the treatment of obstructive lung cancer. Between September 1990 and March 1995, 189 patients with bronchogenic carcinoma were treated with high dose rate endobronchial brachytherapy. Most patients (69.3%) had received prior treatment and presented with symptomatic bronchial obstruction due to either recurrent or residual endobronchial disease. A small group (12%) was medically unfit for either surgical resection or thoracic radiotherapy and benefited from endobronchial brachytherapy alone for small endobronchial tumours. The remainder of the patients had not been treated previously and endobronchial brachytherapy was performed for life-threatening symptoms requiring emergency obstruction relief before other therapy. Treatment was performed weekly and consisted of three to four 8 to 10 Gy fractions at a radius of 10 mm from the centre of the source. Major symptomatic relief was obtained for haemoptysis (74%), dyspnoea (54%), and cough (54%). Complete endoscopic response was observed in 54% of cases. Median survival was 7 months for the entire group. For small, strictly endobronchial tumours, complete response rate was 96%, median survival 17 months, and 30 month survival 46%, with a plateau starting at 18 months. Grade 3 to 4 toxicities occurred at a rate of 17% and included massive haemoptysis (n=13), bronchial stenosis (n=12), soft tissue necrosis (n=8), and bronchial fistula (n=3). By univariate analysis, no factor was found to be predictive of late pulmonary toxicity. The present study confirms the usefulness of endobronchial brachytherapy in alleviating symptoms caused by endobronchial recurrence of bronchogenic carcinoma. In addition, this therapy can be tried with curative intent in patients who present with small endobronchial tumours and are not candidates for other forms of therapy.

[Concomitant radiochemotherapy for locally advanced bronchial cancers: current results and prospects]. / Radio-chimiothérapie concomitante dans les cancers bronchiques localement évolués: résultats actuels et perspectives.

The prognosis of locally advanced lung cancer is reportedly poor in all histologic types. In non-small cell lung cancer, radiation therapy alone results in disappointing long-term survival. Three recent randomized trials, however, have shown a limited but significant improvement of survival with induction chemotherapy, though local control remained poor in these studies as well as in small-cell lung cancer treated with chemotherapy and late radiotherapy. Two randomized trials focusing on small-cell lung cancer have recently shown significant benefit due to the combination of early concurrent mediastinal irradiation and chemotherapy, with major improvement in local control and a more than 40% 2-year survival rate. The concept of concurrent chemoradiotherapy has also been studied in non-small cell carcinoma with several pilot studies leading to both encouraging results and improved survival rate (up to 40% at 2 years). Ongoing phase III trials are comparing sequential versus concurrent chemoradiotherapy and will define the role of radical surgery after chemoradiotherapy in locally advanced non-small cell lung cancer.

[Concomitant radiochemotherapy with cisplatin-etoposide with or without surgery in stage III non-small cell lung cancers: results of a pilot study in 67 patients]. / Radio-chimiothérapie concomitante avec cisplatine-étoposide avec ou sans chirurgie dans les cancers bronchiques non à petites cellules au stade III: résultats d'une étude pilote chez 67 patients.

PURPOSE: This pilot phase II study was aimed at determining the feasibility, toxicity, response rate, local control, and survival of concomitant chemotherapy with cisplatin-etoposide and radiotherapy in stage IIIA or IIIB non small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between February 1992 and February 1994, 67 patients with either medically or technically inoperable stage III NSCLC were treated with concomitant chemoradiotherapy. Thoracic radiotherapy was administered to a median dose of 60 Gy over 6 weeks. Concomitant chemotherapy consisted of cisplatin 20 mg/m2/day plus etoposide 50 mg/m2/day from day 1 to day 5, every 4 weeks over four cycles. Medically operable patients were evaluated for surgical resection after a 45-Gy irradiation and two cycles of concomitant chemotherapy. Only 14 patients could undergo subsequent surgery. RESULTS: With a median 49-month and a minimum 34-month follow-up, the overall survival rate was 42% at 2 years, and 34% at 4 years. The median survival was 19 months and the actuarial local control rate was 57% at 3 years. Toxicity was mainly associated with myelosuppression and esophagitis, but could be treated and was of short duration. CONCLUSION: Concomitant chemoradiotherapy with cisplatin and etoposide at this dose level provides a well tolerated outpatient regimen that results in high local control rate and encouraging survival at 2.4 years. A similar regimen is being compared in a phase III trial including induction chemotherapy followed by radiotherapy.

