Stage I nonseminomatous germ cell tumor management: a comparative analysis.

Size: px

Start display at page:

Download "Stage I nonseminomatous germ cell tumor management: a comparative analysis."

Jonah O’Connor’
5 years ago
Views:

1 ORIGINAL ARTICLE Stage I nonseminomatous germ cell tumor management: a comparative analysis. Hernández-Castellanos V, Camarena-Reynoso HR, Vázquez-Ortega L, Mata MP, Leos-Acosta C, Morales-Montor JG, Pacheco-Gahbler C, Calderón-Ferro F. ABSTRACT RESUMEN Objective: To evaluate stage I nonseminomatous tumor progression in patients in relation to treatment. Materials and methods: An analytical cross-sectional study was carried out. Case records of patients diagnosed with testicular neoplasia who were treated in the authors institution between January 1989 and October 2008 were reviewed. Multiple variables were analyzed using descriptive statistics and measures of central tendency and dispersion. Disease-free period was analyzed using Kaplan-Meier curves and logrank test. Multivariate Cox analysis and chi-square test were used for categorical recurrence analysis. Results: A total of 189 patients with germ cell tumors were identified, 104 of whom (55%) presented with nonseminomatous tumors. Fifty of those patients (48%) were in stage I, 19 (38%) in stage IA, 15 (30%) in stage IB and 16 (32%) in stage in situ. Disease-free period tended to be lower in stage IB patients (45% of patients at 5 years; P= 0.10). In relation to risk factors, there was recurrence in patients with a tumor volume percentage of embryonal cell carcinoma >50% (P = 1) and 13% of patients were disease-free at 5 years (P = 01). There was recurrence in 84% of patients with lymphovascular invasion (P = 5) and 51% of patients were disease-free at 5 years Objetivo: Valorar la evolución de los pacientes con tumores no seminomatosos en estadio I de acuerdo con el tratamiento. Material y métodos: Se realizó un estudio transversal analítico. Se revisaron los expedientes de los pacientes con diagnóstico de neoplasia testicular tratados en la institución de los autores entre enero de 1989 y octubre de Se analizaron múltiples variables mediante estadística descriptiva, medidas de tendencia central y dispersión. El análisis del periodo libre de enfermedad se determinó con curvas de Kaplan-Meier y log rank. Para el análisis categórico de recurrencia se utilizó la X2 y el multivariado de Cox. Resultados: Se identificó a 189 pacientes con tumores germinales, de los cuales 104 (55%) se refirieron como no seminomatosos. De éstos, 50 (48%) se encontraron en estadio I, 19 (38%) en estadio Ia, 15 (30%) en estadio Ib y 16 (32%) en estadio Is. Se reconoció una tendencia en cuanto al periodo libre de enfermedad: fue menor para el estadio Ib (45%) a cinco años (p = 0.10). En cuanto a los factores de riesgo considerados se observó una recurrencia con carcinoembrionario > 50% (p = 1), con un periodo libre de enfermedad de 13% a cinco años (p = 01). Para la invasión linfovascular la recurrencia fue de 84% (p = 5), con un periodo libre de enfermedad de 51% a cinco años Urology and Research Divisions. Corresponding author: Dr. Víctor Hernández Castellanos. Hospital General Dr. Manuel Gea González, Secretaría de Salud. Calzada de Tlalpan Col Sección XVI. Delegación Tlalpan C.P , México, D. F. Telephone: Cell phone: vahcmed@yahoo.com 200

