Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Asian-Oceanian Clinical Oncology Association Nasopharynx Cancer Study Group

BACKGROUND: The aim of this trial was to compare the outcome achieved with neoadjuvant chemotherapy followed by radiotherapy to that achieved with radiotherapy alone for patients with locoregionally advanced undifferentiated or poorly differentiated nasopharyngeal carcinoma (NPC) meeting one of the following criteria: Ho's T3 disease, Ho's N2-N3 disease, or lymph node size > or =3 cm. METHODS: Between September 1989 and August 1993, 334 patients were enrolled in the study, with equal numbers of patients randomized to the neoadjuvant chemotherapy arm (CT arm) and the radiotherapy arm (RT arm). Neoadjuvant chemotherapy consisting of 2-3 cycles of cisplatin (60 mg/m2 on Day 1) and epirubicin (110 mg/m2 on Day 1) followed by radiotherapy was given to the CT arm. For radiotherapy, a dose of 66-74 gray (Gy) (median, 71 Gy) was delivered to the primary tumor and 60-76 Gy (median, 66 Gy) to the neck. Two hundred eighty-six eligible patients completed the treatment and were evaluable for treatment response (134 in the CT arm, 152 in the RT arm). All patients were included in the survival analysis based on the intention to treat. The median follow-up was 30 months for the whole cohort and 41 months for the surviving patients. RESULTS: Analysis of the 334 patients based on the intention to treat showed no significant difference in relapse free survival (RFS) or overall survival (OS) between the 2 treatment arms (3-year RFS rate: 48% in the CT arm vs. 42% in the RT arm, P = 0.45; 3-year OS rate: 78% vs. 71%, P = 0.57). In an efficacy analysis based on only the 286 evaluable patients, a trend of improved RFS favoring the CT arm was observed (3-year RFS rate: 58% vs. 46%, P = 0.053), with again no significant difference in OS (3-year OS rate: 80% vs. 72%, P = 0.21). In the subgroup of 49 patients with bulky neck lymph nodes >6 cm, improved RFS (3-year RFS rate: 63% vs. 28%, P = 0.026) and OS (3-year OS rate: 73% vs. 37%, P = 0.057) were observed, favoring the CT arm. CONCLUSIONS: This multicenter randomized study did not demonstrate any benefit with the addition of cisplatin-epirubicin neoadjuvant chemotherapy for patients with locoregionally advanced nasopharyngeal carcinoma; therefore routine administration of neoadjuvant chemotherapy to this target group cannot be recommended. Although the overall incidence of recurrence was reduced with the addition of chemotherapy in the efficacy analysis, the overall survival was not affected. A more effective chemotherapy regimen, the selection of an appropriate target group, and the use of an alternative strategy for combining chemoradiotherapy should be explored in future trials.     

Induction cisplatin/vinblastine and irradiation vs. irradiation in unresectable squamous cell lung cancer: failure patterns by cell type in RTOG 88-08/ECOG 4588. Radiation Therapy Oncology Group. Eastern Cooperative Oncology Group

PURPOSE: To analyze disease failure patterns by pretreatment characteristics and treatment groups in a prospective randomized trial. METHODS AND MATERIALS: Patients with medically inoperable Stage II, unresectable IIIA and IIIB nonsmall cell lung cancer with KPS > or =70 and weight loss < or =5% were randomized to one of three treatment groups: standard radiation therapy with 60 Gy at 2.0 Gy per day (STD RT), induction chemotherapy with cisplatin 100 mg/m2 days 1 and 29 with vinblastine 5 mg/m2 weekly for 5 weeks followed by 60 Gy at 2.0 Gy per day (CT + RT), or hyperfractionated radiation therapy with 69.6 Gy at 1.2 Gy b.i.d. (HFX RT). Of 490 patients enrolled, 458 were evaluable. Minimum and median periods of observation for this analysis were 4 years and 6 years, respectively. RESULTS: Pretreatment characteristics were equally distributed. Toxicities were previously reported. Median survival rates were 11.4, 13.6, and 12.3 months for STD RT, CT + RT, and HFX RT, respectively (log rank p = 0.05, Wilcoxon p = 0.04). Survivals were 20, 31, and 24% at 2 years, and 4, 11, and 9% at 4 years in the STD RT, CT + RT, and HFX RT groups, respectively. There were no differences in local tumor control rates among the treatments. Patterns of first failure showed less distant metastasis (DM) (other than brain) for CT + RT compared to the RT alone arms (p = 0.04). Within squamous cell carcinoma (SCC), DM (other than brain) rates were 43%, 16%, and 38% in SCC for STD RT, CT + RT, and HFX RT, respectively (p = 0.0015). Patients with peripheral/chest wall lesions were significantly more likely to fail first in the thorax when treated on STD RT compared to CT + RT and HFX RT (p = 0.009). Survival rates were similar among the treatment arms for patients with squamous cell carcinoma. Among patients with nonsquamous cell carcinoma, failure patterns did not differ by treatment group, but survival was significantly better in those who were treated by induction chemotherapy (p = 0.04). CONCLUSION: Patients with squamous cell carcinoma treated on the CT + RT arm had a significant reduction of first DM other than brain, but there was difference in survival. Survival favored CT + RT in nonsquamous carcinoma despite similar failure patterns. Reasons for improved survival with CT + RT in NSCLC are not yet available.     

