Combined Radiochemotherapy with Docetaxel in Patients with Unresectable Locally Advanced Head and Neck Tumors

Background: As the treatment with Docetaxel in metastatic head and neck cancer resulted in an encouraging response rate, the following phase-I study examined the effects of a combined radiochemotherapy with weekly Docetaxel in patients with inoperable advanced head and neck tumors. Patients and Methods: Six patients with Stage IV head and neck cancer were included into the study. Within the treatment regimen the primary tumor and the involved lymph nodes were irradiated up to a total dose of 70 Gy, the non involved cervical and supraclavicular lymph nodes received 50 Gy in conventional fractionation. Simultaneously Docetaxel was given 1 hour before radiotherapy. The initial dose was 15 mg/m². Results: A dose escalation was impossible because of several dose limiting toxicities (NCI-CTC) already in the first dose level. Two patients showed skin reactions Grade 4, 2 patients pulmonary complications Grade 4, 2 patients neurologic side effects Grade 3 and 1 a thrombocytopenia Grade 3. The response rate resulted in 3 complete and 1 partial remission, 1 death, 1 patient was not evaluable. Conclusions: Unexpectedly already in the fist dose level several dose limiting toxicities were evaluated. For that reason the treatment scheme is not feasible. Hintergrund: Da die Behandlung mit Docetaxel bei metastasierten HNO-Tumoren eine günstige Ansprechrate ergeben hat, untersuchte die folgende Phase-I-Studie die Effekte einer kombinierten Radiochemotherapie mit wöchentlicher Gabe von Docetaxel bei Patienten mit inoperablen fortgeschrittenen HNO-Tumoren. Patienten und Methode: In der Zeit von September 1997 bis März 1998 wurden sechs Patienten mit fortgeschrittenen HNO-Tumoren im Stadium IV in der Studie eingeschlossen. Innerhalb des Therapieregimes wurden der Primärtumor und die befallenen Lymphknoten bis 70 Gy bestrahlt, die nicht befallenen zervikalen und supraklavikulären Lymphknoten erhielten 50 Gy in konventioneller Fraktionierung. Simultan wurde Docetaxel eine Stunde vor der Bestrahlung gegeben. Die initiale Dosis lag bei 15 mg/m². Ergebnisse: Eine Dosiseskalation war nicht möglich, da bereits im ersten Dosislevel zahlreiche dosislimitierende Toxizitäten (NCI-CTC) aufgetreten sind. Hautreaktionen Grad 4, pulmonale Komplikationen Grad 4 sowie neurologische Nebenwirkungen Grad 3 zeigten sich bei je zwei Patienten und bei einem Patienten eine Thrombozytopenie Grad 3. Die Ansprechrate ergab drei komplette und eine partielle Remission, einen Todesfall, ein Patient war nicht auswertbar. Schlußfolgerungen: Unerwarteterweise sind bereits im ersten Dosislevel zahlreiche dosislimitierende Komplikationen aufgetreten, so daß die Behandlung so nicht durchführbar ist.     

Combined Radiochemotherapy with Docetaxel in Patients with Unresectable Locally Advanced Head and Neck Tumors

BACKGROUND: As the treatment with docetaxel in metastatic head and neck cancer resulted in an encouraging response rate, the following phase-I study examined the effects of a combined radiochemotherapy with weekly docetaxel in patients with inoperable advanced head and neck tumors. PATIENTS AND METHODS: Six patients with Stage IV head and neck cancer were included into the study. Within the treatment regimen the primary tumor and the involved lymph nodes were irradiated up to a total dose of 70 Gy, the non involved cervical and supraclavicular lymph nodes received 50 Gy in conventional fractionation. Simultaneously docetaxel was given 1 hour before radiotherapy. The initial dose was 15 mg/m2. RESULTS: A dose escalation was impossible because of several dose limiting toxicities (NCI-CTC) already in the first dose level. Two patients showed skin reactions Grade 4, 2 patients pulmonary complications Grade 4, 2 patient neurologic side effects Grade 3 and 1 a thrombocytopenia Grade 3. The response rate resulted in 3 complete and 1 partial remission, 1 death, 1 patient was not evaluable. CONCLUSION: Unexpectedly already in the first dose level several dose limiting toxicities were evaluated. For that reason the treatment scheme is not feasible.     

