The treatment of metastatic germ-cell testicular tumours with bleomycin, etoposide and cis-platin (BEP)

Between July 1979 and December 1981, 43 patients with metastatic germ-cell tumours (36 testicular non-seminomas and 7 testicular seminomas) were treated with 2-6 cycles of bleomycin, etoposide and cis-platin (BEP). Forty (93%) are alive, 37 (86%) with no evidence of disease. Of 36 men with testicular non-seminoma 30 (83.3%) are alive and disease-free at 8-38 months (median 17.0 months). In the latter group 25/28 (89.3%) who had had no prior irradiation are alive and disease-free. Fourteen non-seminoma patients had small volume metastases and 13 are in complete remission, as are 12/14 patients with bulky disease. All 7 patients with advanced seminoma are alive and disease-free. It is concluded that BEP is a well tolerated and effective first line treatment for patients with metastatic germ-cell tumours.     

Primary malignant mediastinal germ-cell tumors and the contribution of radiotherapy: a southeastern multi-institutional study

A retrospective review was performed by a multi-institutional study group to determine the contribution of radiotherapy to the management of primary malignant mediastinal germ-cell tumors. Twenty-seven patients diagnosed with a primary mediastinal germ-cell tumor between January 1965 and July 1985 form the basis of this study. Twenty-five of the 27 patients were male. Thirteen patients' tumors were diagnosed as seminoma and the remaining 14 patients' tumors had other germ-cell histologies. The single most important prognostic factor was histology, with a 5-year actuarial survival of 100% for the seminomas and only 8.8% for the remaining germ-cell varieties. If total surgical extirpation is not possible, biopsy may be adequate. Of the patients with seminoma, 11 of 12 had local control, and 3 of the 12 patients were treated with doses between 3,000 and 3,100 cGy. High doses for this variety of mediastinal germ-cell tumor might not be required. For the germ-cell tumors other than seminoma, no patient had local control with doses over the range of 3,000-4,750 cGy.     

Platinum-based chemotherapy of primary extragonadal germ cell tumours: the Hellenic Cooperative Oncology Group experience.

Extragonadal germ cell tumours (EGCT) are uncommon, most frequently arise in the mediastinum and retroperitoneum and have variable responses to platinum-based chemotherapy. A retrospective analysis was performed on 38 patients with EGCT treated with cisplatin-based (CDDP) or carboplatin-based (CBDCA) chemotherapy between 1984 and 1998. Twenty-four patients had nonseminomatous germ cell tumours (NSGCT) and 14 seminoma. Twenty-two tumours arose in the mediastinum (13 nonseminomas, 9 seminomas) and 16 in the retroperitoneum (11 NSGCT, 5 seminomas). Initial surgery included complete resection in 1 patient, biopsy in 27 patients and debulking surgery in 10 patients. Complete response rates with chemotherapy +/- surgery were as follows: mediastinum 14 of 21 (66.66%) patients (8 of 12-75% NSGCT, 6 of 9-66.66% seminomas) and retroperitoneum 14 of 16 (87.5%) patients (9 of 11-81.81% NSGCT, 5 of 5-100% seminomas). One patient who underwent complete resection of a mediastinal malignant teratoma combined, received PVB chemotherapy on an adjuvant basis and remains alive and disease-free. Three additional seminoma patients who achieved partial response after chemotherapy remain alive and disease-free following mediastinal radiotherapy. All 14 patients with extragonadal seminomas remain alive with no evidence of disease at a median follow-up of 49 months (range 7-164), giving an overall survival of 100%. Nine of 13 (69.23%) patients with mediastinal NSGCT are long-term disease-free at a median follow-up of 43.5 months (range 7-152). Nine of 11 (81.81%) patients with retroperitoneal NSGCT remain alive and disease-free at a median follow-up of 56 months (range 14-110). Complete surgical resection of residual mass was undertaken in 10 patients (3 seminomas, 7 nonseminomas). The histology revealed necrosis/fibrosis in 6 patients (3 seminomas, 3 NSGCT) and viable cancer in 4 patients. Patients who had viable malignant cells in the resected specimens received two more courses of VelP chemotherapy. None of our patients had relapsed at the time of this analysis. None of our 6 patients who underwent testicular biopsy (1 patient) or orchiectomy (5 patients) due to suspicious ultrasound of the testis were found to have testicular tumour or fibrotic scar. In conclusion, this retrospective analysis showed significant responses in patients with either mediastinal or retroperitoneal NSGCT treated with CDDP- or CBDCA-based chemotherapy +/- surgery. All patients with extragonadal seminomas remain alive with no evidence of disease, regardless of the site at presentation.     