Specialty maldistribution. The next nursing crisis?

80 patients with previously untreated stage III-IV non-small cell lung cancer (NSCLC) were randomly assigned to receive chemotherapy (CT) alone (arm I: 26 patients) or the same CT combined with either interferon (IFN)-gamma (arm II: 27 patients) or with both IFN-gamma and IFN-alpha (arm III: 27 patients). The CT comprised cisplatin 60 mg/m2 intravenously (i.v.) day 1 and etoposide 100 mg/m2 i.v. days 1, 3 and 5, once every 28 days; the IFN therapy comprised either recombinant IFN-gamma 1b 0.2 mg/m2, subcutaneously, three times a week until day 25, or recombinant IFN-alpha 2c 6 x 10(6) U given according to the same schedule, and simultaneously with IFN-gamma. A maximum of six cycles were given. The treatment was discontinued if progressive disease (PD) was demonstrated. The mean numbers of cycles per patient given in the different arms were 3.6 (arm I), 3.0 (arm II) and 2.9 (arm III). The main reason for discontinuation in all arms was PD. 17 (28%) of the 61 evaluable patients achieved partial responses (35% in arm I, 29% in arm II and 35% in arm III, non-significant). No complete response was recorded. Haematological toxicity was dose-limiting in all arms: leucopenia (WHO grade 3) was observed universally, but more frequently in arm III (in 18% of cycles given). Only two episodes of grade 4 leucopenia were seen (arms II and III) and six episodes of grade 3-4 thrombocytopenia (arm III). Median survival was 6-7 months in all arms. The survival curve for arm II was slightly more favourable (non-significant) than those for other arms. The addition of IFN-gamma alone or IFN-alpha plus IFN-gamma to platinum-based CT did not improve response rates nor did it produce any significant survival benefit for patients with NSCLC. Increased haematological toxicity was observed when both IFNs were administered concomitantly with CT.     

Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced non-small-cell lung cancer. The European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group

PURPOSE: To compare two cisplatin based chemotherapy schedules in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 332 patients with advanced NSCLC were randomized to receive cisplatin 80 mg/m2 on day 1 either in combination with teniposide 100 mg/m2 on days 1, 3, and 5 (arm A) or paclitaxel 175 mg/m2 by 3-hour infusion on day 1 (arm B); cycles were repeated every 3 weeks. RESULTS: Fifteen patients were ineligible; patient characteristics were well balanced between the two arms: 71% were male, 71% had less than 5% weight loss, 89% had a World Health Organization (WHO) performance status of 0 to 1, 51% had adenocarcinoma, and 61% had stage IV disease. Hematologic toxicity was significantly more severe in arm A (leukopenia, neutropenia, and thrombocytopenia grade 3 or 4: 66% v 19%, 83% v 55%, 36% v 2% in arms A and B, respectively), which resulted in more febrile neutropenia (27% v 3% in arms A and B, respectively), dose reductions, and treatment delays. There were a total of nine toxic deaths, six due to neutropenic sepsis: five in arm A and one in arm B. In contrast, arthralgia/myalgia (grade 2 or 3, 4% v 17%), peripheral neurotoxicity (grade 2 or 3, 6% v 29%), and hypersensitivity reactions (1% v 7%, all grades) were significantly more frequent in arm B. The frequency and severity of other toxicities were comparable between the two arms. Responses were one complete and 44 partial on arm A (28%) and two complete and 61 partial (41%) on arm B (P = .018). There was no significant difference in survival, with median and 1-year survivals 9.9 versus 9.7 months and 41% versus 43%, respectively in arm A and B. Progression-free survival was 4.9 and 5.4 months in arm A and B, respectively. Selected centers participated in a quality-of-life (QoL) assessment, which was performed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and LC-13 administered at baseline and every 6 weeks thereafter. Arm B achieved a better score at week 6 for emotional, cognitive and social functioning, global health status, fatigue, and appetite loss, which was lost at 12 weeks. In conclusion, arm B appears superior to arm A with regard to response rate, side effects, and QoL. CONCLUSION: Although survival was not improved, arm B offers a better palliation for advanced NSCLC patients than arm A.     