Phase II Trial of Hyperfractionated Accelerated Split-Course Radiochemotherapy with 5-FU and Cis-DDP in Advanced Head and Neck Cancer

BACKGROUND:. Simultaneous radiochemotherapy resulted in a significant benefit improving both local control and overall survival in advanced head and neck cancer. In this phase II study the efficacy and toxicity of a hyperfractionated accelerated split course radiotherapy with simultaneous application of 5-FU and cisplatin were evaluated in patients with locally advanced tumors of the oral cavity, oro- and hypopharynx. PATIENTS AND METHODS:. Between 1991 and 2002 the study recruited 45 patients. 41 (92%) presented with stage IV, 2 (4%) with stage II and III tumors, respectively. Radiation was delivered twice daily by a single dose of 1.5 Gy to a median total dose of 72 Gy with a 1 week break scheduled at 30 Gy. Chemotherapy consisting of 5-FU (800 mg/m(2)/d i.v.) and cisplatin (20 mg/m(2)/d i.v. bolus) was administered during the 1st and 5th treatment week. RESULTS:. Overall survival, cause-specific survival, locoregional tumor-free survival and distant metastasis-free survival were 53%, 65%, 77% and 73%, respectively, at 3 years. Mean follow-up was 21 months. Neutropenia was the only grade-4 toxicity that occurred in 2 patients. CONCLUSION:. This regimen is effective and safe, however, distant relapses clearly exceed local failure rates. Future studies have to contemplate the implementation of new chemotherapeutic agents and the feasibility and efficacy of maintenance chemotherapy.     

Hyperfractionated Radiotherapy in Locally Advanced Nasopharyngeal Cancer

BACKGROUND: Despite numerous randomized trials suggesting a benefit of unconventional fractionation in locally advanced head and neck cancer, the role of this approach in nasopharyngeal carcinoma is debatable. Based on the current clinical experience, the authors introduced hyperfractionated irradiation in the treatment of locally advanced head and neck cancer, including nasopharyngeal tumors. The preliminary results of this treatment approach in nasopharyngeal cancer patients are presented, with special focus on the pattern of failure and toxicity. PATIENTS AND METHODS: 43 patients with nasopharyngeal cancer (stage II-IV, TNM 1997) underwent hyperfractionated irradiation. In 34 cases, radiotherapy was preceded by a median of three cycles of cisplatin-based induction chemotherapy. Irradiation was delivered using a shrinking-field technique up to a total dose of 74.4 Gy in 62 fractions of 1.2 Gy twice daily (minimum 6-h interval)/5 days/week. RESULTS: Acute toxicity of hyperfractionated radiotherapy was significant but tolerable. Mucositis proved the most common side effect (grade 3: 24 patients, grade 4: three patients). Severe late toxicity was not observed. 30 of 34 patients (88%) responded to induction chemotherapy. At 6 weeks after completion of radiotherapy, complete response was seen in 35 patients (81%), partial response in five (12%), stable disease in one, and progressive disease in two. After a median follow-up of 32 months, 18 patients (41%) developed progressive disease. Primary tumor progression was observed in three patients, and seven patients each showed regional lymph node progression and distant metastases. In one case both regional lymph node progression and distant metastases were diagnosed. The 2-year progression-free survival and overall survival rates were 58% and 84%, respectively. CONCLUSION: Hyperfractionated radiotherapy seems a feasible and active regimen in locally advanced nasopharyngeal carcinoma. Accompanying acute and late toxicity is acceptable and does not compromise delivery of the planned irradiation dose. This regimen is associated with a high local control rate; relatively high nodal and distant failure, however, call for further treatment modifications, e. g., optimization of irradiation technique and/or dose escalation as well as improved systemic therapies.     