Primary malignant mediastinal germ cell tumours: improved prognosis with platinum-based chemotherapy and surgery.

A retrospective analysis was performed of 18 patients with primary malignant germ cell tumours of the mediastinum treated with platinum-based chemotherapy between 1977 and 1990. All seven patients with pure seminoma were treated initially with chemotherapy and four of these patients received additional mediastinal radiotherapy. Only one patient relapsed; his initial therapy had included radiotherapy and single-agent carboplatin and he was successfully salvaged with combination chemotherapy. With a follow-up of 11 to 117 months (median 41 months) all seven patients with seminoma remain alive and disease free giving an overall survival of 100%. Eleven patients had malignant non seminoma; following chemotherapy eight of these had elective surgical resection of residual mediastinal masses. Complete remission was achieved in nine (82%) patients, however, one of these patients died from bleomycin pneumonitis. With a follow-up of 12 to 113 months (median 55 months) eight of 11 (73%) patients with malignant mediastinal teratoma remain alive and disease free.     

The results of chemotherapy for extragonadal germ-cell tumors in the cisplatin era: the Memorial Sloan-Kettering Cancer Center experience (1975 to 1982)

Thirty-eight patients with extragonadal germ-cell tumors treated at Memorial Sloan-Kettering Cancer Center (New York) between 1975 and 1982 received high-dose cisplatin-based chemotherapy. Complete response was achieved in 89% of patients with pure seminoma and all complete responders are alive without evidence of disease (median follow-up time, 29+ months). Complete response was achieved in only 41% (12 of 29) of patients with extragonadal nonseminomatous germ-cell tumors; only four patients are alive and free of disease (median survival time, 18 months). Although patients with extragonadal seminoma respond well with current cisplatin-based chemotherapy, minimal improvement in CR rates has been achieved in patients with extragonadal nonseminomatous tumors. Patients with extragonadal nonseminomatous germ-cell tumors have a relatively poor prognosis when compared to patients with primary testicular tumors and investigational trials of innovative therapy should be considered.     

Testicular seminoma: analysis of treatment results and failures

Pure testicular seminoma has historically been treated primarily with radiation therapy, and excellent results have been achieved. Recently, several aspects of the treatment of seminoma have been questioned; namely, the value of mediastinal irradiation in Stage II disease, and whether a dose response curve existed for seminoma. Because these questions have remained unanswered, we undertook a retrospective review of all patients with pure testicular seminoma treated in the Department of Radiation Oncology at Indiana University Medical Center. From 1961-1981, 54 patients with pure testicular seminoma were given megavoltage irradiation with curative intent. Thirty three patients were Stage I, with tumor confined to the testicle with no evidence of nodal spread. Fifteen patients were Stage IIA, with metastases less than 5 cm in size in the retroperitoneal nodes. Four patients were Stage IIB, with metastases greater than 5 cm in size in the retroperitoneal nodes. One patient was Stage III, with supradiaphragmatic metastases confined to the mediastinum and supraclavicular area. One patient was Stage IV, with evidence of extralymphatic metastases. The crude survival rate (corrected for intercurrent death, except for treatment toxicity) for the entire group was 87%. For Stage I, it was 91%, Stage IIA-80%, Stage IIB-75%, Stage III-100%, and Stage IV-0%. All patients had a minimum follow-up of 2 years with a range of 2 to 21 years. Evaluation of the Stage I patients reveals that 2500 rad in 3 weeks appears to be adequate in controlling microscopic disease, as there were no in-field recurrences when this dose was given. Those patients with Stage IIA and IIB disease who received greater than or equal to 3500 rad to macroscopic disease had 100% (7/7) survival and local control, while those receiving less than or equal to 3000 rad had a 66.6% (8/12) survival with three of four demonstrating persistent or recurrent abdominal disease. Thus, we feel that macroscopic disease requires 3500 rad to 4000 rad for control. All Stage II and III patients had planned mediastinal irradiation. No patients who received mediastinal irradiation recurred in the mediastinum. Whether this is because of our treatments or the natural disease process remains unanswered. Overall, we were able to salvage 12.5% (1/8) of our recurrences, while 37.5% (3/8) died from toxicity of their salvage therapy.(ABSTRACT TRUNCATED AT 400 WORDS)     

