[The role of an interventional pulmonologist in the management of metastatic pleural effusions (MPE)]. / Place du pneumologue interventionnel dans la gestion des pleurésies métastatiques.

An interventional pulmonologist possesses expertise in minimally invasive diagnostic and therapeutic procedures involving the airways, lungs and pleura. A malignant pleural effusion (MPE), which occurs in 20% of cancer patients, can be a daunting diagnostic challenge insofar as the pleural cavity is a closed cavity. In these patients, treatment may consequently be delayed before a precise diagnosis can be given. In the meantime, an interventional pulmonologist is called upon to carry out a wide range of examinations in order to establish the etiological diagnosis and to treat the symptoms of an MPE patient. Classical medical thoracoscopy, also called "pleuroscopy", is the reference method in MPE diagnosis because it allows visualization of the pleural cavity, pleural biopsy under direct visual control, providing excellent diagnostic yield. Over the past decade, new diagnostic methods have emerged, such as ultrasound-guided biopsy, as well as different interventions, such as indwelling pleural catheters, aimed at improving the quality of life of MPE patients, for whom therapeutic options are limited. The objective of this review of the literature is to point out the role of the interventional pulmonologist in the management of MPE by detailing the various diagnostic and therapeutic methods he possesses at the present time.

Feasibility and safety of treatment switch from Pirfenidone to Nintedanib in patients with idiopathic pulmonary fibrosis: a real-world observational study.

OBJECTIVE: Idiopathic Pulmonary Fibrosis is a disease characterized by a devastating fibrosing process. Two anti-fibrotic agents, pirfenidone and nintedanib, have been found to alter the disease progression. In this study, we sought to determine whether switching treatment to nintedanib is feasible and safe in patients that had to discontinue treatment with pirfenidone due to side effects. PATIENTS AND METHODS: We analyzed patients that had to discontinue pirfenidone due to side effects. Patients were prospectively enrolled for treatment with nintedanib between March 2015 and June 2019. Side effects and Pulmonary Function Tests were recorded. RESULTS: 12 patients received nintedanib after discontinuing treatment with pirfenidone. Side-effects that led to discontinuation were diarrhea (33.3%), nausea (16.6%), photosensitivity (33.3%) and difficulty adhering to pirfenidone's dosage scheme (16.6%). After the initiation of nintedanib, diarrhea was the most common side effect (66.6%). Four patients of these patients could not tolerate the full dose of 300 mg daily and had to reduce it to 200 mg daily. No patient has had experienced liver damage. During the last twelve months of treatment with pirfenidone, mean ΔFCV was +2.47 ± 3.69%, mean ΔDLco was -0.36 ± 2.64% and mean difference of the distance walked during the 6MWT was 5 ± 56.48 meters. During the first year of treatment with nintedanib, mean ΔFCV was -1.32 ± 1.12% (p=0.68), mean ΔDLco was -1.59 ± 3.45% (p=0.54) and mean difference of the distance walked during the 6MWT was 14.17 ± 59 meters (p=0.078). 50% of patients had stable disease under pirfenidone (6-month FVC decline < 5% and/or 6-month DLco decline < 10%) vs. 50% under nintedanib, 33.3% had marginal 6-month decline (5% ≤ 6-month FVC ≤ 10% and/or (≤ 10% 6- month DLco decline ≤15%) under pirfenidone vs. 33.3% under nintedanib and 16.6% had disease progression (6-month FVC decline > 10% and/or 6-month DLco decline > 15%) under pirfenidone vs. 16.6% under nintedanib. CONCLUSIONS: These results suggest that nintedanib is a safe option for the treatment of patients that had to discontinue pirfenidone due to adverse reactions. Further studies with greater patient numbers are needed for accurate results concerning efficacy.

[Silica causes difficulties]. / La silice cause des difficultés.

Silicosis and sarcoidosis are two very distinct entities in the literature. All the additional non-invasive examinations, including the chest CT scan, often do not differentiate them. The history, including occupational exposure to identified silica particles, is a discriminating factor. However, due to the pathogenic power of silica, it would be possible to have the simultaneous development of these two pathologies in the same patient. To illustrate this situation, here is the case of a 62-year-old patient, who presented initially with a picture of dyspnea and productive cough. The chest CT showed micronodular peribronchovascular infiltrates and mediastinal lymphadenopathy. The other additional examinations did not find anything specific. In the diagnostic process, the patient had multiple endoscopic samples which did not make it possible to be conclusive on one or the other of these pathologies. He therefore underwent a surgical lung biopsy which revealed histological lesions compatible with the two pathologies. Recent studies suggest that inhaled particles, especially silica, could be responsible for the pattern of sarcoidosis. However, it is difficult to say whether, in this case, silica was responsible for the development of sarcoidosis.

