Concurrent chemoradiotherapy using protracted infusion of low-dose CDDP and 5-FU and radiotherapy for esophageal cancer]

PURPOSE: We evaluated the effects and safety of concurrent chemoradiotherapy for patients with esophageal cancer. MATERIALS AND METHODS: Between March 1994 and April 1998, concurrent chemoradiotherapy using protracted infusion of low-dose cisplatin (CDDP: 3-6 mg/m2/24h), 5-fluorouracil (5-FU: 200 mg/m2/24h) and radiotherapy was given to 26 patients. The median age was 70 yr, with a range from 58 to 86 yr. With regard to TNM classification (1987), six patients were stage II, five stage III, and 15 stage IV. Radiotherapy was performed by external irradiation alone in 23 patients and external irradiation plus brachytherapy in three patients. One patient underwent surgery after a dose of 40 Gy owing to the possibility of idiopathic bleeding from the stomach. RESULTS: Locally, primary effects resulted in complete response in 11 patients (42.3%) and partial response in 15 (57.7%). Acute toxicity was primarily hematologic. Leukopenia and thrombocytopenia of grade 3 or 4 occurred in eight (30.7%) and six (23.0%) of 26 patients, respectively. In patients administered CDDP at more than 5 mg/m2/day, hemotoxicity was severe because in five of the 10 patients administered 5 mg/m2 CDDP and one of the two patients administered 6 mg/m2 CDDP, thrombocytopenia of grade 3 or 4 occurred. CONCLUSION: Protracted infusion of low-dose CDDP and 5-FU with concomitant radiation therapy is effective, but from the point of acute toxicity, the optimal dose of CDDP and 5-FU needs further investigation.     

Gemcitabine Concurrent with Thoracic Radiotherapy after Induction Chemotherapy with Gemcitabine/Vinorelbine in Locally Advanced Non-Small Cell Lung Cancer

PURPOSE: To determine the maximum tolerated dose (MTD) of gemcitabine every 2 weeks to a concurrent radiotherapy administered during an aggressive program of sequential and simultaneous radio-/chemotherapy for locally advanced, unresectable non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Ten patients with histologically confirmed NSCLC were observed and treated in accordance with a combined radio-/chemotherapy protocol. This included two cycles of induction chemotherapy with gemcitabine (1,200 mg/m(2)) and vinorelbine (30 mg/m(2)) at days 1, 8 and 22, 29, followed by concurrent radiotherapy including [(18)F] fluorodeoxyglucose positron emission tomography-(FDG-PET-)based target volume definition (2.0 Gy/d; total dose 66.0 Gy) and chemotherapy with gemcitabine every 2 weeks at days 43, 57, and 71. The initial dose was 300 mg/m(2). The dose of gemcitabine was increased by 100 mg/m(2) until the MTD was realized. Three patients were enrolled for each dose level. RESULTS: Dose-limiting toxicity (DLT) was identified for the patient group receiving gemcitabine 500 mg/m(2), due to grade 2 esophagitis (next to grade 3) in all patients. 6 weeks after the completion of radio-/chemotherapy, most patients still presented treatment-induced esophagitis. In accordance with expected complications, such as esophagitis, dysphagia and odynophagia, the MTD was defined at this dose level, although no DLT grade 3 was reached. CONCLUSION: After induction chemotherapy, the MTD and frequency of gemcitabine in locally advanced NSCLC is 500 mg/m(2) every 2 weeks during a maximum of 7 weeks of thoracic radiotherapy.     

Long-term prognosis of patients undergoing transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: comparison of cisplatin lipiodol suspension and doxorubicin hydrochloride emulsion.

PURPOSE: To evaluate long-term prognosis of transcatheter arterial chemoembolization (TACE) with use of cisplatin (CDDP) lipiodol (LPD) suspension (CDDP/LPD) compared with that with use of doxorubicin hydrochloride (ADM) LPD emulsion (ADM/LPD) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: One hundred eight patients were treated with use of CDDP/LPD and 26 were treated with use of ADM/LPD. Survival rates and frequency of side effects and complications in the CDDP/LPD group were compared with those in the ADM/LPD group. RESULTS: CDDP/LPD was given at a dose of 15-70 mg (mean dose, 41 mg), whereas ADM/LPD was given at a dose of 20-100 mg (mean dose, 57 mg) throughout the study period. The survival rates in the CDDP/LPD group were 81% at 1 year, 41% at 3 years, 19% at 5 years, and 13% at 7 years, whereas those in the ADM/LPD group were 67% at 1 year, 18% at 3 years, and 0% at 5 years. The CDDP/LPD group showed significantly better survival than the ADM/LPD group (P <.05). In the CDDP/LPD group, there was a significant prolongation of survival in patients with monofocal HCC (P <.05) and patients with HCC assessed as an almost complete LPD accumulation (P <.05). There were no significant differences in survival rates in the ADM/LPD group according to tumor size and number of tumors. Hepatic failure was observed in 8% of all procedures and was not different between the two therapeutic groups. Renal dysfunction was observed in 2% of all treatments involving CDDP/LPD, and it resolved spontaneously with appropriate medications. CONCLUSIONS: TACE with use of low-dose CDDP was efficacious for unresectable HCC and had few complications. TACE with use of CDDP may contribute to prolongation of the life span of patients with HCC versus TACE with use of ADM.     