Controlled clinical trials of hyperfractionated and accelerated radiotherapy in otorhinolaryngologic cancers

From 1978 to March 1998, (1,867 patients) were accrued in head and neck trials comparing hyperfractionation (HF) and accelerated fractionation (AF) to classical fractionation (CF). Two randomized trials (867 pts) led to positive conclusions in favour of the HF & AF arms: 1) EORTC trial 22791 (356 patients, 1980-87) compared CF (70 Gy/35-40 fr/7-8 wks) to HF (80.5 Gy/70 fr/7 wks, using 2 fr x 1.15 Gy/day) in T2 T3, N0-N1 < 3 cm in oropharyngeal carcinoma. Locoregional control (LRC) was higher (p = 0.01) in HF versus CF. At 5 years, 56% of the patients are LRC free with HF versus 38% with CF on the latest update (February 1998). This improvement of LRC also resulted in a significant overall survival (p = 0.05). There was no difference in late normal tissue damage between the two treatment modalities. Overall, this is the largest improvement documented in a randomised trial for oropharyngeal cancers during the past decade. 2) EORTC trial 22851 (511 patients, 1985-1995) compared AF (72 Gy/45 fr/5 wks) to CF (70 Gy/35 fr/7 wks) in T2 T3 T4 head & neck cancers (hypopharynx excluded). Acute and late toxicity were increased in the AF arm. Late severe sequelae occurred in 14% of patients of the AF arm versus 4% in the CF arm. Two cases of radiation-induced myelitis occurred after doses of 42 and 48 Gy to the spinal cord. The AF arm is significantly better for locoregional control (p = 0.017) and for time to progression (p = 0.012) resulting in a 15% locoregional gain at 5 years over the CF arm. This improvement is of larger magnitude in patients with poorer prognosis (N3 any T, T4 any N) than in patients with more favourable stage. Multivariate analysis confirmed AF as an independent pronostic factor for local control (p = 0.03). Specific survival shows a non significant advantage (p = 0.06) in favour of the AF arm. This trial shows that accelerated radiotherapy is able to improve locoregional control in a large variety of head and neck squamous cell carcinomas. A less toxic scheme should however be investigated before moving AF schemes in standard practice. To conclude, these two schemes derived from experimental radiobiology concepts resulted in a significant improvement of locoregional control. Hyperfractionation resulted in an improved locoregional and survival benefit. Although HF is presently the most reliable regimen to improve locoregional control, the validity of the concept of AF is also confirmed. Better schemes of AF should now be evaluated to reduce late toxicity.     

Neonatal appendectomy impairs mucosal immunity in rabbits

Between January 1988 and December 1991, 159 patients with Stage III/IV (M0) squamous cell carcinoma of the head and neck were randomized to receive standard fraction RT (70 Gy) (group I) or the same RT plus either 6 mg/m2 of cisplatin (CDPP) (group II) or 25 mg/ m2 of carboplatin (CBDCA) both given daily during RT (group III). Patients in groups II and III had significantly higher overall response rates then those in group I (P = 0.011 and P = 0.0025, respectively) with no difference between groups II and III (P = 0.60). They also had significantly longer median survival time (MST) and higher 5-year survival rates than those in group I (MST, 32 months (32%) and 30 months (29%) versus 16 months (15%), respectively; P = 0.011 and P = 0.019, respectively), with no difference between the two RT/CHT groups. Median time to local recurrence (MTLR) and 5-year local recurrence-free survival (LRFS) were significantly higher for both RT/CHT when compared to RT alone (MTLR, not attained yet and 30 months versus 10 months, respectively; 5-year LRFS, 51% and 48% versus 27%, respectively; P = 0.018 and P = 0.040, respectively) with no difference between the two RT/CHT groups. There was no difference between the three treatment groups regarding regional lymph node and distant metastasis control. Apart from acute high grade (> or =3) hematological toxicity that was significantly more frequent in the two RT/CHT groups and no different between the two RT/CHT groups, other acute high grade toxicity was similar between the three treatment groups. Late high grade toxicity was infrequent and similar between the three treatment groups.     