2 (P = 0.01). Twenty-eight percent of patients with immature teratoma were disease-free at 5 years (P = 0.04). Regarding treatment, there was recurrence in 29.01% of patients treated with surveillance vs. 12.5% of patients receiving chemotherapy (P = 0.17). Disease-free period was not statistically significant (65% for patients treated with surveillance vs 90% for patients receiving chemotherapy at 5 years; P = 0.29). Conclusions: Recurrence in patients treated with surveillance was not statistically significant (P = 0.17) with a disease-free period at 5 years in only 65% of patients. The risk factors of embryonal cell carcinoma >50% and lymphovascular invasion were statistically significant for predicting recurrence, whether together or as independent factors. Key words: germ cell tumors, nonseminomatous tumors, stage I, Mexico. (p = 0.01). De manera independiente, el teratoma inmaduro presenta un periodo libre de enfermedad de 28% a cinco años (p = 0.04). Respecto del tratamiento, la recurrencia para los pacientes en vigilancia fue de 29.01% vs 12.5% de la quimioterapia (p = 0.17), con tendencia significativa en cuanto al periodo libre de enfermedad (65% vs 90% a cinco años; p = 0.29). Conclusiones: Los pacientes sometidos a vigilancia muestran una tendencia estadística a recurrir (p = 0.17), con un periodo libre de enfermedad a cinco años de sólo 65%. Asimismo, se demostró que los factores de riesgo como el carcinoembrionario > 50% y la invasión linfovascular fueron estadísticamente significativos para predecir recurrencia, juntos o como factores independientes. Palabras clave: tumores germinales, tumores no seminomatosos, estadio I, México. INTRODUCTION Testicular cancer represents 1% of all neoplasms in men. However, it is the most common malignant neoplasm in men from 15 to 45 years of age. 1 It represents 1-1.5% of neoplasms in men of this age range and 5% of urologic tumors. In Mexico in 2000 the Histopathologic Register of Malignant Neoplasms reported 917 cases, representing 1.9 cases per 100,000 inhabitants and 1% of all cancers reported. In the year age group it was the most common cancer, representing 2.9 cases per 100,000 inhabitants. 2-4 Over a period of 10 years ( ) the hospital register of the Instituto Nacional de Cancerología reported 748 cases, making it the most common genital neoplasm in men treated at that facility. 5 Testicular cancer treatment is based on clinical stage. Current classification is based on the 2002 TNM staging system of the International Union Against Cancer (IUAC). 6 Tumors are also classified according to the International Germ Cell Cancer Collaborative Group (IGCCCG) which evaluates clinical stage and prognosis by means of histological origin, primary tumor localization, metastases localization and tumor markers. 7 According to the European Cancer Register, 90% of patients present with early stage disease (TNM stages I-IIB). The majority of testicular cancer patients (61-78%) are diagnosed with clinical stage I cancer confined to the testis with marker normalization after orchiectomy. 8,9 Remission is expected in 100% of patients with clinical stage I disease. 10,11 Nonseminomatous germ cell tumors (NSGCT) can be divided into tumors with a seminomatous component, embryonal cell carcinoma (pure in 3 4% and present in 40% of NSGCT), teratoma (5 10%), choriocarcinoma (1%) and mixed tumors (60%). 12,13 Surveillance after orchiectomy with stage I NSGCT has shown a 28% recurrence rate and a recurrence-free period with a 4-13 month range. About 60% of recurrences are found in the retroperitoneum, 25% are found in the lungs and 10% show only elevated markers. 14 The most important aspect of adjuvant treatment in relation to stage I NSGCT patients is adapting the treatment to the 28% of patients with occult metastatic disease. 14 In surveillance treatment without previous risk factor evaluation, a third of patients end up receiving recurrence treatment with multiple cycles of chemotherapy as well as residual mass resection. Adjuvant chemotherapy in stage I NSGCT with no risk factor evaluation represents overtreatment in 70% of patients, underlying the importance of this evaluation in identifying patients at high risk of occult metastatic disease. 14 The Medical Research Council has carried out studies to identify recurrence risk factors in stage I NSGCT patients, demonstrating 4 recurrence prognostic factors: vascular invasion, lymphatic invasion, the presence of embryonal cell carcinoma 201