Multimodality treatment of malignant germ cell tumours of the mediastinum

Of 15 patients with malignant germ cell tumours of the mediastinum, 9 patients had pure seminomas and 6 had non-seminomas. Resection was radical in only 4 non-seminomas, 1 of which was resected after chemotherapy; radiotherapy was delivered to all seminoma patients as sole therapy (2 patients) or as part of combined modality therapy. All patients with non-seminomatous tumours underwent chemotherapy (cisplatin-based combination). Therapy was generally well tolerated, but 1 seminoma patient died of sepsis. Chemotherapy achieved a 71% complete response rate in pure seminoma patients and a 33% complete response rate in non-seminoma patients. 53% of patients are alive and free of disease beyond 36 months from start of any treatment. Pure seminoma patients survived longer than non-seminoma patients (3 and 5 year survivals were 67% and 33%, respectively). Although cisplatin-based chemotherapy is highly effective in pure seminomas and also in non-seminomas, a better therapeutic approach is needed in non-seminomas.     

Primary Mediastinal Germ Cell Tumors—The University of Western Ontario Experience

Extragonadal germ cell tumors account for 2–5.7% of germ cell tumors (GCTs). Of these, primary mediastinal GCTs (PMGCTs) are responsible for 16–36% of cases. Given the rarity of these tumors, specific treatment strategies have not been well defined. We report our experience in treating these complex patients. In total, 318 men treated at our institution with chemotherapy for GCTs between 1980 and 2016 were reviewed. PMGCT was defined as clinically diagnosed mediastinal GCT with no evidence of testicular GCT (physical exam/ultrasound). We identified nine patients diagnosed with PMGCT. All patients presented with an anterior mediastinal mass and no gonadal lesion; four patients also had metastatic disease. Median age at diagnosis was 30 years (range, 14–56) and median mass size at diagnosis was 9 cm (range, 3.4–19). Eight patients had non-seminoma and one had pure seminoma. All patients received cisplatin-based chemotherapy initially. Surgical resection was performed in four patients; three patients had a complete resection and one patient was found to have an unresectable tumor. At a median follow-up of 2 years (range, 3 months–28 years) six patients had progressed. Progression-free survival was short with a median of 4.1 months from diagnosis (range 1.5–122.2 months). Five patients died at a median of 4.4 months from diagnosis. One and 5-year overall survivals were 50% and 38%, respectively. PMGCT are rare and aggressive. Our real-life Canadian experience is consistent with current literature suggesting that non-seminoma PMGCT has a poor prognosis despite prompt cisplatin-based chemotherapy followed by aggressive thoracic surgery.     

Radiation therapy of testicular seminoma: a 15-year survey.

A retrospective review of 69 patients with testicular seminoma, stage I and II, treated by orchiectomy and adjuvant irradiation at McGill University Hospitals from 1972 to 1987 was performed. All patients underwent either lymphangiogram or computed axial tomography scan for evaluation of retroperitoneal disease. There were 52 stage I (75%), 13 stage IIA (11%), 2 stage IIB (3%), and 2 stage IIC (Royal Marsden Hospital staging criteria). Median follow-up time was 6.2 years. The 10-year actuarial survivals were 94% and 93% for stages I and II, respectively. Only two stage I patients failed treatment, and both died from metastatic disease. Interestingly, both developed biopsy-proven metastatic brain disease and had no evidence of intra-abdominal recurrence. In stage II disease, only one patient failed the treatment. There was no serious acute toxicity and no late complications have been encountered. Radiation therapy following orchiectomy is the treatment of choice for stage I and for most stage II patients with testicular seminoma. The controversial aspects of radiographic retroperitoneal staging, the use of prophylactic mediastinal irradiation for stage II patients, and the role of surveillance only for stage I patients are discussed.     