Serum creatine kinase in fasciocutaneous and musculocutaneous flap surgery

BACKGROUND: Stage III and IV squamous cell cancers of the head and neck are often unresectable at presentation and are associated with poor disease-free and overall survival rates. A phase II study using concurrent cisplatin and radiotherapy in advanced head and neck cancer indicated impressive local-regional control and survival with organ preservation. METHODS: A multicentered phase II study was undertaken consisting of 1.8 Gy fraction radiotherapy for 2 weeks followed by 1.2 Gy BID hyperfractionation to 46.8 Gy. Continuous infusion cisplatin 20 mg/m2 was given on days 1 through 4 and 22 through 25. Biopsy of the primary tumor was done at this point, and patients with clinical and pathologic complete response continued with hyperfractionated radiotherapy to 75.6 Gy plus simultaneous carboplatin 25 mg/m2 BID for 12 consecutive days. Residual disease at 46.8 Gy required curative surgery. RESULTS: Seventy-four patients entered the study, and 73 completed their treatment. Twenty were stage III and 54 were stage IV. Fifty patients had involved regional lymph nodes. Treatment was well tolerated with only one grade IV hematologic toxicity. At 46.8 Gy, biopsy revealed a complete response in 75% of the primary sites and 47% of the nodes. Only 12 patients required resection of the primary lesion. At 4 years (median follow-up is 26 months), 29 patients have recurred. CONCLUSIONS: Accelerated hyperfractionated radiotherapy with concurrent chemotherapy in stage III and IV head and neck cancer yields excellent local-regional control with organ preservation. This protocol is intensive, and some patients have distant failures.     

Long-term follow-up of a randomized post-induction therapy trial in acute myelogenous leukemia (a Southeastern Cancer Study Group trial)

A phase III clinical trial was designed to determine if more intensive induction and consolidation therapy for acute myeloblastic leukemia increases the remission rate and prolongs survival. A minor objective was to determine if the use of non-cross resistant drugs was more effective than the same drugs used for induction. Patients with untreated leukemia between the ages of 15 and 50 were given daunorubicin 45 mg/m2 for the first 3 days of a 10-day continuous infusion of cytosine arabinoside, initially at a dose of 2000 mg/m2 but reduced to 100 mg/m2 because of toxicity. Those under 36 achieving a complete remission and with an histocompatible donor were assigned to a transplant arm. The rest were randomized to receive one of three consolidation arms: A, cytosine arabinoside, 200 mg/m2 daily for 7 days and daunorubicin 45 mg/m2 daily for 3 days for three courses; B, one course as in Arm A followed by amsacrine, 120 mg/m2 daily for 5 days followed by a 5-day continuous infusion of azacytidine, 150 mg/m2/day; C, thioguanine and cytosine arabinoside, 100 mg/m2 every 12 h and daunorubicin 10 mg/m2 daily for 5 days for three courses followed by four maintenance courses of cytosine arabinoside, 100 mg/m2 daily for 5 days and daunorubicin, 45 mg/m2 for 2 days every 13 weeks. From 1981 to 1986, 398 eligible patients were enrolled and 219 achieved a complete remission. The initial induction dose of cytosine arabinoside was reduced after five of 29 patients exhibited fatal gastrointestinal toxicity. Only 11 patients were assigned to the transplant arm. There were no significant differences in the consolidation arms. The 5 year disease-free survivals were 38, 31 and 27% in arms A, B, and C respectively. Intensive consolidation therapy with the same or different drugs used in induction was as effective as lower dose consolidation followed by maintenance therapy.     

Weekly paclitaxel and cisplatin with concurrent radiotherapy in locally advanced non-small-cell lung cancer: a phase I study

PURPOSE: Both cisplatin (CDDP) and paclitaxel have shown good antitumor activity in non-small-cell lung cancer (NSCLC) patients and are able to potentiate the antitumor effects of radiation therapy (RT). This study aimed to determine the maximum-tolerated doses (MTDs) of CDDP and paclitaxel (escalated alternately) when given concurrently with RT and to define the nature of the dose-limiting toxicity (DLT). PATIENTS AND METHODS: Chemotherapy-naive patients with locally advanced NSCLC received six weekly administrations of a CDDP-paclitaxel combination with concurrent local RT. The starting doses of CDDP and paclitaxel were 30 mg/m2/wk and 35 mg/m2/wk, respectively. RT was initially given at the dose of 1.2 Gy twice daily for 5 days per week for 5 weeks (total dose, 60 Gy) and at a single daily dose of 2 Gy for 5 days per week for 6 weeks in the last two cohorts of patients. The drug doses were escalated alternately until DLT occurred in more than one third of the patients in a given cohort. RESULTS: Overall, 25 patients were recruited through five different cohorts. All were assessable for toxicity. Esophagitis was the main toxicity and occurred in 16 of 25 patients (64%) and was grade 3 or 4 in five of them. At step 3 (CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk), two of five patients had to discontinue treatment because of severe esophagitis and one of these died of complications related to grade 4 esophagitis. However, keeping the same doses of chemotherapy and replacing hyperfractionation with a standard single-day fraction, weekly doses of CDDP and paclitaxel of 35 mg/m2 and 45 mg/m2 could be safely administered. Neutropenia was by far the most relevant hematologic toxicity and occurred in 33 of 141 weekly delivered courses, but it was of grade 4 in only four courses. Substantial pulmonary or neurologic toxicity was not observed in this study. Two complete responses (CRs) and 13 partial responses (PRs) were observed, for a 60% overall response rate (95% confidence interval [CI], 39% to 79%). The median survival time was 16 months, with a 66% 1-year survival probability. CONCLUSION: CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk can be safely administered with concurrent standard RT. The use of hyperfractionation is associated with a more frequent occurrence of severe esophagitis and requires a reduction of the CDDP dose to 30 mg/m2/ wk. Only future randomized trials will elucidate which of these two approaches (standard or hyperfractionated RT) is the better option to improve the outcome of patients with locally advanced NSCLC.     