Multimodality Treatment Including Postoperative Radiation and Concurrent Chemotherapy with Weekly Docetaxel is Feasible and Effective in Patients with Oral and Oropharyngeal Cancer

BACKGROUND: To examine the feasibility and efficacy of weekly docetaxel with concurrent radiation as postoperative treatment in a multimodality approach to oral and oropharyngeal cancer. PATIENTS AND METHODS: 94 patients (Table 1) with primary resectable squamous cell carcinoma of the oral cavity and oropharynx (UICC stage I 14%, II 15%, III 18%, IV 53%; Table 2) were treated with a multimodality therapy program consisting of neoadjuvant intra-arterial high-dose chemotherapy (cisplatin 150 mg/m(2) with parallel systemic sodium thiosulfate 9 g/m(2) for neutralization), followed by surgery of the primary and neck, and postoperative concurrent radiation and chemotherapy with weekly docetaxel (20-30 mg/m(2); Table 3). Chronic toxicities were followed over a period of 5 years. RESULTS: At a median follow-up of 4 years, the 5-year survival rate for all 94 patients was 80%, and disease-free survival was 73% (Figures 1 and 2). Among patients with advanced disease (stage III and IV), survival was 83 and 59%, respectively (Figure 4). Grade 3 and 4 mucositis was the main acute toxicity necessitating supportive care. Long-term toxicity appears to be moderate (Table 4). The maximum tolerated dose of weekly docetaxel was 25 mg/m(2). CONCLUSIONS: Concurrent radiation and chemotherapy with weekly docetaxel is a feasible postoperative treatment in a multimodality approach to oral and oropharyngeal cancer, resulting in high overall and disease-free survival. This approach warrants further evaluation in prospective randomized trials.     

Aggressive Simultaneous Radiochemotherapy with Cisplatin and Paclitaxel in Combination with Accelerated Hyperfractionated Radiotherapy in Locally Advanced Head and Neck Tumors

BACKGROUND: Simultaneous radiochemotherapy (sRCT) is the treatment of first choice in locally advanced head and neck cancers. We have tested a very aggressive combination protocol with cisplatin and escalated paclitaxel in combination with accelerated hyperfractionated radiotherapy to assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), overall toxicity, and response rate. PATIENTS AND METHODS: The trial recruited 24 patients (21 males, three females, mean age 57 years) treated at our department from 1998 through 2001. Irradiation was administered in daily doses of 2 Gy up to 30 Gy followed by 1.4 Gy twice daily up to 70.6 Gy to the primary tumor and involved nodes and 51 Gy to the clinically negative regional nodes. The chemotherapy schedule included cisplatin in a fixed dose of 20 mg/m(2) on days 1-5 and 29-33 and paclitaxel at increasing dose levels of 20, 25, 30 mg/m(2) twice weekly over the whole treatment time. Patients were recruited in cohorts of three to six, and the MTD was reached if two out of six patients in one cohort developed DLT. DLT was defined as any grade 4 toxicity or any grade 3 toxicity requiring treatment interruption or unplanned hospitalization or any grade 3 neurotoxicity. We recruited mainly patients with large tumors for this protocol; all patients were stage IV, and the mean tumor volume (primary + metastases) amounted to 72 +/- 61 cm(3). The mean follow-up was 30 months (range 4-39 months). RESULTS: One early death (peritonitis and sepsis at day 10) occurred, and 23 patients were evaluable for acute toxicity and response. The MTD of paclitaxel was reached at the third dose level (30 mg/m(2) paclitaxel twice weekly). The DLT was severe mucositis grade 3 (n = 1) and skin erythema grade 4 (n = 2). After determining the MTD, another 14 patients were treated at the recommended dose level of paclitaxel with 25 mg/m(2) twice weekly. In summary, 13/23 patients (57%) developed grade 3 and 10/23 (43%) grade 2 mucositis. Two patients (9%) had grade 4, five (22%) grade 3, and 16 (69%) grade 2 dermatitis. One patient died at day 30 of neutropenic infection. In one patient, a grade 2 nephrotoxicity appeared requiring cessation of cisplatin chemotherapy. 18/23 patients (78%) required blood transfusion (1-3 units) and 16/23 (70%) i.v. antibiotics. 14 patients (61%) achieved a complete and nine (39%) a partial remission, yielding an overall response rate of 100%. In summary, six patients died of local tumor progression (n = 2), distant metastases (n = 2), or therapy-related complications (n = 2) during follow-up. The 3-year overall survival was 71%. Tumor volume was not a risk factor for failure in this protocol (mean tumor volume in relapse-free vs. progressive patients 71 +/- 65 cm(3) vs. 64 +/- 38 cm(3)). All patients have, so far, developed only slight late effects (fibrosis, lymphedema) with no grade 3-4 late sequelae. CONCLUSIONS: This very aggressive sRCT protocol yielded excellent response and survival figures but was associated with a very high rate of acute toxicity (8% therapy-related deaths). A maximal supportive treatment is therefore required.     