原发于纵隔和腹膜后的生殖细胞肿瘤37例临床报告

目的 探讨原发于纵隔和腹膜后的生殖细胞肿瘤的临床特点、治疗方法、疗效以及影响预后的因素。方法 回顾性分析37例原发于纵隔和腹膜后的生殖细胞肿瘤的临床资料，其中25例原发于纵隔，12例原发于腹膜后；精原细胞瘤13例，非精原细胞瘤24例。结果 原发于纵隔的精原细胞瘤、非精原细胞瘤和原发于腹膜后的精原细胞瘤、非精原细胞瘤的5年生存率分别为40％、34％、100％和67％；相应的5年无进展生存率分别为34％、32％、100％和67％。单因素分析显示，病理类型、原发部位和国际预后评分均为有显著意义的预后因素。结论 原发于纵隔和腹膜后的生殖细胞肿瘤是1组有潜在治愈可能的疾病。影响预后的因素主要包括肿瘤原发部位、病理类型及国际预后评分。     

Extragonadal seminoma: an international multicenter analysis of prognostic factors and long term treatment outcome

BACKGROUND: The objectives of this study were to evaluate the long term outcome of patients with extragonadal seminomatous germ cell tumors (GCT) so that prognostic variables for disease recurrence and patient survival could be identified and to access the efficacy of different treatment modalities. METHODS: Six hundred thirty-five patients with extragonadal GCT who were treated consecutively at 11 centers in the United States and Europe during the cisplatin-based chemotherapy era between 1975 and 1996 were evaluated retrospectively. RESULTS: Fifty-two patients with primary retroperitoneal GCT (50%) and 51 patients with primary mediastinal GCT (49%) of pure seminomatous histology were identified (n = 1 patient with a primary cervical lymph node) representing 16.4% of 635 patients with extragonadal GCT who were included in the data base. The median age was 37 years (range, 18-70 years). Treatment consisted of platin-based chemotherapy in 77 patients (74%), radiotherapy in 9 patients (9%), and combined modality in 18 patients (17%). Ninety-two percent of patients (95% confidence interval, 87-97%) achieved a favorable response to primary therapy. After a median follow-up of 61 months (range, 1-211 months), 18 patients (17%) have had recurrent disease: 14% of those who received chemotherapy and 67% of those who received radiation therapy. The 5-year progression free survival rate favored the chemotherapy group, with 87% compared with 33% for irradiated patients (P = 0.006), whereas the overall survival rates were equal (90% vs. 67%; P = 0.13). No differences in overall survival or progression free survival were observed among patients with primary retroperitoneal and mediastinal seminoma. Prognostic factors that were identified to influence survival negatively were liver metastases (P = 0.01) and two or more metastatic sites (P = 0.04). CONCLUSIONS: In patients with extragonadal seminoma, a survival rate of > 90% at 5 years is achieved with adequate cisplatin-based chemotherapy. Compared with patients with nonseminomatous extragonadal GCT, no difference in long term survival exists between patients with primary retroperitoneal or mediastinal seminoma location. Primary radiotherapy seems to be associated with a significantly higher rate of disease recurrence, although most patients will be salvaged by subsequent chemotherapy.     

Malignant testicular germ cell tumors in a father and two sons. Case report and literature review

The authors report the 17th case of primary malignant testicular tumors in father-son pairs, the 61st case occurring in male first-degree relatives, and the first case identified in a father and two sons. The father had bilateral seminomas at ages 31 and 44 years. His oldest son developed left testicular teratoma with elements of seminoma and embryonal carcinoma at age 29 years. The second son developed pure seminoma of the right testicle at age 26 years. The father had mumps orchitis at age 17 years. None of the three had a history of cryptorchism, trauma, or hernia. Literature reports of familial testicular neoplasia are becoming more frequent, and evidence is presented that family history may represent a risk factor independent of cryptorchism for the development of testicular cancer. Aggressive follow-up of closely-related male relatives is advocated.     