Amifostine: a radioprotector in locally advanced head and neck tumors

Patients with locally advanced head and neck tumors were treated +/-amifostine (200 mg/m2, i.v.) before radiotherapy (5x 2 Gy, for 6 weeks). A significant decrease in side effects (p=0.034) using the oral assessment score and duration of mucositis (p=0.02) in the amifostine group was observed. Amifostine is feasible and effective, decreasing acute and late side effects in patients with head and neck tumors.     

The role of transcription factor PU.1 in the activity of the intronic enhancer of the eosinophil-derived neurotoxin (RNS2) gene

PURPOSE: To evaluate the therapeutic significance of cisplatin, vincristine, doxorubicin, and etoposide (CODE) plus granulocyte colony-stimulating factor (G-CSF) compared with cyclophosphamide, doxorubicin, and vincristine, alternating with cisplatin and etoposide (CAV/PE) for extensive-disease (ED) small-cell lung cancer (SCLC). PATIENTS AND METHODS: Two hundred twenty-seven patients were randomized. CODE consisted of cisplatin 25 mg/m2 weekly for 9 weeks; vincristine 1 mg/m2 on weeks 1, 2, 4, and 6; and doxorubicin 40 mg/m2 and etoposide 80 mg/m2 for 3 days on weeks 1, 3, 5, 7, and 9. G-CSF 50 micrograms/m2 was administered on the days when chemotherapy was not administered. CAV/PE consisted of cyclophosphamide 800 mg/m2; doxorubicin 50 mg/m2; and vincristine 1.4 mg/m2 on day 1, which alternated every 3 weeks with cisplatin 80 mg/m2 on day 1 and etoposide 100 mg/m2 on days 1 to 3. RESULTS: Overall response rates were 77% for the CAV/PE arm and 84% for the CODE arm respectively (15% complete response in both arms). The median survival times were 10.9 months in the CAV/PE arm and 11.6 months in the CODE arm (P = .1034). The achieved dose-intensity for CODE was approximately twice that for CAV/PE for those drugs common to both arms. The incidence of leukopenia did not differ between the two arms, but anemia and thrombocytopenia had a significantly higher incidence in the CODE arm. Four treatment-related deaths from neutropenic fever occurred in the CODE arm. CONCLUSION: The CODE group had a similar median survival to the CAV/PE group. It does not appear that CODE is a useful approach to improve survival in ED SCLC.     

Corticosteroids significantly delay the onset of docetaxel-induced fluid retention: final results of a randomized study of the European Organization for Research and Treatment of Cancer Investigational Drug Branch for Breast Cancer

PURPOSE: To confirm the efficacy of docetaxel in patients with breast cancer previously treated with one chemotherapy regimen for advanced or metastatic disease and to compare the incidence of fluid retention (FR) and skin toxicity when docetaxel is administered with and without prophylactic corticosteroids. PATIENTS AND METHODS: Eighty-three patients, pretreated with one chemotherapy regimen for metastatic breast cancer (MBC) with bidimensionally measurable and progressive disease, were eligible for this randomized trial. Docetaxel with prophylactic oral antihistamine was administered at a dose of 50 mg/m2 as a 1-hour infusion on days 1 and 8 every 21 days and patients were randomized to receive methylprednisolone (40 mg days -1, 0, 1, 7, 8, and 9 of each cycle) (arm A) or no methylprednisolone (arm B). RESULTS: Twenty-eight patients (34%, 95% confidence interval [CI], 23% to 45%) achieved on objective response. The median time to disease progression and median overall survival time were 5 and 13.5 months, respectively. In total, 415 cycles of docetaxel were administered (arm A: N = 219, median = six; arm B: N = 196, median = five). The most common toxicity observed was grade 3 or 4 neutropenia, which occurred in 79% of patients. Clinically significant nonhematologic side effects included skin reactions and asthenia. In an intent-to-treat analysis, patients who received methylprednisolone premedication had a delayed onset of FR (median time to onset of FR: arm A, 84 days; arm B, 62 days; P = .01) and received a higher median cumulative dose of docetaxel before the onset of FR (arm A, 333 mg/m2; arm B, 215 mg/m2; P = .001). There was no statistically significant difference in the incidence of skin toxicity between the two arms. CONCLUSION: Docetaxel, at this dose and schedule, has definite antitumor activity in pretreated MBC patients. Moreover, this is the first randomized trial to show that corticosteroids have a favorable impact on docetaxel-induced FR.     