Weekly paclitaxel and carboplatin with concurrent radiation therapy in locally advanced non-small cell lung cancer: phase I study

PURPOSE: The optimal dose of weekly paclitaxel in combination with carboplatin and concurrent radiation therapy (CRT) in patients with locally advanced non-small cell lung cancer (NSCLC) is not well defined in Japan. The purpose of this study was to define the maximum-tolerated dose (MTD) of paclitaxel in this combination. MATERIALS AND METHODS: Treatment consisted of weekly paclitaxel plus carboplatin fixed AUC 2 and CRT for a total 60 Gy at 2 Gy/fraction/day 5 times weekly for 6 weeks. The dose of paclitaxel was 25 mg/m2 in the first cohort and escalated by 5 mg/m2 per cohort. RESULTS AND CONCLUSION: A total of 18 patients were enrolled and analyzed. The dose limiting toxicity of this study was considered to be pulmonary toxicity, and the MTD of it was determined to be 45 mg/m2 of paclitaxel in patients with NSCLC. Further evaluation of this regimen in a phase II trial is underway.     

Induction Chemotherapy with Cisplatin, Epirubicin, and Paclitaxel (CEP), Followed by Concomitant Radiotherapy and Weekly Paclitaxel for the Management of Locally Advanced Nasopharyngeal Carcinoma

BACKGROUND: Clinical research on the treatment of nasopharyngeal cancer (NPC) has been focused primarily on the reduction of incidence of the development of distant metastases as well as the improvement of locoregional control. PATIENTS AND METHODS: Untreated patients with stage IIB-IVB nonmetastatic NPC were treated with three cycles of induction chemotherapy (IC) consisting of epirubicin 75 mg/m(2) followed by paclitaxel 175 mg/m(2) as 3-h infusion on day 1 and cisplatin 75 mg/m(2) on day 2 every 3 weeks, followed by concomitant radiation therapy (70 Gy), and chemotherapy (CCRT) with weekly paclitaxel 60 mg/m(2). RESULTS: From November 1999 until April 2003, 47 patients entered the study. Complete response rate post IC therapy was 15%, which was raised to 66% after the completion of CCRT. The most frequent side effect from IC was myelotoxicity (55%), whereas stomatitis and xerostomia were the most pronounced (grade 3, 4) toxicities during CCRT. The presence of Epstein-Barr virus (EBV) was detected either by in situ hybridization in tumor tissue sections or by polymerase chain reaction in the peripheral blood in 37 out of 46 patients tested (80%). All three histological types were associated with the presence of EBV. After a median follow-up of 23.5 months, median time to treatment failure was 17.9 months, whilst median survival has not been reached yet. CONCLUSION: IC followed by CCRT is feasible and produces durable complete responses in the majority of patients with NPC. The case detection rate of EBV in this study appears to be similar to that reported from endemically infected regions.     

Gonadenbelastung bei lymphabflußbestrahlung operierter seminome

BACKGROUND: This article should demonstrate the problems concerning gonadal dose in seminoma patients, the impact of shielding and possible consequences for therapy and advising of patients with desire to have children. PATIENTS AND METHOD: Since November 1993 gonadal doses of 43 patients (Stage I/II, Royal Marsden) have been determined in 80 measurements with 2 ionization chambers on the ipsi- and contralateral side of the remaining testicle. The patients were all treated with ap/pa "hockey-stick"-shaped fields on a 6 MV linear accelerator. With single doses of 1.8 Gy in midplane, total doses of 34.2 Gy were applied in 13, and 30.6 Gy in 30 men. Protection was used in 33 patients, 6 times with conventional shielding, later plus an additional clam-shell from ap. The results of 22 measurements on 6 men with and without protection are of special interest. In 25 patients a sperm analysis before radiotherapy was conducted. RESULTS: Before the beginning of radiotherapy (RT) 56% of available patients have shown an impaired spermatogenesis. The mean gonadal doses were 2.4% of midplane dose-MD (4.8 cGy), 1.8% MD (3.2 cGy) and 1% MD (1.8 cGy) per fraction for patients without (n-patients = 10, m-measurements = 15), with conventional (n = 6, m = 7), and additional clam-shell shielding (n = 33, m = 58). The corresponding median values were 2.1% (SD 1.07), 1.7% (SD 0.28) and 1% (SD 0.41) of midplane dose (Table 1, Figure 1). According to direct comparisons, a dose reduction of about half can be expected in most cases (Figure 2). Mean dose fluctuations of 11.6% (median 10%) have to be taken into account. CONCLUSION: Effective shielding can diminish gonadal dose in seminoma patients to about 1% of midplane and gives a good possibility of taking the maintenance of fertility and the desire to have children into account (Table 2). The application should be considered especially for patients with impaired spermatogenesis before RT. Eventual fluctuations induced us to determine the gonadal dose 3 times per patient in direct measurements (Table 3).     