Concurrent cisplatin, etoposide, and radiotherapy for unresectable stage III nonsmall cell lung cancer: a phase II study.

PURPOSE: Prognosis of unresectable Stage III nonsmall cell lung cancer (NSCLC) treated with thoracic radiotherapy alone has been disappointing. In recent years, several Phase III trials have demonstrated encouraging results with induction chemotherapy, but with poor long-term local control. Concurrent cisplatin alone during the radiation therapy course has resulted in improved local control, but without efficacy on occult metastatic disease. Intensification of chemotherapy during radiation has the potential of improving both local control and metastasis-free survival. This Phase II study was undertaken to determine the feasibility, toxicity, response rate, local control, and survival of concurrent chemotherapy with cisplatin-etoposide and radiotherapy in unresectable Stage IIIA and IIIB nonsmall cell lung cancer. METHODS AND MATERIALS: Between February 1992 and April 1993, 50 patients with either medically or technically inoperable Stage III NSCLC were treated with concurrent chemoradiotherapy. Thoracic radiotherapy was administered to a total dose of 60 Gy. Concurrent chemotherapy consisted of cisplatin 20 mg/m2/day plus etoposide 50 mg/m2/day, from day 1 through day 5, every 4 weeks for four cycles. Medically operable patients were evaluated for surgical resection after 45 Gy and two cycles of concurrent chemotherapy. All patients received an esophagitis preventive regimen. RESULTS: Response rate was 84%, including 68% complete response. With a minimum follow-up of 23 months, overall survival was 70% at 1 year, 39.7% at 2 years, and 34.7% at 3 years. Median survival was 18 months. Age, performance status, histologic type and grade, and stage and tumor size, did not influence survival, with the exception of contralateral nodal involvement (p = 0.0055). Patients achieving a complete response (n = 34) had a 2-year survival of 58.4% compared to 0% for nonresponders (p < 0.0001). Patients who could benefit from surgery (n = 9) had a 2-year survival of 77.8% compared to 31.2% for nonoperated patients (p < 0.013). Seventeen patients (34%) are currently alive and free of disease. Actuarial local control was 63.4% at 1 year, and 58.5% at 2 and 3 years, respectively. Major hematologic toxicity occurred in 24% of the patients. CONCLUSIONS: Concomitant chemoradiotherapy with cisplatin and etoposide at this dose level is a well tolerated outpatient regimen, which resulted in a high local control rate, and an encouraging survival at 1, 2, and 3 years. A direct comparison of this treatment schedule to induction chemotherapy followed by radiotherapy, or concurrent chemoradiation therapy using cisplatin alone, appears warranted.

[Preoperative radio-chemotherapy of stage III unresectable non-small cell lung cancer: results of a pilot study]. / Radio-chimiothérapie préopératoire des cancers bronchiques non à petites cellules au stade III inopérables d'emblée: résultats d'une étude pilote.