Chemotherapy of extragonadal germ cell tumors

Forty-nine patients with histologically proven germ cell tumors arising in extragonadal sites were retrospectively reviewed. Included in the review were an additional seven patients with undifferentiated tumors with a pathologic appearance compatible with that of a germ cell tumor and elevated levels of serum biomarkers (beta subunit of human chorionic gonadotropin [beta-HCG] +/- alpha-fetoprotein [AFP]. Nineteen patients had a pure seminoma arising in an extragonadal site, whereas 30 patients had nonseminomatous germ cell tumors. Seven patients had primary undifferentiated tumors with elevated levels of serum biomarkers. Sixteen (84%) of the 19 patients with pure extragonadal seminomas with normal levels of serum AFP are alive and free of disease. Eighteen of these 19 patients received platinum-containing regimens and four had received prior chemotherapy that failed. Of the patients with nonseminomatous germ cell tumors, 12 (40%) of the 30 are alive and free of disease with vinblastine/bleomycin +/- cisplatin (13 patients) or CISCAII (cisplatin, cyclophosphamide, and doxorubicin) (nine patients) alternating CISCAII/VBIV (eight patients) chemotherapy. None of the seven patients with undifferentiated germ cell tumors are alive and free of disease. Three of the five patients with pure anterior mediastinal endodermal sinus tumors treated with chemotherapy remain alive and free of disease. Of the seven patients with choriocarcinomas arising in extragonadal sites, three are alive and free of disease. A classification for patients with extragonadal germ cell tumors incorporating site of origin, histology, and likelihood of being truly extragonadal is proposed. The implications of this classification are discussed.     

The treatment of extragonadal seminoma

Primary extragonadal seminoma (EGS) is a rare tumor of young adults that often presents with bulky primary tumors and metastatic disease. Long-term survival is inadequate with conventional therapy consisting of radiotherapy with or without surgery. The charts of 21 patients with EGS treated initially either with conventional therapy (group I) or with multimodality therapy including initial chemotherapy with high doses of cisplatin followed by either radiotherapy or surgery or both (group II) were reviewed. Five of the ten patients in group I developed recurrent disease and four of them eventually died of disease. Only one of 11 patients in group II died of metastatic disease and the remaining patients are free of disease with 19+ to 46+ months of follow-up. Of the six patients from group II who underwent surgical resection of apparently residual disease after chemotherapy but prior to radiotherapy, five were found to have completely necrotic tumor and one had microscopic disease on histologic examination, proving the efficacy of chemotherapy. Combined modality therapy including initial chemotherapy containing high doses of cisplatin provided rapid reduction in tumor burden and the results appeared superior to treatment that did not include initial chemotherapy.     

Cisplatin, vincristine and ifosphamide combination chemotherapy of metastatic seminoma: results of EORTC trial 30874. EORTC GU Group.

The aims of the trial were to establish the response rate and determine the toxicity of combination chemotherapy with ifosphamide, vincristine and cisplatin (HOP regimen) in advanced metastatic seminoma and to study the role of post-chemotherapy consolidation treatment. Patients with bulky metastatic non-alpha-fetoprotein-producing seminomas were eligible for this phase II study [serum human chorionic gonadotropin < 200 U l-1 (< 40 ng l-1)] if they presented with abdominal masses > or = 10 cm or had extra-gonadal seminoma or had relapsed after previous radiotherapy. The HOP regimen consisted of four 3-weekly cycles of the following drug combination: ifosphamide (days 1-5, 1.2 mg m-2 day-1), vincristine (day 1, 2 mg) and cisplatin (days 1-5, 20 mg m-2 day-1). Residual masses persisting 6 months after chemotherapy could be considered for consolidation surgery or radiotherapy. Maximal response to the HOP chemotherapy (evaluated at any time) was based on the WHO criteria. The median observation time was 2.5 years (range 1.8-5.5 years). Thirteen institutions treated 42 eligible patients within the study (testicular cancer stage > or = IID, 25; extragonadal, 5; relapse after previous radiotherapy, 12). Two patients were not evaluable for response owing to premature treatment discontinuation. Maximal response was as follows: complete remission (CR), 26 (65%); partial remission (PR) 11 (28%); no change (NC), 2 (5%); progressive disease (PD), 1 (3%). Four patients have died, three from their malignancy (two without previous irradiation and one with prior radiotherapy). The fourth patient died of treatment-related toxicity. The 3 year survival for all 42 eligible patients was 90%. Dose reduction and treatment postponement were necessary in 25 and 14 patients respectively. Ten patients experienced granulocytic fever. Previously irradiated patients tolerated chemotherapy as well as non-irradiated patients. Immediately after HOP chemotherapy a mass persisted in 16 of 17 patients with retroperitoneal masses of > or = 100 mm at presentation. Three of these residual lesions were resected within the following 6 months showing complete necrosis. Four lesions dissolved spontaneously during the first year of follow-up. Nine lesions persisted for > or = 1 year (one after consolidation radiotherapy) without leading to relapse. Four of seven patients with mediastinal lesions achieved CR and three a PR after HOP chemotherapy. The HOP chemotherapy regimen is highly effective in patients with advanced metastatic seminoma or those relapsing after previous radiotherapy, but is associated with a high risk of toxicity, in particular myelotoxicity.     