Selective Lymph Node Dissection Following Hyperfractionated Accelerated Radio-(Chemo-)Therapy for Advanced Head and Neck Cancer

Background: 2-year results of a German multicenter randomized trial showed that accelerated chemoradiation with MMC/5-FU to 70.6 Gy is more effective than accelerated radiation to 77.6 Gy alone at equivalent levels of acute and late radiation morbidity. Frequency, histopathology and impact on local tumor control of selective lymph node dissection were analyzed. Patients and Methods: Between February 1996 and October 2000 at Tübingen University 42 randomized patients plus 45 non-randomized patients with stage III/IV M0 head and neck cancer were treated according to this protocol. After completion of hyperfractionated accelerated (chemo-)radiation a selective lymph node dissection was performed, if the primary tumor was in complete remission and clinical plus computed tomography proved residual lymph node disease. 17 of 38 patients with residual node metastasis underwent uni- or bilateral selective node dissection, the remaining patients had residual primary tumors, clinical deterioration or refused neck dissection. Results: After a median follow-up 26 months, the Kaplan-Meier analysis showed a 2-year overall survival of 49%, disease-specific survival of 64% and loco-regional tumor control of 60%, respectively. 3-year loco-regional tumor control in randomized patients was 52% compared to 58% in non-randomized patients (log rank p = 0.23). 2-year loco-regional tumor control in stage cT4cN0 was 76% compared to 57% in cT2-4 cN1-3 tumors. Subgroup analysis of patients with involved nodes revealed a 2-year loco-regional tumor control of 74% after complete remission of primary tumor and neck disease, 53% after complete remission of primary tumor and partial remission of neck disease. In patients with selective lymph node dissection loco-regional tumor control was 62%. Histopathological examination showed viable tumor in eight of 17 patients. Conclusions: Selective lymph node dissection of residual neck masses after completion of hyperfractionated accelerated radio-(chemo-)therapy is likely to contribute to loco-regional tumor control in advanced head and neck cancer. Hintergrund: Die multizentrische Phase-III-Studie (ARO 95-6) zur akzelerierten hyperfraktionierten Strahlentherapie - 5-Fluorouracil/Mitomycin C bei lokal fortgeschrittenen Kopf-Hals-Tumoren konnte nachweisen, dass die kombinierte Radiochemotherapie bezüglich lokaler Tumorkontrolle und Gesamtüberleben wirksamer ist als die alleinige Strahlentherapie. Wir untersuchen Häufigkeit, histopathologisches Ergebnis und den Einfluss der selektiven Neck-Dissection auf die lokale Tumorkontrolle. Patienten und Methoden: Zwischen Februar 1996 und October 2000 wurden in Tübingen insgesamt 42 randomisierte und 45 nicht randomisierte Patienten mit fortgeschrittenen Kopf-Hals-Tumoren im Stadium III/IV M0 nach diesem Protokoll behandelt. Nach Abschluss der akzelerierten hyperfraktionierten Strahlentherapie - 5-Fluorouracil/Mitomycin C wurde eine selektive Neck-Dissection bei kompletter Remission des Primärtumors und partieller Remission der Halslymphknotenmetastasen angestrebt. Bei 17 von 38 Patienten mit residuellen Halslymphknotenmetastasen wurde eine uni- oder bilaterale selektive Neck-Dissection durchgeführt. Bei 21 Patienten wurde die Neck-Dissection wegen partieller Remission des Primärtumors, klinischer Verschlechterung oder Ablehnung durch den Patienten nicht durchgeführt. Ergebnisse: Nach einem medianen Follow-up von 26 Monaten betrugen das 2-Jahres-Gesamtüberleben 49%, das krankheitsspezifische Überleben 64% und die lokoregionäre Tumorkontrolle 60% (Kaplan-meier-Analyse). Für cT4-cN0-Tumoren betrug die lokoregionäre 2-Jahres-Tumorkontrolle 76% im Vergleich zu 57% bei cT2-cN1-3-Tumoren. Es bestand kein Unterschied bezüglich der lokoregionären Tumorkontrolle zwischen randomisierten und nicht randomisierten Patienten. Bei kompletter Remission des Primärtumors und der lokoregionären Lymphknoten betrug die 2-Jahres-Tumorkontrolle 74%, bei partieller Remission der lokoregionären Lymphknoten 53%. Nach partieller Remission der lokoregionären Lymphknoten und selektiver Neck-Dissection betrug die 2-Jahres-Tumorkontrolle 62% (Abbildung 3). Die histopathologische Aufarbeitung wies bei acht von 17 Patienten vitale Tumorzellen nach. Schlussfolgerungen: Die selektive Neck-Dissection von residuellen Halslymphknotenmetastasen nach akzelerierter hyperfraktionierter Strahlentherapie - 5-Fluorouracil/Mitomycin C bei lokal fortgeschrittenen Kopf-Hals-Tumoren kann möglicherweise zur lokalen Tumorkontrolle beitragen.     