3 and the absence of yolk-sac tumor. Prospective studies based on these factors have shown that the presence of 3 out of 4 factors is recurrence predictive in 48% of patients. 14,15 Vascular invasion was the predominant and most important finding. In multivariate studies 3 factors have been identified: vascular invasion, proliferation rate through immunostaining with MIB-1 (>70% of tumor cells) and percentage of embryonal cell carcinoma (>50% as a component of primary tumor). The combination of these three factors was predictive of occult metastasis in 64% of cases. In contrast, patients with no vascular invasion and low MIB proliferation rate (<70%) have only a 13% probability of developing metastasis. Based on these prognostic combinations therapeutic strategies have been adapted according to risk group, reporting recurrence rates of 0% in high risk groups treated with chemotherapy. Studies carried out at the M.D. Anderson Cancer Center and the Toulouse Cancéropole concluded that in order to define a group as high risk there must be at least a combination of vascular invasion with embryonal cell carcinoma Recurrence rate in patients treated with surveillance who present with lymphatic or vascular invasion is 48% and is 14-22% in patients with no lymphatic or vascular invasion; these are the most important prognostic factors. Proliferation rate and embryonal cell carcinoma percentage are also prognostic factors but they are not independent ones. They become relevant when combined with lymphatic or vascular invasion. 26 Immunohistochemical MIB-1 was a promissory predictive factor. Embryonal cell carcinoma in the primary tumor and advanced pathological stages had intermediate effects. Up until now, models have included vascular invasion and embryonal cell carcinoma and one or two weaker factors. None of the publications on risk-adapted treatments have evaluated MIB In short, risk factors have been identified in order to define high and low risk groups with a recurrence rate of 64% and 13%, respectively. This has led to the riskrelated treatment regimens of surveillance for low risk patients and chemotherapy for high risk patients. OBJECTIVE The objective of the present study was to compare disease progression of patients with stage I nonseminomatous testicular tumor managed with chemotherapy vs. those managed with surveillance. MATERIALS AND METHODS An analytical cross-sectional study was carried out. The case records of patients diagnosed with testicular neoplasia and treated at the Dr. Manuel Gea González General Hospital from January 1989 to October 2008 were reviewed. Patients with histologically corroborated 2002 TNM classified stage I nonseminomatous germ cell tumor whose case records and follow-up care were complete were included in the study. Patients with other neoplasms or incomplete case records and follow-up care were excluded. Stage was determined in the hospital by means of histopathological findings, chest X-ray, post-orchiectomy tumor markers and abdominopelvic tomography. All study patients had undergone orchiectomy. For patients receiving chemotherapy, 2 cycles of bleomycin, etoposide and cisplatin (BEP) were administered in the medical oncology service. All follow-up protocol was carried out at the hospital urology service. Routine checkups consisted of physical examination, chest X-ray and tumor markers. The first year, patients were checked every month and had a computed axial tomography (CAT) scan every 3 months. The second year, check-ups were every two months and CAT scan every 4 months. The third year, check-ups were every three months and CAT scan every 6 months. The fourth and fifth year, check-ups and CAT scan were every six months and in the following years check-ups and CAT scan were annual. The following variables were analyzed: age, affected testis, TNM stage, lymphovascular invasion, embryonal cell carcinoma percentage, endodermal sinus tumor (EST), histological origin, prognostic group (IGCCCG), treatment and follow-up time. Variables were all correlated with recurrence and disease-free period. Disease-free period was defined as the interval from the date of orchiectomy to documented disease recurrence (event). Statistical analysis was done with descriptive statistics and measures of central tendency and dispersion. Disease-free period analysis was determined by means of Kaplan-Meier curves and logrank test. Categorical recurrence analysis was done by chi-square test and multivariate Cox analysis. Results were considered significant when p Type I error rate was controlled at 5%. Windows Stata/SE Version 9.1, Stata Corp LP software package was used for statistical calculations. RESULTS From a total of 319 patients diagnosed with testicular neoplasia, 196 had complete case records and followup care. Of those 196 patients, 189 presented with germ cell tumors. Only 104 (55%) of germ cell tumor patients had nonseminomatous tumors, 50 (48%) of which presented with stage I tumors. Those 50 patients made up the final sample: 19 of them (38%) had stage IA tumors, 15 (30%) had stage IB and 16 (32%) had stage 202