The calretinin-containing mossy cells survive excitotoxic insult in the gerbil dentate gyrus. Comparison of excitotoxicity-induced neuropathological changes in the gerbil and rat

BACKGROUND: The locoregional failure rate remains high in advanced cervical carcinoma. Chemotherapy (CT) was added to radiotherapy (RT) in order to increase disease control and to improve 5-year survival. METHODS: CT + RT included cisplatin administered 100mg/m2, d.1 plus 5-fluorouracil 1000 mg/m2 D.1 to 5, ci (120 hrs), q every 3rd week for 3 cycles, followed by RT. RT included external beam irradiation 64.8 Gy in 1.8 Gy fractions, five days a week, by 4-field box technique. The median follow-up was 46 months. Ninety-four patients were evaluable for survival, 47 in the CT + RT group and 47 in the RT group. Ninety-two patients were evaluable for response. Known prognostic factors were equally distributed between the two groups. RESULTS: Of the 43 patients evaluable before RT, 31 (72%) achieved a partial or complete response after CT alone. After RT, 52 patients attained a complete response, 25 in the CT + RT group and 27 in the RT-group. Sixty-three patients developed distant metastases or local relapse, 30 in the CT + RT group and 33 in the RT group. In the CT + RT group 6 of the 9 patients with metastases also had local progression at relapse, in the RT group, 7 of 17 patients. The survival rates for the two groups are not statistically different. Thirty-seven patients are alive, 29 have no evidence of disease. Fifty-seven have died, 29 in the CT + RT group and 28 in the RT group. Fifty-four deaths were related to cancer, and 3 to therapy. CONCLUSIONS: Sequential CT and RT did not improve the survival, local control, or metastasis rate compared with RT alone.     

Comparative study on quality of life between weekly and monthly chemotherapy with cisplatin, vindesine and mitomycin C in patients with non-small cell lung cancer

A comparative study between weekly and monthly chemotherapy with CDDP, VDS and MMC was performed on the basis of QOL in patients (stage III A/III B/IV) with non-small lung cancer from September 1993 to August 1996. Arm A received CDDP (80 mg/m2) monthly on day 1, VDS (3 mg/m2) on days 1 and 8, MMC (8 mg/m2) on day 1. Arm B received CDDP (40 mg/m2), VDS (3 mg/m2) and MMC (4 mg/m2) on day 1, and followed by CDDP (20 mg/m2), VDS (1.5 mg/m2) and MMC (2 mg/m2) weekly. A diary-type QOL self-rating questionnaire was devised for this study, consisting of 5 scales including 13-item questionnaires and a face scale as the global scale. Chronological QOL data from 20 days during chemotherapy (total dose of CDDP was 80 mg/m2 in both A and B arm) were analyzed using summary measures. In the 78 eligible subjects of the study, 34 were QOL subjects of the 27 eligible subjects, 13 were in arm A and 14 in arm B. 1. The questionnaire was confirmed to be satisfactory with regard to reliability and validity as a questionnaire for the evaluation of this study by factor and correlation analysis. 2. Although each scale changed to the worth level after chemotherapy, there was no significant difference between arm A and B. 3. Summary statistics were assessed using indices of the area under the curve (AUC) and the maximum fluctuations of QOL scores (Dif max) arm B showed a tendency to smaller changes than arm A in AUC and Dif max. There was a significant difference in the physical well-being scale of Dif max. 4. Three items, including the physical well-being in arm B, revealed a better score than those of arm A. Abdominal condition showed a significant difference between the two arms. 5. No obvious difference in anti-cancer effectiveness was found between arm A and B. Arm B showed a longer median survival, less nausea and vomiting, leukopenia and thrombocytopenia compared with arm A. The above results suggested that weekly chemotherapy is as effective, less toxic and shows less influence against patients QOL than the conventional monthly chemotherapy in this study.     