Selective Lymph Node Dissection Following Hyperfractionated Accelerated Radio-(Chemo-)Therapy for Advanced Head and Neck Cancer

BACKGROUND: 2-year results of a German multicenter randomized trial showed that accelerated chemoradiation with MMC/5-FU to 70.6 Gy is more effective than accelerated radiation to 77.6 Gy alone at equivalent levels of acute and late radiation morbidity. Frequency, histopathology and impact on local tumor control of selective lymph node dissection were analyzed. PATIENTS AND METHODS: Between February 1996 and October 2000 at Tübingen University 42 randomized patients plus 45 non-randomized patients with stage III/IV MO head and neck cancer were treated according to this protocol. After completion of hyperfractionated accelerated (chemo-)radiation a selective lymph node dissection was performed, if the primary tumor was in complete remission and clinical plus computed tomography proved residual lymph node disease. 17 of 38 patients with residual node metastasis underwent uni- or bilateral selective node dissection, the remaining patients had residual primary tumors, clinical deterioration or refused neck dissection. RESULTS: After a median follow-up of 26 months, the Kaplan-Meier analysis showed a 2-year overall survival of 49%, disease-specific survival of 64% and loco-regional tumor control of 60%, respectively. 3-year loco-regional tumor control in randomized patients was 52% compared to 58% in non-randomized patients (log rank p = 0.23). 2-year loco-regional tumor control in stage cT4cN0 was 76% compared to 57% in cT2-4 cN1-3 tumors. Subgroup analysis of patients with involved nodes revealed a 2-year loco-regional tumor control of 74% after complete remission of primary tumor and neck disease, 53% after complete remission of primary tumor and partial remission of neck disease. In patients with selective lymph node dissection loco-regional tumor control was 62%. Histopathological examination showed viable tumor in eight of 17 patients. CONCLUSIONS: Selective lymph node dissection of residual neck masses after completion of hyperfractionated accelerated radio-(chemo-)therapy is likely to contribute to loco-regional tumor control in advanced head and neck cancer.     

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.     

Early Morbidity after Radiotherapy with or without Chemotherapy in Advanced Head and Neck Cancer

BACKGROUND: Data on early treatment-related morbidity after radiotherapy alone (RT; 217 patients) or combined with chemotherapy (RT + CT; 182 patients) of head and neck squamous cell carcinoma are analyzed. PATIENTS AND METHODS: The patients were treated between November 1985 and November 1996 in four Swiss centers that independently introduced combined-modality therapy in selected cases of head and neck cancer. RT schedules varied among the four centers, but within each institution all patients received the same dose-fractionation schedule irrespective of whether they had CT or not. The following early morbidity items were evaluated: skin, mucosa, larynx, salivary glands, dysphagia, weight loss, and toxic death. Toxicity was scored using the EORTC/RTOG scale. RESULTS: Although considerable variation was noted among the treatment schedules/centers, the main findings are as follows: (1) early morbidity was significantly enhanced after all five RT + CT schedules compared with RT alone; (2) typically, a third of the patients lost > 10% of their body weight during concurrent RT + CT as compared with 10% of the patients receiving RT alone; (3) at 12 weeks, the prevalence of grade 2 morbidity was 25-60% after RT + CT as compared with 4-20% after RT alone. CONCLUSION: A number of early morbidity items were found to be more prevalent and/or more severe after RT + CT than after RT alone.     