Prognosis of Stage III NSCLC remains dismal, particularly when mediastinal nodal involvement is present. In order to improve local control and to reduce early distant failures, we have treated Stage III patients with concurrent chemoradiotherapy since 1989. From September 1989 to February 1994, 140 patients were treated with concurrent chemoradiotherapy. Among these, 24 initially inoperable patients became operable after induction chemoradiotherapy. Characteristics: median age 51 years (35-70); squamous: 45.8%; non squamous: 41.7%; median tumor size: 8 cm; T3 (79.2%); T4a (12.5%); N2 (62.5%) and N3 (8.3%). Preoperative radiotherapy was delivered at a dose of 45 Gy (25 f) over 5 weeks to the mediastinum. Concurrent chemotherapy was continuous infusion cisplatin (n = 10) or cisplatin plus etoposide (n = 14). Five weeks later, radical surgery was carried out (lobectomy n = 14, pneumonectomy n = 10), followed by additional chemotherapy (n = 12) and/or radiotherapy (n = 6), according to histological response. Pathological CR rate was 29.2%. Grade III toxicities were digestive (12.5%), hematologic (8.3%) and infectious (4.2%). Three patients had severe non-lethal postoperative complications with one hemorrhage and two pneumothorax (12.5%). With a median follow-up of 41 months, overall survival at 2 and 5 years was 77.5%, and 72%, respectively. Actuarial local control at 5 years was 82.4%. Nine patients presented with distant metastases, including six with isolated brain metastases. This preoperative chemoradiotherapy regimen appears feasible without overwhelming toxicity and with an acceptable rate of postoperative complications. Despite a significant incidence of isolated brain metastases (25%), 5-year survival is highly encouraging since and appears substantially better than primary surgery.

[High-dose rate endobronchial brachytherapy: results and complications in 189 patients]. / Curiethérapie endobronchique à haut débit de dose: résultats et complications chez 189 patients.

Between September 1990 and March 1995, 189 patients were treated with high-dose-rate endobronchial brachytherapy. Most patients (70%) presented with either recurrent or persistent symptomatic endobronchial tumor after standard therapy. A minority of the patients (12%) had small endobronchial tumor and were unfit for surgical resection or radiotherapy. Treatment was delivered weekly and consisted of three to four 8- to 10-Gy radiotherapy fractions applied at 10 mm from the source. Major symptomatic improvement was obtained on hemoptysis (74%), dyspnea (54%), and cough (54%). Complete endoscopic response occurred in 54.5% of the cases. Median survival was 7 months for the entire group. For small strictly endobronchial tumors, complete response rate was 95.5%, median survival was 17 months, and 30-month survival was 46%, with a plateau starting at 18 months. The rate of late grade 3 to 4 toxicity was 17%, including hemoptysis (n = 13), stenosis (n = 12), local necrosis (n = 8), and bronchial fistula (n = 3). By univariate analysis, no factor was found to be predictive of late toxicity. Our study confirms the benefit of endobronchial brachytherapy in the palliative treatment of endobronchial recurrences and in the curative intent treatment of small endobronchial tumors in patients not suitable for other forms of therapy.

[Localized small-cell lung cancers: prospects of concomitant radiochemotherapy]. / Cancers bronchiques á petites cellules localisés: perspectives de la radio-chimiothérapie concomitante.

Concurrent chemoradiotherapy in the treatment of small-cell lung cancer: current results and future prospects. The prognosis of small cell carcinoma of the lung is reportedly poor, even in limited disease. However, new modalities of combined chemotherapy and radiotherapy may actually result in improved survival in these patients. First-line chemotherapy regimens with cisplatin and etoposide are effective and allow early and concurrent administration of thoracic radiotherapy, without overwhelming toxicity. Radiosensitizing properties of cisplatin and etoposide have been demonstrated, and concurrent delivery of radiotherapy results in a high complete response rate on the primary tumor, and improved long-term local control, which is a prerequisite for cure. In addition, a reduction of the irradiated volume, restricted to the macroscopic tumor, appears feasible without compromising local control and results in a reduced long-term complication rate of the combined treatment. Acute toxicities of these concurrent regimens are mainly hematological and esophageal, but are reversible and without late effect in the majority of the patients. The potential benefit of a twice-daily over standard once-daily irradiation has not been conclusively demonstrated in recent trials. However, these trials have demonstrated excellent outcome after short duration chemotherapy (four courses) with early concurrent radiotherapy (45 Gy), resulting in a 40% survival at 2 years, which appears substantially higher than that obtained with the sequential or alternating regimens. The benefit of prophylactic cranial irradiation has also been confirmed in a large trial in terms of reduction of brain relapses, but with only marginal benefit upon survival. Further improvement of the prognosis of these patients may result form an early intensification of chemotherapy with the support of hematopoietic growth factors and from a dose escalation of radiotherapy with the support of three dimensional computerized dosimetry.