Clinical ACO phenotypes: Description of a heterogeneous entity.

BACKGROUND: Because ACO (Asthma-COPD-Overlap) does not fill out asthma or COPD (Chronic Obstructive Pulmonary Disease) criteria, such patients are poorly evaluated. The aim of this study was to screen asthma and COPD for an alternative diagnosis of ACO, then to determine subgroups of patients, using cluster analysis. MATERIAL AND METHODS: Using GINA-GOLD stepwise approach, asthmatics and COPD were screened for ACO. Clusterization was then performed employing Multiple Correspondent Analysis (MCA) model, encompassing 9 variables (age, symptoms onset, sex, BMI (Body Mass Index), smoking, FEV-1, dyspnea, exacerbation, comorbidity). Finally, clusters were compared to determine phenotypes. RESULTS: MCA analysis was performed on 172 ACO subjects. To better distinguish clusters, the analysis was then focused on 55 subjects, having at least one cosine squared >0.3. Six clusters were identified, allowing the description of 4 phenotypes. Phenotype A represented overweighed heavy smokers, with an early onset and a severe disease (27% of ACO patients). Phenotype B gathered similar patients, with a late onset (29%). Patients from Phenotypes C-D were slighter smokers, presenting a moderate disease, with early and late onset respectively (respectively 13% and 31%). CONCLUSIONS: By providing evidences for clusters within ACO, our study confirms its heterogeneity, allowing the identification of 4 phenotypes. Further prospective studies are mandatory to confirm these data, to determine both specific management requirements and prognostic value.

Vitamin D Levels in Middle-Aged Patients with Obstructive Sleep Apnoea Syndrome.

BACKGROUND: Vitamin D (Vit D) insufficiency has been implicated in the pathophysiology of numerous diseases. Obstructive sleep apnoea syndrome (OSAS), a disorder associated with increased cardiovascular and cerebrovascular morbidity, has been associated with decreased Vit D levels, but reports are inconclusive. AIM: To evaluate the association between serum 25-hydroxyvitamin D [25(OH)D], a marker of Vit D status, with anthropometric and sleep characteristics of OSAS patients and to compare those levels between OSAS patients and non-apnoeic controls. METHOD: Consecutive subjects who had undergone polysomnography and pulmonary function testing were divided into controls (apnoea-hypopnea index, AHI <5/h) and OSAS group (AHI ≥5/h). RESULTS: A total of 169 subjects (135 men) were included. OSAS patients (n=139) significantly differed from non-apnoeic controls in terms of age (53.9±12.8 vs. 44.9±12.8 years, p=0.002) and body mass index (BMI) (35.9±6.9 vs. 29.9±6.8 kg/m2, p<0.001). Serum 25(OH)D levels were lower in OSAS patients (17.8±7.8 vs. 23.9±12.4 ng/ml, p=0.019). In OSAS patients, levels of serum 25(OH)D were negatively correlated with sleep stage transitions (r=-0.205, p=0.028), AHI (r=-0.187, p=0.045), oxygen desaturation index (r=-0.234, p=0.011) and percentage of time with oxyhaemoglobin saturation <90% (r=-0.172, p=0.041). In contrast, they were positively correlated with average oxyhaemoglobin saturation during sleep (r=0.179, p=0.033), forced expiratory volume in 1 sec (r=0.207, p=0.037) and oxygen partial pressure (r=0.197, p=0.029). CONCLUSION: Vit D levels were lower in OSAS patients compared with non-apnoeic controls. Several indices of OSAS severity also correlated with Vit D levels.

Insulin Sensitivity and Insulin Resistance in Non-Diabetic Middle-Aged Patients with Obstructive Sleep Apnoea Syndrome.

BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) has been linked with abnormal glucose metabolism, insulin resistance (IR) and development of diabetes mellitus. METHODS: Non-diabetic patients (n=69) with OSAS, diagnosed by polysomnography, were prospectively recruited. To evaluate IR among OSAS patients, the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Insulin sensitivity by Quantitative Insulin sensitivity Check Index (QUICKI) were used. RESULTS: HOMA-IR was positively associated with body-mass index (BMI) (ρ=0.364, p=0.002), time with oxyhaemoglobin saturation <90% (ρ=0.291, p=0.015), arousal index (ρ=0.268, p=0.027), Epworth sleepiness scale (ESS) score (ρ=0.293, p=0.019) and negatively with average oxyhaemoglobin saturation (ρ=-0.398, p=0.001) and minimum oxyhaemoglobin saturation (ρ=-0.327, p=0.006). QUICKI was positively associated with forced vital capacity (r=0.301, p=0.014), average oxyhaemoglobin saturation (r=0.443, p<0.001), minimum oxyhaemoglobin saturation (ρ=0.318, p=0.008), and negatively associated with sleep stage transitions (r=-0.266, p=0.032), oxygen desaturation index (r=-0.404, p=0.005), time with oxyhaemoglobin saturation <90% (r=-0.311, p=0.019), arousal index (r=-0.344, p=0.004) and ESS score (r=-0.299, p=0.016). After adjustment for age and BMI, HOMA-IR was associated with sleep stage transitions, time with oxyhaemoglobin saturation <90%, average oxyhaemoglobin saturation, minimum oxyhaemoglobin saturation and arousal index. QUICKI was associated with oxygen desaturation index, sleep stage transitions, ESS score, minimum oxyhaemoglobin saturation and arousal index. CONCLUSIONS: An independent association between OSAS and IR in patients without pre-existing diabetes mellitus was observed. Recurrent hypoxia and sleep fragmentation in OSAS are associated with IR in these patients.

Mean Platelet Volume as a Surrogate Marker for Platelet Activation in Patients With Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is associated with a prothrombotic state. AIM: To study mean platelet volume (MPV) and Platelet Distribution Width (PDW) as markers of platelet activation and their potential association with lung function in patients with recently diagnosed IPF. MATERIALS AND METHODS: This study included 56 patients with IPF (age 64.9±7.4 years) and 79 controls (age 64.2 ± 5.9 years). RESULTS: An inverse relation was demonstrated between platelet count and MPV in the control group but not among patients with IPF. Platelet count was significantly lower in patients with IPF compared with controls (230 ± 60 vs 256 ± 75 × 10(3)/µL, P = .038). Conversely, MPV was higher in patients versus controls (10.3 ± 1.2 vs 9.8 ± 1.2 fl, P = .024), while there was no difference between the groups in PDW. Respiratory function was, as expected, significantly impaired in patients with IPF versus controls in terms of forced expiratory volume in first second (FEV1; 67.2 ± 23.1 vs 102.6 ± 15.9% of predicted value, P < .001), forced vital capacity (FVC; 65.3 ± 21 vs 95.2 ± 16.1% of predicted value, P < .001), FEV1/FVC (83.1 ± 15 vs 87.5 ± 6.4%, P = .041) and partial pressure of oxygen in arterial blood (PaO2; 67.1 ± 10.3 vs 81.5 ± 15.2 mm Hg, P < .001). No significant correlation was seen between MPV and FVC (r = -.1497, P = .275), MPV and lung diffusion capacity for carbon monoxide (r = .035, P = .798) and total lung capacity (r = .032, P = .820). CONCLUSIONS: Patients with IPF exhibit higher MPV values and lower platelet count. Further studies are needed to assess the clinical implications of these findings.

Mean platelet volume and platelet distribution width in patients with chronic obstructive pulmonary disease: the role of comorbidities.

We evaluated mean platelet volume (MPV; an indicator of vascular risk) and platelet distribution width in patients with stable chronic obstructive pulmonary disease (COPD; n = 85). We also included a control group of 34 smokers without airflow limitation. Mean platelet volume was significantly higher in patients with COPD (10.69 ± 1.0 vs 9.96 ± 1.10 fL, P < .001) than in the smoker controls. White blood cell (WBC) count was also significantly higher in patients with COPD than in the smoker controls (10,642 ± 1247 vs 7136 ± 1887/µL, P < .001). There was a correlation between MPV and WBC in patients with COPD, especially in those at stage III (r = .530, P = .004) and IV (r = .389, P = .023). Mean platelet volume did not correlate with any indices of COPD severity. In patients with COPD, MPV and WBC levels are higher than those of smokers with normal pulmonary function and are significantly correlated. Whether these effects relate to vascular risk in patients with COPD remain to be established.

Short-term safety of thoracoscopic talc pleurodesis for recurrent primary spontaneous pneumothorax: a prospective European multicentre study.