Hemoglobin as an Independent Prognostic Factor in the Radiotherapy of Head and Neck Tumors

PURPOSE: The purpose of this study was to analyze the prognostic value of baseline hemoglobin levels before radiotherapy in patients with head and neck tumors. PATIENTS AND METHODS: In a retrospective study with a median follow-up of 43 months, we analyzed the results of 214 patients irradiated for head and neck cancer between January 1, 1990 and January 1, 1998 (180 men and 34 women; median age 58 years). The treatment concept consisted in adjuvant radiotherapy in 58 patients, 77 patients received definitive radiochemotherapy, 42 patients definitive radiotherapy, and 37 patients reirradiation for in-field recurrence. Baseline hemoglobin values were divided in four groups of the same patient number (quartiles). Several known prognostic factors like sex, age, tumor stage, histologic grading, performance status, and treatment scheme were analyzed for their influence on overall and event-free survival and correlated with pretreatment hemoglobin values (Kaplan-Meier method). In addition, univariate und multivariate logistic regression analyses were carried out to evaluate the effect of baseline hemoglobin on response rates. RESULTS: The median survival (event-free survival) of all patients amounted to 15 months (10 months). 25%, 50%, and 75% of patients had hemoglobin values < 11.2 g/dl, < 12.7 g/dl, and < 13.9 g/dl, respectively. In the univariate analysis, the following variables were significant prognostic factors for overall/event-free survival (log-rank test): treatment concept (p < 0.001/p < 0.001), tumor stage (p < 0.001/p < 0.001), general condition (p < 0.001/p < 0.001), and pretreatment hemoglobin (p = 0.014/p = 0.05). Multivariate analysis (Cox) proved these parameters to be independent of each other. In addition, response rate after radiation showed a strong association between hemoglobin and local control probability (p = 0.02). CONCLUSION: In this retrospective analysis, baseline hemoglobin level was shown to be an independent significant prognostic factor in radiotherapy of head and neck cancer patients. Therefore, the value of tumor anemia as a prognostic factor should be emphasized more.     

胸大肌肌皮瓣在晚期头颈肿瘤手术缺损重建中的应用

目的总结胸大肌肌皮瓣在晚期头颈肿瘤手术缺损重建中的应用。方法回顾性总结1988年1月1日-2003年12月31日14例在我科因头颈部肿瘤手术后巨大组织缺损应用胸大肌肌皮瓣进行修复的临床资料。结果肌皮瓣全部成活13例，1例肌皮瓣远端部分坏死，经换药后愈合。1例与受区组织伤口部分裂开，换药处理后愈合；1例胸部皮下积液，经穿刺抽液后消失。成活胸大肌肌皮瓣色泽良好，但多显有些臃肿。结论胸大肌肌皮瓣是一种非常实用而优良的修复材料。它具有丰富的组织量，优良的血液供应，且与头颈部邻近，在多种情况下可以应用，特别适用于头颈部肿瘤扩大切除术后缺损的即刻修复重建。     

Hyperfractionated-Accelerated Radiotherapy Followed by Radical Surgery in Locally Advanced Tumors of the Oral Cavity

PURPOSE: To evaluate the outcome of hyperfractionated-accelerated radiotherapy and subsequent planned primary tumor resection and radical neck dissection in locally advanced tumors of the oral cavity. PATIENTS AND METHODS: This retrospective analysis evaluates 126 subsequent patients who were treated between 1988 and 1997 for locally advanced tumors of the oral cavity (with extension into the oropharynx in 17 patients), 34 (27%) AJCC stage III and 92 (73%) stage IV. Primary tumor and nodal metastases were irradiated with 1.4 Gy bid to a median total dose of 72.8 Gy (range 58.8-75.6 Gy). Then, planned radical surgery of the primary site according to the initial tumor extent and cervical nodes was performed. Median follow-up of living patients was 6 years (range 1-11 years). RESULTS: 4 weeks after radiotherapy, 14 patients (11%) had complete tumor remission, 92 (73%) partial remission, 15 (12%) no change, and five (4%) progressive disease. Complete resection was achieved in 117 (93%) patients (nine incomplete resections). 5-year locoregional control rate was 62 +/- 9%, overall survival 36 +/- 9%. Surgery-related morbidity occurred in 42 patients (33%; mainly delayed wound healing and fistulae), overall severe treatment-related morbidity in 46 patients (36%). 24/84 relapse-free patients (29%) required a percutaneous gastrostomy or nasal tube > or = 1 year after therapy. CONCLUSION: In this study, the outcome of combined curative radiotherapy and planned surgery of the primary tumor and neck nodes was comparable to reported results of hyperfractionated radiotherapy with or without salvage surgery of the neck nodes with respect to locoregional control and overall survival. Planned surgery carries a substantial risk of morbidity and seems to offer no benefit in comparison to salvage surgery of the neck nodes only. Therefore, salvage surgery is preferred.     