4 Kaplan-Meier Disease-free period by stage Ia Is Kaplan-Meier Disease-free period for embryonal cell carcinoma Embryonal cell carcinoma < 50 %. Ib Embryonal cell carcinoma >50%. Ia Is Ib Embryonal cell Ca < 50% Embryonal cell Ca > 50% Image 1. Curve for disease-free period by stage unrelated to treatment group. Image 2. Curve for disease-free period in patients with embryonal cell carcinoma percentage > or < 50%. in situ. Mean age at the time of diagnosis was 25 years. The right testis was affected in 17 patients (34%), the left testis was affected in 32 (64%) and 1 patient (2%) had bilateral affectation. All patients were classified in the IGCCCG low risk prognostic group. Histologically there were 13 (26%) mixed tumors with a seminomatous component, 11 (22%) choriocarcinomas, 23 (43%) embryonal cell carcinomas, 10 (20%) EST and 33 (66%) teratomas. Of the teratomas 19 (57%) were mature, 10 (30%) were immature and 4 (12%) were mixed. Fifteen (30%) tumors had more than one histological origin. Upon recurrence risk factor evaluation 24 patients (48%) presented with vascular invasion, 10 (20%) presented with embryonal cell carcinoma > 50% and 10 (20%) presented with protective factor EST. In relation to treatment, 16 patients (32%) received chemotherapy while 34 (68%) were treated with surveillance. Recurrence presented in 12 patients (24%) in a mean time of 13.5 months. Mortality was 4% with the death of 2 patients. Disease-free period was lower for stage IB patients (45% of patients at 5 years, P =0.10). (Image 1). Recurrence in relation to risk factors in patients with embryonal cell carcinoma >50% presented in 60% of patients (P =1) with a disease-free period in 13% of patients at 5 years (P =01). Recurrence in patients with lymphovascular invasion presented in 84% of patients (P =5) with disease-free period in 51% at 5 years (P =0.01). In relation to histological origin there was statistical difference in the case of teratoma; 28% of immature teratoma patients were disease-free at 5 years (P =0.04) (Images 2, 3 and 4). There was no statistical difference for disease-free period in patients with EST, choriocarcinoma or tumor with or without seminoma. In relation to treatment, recurrence presented in 29.01% of patients treated with surveillance compared with 12.5% of patients receiving chemotherapy (P = 0.17). Sixty-five percent of patients treated with surveillance were disease-free at 5 years compared with 90% of patients receiving chemotherapy (P=0.29) (Image 5). Multivariate Cox analysis showed relative risk for recurrence of 1.7 (95% CI, ) (P= 0.76) in patients with lymphovascular invasion and of 1.7 (95% CI, ) (P= 0.08) for patients with embryonal cell carcinoma > 50%. DISCUSSION Management for stage 1 nonseminomatous germ cell tumor after radical orchiectomy may be surveillance, chemotherapy or even lymphadenectomy. Given the possible 28% recurrence rate reported in the international literature 14 and the 24% reported at the authors institution, recurrence risk factors that modify treatment and indicate early chemotherapy for high risk patients were studied. The present study showed IB to be the stage with higher disease recurrence due to the fact that many patients were treated with surveillance despite having presented with lymphovascular invasion, unlike the stage in situ patients who received chemotherapy. Study data described recurrence in patients treated with surveillance as P =0.17 with a disease-free period at 5 years of only 65%. Study results also showed that risk factors such as embryonal cell carcinoma >50% and lymphovascular invasion were statistically significant for predicting recurrence, both together and as independent 203