Long-term outcome after neoadjuvant radiochemotherapy in locally advanced noninflammatory breast cancer and predictive factors for a pathologic complete remission

BACKGROUND: An earlier published series of neoadjuvant radiochemotherapy (NRT-CHX) in locally advanced noninflammatory breast cancer (LABC) has now been updated with a follow-up of more than 15?years. Long-term outcome data and predictive factors for pathologic complete response (pCR) were analyzed. PATIENTS AND METHODS: During 1991-1998, 315 LABC patients (cT1-cT4/cN0-N1) were treated with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50?Gy (5?×?2?Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or-in case of breast conservation-a 10-Gy interstitial boost with (192)Ir afterloading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10?patients received no chemotherapy. The update of all follow-up ended in November 2011. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX, and the time interval between end of RT and surgery were examined in multivariate terms with pCR and overall survival as end point. RESULTS: The total pCR rate after neoadjuvant RT-CHX reached 29.2%, with LABC breast conservation becoming possible in 50.8% of cases. In initially node-positive cases (cN+), a complete nodal response (pN0) after NRT-CHX was observed in 56% (89/159). The multivariate analysis revealed that a longer time interval to surgery increased the probability for a pCR (HR 1.17 [95% CI 1.05-1.31], p??2 months) increases the probability of pCR after NRT-CHX.     

Locoregional Failure 15 Years after Mastectomy in Women with One to Three Positive Axillary Nodes with or without Irradiation

BACKGROUND: There is insufficient evidence to suggest the routine use of postmastectomy radiotherapy (PMRT) in patients with one to three positive axillary nodes and T1/2 tumors. We have assessed the risk of locoregional recurrence (LRR) with or without RT in this group of patients, and focused on the results in subgroups defined by tumor size. PATIENTS AND METHODS: 249 women with T1/2 tumors and one to three positive nodes underwent mastectomy and axillary dissection between 1983 and 1987. Locoregional RT of 50 Gy was given to 175 patients. Chemotherapy or hormonal therapy was administered to 41 and 71 women, respectively. The median follow-up time of survivors was 189 months (range, 167-227 months). RESULTS: The rates of isolated LRR without or with RT were 16% (12/74) and 8% (14/175), respectively (p = 0.05), and the total (with or without distant relapse) LRR rates 23% and 12%, respectively (p = 0.03). 15-year overall survival amounted to 41% without RT and to 52% with RT (p = 0.2). The rates of isolated LRR for patients treated with chemotherapy or hormonal therapy only were 25% and 12%, respectively. In the absence of RT, age (> 45 vs = 45 years; p = 0.06), tumor size (T1 vs T2; p = 0.07), and extranodal invasion (ENI; absent vs present; p = 0.09) were related to the risk of developing an isolated LRR. On multivariate analysis, only tumor size (relative risk [RR], 3.92; 95% confidence interval [CI], 1.11-15.14) and age (RR, 3.37; 95% CI, 1.03-11.09) emerged as independent significant predictors, whereas ENI (RR, 1.50; 95% CI, 0.81-2.77) did not. In the T1 subgroup, the estimated 15-year isolated LRR rate was 9% (3/36) without and 9% (8/99) with RT (p = 0.9775). 15-year disease-free survival amounted to 62% and 57%, respectively (p = 0.5153). For patients without RT, according to the age groups (= 45 vs > 45 years), the 15-year rates of isolated LRR were 9% and 9%, respectively (p = 0.9910). In the T2 subgroup, the estimated 15-year isolated LRR rate was 30% (9/38) without and 10% (6/76) with RT (RR, 0.33; 95% CI, 0.12-0.92; p = 0.0244). 15-year disease-free survival amounted to 32% and 50%, respectively (p = 0.1213). For patients without RT, according to the age groups (< or = 45 vs > 45 years), the 15-year rates of isolated LRR were 57% and 16%, respectively (p = 0.0049). CONCLUSION: Patients with T1 tumor and one to three positive nodes are at low risk of isolated LRR either with or without RT. Patients with T2 tumor and one to three positive nodes are at high risk of isolated LRR without RT. Our findings support the routine use of PMRT in patients with T2 tumor, especially those aged < or = 45 years.     