[Radiotherapy and concomitant cisplatin in stage III non-small cell bronchial cancer: results of a pilot study]. / Radiothérapie et cisplatine concomitant dans les cancers bronchiques inopérables non à petites cellules stade III: résultats d'une étude pilote.

From July 1989 to July 1991, 73 previously untreated patients with histologically proven stage III inoperable non-small cell lung cancer have been treated with standard fractionation radiation therapy and concomitant cisplatin by continuous infusion. Thoracic irradiation was delivered at a dose of 40 grays in 20 fractions over 4 weeks to the entire mediastinum, ans was followed after a two-week rest by a boost of 30 grays in 15 fractions over 3 weeks with oblique fields sparing the spinal cord. Continuous infusion cisplatin was given during the second week or each radiation therapy sequence at a dose of 20 mg/sqm/24 hours during five days (120 hours) with usual hyperhydratation and antiemetic measures. Toxicity was essentially hematologic and gastro-intestinal but there was only 4.1% grade 3 or grade 4 complications. Radical surgery became feasible after the first cycle of treatment in 10 patients (13.7%). Complete response rate as determined by CT-scan and fiberoptic bronchoscopy was 61.6%. At a median follow-up of 26 months, actuarial overall survival at 1, 2 and 3 years was 46.6%, 27.7% and 24.5%, respectively. There were no local recurrence or distant relapses after 3 years, which will hopefully result in long-term survival in one quarter of these patients. These results compare favorably with other studies combining radiation therapy and concomitant cisplatin with different dosage and schedule. Local control appears substantially improved by this combined modality treatment over radiation therapy alone. However, the incidence of distant metastasis remains significant, especially during the first year of follow-up. Further improvement of early and long-term survival could possibly result from the incorporation in this protocol of a second drug active against subclinical dissemination.

[Stage III non-small cell lung cancers: prospects of concomitant radiochemotherapy]. / Cancers bronchiques non à petites cellules stade III: perspectives de la radiochimiothérapie concomitante.

The prognosis of stage III non small cell lung cancer is reportedly poor, particularly in patients with mediastinal lymph node involvement. These patients may be either good surgical candidates, marginally resectable, or inoperable for technical or medical reasons, but, in any case, surgery and/or radiotherapy are curative in only a minority of them. The high incidence of early distant failures underscores the need for early and effective systemic therapy in association with local treatment, since occult metastatic disease is present in most patients at the time of diagnosis. Recent phase III trials have demonstrated significant benefit to induction chemotherapy prior to irradiation or surgery in reducing the distant metastasis rate. However, poor local control remains a major issue in these locally advanced tumors. In patients with inoperable disease, the concomitant use of chemotherapy along with radiotherapy substantially improves local control. For operable patients, induction chemotherapy with concomitant moderate-dose radiotherapy improves local control as well, and may facilitate surgical resection in marginally operable cases. Currently, a number of phase II clinical trials report encouraging results with concomitant chemoradiotherapy used either prior to surgery or with curative intent in locally advanced non small cell lung cancer.

Radiation therapy with concomitant continuous infusion cisplatin for unresectable nonsmall cell lung carcinoma.