Concurrent Radiochemotherapy with Vinorelbine plus Cisplatin or Carboplatin in Patients with Locally Advanced Non-Small-Cell Lung Cancer (NSCLC) and an Increased Risk of Treatment Complications

BACKGROUND: In elderly patients, patients with multiple morbidities, and patients with a reduced general condition, the standard treatment of inoperable non-small-cell lung cancer (NSCLC) consists of either chemotherapy or radiation therapy alone and is associated with an extremely poor prognosis. We therefore investigated the feasibility, toxicity, and efficacy of radiotherapy with concurrent chemotherapy using vinorelbine plus cisplatin or carboplatin in NSCLC patients at risk for treatment complications. PATIENTS AND METHODS: A total of 33 patients (six women, 27 men, median age 65 years) with locally advanced, functionally inoperable pulmonary carcinomas, recurrent lung cancer or postoperative macroscopic residual tumors (R2) with an increased risk of treatment complications (WHO performance status 2/3; cardiac, renal or pulmonary failure; marked pretherapeutic weight loss; age between 71-75 years) received 12.5 mg of vinorelbine per m(2) body surface area (BSA) on days 1, 8, 15, 29, 36 and 43 plus either cisplatin 20 mg/m(2) BSA (ten patients) or carboplatin 70 mg/m(2) BSA (23 patients) on days 1-5 and 29-33 together with conventionally fractionated radiotherapy. The tumor regions were irradiated with doses of up to 63 Gy (90% isodose), and potentially affected lymph nodes received doses of up to 45.0 or 50.4 Gy (90% isodose). RESULTS: Briefly, 31 of 33 patients successfully completed radiation therapy and 26 received four cycles of vinorelbine plus at least two cycles of cisplatin or carboplatin. Hematotoxic side effects included grade III leukocytopenia (n = 8), grade III thrombocytopenia (n = 5), and grade IV thrombocytopenia (n = 2). Other side effects consisted of peripheral neuropathy grade III (n = 1) and esophagitis grade IV (n = 1). Severe pneumonitis did not occur. Six patients had pneumonia before radiochemotherapy. 21 patients (63%) exhibited a complete (n = 7) or partial response (n = 14) to chemoradiation. The twelve nonresponders had either stable (n = 9) or progressive disease (n = 3). The survival rates plus standard deviations were as follows: 1-year survival: 60 +/- 8%, 2-year survival: 36 +/- 9%, 3-year survival: 24 +/- 9%, median survival time: 17 months (5;29 months; 95% confidence interval [CI]), median progression-free survival: 11 months (9;13 months; 95% CI). The median follow-up time was 14 months. CONCLUSION: Conventionally fractionated radiochemotherapy with vinorelbine plus a platinum derivative is feasible in patients with NSCLC and increased risk of treatment complications. Compared to patient populations described in the literature, the survival rates achieved by concurrent radiochemotherapy appear to be better than those achieved with radiotherapy alone.     