Neo-adjuvant chemotherapy +/- immunotherapy with s.c. IL 2 in advanced squamous cell carcinoma of the head and neck: a pilot study

We carried out a pilot nonrandomized phase II study to compare the neo-adjuvant chemotherapic regimen with cisplatin, 5-FU and vinorelbine with the same combination plus s.c. IL 2 in advanced head and neck squamous cell carcinoma (HNSCC). The primary goals of the trial were to evaluate the feasibility and response rates of the two regimens. The study design consisted of a patient's assignment to either of the two following arms: Arm A: Cisplatin 80 mg/m2 i.v. on day 1; 5-FU 600 mg/m2 i.v. on days 2-5; and vinorelbine 20 mg/m2 i.v. on days 2 and 8, Arm B: the same chemotherapic regimen plus recombinant IL 2 (Proleukin, Eurocetus) 9 MIU s.c. daily from day 9 to 13 and from day 16 to 20 for every cycle. From March 1993 to November 1993 twenty three patients with Stage III-IV HNSCC were enrolled in the study. Patients could be evaluated for response to treatment if they had received at least 2 complete cycles of therapy. The overall response rate (ORR) was 63% in Arm A and 100% in Arm B. The differences for ORR and CR rates were statistically significant in favor of Arm B. The analysis for each of the three drugs included in the chemotherapy schedule shows that both the actually received average dose-intensity and the actually delivered average cumulative doses/patient were higher for Arm B (chemo-plus IL 2 therapy) (approximately 80% of programmed dose-intensity) than for Arm A (approximately 70% of programmed dose-intensity). Both the actually received average dose-intensity and the actually delivered average cumulative doses/patient for IL 2 were more than 80%. In both arms the most frequent side effects were myelosuppression, phlebitis and electrolyte disturbances. There were 2 toxic deaths, 1 in Arm A and 1 in Arm B, both for hematologic toxicity. Our "pilot" study suggests that the combination of cisplatin, 5-FU, vinorelbine plus IL 2 is a highly active, but rather toxic, neo-adjuvant treatment in advanced HNSCC with very high ORR and CR rates.     

Studies on the phototoxic effects of oral antidiabetics and diuretics

Combined chemoradiotherapy (CT/RT) treatments appear to yield better results for advanced tumours of the head and neck than do conventional therapies. In the present study, CT/RT was used preoperatively in unresectable tumors of the oral cavity and oropharynx. Forty patients were entered prospectively into a phase II study. Treatment consisted of three cycles of chemotherapy with cisplatin and 5-day infusion of fluorouracil (FU), and the addition of simultaneous radiotherapy (30 Gy) from the second to third cycles. Patients with resectable residual disease or complete clinical response underwent surgery. All patients later received a second phase of irradiation (30 Gy) and two cycles of chemotherapy only in responders. During the first phase of treatment, 22 (55%) patients presented mucositis grades III-IV. Mean weight loss was 7%. Twelve patients were admitted for parenteral nutrition. Thirty-six (90%) patients obtained clinical response, which was complete in 15 (37%). Thirty-two of the 40 underwent surgery. The percentage of pathologic complete responses (PCR) was 35% (14 patients). With a median follow-up of 21 months, the median survival of patients was 23 months, and 19 (47%) of them are disease-free. A high PCR rate was attained with this treatment regimen. Toxicity was significant, but tolerable with adequate support measures.     

Hyperfractionated radiotherapy and simultaneous cisplatin for stage-III and -IV carcinomas of the head and neck. Long-term results including functional outcome

PURPOSE: To assess the survival rate, the probability of local control, the patterns of relapse and late sequelae including self-reported quality of life in patients treated with hyperfractionated radiotherapy (RT) and simultaneous CDDP chemotherapy for stage-III to stage-IV carcinomas of the head and neck. METHODS: From 1988 to 1994, 64 patients (median age 55.5 years) with carcinomas of different subsites, excluding the nasopharynx, were treated in a pilot study with 1.2 Gy bid (6 h interval; total dose 74.4 Gy) and simultaneous CDDP (20 mg/m2 daily, 5 days in week 1 and 5) and followed at regular intervals. Overall survival and local control, as well as the rates of late toxicity, were estimated using the actuarial method. Median follow-up was 3.3 years for all and 5.2 years for surviving patients. To assess the quality of life, the EORTC QLQ-C 30 questionnaire and the H&N35 module questionnaire were sent to the patients surviving with no evidence of disease or second primary tumors; they were answered by 15/23 (67%). RESULTS: Overall survival was 37% at 5 years, whereas disease-specific survival was 59%. Twenty-three patients died from uncontrolled head and neck cancer. Second primary tumors were observed in 13 patients, most frequently in the lung. Local control without salvage surgery was 74% at 5 years for all subsites and stages, and loco-regional disease-free survival was 72%. Eleven patients developed distant metastases, which was the only site of failure in 6 cases. Salvage surgery was successful in 2 cases. The actuarial estimates of > or = grade-3 late toxicity was 4% for the mandibular bone and 23% for dysphagia, and 50% of the patients experienced a permanent xerostomy. Self-reported global quality of life in surviving patients was good (mean 68 points on a scale 0 to 100); consequences of impaired salivary function had most impact on nutritional and social aspects. CONCLUSIONS: Hyperfractionated RT with concomitant CDDP is well tolerated and highly efficient in controlling moderately advanced to advanced cancers of the head and neck. Second primary tumors are the main cause of death after 3 years and were observed outside of the irradiated area, most frequently in the lung. Even after RT of large volumes to a high dose, salvage surgery can be successfully performed in individual cases. Self-reported quality of life of surviving patients is good, despite xerostomy-associated nutritional difficulties.     