PURPOSE: This pilot study was designed to test the tolerance and effectiveness of concurrent continuous infusion cisplatin and radiotherapy in the treatment of unresectable nonsmall cell lung (NSCL) cancer. METHODS AND MATERIALS: Between July 1989 and July 1991, 92 consecutive patients with either medically or technically inoperable NSCL cancer were treated with thoracic radiotherapy and concomitant chemotherapy. Radiotherapy consisted of a total dose of 70 Gy delivered in 2 Gy daily fractions over 9 weeks with a planned 2-week break after 40 Gy. During the second week of each cycle of radiotherapy, cisplatin was administered, 20 mg/m2/day for 5 days as a continuous infusion. Eighty-five patients were evaluable. RESULTS: Overall response rate was 81.7% (65.9% complete response). Medically operable patients were considered for curative surgical resection following 40 Gy and one cycle of chemotherapy; 11 patients underwent resection with 3/11 having no pathologic evidence of tumor. Median survival for all 85 patients was 11.4 months with a median follow-up of 27 months. Overall survival was 48.2%, 27.5%, and 25% at 12, 24, and 36 months, respectively. Survival was independent of tumor stage, histology and grade, and patient age and gender. Patients having a complete response (n = 54) had a 2-year survival of 42.1% compared to 3.2% for partial-responders and nonresponders (n = 31; p < 0.0001). Patients undergoing surgical resection (n = 11) had a 2-year survival of 75.8% compared to 20.6% for those treated with chemoradiotherapy alone (n = 74). Forty-eight patients have died of their disease. There were two treatment-related deaths, seven deaths of intercurrent disease and three of unknown causes. Eighteen of 25 patients alive at the time of analysis were without evidence of disease. Actuarial local control was 50.6% at 1 year, and 33.3% at 2 years. The distant failure rate was 47.8% at 2 years. Major acute toxicities, mainly hematologic or gastrointestinal, occurred in less than 10% of patients. Esophagitis was mild and infrequent (8.4%). Severe late pulmonary fibrosis occurred in 5.2% of patients and resulted in two treatment-related deaths. CONCLUSION: Concomitant chemoradiotherapy was well tolerated, resulted in a high rate of local control, and in a survival benefit for patients demonstrating a complete response or going on to surgical resection. The incidence of distant metastases continues to be high and future strategies should be directed at improving systemic therapy.

[Treatment of obstructive bronchial cancers with high dose, endobronchial curietherapy. Technical aspects and clinical results]. / Traitement des cancers bronchiques obstructifs par curiethérapie endobronchique à haut débit. Aspects techniques et résultats cliniques.

Between September 1990 and September 1991, 35 patients with mainly recurrent or residual endobronchial carcinoma were treated with 91 high-dose-rate endobronchial brachytherapy applications. Treatment technique was fairly simple and could easily be performed on an outpatient basis. Endoscopic placement of one or two applicators is followed by computerized dosimetry and irradiation during a median time of 10 minutes. Treatment included 3 sessions of 10 grays measured at 10 mm from the center of the radioactive source at 2-week intervals. Response rate was 81.8% including 51.5% complete clinical response. There were 12 microscopically complete response out of 14 patients biopsied. Immediate tolerance was excellent in 90% of cases. However, late complications were severe in 25% of cases. Ongoing radiobiological research should determine an optimal therapeutic approach in term of efficacy and long term toxicity before using endobronchial brachytherapy as a part of the initial management of unresectable lung cancers.

[Re-expansion pulmonary edema after iatrogenic pneumothorax. A propos of 1 case]. / OEdème pulmonaire de réexpansion (ORP) après pneumothorax iatrogène. A propos d'un cas.

Re-expansion pulmonary edema (RPE) due to pneumothorax aspiration can lead to a fatal outcome, as in the case reported, the chronic nutritional deficiency and hypoproteinemia that it provokes probably playing a contributing role. Pathogenesis and factors affecting prognosis of RPE are discussed. These include the duration of the pulmonary collapse, though this is not an essential factor, the alterations in alveolar surfactant activity possibly related to the chronicity of the collapse, and the abruptness of aspiration which is, in contrast, a determining mechanical factor. Finally, the hypoproteinemia present in certain cases could facilitate fluid extravasation towards the alveolus. It is concluded that aspiration should be a gentle procedure in all cases, and should be conducted with extreme caution in the presence of hypoproteinemia.