The safety of talc pleurodesis is under dispute following reports of talc-induced acute respiratory distress syndrome (ARDS) and death. We investigated the safety of large-particle talc for thoracoscopic pleurodesis to prevent recurrence of primary spontaneous pneumothorax (PSP). 418 patients with recurrent PSP were enrolled between 2002 and 2008 in nine centres in Europe and South Africa. The main exclusion criteria were infection, heart disease and coagulation disorders. Serious adverse events (ARDS, death or other) were recorded up to 30 days after the procedure. Oxygen saturation, supplemental oxygen use and temperature were recorded daily at baseline and after thoracoscopic pleurodesis (2 g graded talc). During the 30-day observation period following talc poudrage, no ARDS (95% CI 0.0-0.9%), intensive care unit admission or death were recorded. Seven patients presented with minor complications (1.7%, 95% CI 0.7-3.4%). After pleurodesis, mean body temperature increased by 0.41°C (95% CI 0.33-0.48°C; p<0.001) at day 1 and returned to baseline value at day 5. Pleural drains were removed after day 4 in 80% of patients. Serious adverse events, including ARDS or death, did not occur in this large, multicentre cohort. Thoracoscopic talc poudrage using larger particle talc to prevent recurrence of PSPS can be considered safe.

A phase I trial of weekly docetaxel and cisplatinum combined to concurrent hyperfractionated radiotherapy for non-small cell lung cancer and squamous cell carcinoma of head and neck.

We conducted a phase I study to evaluate the activity and tolerability of concurrent docetaxel and cisplatinum radiosensitization with hyperfractionated irradiation, in patients with advanced non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN). Nine patients (5 stage III(A) and 4 III(B)) with NSCLC, and 15 with SCCHN (10 stage III and 5 IV) were treated with a b.i.d. hyperfractionated (HF) radiotherapy schedule. The normalized total dose for alpha/beta ratio = 10 Gy was 69.6 Gy for NSCLC and 80.5 Gy for SCCHN patients. The standard dose of cisplatin (10 mg/m(2)) was given combined to docetaxel on a weekly basis. The docetaxel starting dose level was 10 mg/m(2)/week and was escalated by 3 mg/m(2) increments in cohorts of 8 patients (5 SCCHN and 3 NSCLC). DLT (grade 3 malaise) was observed in 4 out of 8 patients treated at the 16 mg/m(2)/week docetaxel dose level. The 13 mg/m(2)/week docetaxel dose level was defined as the MTD causing grade 3 mucositis in 4 out of 8 patients. In total 4 (17%) patients developed grade 3 neutropenia. G-CSF support was given in 1/8, 4/8, and 5/8 patients treated at the 10, 13 and 16 mg/m(2) docetaxel dose levels respectively. Fatigue was the most common adverse event (5/24: 21%) and was responsible for more than 1 week treatment delay in 4 out of 8 patients treated at the 16 mg/m(2)/week docetaxel dose level. Nine (3 NSCLC and 6 SCCHN patients: 37.5%) had treatment delay of 1 week, while 7 (3 NSCLC and 4 SCCHN: 29%) had delays of 2 weeks for combined chemoradiation sequelae. Acute hypersensitivity reactions occurred in 3 (12.5%) patients, and grade 3 mucositis in 2/8, 5/8 and 6/8 patients, treated at 10, 13 and 16 mg/m(2)/week docetaxel dose levels respectively. The overall response rate was 79% (CI = 63-96%) with 33% and 53% CRs for NSCLC and SCCHN patients respectively. There were 3 deaths among 9 NSCLC and 4 among 15 SCCHN patients. Local and/or distant disease recurrences were shown in 4 NSCLC and in 6 SCCHN patients; 5 NSCLC and 9 SCCHN patients are alive with no evidence of tumor progression at 8.5 months mean follow-up time. Radiosensitization with docetaxel and cisplatin given concurrently with HF (b.i.d.) radiotherapy on a weekly basis is a promising approach and the recommended dose for further phase II studies is 10 mg/m(2)/week for both drugs. The antitumor activity shown was significant in both types of tumors. The incorporation of docetaxel in chemoradiotherapy regimens for future treatment of squamous cell carcinoma of the lung and head and neck, merits evaluation in phase II and III trials.

Concurrent administration of Docetaxel and Stealth liposomal doxorubicin with radiotherapy in non-small cell lung cancer : excellent tolerance using subcutaneous amifostine for cytoprotection.