Radiotherapy and High-Dose Chemotherapy in Advanced Ewing's Tumors

Background: Ewing's tumors are sensitive to radio- and chemotherapy. Patients with multifocal disease suffer a poor prognosis. Patients presenting primary bone marrow involvement or bone metastases at diagnosis herald a 3-year disease-free survival below 15%. The European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) has established the following indications for high-dose therapy in advanced Ewing's tumors: Patients with primary multifocal bone disease, patients with early (<2 years after diagnosis) or multifocal relapse. Patients and Method: As of 1987, 83 patients have been treated in the EICESS group, 39 of them at the transplant center in Düsseldorf, who have been analyzed here. All individuals received 4 courses of induction chemotherapy with EVAJA and stem cello collection after course 3 and 4. Consolidation radiotherapy of the involved bone compartments was administered in a hyperfractionated regimen 2 times 1.6 Gy per day, up to 22.4 Gy simultaneously to course 5 and 22.4 Gy to course 6 of chemotherapy. The myeloablative chemotherapy consisted of melphalan and etaposide (ME) in combination with 12 Gy TBI (Hyper-ME) or Double-ME with whole lung irradiation up to 18 Gy (without TBI). Results: The survival probability at 40 months was 31% (44% DOD; 15% DOC). Pelvic infiltration did not reach prognostic relevance in this cohort. Radiotherapy encompassed 75% of the bone marrow at maximum (average 20%). Engraftment was not affected by radiotherapy. Conclusion: High-dose chemotherapy can improve outcome in poor prognostic advanced Ewing's tumors. The disease itself remains the main problem. The expected engraftment problems after intensive radiotherapy in large volumes of bone marrow can be overcome by stem cell reinfusion. Hintergrund: Ewing-Tumoren sind radio- und chemosensibel. Im metastasierten Stadium ist die Prognose schlecht. Patienten mit Knochen- oder Knochenmarkinfiltration haben nach drei Jahren eine erkrankungsfreie Überlebenswahrscheinlichkeit von weniger als 15%. Die EICESS-Gruppe hat folgende Indikationen für die Hochdosistherapie bei fortgeschrittenen Ewing-Tumoren etabliert: Patienten mit primären multifokalen Knochenmetastasen und Patienten mit einem frühen (<2 Jahren) oder multifokalen Rezidiv. Patienten und Methode: Seit 1987 wurden 83 Patienten in der EICESS-Gruppe behandelt, 39 von ihnen in Düsseldorf, deren Analyse hier vorgestellt werden soll. Alle Patienten erhielten vier Kurse einer Induktionschemotherapie mit EVAJA und nachfolgender Stammzellasservation. Anschließend erfolgte eine konsolidierende Bestrahlung aller befallenen Knochenkompartimente, hyperfraktioniert, 2mal 1,6 Gy pro Tag bis zu einer Zielvolumendosis von 22,4 Gy simultan zu Kurs 5 und 6 der Chemotherapie, entsprechend 44,8 Gy Gesamtdosis. Die myeloablative Therapie bestand aus Melphalan und Etoposid (ME) und 12 Gy TBI (Hyper-ME) oder bei zusätzlichem Lungenbefall aus zwei Kursen ME und Ganzlungenbestrahlung bis 18 Gy (Double-ME). Ergebnisse: Die Überlebenswahrscheinlichkeit nach 40 Monaten betrug 31% (44% starben am Tumor und 15% an Komplikationen). Beckentumoren hatten in dieser Gruppe keine prognostische Relevanz. Im Durchschnitt wurden 20% des Knochenmarkvolumens (maximal 75%) bestrahlt. Das Engraftment wurde durch die Bestrahlung nicht beeinflußt. Schlußfolgerung: Die Prognose bei multifokalen, fortgeschrittenen Ewing-Tumoren kann durch die Hochdosistherapie verbessert werden. Das Hauptproblem bleibt die Krankheit selbst. Die nach intensiver Strahlentherapie großer Knochenmarkvolumia erwarteten Engraftment-Probleme können durch Stammzellreinfusion überwunden werden.     