Concurrent Radiotherapy and Taxane Chemotherapy in Patients with Locoregional Recurrence of Breast Cancer

BACKGROUND AND PURPOSE: Locoregional breast cancer recurrence is characterized by a high rate of systemic and local re-recurrence. Data on concurrent radiochemotherapy (RCT) in these cases are scarce. The purpose of this study was to evaluate feasibility, toxicity and efficacy of local control of a radiotherapy combined with a chemotherapy containing a taxane. PATIENTS AND METHODS: Between May 1999 and November 2004, 36 women referred to the authors' clinic because of locoregional breast cancer recurrence that was either inoperable (n = 29) or resected (n = 7) received concurrent irradiation and taxane monotherapy weekly (TAX/RT; n = 28: paclitaxel 90 mg/m(2), n = 24, or docetaxel 35 mg/m(2), n = 4) or taxane + cisplatin therapy (TAX/CIS/RT; n = 8; paclitaxel 135 mg/m(2) d1 and cisplatin 20 mg/m(2) d1-5 q28). RESULTS: Comparing TAX/RT with TAX/CIS/RT, the complete remission rate in patients with macroscopic tumor prior to RCT was significantly higher for TAX/RT than for TAX/CIS/RT (7/19 vs. 0/8; p = 0.046), but overall remission rates were comparable, i.e., partial remission: 11/20 versus 6/8 cases, stable disease (no change): 1/20 versus 2/8 cases, and response rate: 95% versus 75%, respectively. The cumulative local recurrence-free survival rate at 1 and 2 years post-treatment was 83% and 68% and that of systemic recurrence-free survival 56% and 29%, respectively. The main toxic reactions of third-degree and higher were dermatitis in TAX/RT (57% vs. 11% for TAX/CIS/RT) and leukocytopenia in TAX/CIS/RT (62% vs. 7% for TAX/RT). CONCLUSION: Concurrent irradiation and taxane chemotherapy weekly, in particular with paclitaxel, is recommended due to response and acceptable side effects for treatment of inoperable locoregional breast cancer recurrence.     

Radiotherapy plus a combination of cisplatin and 5-fluorouracil for locally advanced head and neck neoplasms. Study of feasibility and preliminary results

In March 1989 we started a feasibility study of combined radio-chemotherapy in patients with locally-advanced head and neck cancer. The first phase of treatment consisted of conventional radiotherapy (2 Gy/day, 5 days/week for a total dose of 70 Gy to primary tumor and +/- 50 Gy to nodes) and cisplatinum (20 mg/m2, i.v., for 4 days) +5FU (200 mg/m2, i.v., for 4 days) every 4th week, during radiant sessions. The second phase of treatment was started about one month after the end of simultaneous chemotherapy and radiotherapy: patients in complete remission received 1 more cycle of chemotherapy, as consolidation, while patients in partial remission received two more cycles of chemotherapy. Non-responding patients received no more chemotherapy. During the second phase the days of cisplatinum and 5FU were 5. Up to April 1990, 17 patients have been included in the study. They were stage III (64%) and IV (36%). The mean administered dose of radiotherapy was 66 Gy (range: 60-70 Gy) to primary tumor and 60 Gy (range: 40-70 Gy) to nodes. The total number of chemotherapy cycles administered during radiant sessions was 37, the mean number of cycles was 2 (range: 1-3), with 100% dose percentage. The interval between cycles was 3 weeks in 84% of patients. The relationship between number of cycles administered and planned cycle was 37/39 (feasibility: 95%). Acceptability was 100% (no patient refused the treatment). Feasibility of the second phase was 77% and acceptability 90% (1 patient refused the treatment). Toxicity was moderate during the first and the second phases. After the first phase 14/15 evaluable patients (92%) had major response (complete remission: 46%). After the second phase 10/10 evaluable patients had a complete remission. In conclusion, this combined treatment is very easy to administer, and very well accepted. Moreover, it yields a high number of objective responses.     

Follow-up data of our pilot study on concomitant hyperfractionated radiotherapy and cisplatinum (CDDP) in patients with advanced cancer of the head and neck.