The substantial augmentation of the radiation sequelae during chemo-radiotherapy with novel drugs masks the real potential of such regimens. In this study we examined whether subcutaneous administration of amifostine can reduce the toxicity of a highly aggressive chemo-radiotherapy scheme with Stealth liposomal doxorubicin (Caelyx and Docetaxel (Taxotere in non-small cell lung cancer. Twenty-five patients with stage IIIb non-small cell lung cancer were recruited in a phase I/II dose escalation trial. The starting dose of Taxotere was 20 mg m(-2) week and of Caelyx was 15 mg m(-2) every two weeks, during conventionally fractionated radiotherapy (total dose of 64 Gy). The dose of Taxotere/Caelyx was, thereafter, increased to 20/25 (five patients) and 30/25 mg m(-2) (15 patients). Amifostine 500 mg was given subcutaneously before each radiotherapy fraction, while an i.v. amifostine dose of 1000 mg preceded the infusion of docetaxel. The 'in-field' radiation toxicity was low. Grade 3 esophagitis occurred in 9 out of 25 (36%) patients. Apart from a marked reduction of the lymphocyte counts, the regimen was deprived from any haematological toxicity higher than grade 1. No other systemic toxicity was noted. The CR and CR/PR rates in 15 patients treated at the highest dose level was 40% (6 out of 15) and 87% (13 out of 15) respectively. It is concluded that the subcutaneous administration of amifostine during high dose Taxotere/Caelyx chemo-radiotherapy is a simple and effective way to render this aggressive regimen perfectly well tolerated, by reducing the systemic and the 'in-field' toxicity to the levels expected from simple conventional radiotherapy. The impressive tolerance and the high CR rate obtained encourages the conduct of a relevant randomized trial to assess an eventual survival benefit in patients with non-small cell lung cancer.

Invasive thymoma: a clinical study of 23 cases.

BACKGROUND: Invasive thymoma is a rare mediastinal tumor. Clinicopathological characteristics that influence survival of patients with this tumor are under debate. Treatment is based on tumor resection. The benefice of therapies, such as radiation therapy (RT) and/or chemotherapy (CT) as adjuvant treatments to surgery, or palliative therapy to unresectable or recurrent thymoma are discussed. OBJECTIVES: The aim of this study was to assess patients with invasive thymoma, with specific emphasis on factors predicting survival. METHODS: We studied retrospectively 23 patients with invasive thymoma. Parameters assessed were age, presenting symptoms, histological features, stage at diagnosis, treatment modalities and survival. All patients received primary therapy: 11 patients (48%) had tumor resection associated with CT and/or RT, while 12 patients had palliative therapy including RT and/or CT. Regimens for CT were based on cisplatin. RESULTS: Patients' mean age was 58 years. Three patients had stage II disease at diagnosis (13%), 8 patients had stage III (35%) and 12 patients had stage IV (52%). Median overall survival was 20 months (range: 4-160) and five-year survival rate was 43.5% (10 patients). Surgical resection had a significant impact on survival (p < 0.0001). Survival was also related to stage of the disease at diagnosis (p = 0.006), but not to histology of the tumor (p = 0.12). Salvage treatment was of clinical importance: 5 out of 15 patients (33.3%) who relapsed during a 5-year follow-up responded to a multimodality therapeutic approach that affected survival (p = 0.019). CONCLUSION: Factors determining the outcome of these tumors are the stage of the disease at diagnosis, and the adequacy of surgical removal. Salvage treatment of recurrent thymoma may give a moderate response rate and improve survival.

Cryotherapy in early superficial bronchogenic carcinoma.

BACKGROUND: Treatment of early superficial bronchogenic carcinoma (ESBC) is under debate, and no consensus has been achieved. Different therapeutic methods have been proposed, including surgical resection and endoscopic methods. STUDY OBJECTIVE: To assess the efficacy of cryotherapy in patients with ESBC. PATIENTS AND METHODS: Patients included in the study had histologically proven ESBC after fiberoptic bronchoscopy. Cryotherapy was performed through a rigid bronchoscope. Efficacy was assessed by endoscopy with multiple biopsies 1 month after treatment and during the follow-up period. Parameters studied were response to treatment, adverse effects, and survival. RESULTS: We included 35 patients (34 men and 1 woman). The mean age was 61 +/- 9 years. Multiple locations of ESBC were observed in seven patients (20%). Complete response rate at both 1 month and 1 year was 91% (32 patients). No severe adverse effects were noted. Local recurrence was observed within 4 years in 10 patients (28%). A follow-up period of at least 4 years was available in 22 patients; of them, 11 patients (50%) were long-term survivors. CONCLUSION: Our results suggest that cryotherapy is an effective method of treatment in patients with ESBC. Due to its relative tolerance compared to surgery, cryotherapy could be proposed as a first-line therapy in this population with high carcinogenic risk.