5 Kaplan-Meier Disease-free period for lymphovascular invasion No invasion Invasion factors. Proliferation rate mentioned in the bibliography was not evaluated because the authors institution is not equipped for carrying out immunohistochemistry and it has not been shown to be an important predictor. The absence of endodermal sinus tumor in patients at this institution did not influence recurrence prediction. Although immature teratoma was not considered to be a risk factor, it showed statistically significant difference in the present study in relation to other tumor variants. No invasion Invasion Image 3. Curve for disease-free period for patients with or without vascular invasion. CONCLUSIONS Surveillance is not recommended for patients with stage I embryonal cell carcinoma >50% and/or lymphovascular invasion and retroperitoneal lymphadenectomy is recommended in patients with immature teratoma. It is important to carry out these same protocols in different centers on a national level so that management guides can be established. Kaplan-Meier Disease-free period for teratoma Mature teratoma BIBLIOGRAPHY Immature teratoma Immadure Mature Image 4. Curve for disease-free period for patients with mature or immature teratoma. Kaplan-Meier Disease-free period by treatment group. Surveillance Chemotherapy Surveillance Chemotherapy Image 5. Curve for disease-free period in relation to treatment group. 1. Brown LM, Pottern LM, Hoover RN, Devesa SS, et al. Testicular cancer in the United States: trends in incidence and mortality. Int J Epidemiol 1986; 15: Registro Histopatológico de Neoplasias Malignas de México Registro Histopatológico de Neoplasias Malignas de México Viveros Contreras. Cáncer de testículo. Rev Med Hosp Gen Mex 1998; 65:1. 5. Mohar A. Epidemiología descriptiva de cáncer en el Instituto Nacional de Cancerología de México. Salud Pública de México 39: Sobin LH, Wittekind Ch, editors. UICC: TNM classification of malignant tumors. 6th ed. Wiley-Liss, International Germ Cell Cancer Collaborative Group. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997; 15: Powles TB, Bhardwa J, Shamash J, Mandalia S, Oliver T. The changing presentation of germ cell tumours of the testis between 1983 and BJU Int 2005; 25: Sonneveld DJ, Hoekstra HJ, van der Graaf WT, Sluiter WJ, Schraffordt Koops H, Sleijfer DT. The changing distribution of stage in nonseminomatous testicular germ cell tumours from 1997 to BJU Int 1999; 84: Schmoll HJ, Souchon R, Krege S, et al. European Germ Cell Cancer Consensus Group. European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: Albers P, Albrecht W, Algaba F, et al. Guidelines on testicular cancer. Eur Urol 2005; 48: National Comprehensive Cancer Network clinical practice guidelines in oncology testicular cancer, Richie JP. Neoplasms of the testis. In: Walsh PC, et al. Camepbells urology. 9th ed. Philadelphia: WB Saunder Elsevier Abers P. Management of stage I testis cancer. Eur Urol : Read G, Stenning SP, Cullen MH, et al. Medical Research Council prospective study of surveillance for stage I testicular teratoma. Medical Research Council Testicular Tumors Working Party. J Clin Oncol 1992;10: Albers P, Siener R, Krege S, et al. One course of adjuvant PEB chemotherapy versus retroperitoneal lymph node dissection in patients with stage I non-seminomatous germ-cell tumors (NSGCT): results of the German Prospective Multicenter Trial (Association of Urological Oncology [AUO]/German Testicular Cancer. J Clin Oncol 2006 ASCO Annual Meeting Proceedings part I 2006; 24(18): Pont J, Albrecht W, Postner G, Sellner F, Angel K, Holtl W. Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long-term results of a prospective trial. J Clin Oncol 1996; 14:

6 18. Cullen MH, Stenning SP, Parkinson MC, et al. Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report. J Clin Oncol 1996; 14: Klepp O, Dahl O, Flodgren P, et al. Risk-adapted treatment of clinical stage 1 non-seminoma testis cancer. Eur J Cancer 1997; 33: Ondrus D, Matoska J, Belan V, Kausitz J, Goncalves F, Hornak M. Prognostic factors in clinical stage I nonseminomatous germ cell testicular tumors: rationale for different risk-adapted treatment. Eur Urol 1998; 33: Böhlen D, Burkhard FC, Mills R, Sonntag RW, Studer UE. Fertility and sexual function following orchiectomy and 2 cycles of chemotherapy for stage I high risk nonseminomatous germ cell cancer. J Urol 2001; 165: Maroto P, Garcia del Muro X, Aparicio J, et al. Multicentre risk-adaptedmanagement for stage I non-seminomtous germ cell tumours. Ann Oncol 2005; 16: Vergouwe Y, Steyerberg EW, Eijkemans MJ, Albers P, Habbema JD. Predictors of occult metastasis in clinical stage I nonseminoma: a systematic review. J Clin Oncol 2003;21: Amato RJ, Ro JY, Ayala AG, Swanson DA. Risk-adapted treatment for patients with clinical stage I nonseminomatous germ cell tumor of the testis. Urology 2004;63: Chevreau C, Mazerolles C, Soulié M, et al. Long-term efficacy of two cycles of BEP regimen in high-risk stage I nonseminomatous testicular germ cell tumors with embryonal carcinoma and/or vascular invasion. Eur Urol 2004;46: Susanne Frege, Jorg Bayer, et al. Review Testis Cancer. European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer (EGCCCG): Part I. Eur Urol 2008; 53: Vergouwe Y. Predictors of occult metastasis in clinical stage I nonseminoma: a systematic review. J Clin Oncol 2003; 21(22):

Received February 1, 2007

Received February 1, 2007 NEOPLASMA 54, 5, 2007 437 Nonseminomatous germ cell testicular tumors clinical stage I: differentiated therapeutic approach in comparison with therapeutic approach using surveillance strategy only D. ONDRUS