Since 1988, 52 patients with stage III/IV squamous cell cancer of the head and neck have been treated by concomitant irradiation with 2 x 1.2 Gy/d on five days per week up to a total dose between 72 and 76.8 Gy without split and 5 x 20 mg/m2 cisplatinum (CDDP) as short infusion finished approximately 30 min before the second session on five days of the first and the fifth week of radiotherapy. Radiotherapy has been suspended after 30 and 50 Gy in three patients for insufficient response. In all other patients, radiotherapy has been completed. Due to a slow haematologic recovery, 34% of the patients received only one cycle of CDDP Grade 3 mucositis, occurring during radiotherapy in all patients, healed in a couple of weeks after radiotherapy. Three patients have a persisting ulcer between eight and 36 months after radiotherapy with biopsies negative for tumour and also no other signs of tumour. The ulcers are situated in the region of the former primary tumour with an extensive destruction of tissue already before radiotherapy (cumulative risk of this complication after three years 8%). There were no other major complication. Cumulative local control after three years was 67% (75% including salvage surgery in two patients) with a plateau after twelve months. Total survival after three years was 62%. For the whole follow-up period, local control in the region of the primary tumour after radiotherapy was: 19/29 (T4), 10/15 (T3), 7/10 (T1 + 2, including salvage surgery: 8/10). Local control in the region of the nodal metastasis after radiotherapy was: 5/14 (N3, including salvage surgery: 6/14). 18/21 (N2) and 6/8 (N1).     

Phase I therapy study of 186Re-labeled chimeric monoclonal antibody U36 in patients with squamous cell carcinoma of the head and neck.

A phase I therapy study was conducted to determine the safety, maximum tolerated dose (MTD), pharmacokinetics, dosimetry, immunogenicity, and therapeutic potential of 186Re-labeled anti-CD44v6 chimeric monoclonal antibody (cMAb) U36 in patients with squamous cell carcinoma of the head and neck (HNSCC). The potential of a diagnostic study with 99mTc-cMAb U36 to predict the biodistribution of 186Re-cMAb U36 was evaluated. METHODS: Thirteen patients with recurrent or metastatic HNSCC were given 750 MBq 99mTc-cMAb U36 (2 mg) followed 1 wk later by a single dose of 186Re-cMAb U36 (12 or 52 mg) in radiation dose-escalating steps of 0.4, 1.0, and 1.5 GBq/m2. After each administration, planar and SPECT images were obtained, and the pharmacokinetics and development of human antimurine as well as anti-cMAb responses were determined. Radiation absorbed doses to tumor, red marrow, and organs were calculated. RESULTS: Administration was well tolerated, and excellent targeting of tumor lesions was seen in all patients. Dose-limiting myelotoxicity (thrombocytopenia being most prominent) was the only toxicity observed, resulting in grade 4 myelotoxicity in 2 patients treated with 1.5 GBq/m2. The MTD was established at 1.0 GBq/m2, at which a transient grade 3 thrombocytopenia was seen in 1 patient. One patient showed stable disease for 6 mo after treatment at the MTD. The 2 patients with dose-limiting myelotoxicity showed a marked reduction in tumor size. The reduction was of short duration and, therefore, not considered an objective response. Tumor absorbed doses at MTD ranged from 3.0 to 18.1 Gy. Red marrow doses ranged from 20 to 112 cGy (mean, 51 +/- 16 cGy/GBq) and correlated with platelet nadir (r = 0.8; P < 0.01). Pharmacokinetics varied between patients treated at the same dose level and were accurately predicted by the diagnostic procedure. Five patients experienced a human anti-cMAb response, 1 of which was a human antimouse antibody response. CONCLUSION: This study shows that 186Re-cMAb U36 can be safely administered, with dose-limiting myelotoxicity at 41 mCi/m2. The use of cMAb U36 instead of its murine counterpart did not decrease the induction of human antibody responses. The availability of a 99mTc-labeled diagnostic study that can predict the pharmacokinetics of 186Re-cMAb U36 offers the possibility of using such a study for selection of a safe radioimmunotherapy dose.     

Long-term Results of Radiotherapy in Patients with Chronic Palmo-plantar Eczema or Psoriasis

BACKGROUND AND PURPOSE: Radiotherapy (RT) is well accepted for therapy-refractory palmo-plantar eczema or psoriasis, despite of lacking evidence regarding beneficial long term effects. Furthermore, the optimal irradiation dose is unknown. We evaluated the outcome of RT with two different RT single/total dose (SD/TD) treatment policies. PATIENTS AND METHODS: 28 consecutive patients with therapy-refractory eczema (n = 22) or psoriasis (n = 6) of palms and/or soles were irradiated twice a week either with a D(max) SD of 1 Gy (6/98-5/03; median TD: 12 Gy) or 0.5 Gy (6/03-7/04; median TD: 5 Gy). Median age was 52 years (27-71), median follow-up 20 months (4-76). Totally 88 regions were treated, 49 with 1 Gy, 39 with 0.5 Gy SD. Eight different symptoms were scored from 0 (absent) -3 (severe), giving a possible sum score of 0-24. Patients' rating of RT result was also documented (worse/stable/better/complete remission). RESULTS: The sum score was 15 (6-23) before RT, 2 (0-16) at the end of RT, and 1 (0-21) at last follow-up, respectively. The improvement was highly significant in both treatment regimens. Better or complete remission by the patients were reported in 44 and 39 (= 83 out of 88) localisations, that was often stable during the follow-up. 5 (6%) regions in 3 (11%) patients didn't benefit from RT. CONCLUSION: RT reveals excellent results in palmo-plantar eczema or psoriasis. We recommend a SD of 0.5 Gy twice a week up to a TD of 4-5 Gy.     