Chemotherapy-induced noncardiogenic pulmonary edema related to gemcitabine plus docetaxel combination with granulocyte colony-stimulating factor support.

Several cancer therapeutic agents have been associated with pulmonary toxicity. Herein, we describe the case of a 73-year-old woman with breast cancer metastatic to the liver, who developed noncardiogenic pulmonary edema (NPE) while on treatment with gemcitabine plus docetaxel combination with granulocyte colony-stimulating factor (G-CSF) support. Gemcitabine, a deoxycytidine analogue, is reported to produce mild self-limiting and only occasionally severe pulmonary toxicity. The microtubule stabilizer docetaxel has been associated with water retention complications. The combination of these two agents has shown promising activity in several solid tumors and is in a phase of clinical development with prophylactic G-CSF in most of the trials due to the high rate of dose-limiting neutropenia observed with this combination. In our case pulmonary toxicity resolved rapidly following the administration of corticosteroids. A possible deleterious synergy of the compounds involved in this case is discussed and the medical literature on NPE related to cancer therapy is shortly reviewed. We conclude that NPE should always be considered in patients with respiratory function deterioration while on therapy with the gemcitabine-docetaxel combination and G-CSF. Corticosteroids can provide maximum benefit if started early upon diagnosis coupled with withdrawal of the causative drugs.

Phase I/II dose escalation study of docetaxel and carboplatin combination supported with amifostine and GM-CSF in patients with incomplete response following docetaxel chemo-radiotherapy: additional chemotherapy enhances regression of residual cancer.

Taxanes have been shown to interact with anti-apoptotic proteins. In the present study we investigated whether the addition of taxane in combination with DNA damaging drugs can further enhance tumor shrinkage in cases with incomplete response to radiotherapy. Since the dose of docetaxel in combination with carboplatin is not known, the above hypothesis was tested in the context of a dose escalation phase I study. Twenty-eight patients with locally advanced chest or pelvic tumors, showing residual disease on CT scans performed 40 d following docetaxel radio-chemotherapy, were recruited in a dose escalation protocol of docetaxel/carboplatin supported with amifostine and GM-CSF. The starting dose of docetaxel was 40 mg/m2 every 2 weeks. Carboplatin dose was calculated using the Calvert formula and was escalated in cohorts of 4 patients (starting dose AUC2 every two weeks; AUC0.5 increments up to AUC3). Thereafter the docetaxel dose was increased to 50 and 60 mg/m2, while carboplatin was escalated (by AUC0.5 increments) starting from AUC3 and AUC4 respectively. Amifostine (600 mg/m2) was administered i.v. before carboplatin and GM-CSF (480 microg) was injected s.c. on days 5, 6 and 10, 11 of each cycle. Six cycles were given and response was assessed 2 weeks after the end of chemotherapy. None out of four patients treated in the 6th dose level cohort (50 mg/m2 of docetaxel and AUC4 of carboplatin every 2 weeks) showed any grade 2-4 hematologic toxicity. Mild non-hematologic toxicity such as neuropathy, leg edema, pleural effusion, pyrexia, alopecia grade 2 and hypersensitivity was observed in 4-12% of patients. Out of four patients treated in a 7th cohort (docetaxel 60 mg/m2 and carboplatin AUC4), one developed grade IV neutropenia and two developed grade 3 severe asthenia requiring treatment delay for 2 weeks. Out of 11 patients with PR following docetaxel radio-chemotherapy, 7 (63%) showed CR after docetaxel/carboplatin additional chemotherapy. Eight out of 17 patients with MR following docetaxel radio-chemotherapy showed PR (47%) and one showed CR (6%) after additional chemotherapy. High dose combined docetaxel (50 mg/m2) and carboplatin (AUC4) chemotherapy can be safely administered on a two-weekly basis if supported with amifostine and GM-CSF. Such an additional therapy may be important in patients with incomplete response after chemo-RT. Broad spectrum cytoprotection with amifostine and GM-CSF may also contribute to the reduction of incidence of neurosensory reactions and asthenia in patients treated with taxanes.