Radiotherapy and High-Dose Chemotherapy in Advanced Ewing's Tumors

BACKGROUND: Ewing's tumors are sensitive to radio- and chemotherapy. Patients with multifocal disease suffer a poor prognosis. Patients presenting primary bone marrow involvement or bone metastases at diagnosis herald a 3-year disease-free survival below 15%. The European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) has established the following indications for high-dose therapy in advanced Ewing's tumors: Patients with primary multifocal bone disease, patients with early (< 2 years after diagnosis) or multifocal relapse. PATIENTS AND METHOD: As of 1987, 83 patients have been treated in the EICESS group, 39 of them at the transplant center in Düsseldorf, who have been analyzed here. All individuals received 4 courses of induction chemotherapy with EVAJA and stem cell collection after course 3 and 4. Consolidation radiotherapy of the involved bone compartments was administered in a hyperfractionated regimen 2 times 1.6 Gy per day, up to 22.4 Gy simultaneously to course 5 and 22.4 Gy to course 6 of chemotherapy. The myeloablative chemotherapy consisted of melphalan and etoposide (ME) in combination with 12 Gy TBI (Hyper-ME) or Double-ME with whole lung irradiation up to 18 Gy (without TBI). RESULTS: The survival probability at 40 months was 31% (44% DOD; 15% DOC). Pelvic infiltration did not reach prognostic relevance in this cohort. Radiotherapy encompassed 75% of the bone marrow at maximum (average 20%). Engraftment was not affected by radiotherapy. CONCLUSION: High-dose chemotherapy can improve outcome in poor prognostic advanced Ewing's tumors. The disease itself remains the main problem. The expected engraftment problems after intensive radiotherapy in large volumes of bone marrow can be overcome by stem cell reinfusion.     

Randomized Phase III Trial of Postoperative Radiochemotherapy ± Amifostine in Head and Neck Cancer

PURPOSE: Experimental and clinical data suggest a reduction of radiation-induced acute toxicity by amifostine (A). We investigated this issue in a randomized trial comparing radiochemotherapy (RT + CT) versus radiochemotherapy plus amifostine (RC + CT + A) in patients with head and neck cancer. PATIENTS AND METHODS: 56 patients with oro-/hypopharynx or larynx cancer (T1-2 N1-2 G3, T3-4 N0-2 G1-3) were randomized to receive RC + CT alone or RC + CT + A. Patients were irradiated up to 60 Gy (R0) or 70 Gy (R1/2) and received chemotherapy (70 mg/m(2) carboplatin, day 1-5 in week 1 and 5 of radiotherapy). 250 mg amifostine were applied daily before each radiotherapy session. Acute toxicity was evaluated according to the Common Toxicity Criteria (CTC). As for acute xerostomia, patients with laryngeal cancer were excluded from evaluation. RESULTS: 50 patients were evaluable (25 patients in the RC + CT, 25 patients in the RC + CT + A group). Clinical characteristics were well balanced in both treatment groups. Amifostine provided reduction in acute xerostomia and mucositis but had no obvious influence on Karnofsky performance status, body weight, cutaneous side effects, and alopecia. The differences between both groups were statistically significant for acute xerostomia and nonsignificant, but with a trend for mucositis. CONCLUSIONS: According to our results, there is a radioprotective effect on salivary glands and a potential effect on oral mucosa by amifostine in postoperative radiotherapy combined with carboplatin. To improve the radio- and chemoprotective effects of amifostine in clinical practice, the application of a higher dose (> 250 mg) seems to be necessary.     

紫杉醇与替尼泊苷联合化疗治疗脑恶性胶质瘤

目的评价紫杉醇与替尼泊苷联合化疗方案对恶性脑神经胶质瘤的治疗效果和毒副作用,探讨有效的辅助化疗方案,以提高恶性脑神经胶质瘤的疗效,延长患者的生存期.方法不能手术、术后残留或复发的恶性脑神经胶质瘤患者,随机分为两组,试验组(21例):紫杉醇135 mg/m2,静脉滴注,第1天;替尼泊苷 200 mg/m2,分 3 d(d1-3),静脉滴注,3周可重复;对照组(19例):司莫司汀100 mg/m2,第1天 ,晚顿服;替尼泊苷用法同前,4～6周可重复.第1周期化疗后常规局部外放疗,肿瘤组织量 50～60 Gy.结果 40例患者有效28例,总有效率70.0%;其中大脑半球胶质瘤有效率65.5%(19/29), 脑干胶质瘤有效率88.9%(8/9),小脑胶质瘤有效率50%(1/2).经χ2检验,两种化疗方案有效率差异无显著性.主要毒性为骨髓抑制,特别是中性粒细胞减少;其中Ⅲ、Ⅳ度毒性反应5例,占12.5%;经对症处理均恢复正常.远期疗效正在观察中.结论紫杉醇与替尼泊苷联合化疗治疗恶性脑胶质瘤安全、有效,为脑瘤辅助化疗提供了新方案.