Reduced training maintains performance in distance runners

This investigation examined endurance runners during a 3-week reduction in training volume and frequency. Ten well-conditioned runners were monitored for 4 weeks while training at their normal weekly training distance (mean +/- SE) (81 +/- 5 km/week, 6 days/week). This period was designated as baseline training (BT). Sixty km/week were run at approximately 75% VO2max, and the remainder (21 km/week) at approximately 95% VO2max in the form of intervals and races. The runners then reduced weekly training volume (RT) by 70% of BT to 24 +/- 2 km/week and frequency by 17% to 5 days/week for 3 weeks. During RT 17 km/week was performed at approximately 75% VO2max and the remainder (7 km/week) at approximately 95% VO2max (intervals and races). The runners were tested weekly and performed 5-km races on a 200-m indoor track during Bt and after 2 and 3 weeks of RT. Maximal heart rate (HR) increased (P less than 0.05) by approximately 4 beats/min at RT week 3, which may have been associated with a decrease in estimated plasma volume (P less than 0.01) of 5.62 +/- 0.43%. Time to exhaustion during the VO2max tests increased (P less than 0.05) by 9.5% at RT week 3. No significant (P greater than 0.05) changes occurred with RT in body weight, % body fat, overall 5 km race times, VO2max, muscular power (vertical leap and Margaria power test), and citrate synthase activity (at 2 weeks of RT). No alterations in venous lactate, energy expenditure, and HR were observed during submaximal running at two speeds (approximately 65% and 85% VO2max) with RT.(ABSTRACT TRUNCATED AT 250 WORDS)     

An organ-preserving selective arterial chemotherapy strategy for head and neck cancer.

PURPOSESquamous cancer of the upper aerodigestive tract is a disheartening disease. Despite our best efforts, the long-term survival rate remains only 15% to 40%, and surgical cures often decrease the quality of life owing to the loss of swallowing and speech organs. A better understanding of tumor dynamics and the discovery that thiosulfate can neutralize cisplatin led us to develop a treatment plan that combines a rapid superselective high-dose intraarterial delivery of cisplatin (CDDP), simultaneous intravenous infusion of its antagonist, thiosulfate, and radiation therapy.METHODSPatients with advanced head and neck squamous cancer were entered into the protocol after a multidisciplinary evaluation that included CT or MR imaging. Forty-two patients constituted the first cohort. After baseline angiography, an arterial acceptance test determined the maximum infusion rate that the tumor''s nutrient artery would accept. CDDP was then infused at that rate, usually within 3 to 5 minutes, while the antagonist thiosulfate was given intravenously. In the second cohort of 85 patients with stage 3 or 4 previously untreated and unresectable disease, local radiation was added to the treatment plan. The radiation dose (180-200 cGy/d x 35) was delivered regionally on the basis of the known radiosensitizing effect of CDDP.RESULTSCohort 1 allowed us to develop the infusion technique and to establish a dose quantity and delivery frequency. When 150 mg/m2 was administered weekly for 4 weeks, no severe toxicity was found. In cohort 2, 72 (92%) of the remaining 78 patients had complete disappearance of their tumor. Seventeen severe toxic events were associated with 323 femoral catheterizations. One patient died of pulmonary embolus, precluding follow-up evaluation. Six patients had neurologic sequelae, three with transient and three with permanent strokes.CONCLUSIONRapid superselective chemotherapy with CDDP combined with a circulatory systemic antagonist allowed delivery of an antitumoral drug directly into the lesion while protecting the kidneys and bone marrow from the agent''s systemic effects. Use of a dose regimen of 150 mg CDDP/m2 per week for 4 weeks resulted in the disappearance of a large percentage of advanced squamous cancers.     

Randomised,controlled walking trials in postmenopausal women: the minimum dose to improve aerobic fitness?