纵隔生殖细胞瘤临床分析

目的:分析生殖器外纵隔生殖细胞瘤诊断和影响预后的因素。方法:65例纵隔生殖细胞瘤均行开胸手术治疗。单纯完全摘除肿瘤59例;姑息性切除1例;肿瘤摘除联合肺叶切除或胸膜纤维板剥脱术3例;开胸探查2例。恶性生殖细胞瘤术后均行辅助放、化疗。结果:良性畸胎类肿瘤手术摘除或合并肺、胸膜切除后效果良好。恶性生殖细胞瘤,尤其是精原细胞瘤切除后,辅助放、化疗仍可获得较好的远期生存。3年生存率66.7%。结论:纵隔生殖细胞瘤是常见的纵隔肿瘤,诊断后积极手术治疗可获得较好的结果。     

Combination cisplatin, vinblastine, and bleomycin chemotherapy (PVB) for malignant germ-cell tumors of the ovary

Nine women with germ-cell tumors of the ovary (three endodermal sinus tumors, four immature teratomas, and two mixed germ-cell tumors) were treated with cisplatin, vinblastine, and bleomycin (PVB) chemotherapy after cytoreductive operations. Five patients were stage I, three were stage III, and one patient had recurrent disease. All nine women are alive and without evidence of disease with a median follow-up of 31 months from diagnosis and 27 months since completion of PVB. Treatment toxicity although occasionally severe was rapidly reversible.     

Occurrence of malignant non-germ cell components in primary mediastinal germ cell tumours.

METHODS: Thirty-five patients with primary mediastinal germ cell tumours (PMGCT) underwent primary thoracotomy in a 30-year period (1965-1994). Of the 35 patients, 12 had benign teratomas, five pure seminomas and 18 non-seminomatous germ cell tumours. RESULTS: Out of 18 non-seminomatous germ cell tumours, 14 comprised more than one malignant component. In two cases malignant teratomas had an additional malignant non-germ cell component: one a mixed sarcomatous component and the other a neuroendocrinal component. There were different methods of treatment between 1965 and 1994. All but one of patients with seminomas survived for 5 years. Among 18 patients with malignant PMGCT, all but two died within 5 years (mean survival rate was 15 months). CONCLUSIONS: When planning treatment of patients with malignant PMGCT we have to take into account the fact that malignant non-germ-cell components may occur. In this circumstances, surgical resection after initial chemotherapy is recommended.     

Primary malignant mediastinal germ cell tumors: a study of eleven cases and a review of the literature

From 1957 to 1988 eleven cases of primary mediastinal germ cell tumor were referred to the Peter MacCallum Cancer Institute (PMCI). Four were seminomas, three were mixed germ cell tumors, two were embryonal carcinomas and two were teratocarcinomas. Two of the eleven patients were female. For seminoma, surgical debulking and post-operative irradiation produced the best results. Mediastinal doses ranged from 30 to 37.5 Gy. Local control was achieved in all cases; two patients survive disease-free. The non-seminomatous germ cell tumors showed a significantly poorer survival with only one of seven patients remaining alive in remission at 15 months. One other case of non-seminomatous tumor remains alive but in relapse at 23 months. Attention is focused on the anterior position of primary germ cell tumors in the mediastinum. A review of the literature is presented.     

Successful chemotherapy for mediastinal seminoma--a case report

A case with large primary mediastinal seminoma responded very well to chemotherapy. A 13-year-old boy was evaluated for complaints of edematous face and neck. Chest radiography and computerized tomography revealed a large anterior superior mediastinal mass. Needle biopsy demonstrated seminoma. After two-drug combination chemotherapy with vincristine and prednisolone and three-drug combination with vincristine, prednisolone and cyclophosphamide, there was a considerable regression of the mediastinal mass. The lower neck and mediastinum were irradiated at a dose of 3,750 rad after cessation of chemotherapy. The patient has been asymptomatic without evidence of recurrence for a follow-up period of more than four years.