Randomized phase II noncomparative trial of oral and intravenous doxifluridine plus levo-leucovorin in untreated patients with advanced colorectal carcinoma

BACKGROUND: Doxifluridine (5-dFUR) is a fluoropyrimidine derivative that has been shown to be active on a variety of solid tumors. The clinical use of intravenous (i.v.) 5-dFUR as a bolus injection or short term infusion has been limited because of its unpredictable severe neurotoxicity. Unlike fluorouracil (5-FU), 5-dFUR is effective when administered orally. METHODS: This randomized, parallel-group, Phase II trial of two schedules of 5-dFUR was conducted between April 1993 and September 1994. A total of 130 previously untreated patients with locally advanced or metastatic colorectal carcinoma were randomized to receive oral levo-leucovorin (1-leucovorin) 25 mg/dose followed by oral 5-dFUR 750 mg/m2 twice daily for 4 days every 12 days (arm A) or i.v. 1-leucovorin 25 mg/dose followed by i.v. 5-dFUR 3000 mg/m2 for 5 days every 21 days (arm B). RESULTS: The two treatment arms were well balanced in terms of age, sex, and disease extension. Metastases were present in more than 90% of the total population, with the liver being the most common site. A median of 7 oral courses (range, 1-15) and 5 intravenous courses (range, 1-9) were administered. Intent-to-treat analysis rate of the randomized patients revealed a response rate of 15% (95% confidence interval [CI], 7-26) in arm A and 41% (95% CI, 29-54) in arm B. However, 7 cases in arm A and 12 in arm B were inadequately treated, and the response rates, according to standard analysis, were respectively 17% (95% CI, 8-28) and 51% (95% CI, 37-65). The median time to treatment failure was 4 months (range, 1-23) and 7 months (range, 1-9), respectively, for the two groups; median survival was 11 months (range, 1-24) in both groups. National Cancer Institute Grade 3 and 4 diarrhea were observed in 25% of the orally treated patients and in 18% of those receiving i.v. treatment. Stomatitis was reported mainly in arm B (15%). Mild and moderate neurotoxicity was observed in 6% of the patients in both arms; no severe neurotoxicity was reported. CONCLUSIONS: 5-dFUR with l-leucovorin, administered either orally or intravenously, produces response rates that are similar to those offered by the regimens containing 5-FU that are usually used to treat advanced colorectal carcinoma. This study documents the good tolerance of the i.v. schedule administered as a 1-hour infusion; furthermore, oral administration seems to be promising and feasible as a home treatment.     

Radiotherapy and concomitant weekly 1-hour infusion of paclitaxel in the treatment of head and neck cancer--results from a Phase I trial

PURPOSE: To define the maximum tolerated dose (MTD) by describing the dose-limiting toxicity (DLT) of weekly paclitaxel (PAC) given as a 1-h I.V. infusion in patients with head and neck cancer concomitant to irradiation. METHODS AND MATERIALS: Patients with unresectable or incompletely resected head and neck cancer were enrolled into a prospective, dose-escalating Phase I study. Toxicity was graded according to the WHO toxicity score. MTD dose was defined when two out of six patients developed DLT. The starting dose of PAC was 20 mg/m2 once weekly I.V. over 60 min, with a subsequent dose escalation of 10 mg/m2 in cohorts of three new patients. Radiation therapy was administered in three field technique over 6-7 weeks in 2.0 Gy/daily fractions for 5 consecutive days/week up to total doses of 60-70 Gy. RESULTS: From 1994-1996, 18 patients completing three dose levels were included into the study. Altogether, 101 courses of chemotherapy were evaluable for toxicity. On the second dose level (30 mg/m2) one of three patients experienced DLT with Grade IV mucositis. On the next dose level with 40 mg/m2 PAC weekly one patient experienced DLT being prolonged Grade III mucositis. From the following three patients required, two patients showed no DLT. The third patient showed mucositis of WHO Grade 4 and died from hemorrhage caused by a rupture of the a pharyngeal wall. Dose level 2 (30 mg/m2) was repeated and one of the three newly treated patients again suffered from mucositis WHO Grade 4. CONCLUSION: When PAC is given weekly as a 1-h infusion concomitant to radiotherapy, MTD is 30 mg/m2 with mucositis being DLT; hematological and further nonhematological toxicity is mild.