BACKGROUND: The American College of Sports Medicine recommends 20-60 minutes of aerobic exercise three to five days a week at an intensity of 40/50-85% of maximal aerobic power (VO(2)MAX) reserve, expending a total of 700-2000 kcal (2.93-8.36 MJ) a week to improve aerobic power and body composition. OBJECTIVE: To ascertain the minimum effective dose of exercise. METHODS: Voluntary, healthy, non-obese, sedentary, postmenopausal women (n = 121), 48-63 years of age, were randomised to four low dose walking groups or a control group; 116 subjects completed the study. The exercise groups walked five days a week for 24 weeks with the following intensity (% of VO(2)MAX) and energy expenditure (kcal/week): group W1, 55%/1500 kcal; group W2, 45%/1500 kcal; group W3, 55%/1000 kcal; group W4, 45%/1000 kcal. VO(2)MAX was measured in a direct maximal treadmill test. Submaximal aerobic fitness was estimated as heart rates at submaximal work levels corresponding to 65% and 75% of the baseline VO(2)MAX. The body mass index (BMI) was calculated and percentage of body fat (F%) estimated from skinfolds. RESULTS: The net change (the differences between changes in each exercise group and the control group) in VO(2)MAX was 2.9 ml/min/kg (95% confidence interval (CI) 1.5 to 4.2) in group W1, 2.6 ml/min/kg (95% CI 1.3 to 4.0) in group W2, 2.4 ml/min/kg (95% CI 0.9 to 3.8) in group W3, and 2.2 ml/min/kg (95% CI 0.8 to 3.5) in group W4. The heart rates in standard submaximal work decreased 4 to 8 beats/min in all the groups. There was no change in BMI, but the F% decreased by about 1% unit in all the groups. CONCLUSIONS: Walking (for 24 weeks) at moderate intensity 45% to 55% of VO(2)MAX, with a total weekly energy expenditure of 1000-1500 kcal, improves VO(2)MAX and body composition of previously sedentary, non-obese, postmenopausal women. This dose of exercise apparently approaches the minimum effective dose.     

Evaluation of remission of progressive tumors treated with a simultaneous combination of radiation and platinum therapy

Since January 1982, we have treated in a phase-II study 28 patients with a low-dose cis-platinum therapy combined with radiotherapy. We wanted to study the effect of reduced doses of cis-diamino-dichloroplatinum (II) in three different dose patterns: 1. "higher" dosage (150 mg/m2 within six weeks), single dose: 25 mg/m2 one time per treatment week), 2. "medium" dosage (80 mg/m2 within six weeks), single dose: 20 mg/m2 two times weekly during the first, fourth, seventh, and tenth treatment week, 3. "lower" dosage (75 mg/m2 within six weeks), single dose: 12.5 mg/m2 three times weekly during the first, fourth, seventh, and tenth treatment week. In one patient group the simultaneous radiotherapy was performed with a tumoricide dose of 2 Gy single dose with 4 fractions per week in two series (first series about 40 to 48 Gy tumor dose, pause of three to four weeks, second series about 16 Gy focal dose). The other group received palliative radiation doses (10 to 35 Gy tumor dose in one series), and the total platinum doses were lower corresponding to the shorter irradiation time. All patients were in advanced or recurrent stages of the disease. They suffered from different carcinomas and sarcomas with measurable parameters of response. Results: 1. Manifestations beyond the irradiation field showed no remission. Within the irradiation field, all cases responded (CR/PR) for at least two months. 2. There was no reliable dependence from the platinum dose. A tendency in favor of higher single doses could be supposed. The response of even extreme palliative cases with low radiation and platinum doses was surprising. Limitating toxicities were not observed.     

A primary care walking exercise program for patients with intermittent claudication

PURPOSE: In a pilot study, the hypothesis was tested that a home-based walking exercise program with structured coaching would improve walking performance and adherence in patients with intermittent claudication (IC). METHODS: Thirty-one IC patients with a rest ankle-brachial pressure index < 0.90 started a 24-wk walking program in the home environment. They were coached according to the Health Counseling Model (HCM). Patients were instructed to walk at least 9 bouts.wk-1 and to walk through the pain. The main effect measures were pain-free (initial claudication distance (ICD)) and maximum walking distance (absolute claudication distance (ACD)) measured with a graded treadmill test, a corridor exercise test, a walking-diary, and the score on the Walking Impairment Questionnaire (WIQ). RESULTS: Twenty-four participants completed the program. The reported walking frequency was 7.4 times.wk-1. The average ICD improved from 289 m (95% CI, 209-369) to 347 m (95% CI, 244-449) (P < 0.05) and from 241 m (95% CI, 171-310) to 373 m (95% CI, 273-472) on the treadmill and the corridor test, respectively. The average ACD improved from 490 m (95% CI, 397-583) to 544 m (95% CI, 438-650) and from 564 m (95% CI, 412-717) to 726 m (95% CI, 546-906) (P < 0.01) on the treadmill and the corridor test, respectively. The average maximum distance reported in the walking-diary improved from 957 m (95% CI, 291-1623) to 1294 m (95% CI, 646-1941). The score of the walking distance on the WIQ improved from 57% (95% CI, 42-71%) to 60% (95% CI, 46-74%). CONCLUSION: IC patients improved their average ICD and ACD. The walking exercise program in the home environment with coaching according to the HCM seems a promising intervention to be tested in a randomized controlled trial.