Controversies in the Management of Clinical Stage I Nonseminomatous Germ Cell Testicular Cancer

Overview

Surveillance after orchiectomy alone has become popular in the management of clinical stage Iof nonseminomatous germ cell testicular tumors (CSI NSGCTT). Efforts to identify patients at high-risk of relapse led to a search for risk factors in CSI NSGCTT. The aim of the current study was to analyze long‑term experiences with risk‑adapted therapeutic approaches (active surveil­lance and adjuvant chemotherapy). From 1/ 1992 to 2/ 2015, a total of 454 CSI NSGCTT patients were included in the study and stratified into two groups according to risk‑adapted therapeutic approaches. In Group A (low‑ risk CSI NSGCTT), which consisted of 287 patients who underwent surveillance, relapse occurred in 48 (16.7%) patients with a median follow‑up of 7.0 months. Six patients (2.1%) of this group died with a median follow‑up of 34.3 months. In Group B (high‑risk CSI NSGCTT), which consisted of 167 patients who were treated with adjuvant chemotherapy, relapse occurred in two (1.2%) patients with a median follow‑up of 56.2 months. One patient (0.6%) died 139.4 months following orchiectomy. Statistically significant difference in progression free survival between these two groups was found, but no significant difference in overall survival.

Key words:
testicular cancer –  surveillance –  adjuvant chemotherapy –  disease progression

Introduction

Testicular cancer is the most common cancer in males between 15 and 40 years. The introduction of cisplatin‑based combination chemotherapy has revolutionized the treatment of metastatic testicular cancer [1]. Owing to high success rate in the salvage of dis­seminated cancer, it has become reasonable to propose for managing clinical stage I of nonseminomatous germ cell testicular tumors (CSI NSGCTT) patients with orchiectomy alone followed by surveillance only [2]. Patients who relapse are treated with systemic chemotherapy, whereas those who do not relapse are spared unnecessary treatment.

Surveillance after orchiectomy alone has gained a lot of popularity in the man­agement of CSI NSGCTT. Preliminary results were enthusiastic [2– 4], but critical voices have been raised against general use of this option as routine management [5]. With longer observation, relapse rate has been found to increase up to 25% or more after orchiectomy [6,7]. Several studies [5,7– 9] identified statistically significant predictors of relapse in CSI NSGCTT patients who might therefore benefit from a program other than surveil­lance. Lymphovascular invasion (LVI) in the primary tumor was the most consistent prognostic feature identified. Predominantly embryonal carcinoma histology and T2– 4 stage were also frequently associated with rate of relapse. The results of our previous reports [6,10– 13] indicate that prognostic factors useful for stratification of CSI NSGCTT patients to different therapeutic approaches may be estab­lished. There have been identified risk factors which define a low-risk and a high-risk group of patients and have led to a risk‑adapted approach of treatment favoring surveillance for patients with low-risk and chemotherapy for patients with high-risk of relapse [14,15].

The aim of contemporary study was to correlate own long‑term experiences with active surveillance and adjuvant chemotherapy, resp. in CSI NSGCTT patients.

Material and methods

This cross‑ sectional longitudinal epidemiological study with prospective design was carried out in a single center which is focused on dia­gnosis and treatment of testicular cancer. The study began on January 31, 1992, by recruiting patients with newly dia­gnosed CSI NSGCTT from different regions of the Slovak Republic; last patient was included on August 31, 2014. The size of the total cohort, which consisted of all histological types of testicular tumors and was analyzed between 1993 and 2007, represented 92% of all cases registered at the National Cancer Registry SR, i.e. the sample was representative. It is not possible to correlate the size of the whole study group (years 1992– 2014) with the data from the NCR SR, due to insufficiency of published data from the NCR SR. However, we assumepersistence of representativeness. A total number of 454 newly dia­gnosed patients with CSI NSGCTT were followed until February 28,2015, and their results were analyzed. At the time of patients’ inclusion into the study, they were stratified according to selected risk factors (presence of LVI, majority of embryonal carcinoma components) for risk‑adapted therapeutic approaches (surveillance and adjuvant chemotherapy, respectively). Minimal follow‑up of these patients was six months.

The patients were assigned to their appropriate clinical stage on the basis of physical examination, CT of the chest, abdomen and pelvis, postorchiectomy serum levels of tumor markers –  alpha fetoprotein (AFP) and human chorionic gonadotropin (β‑ hCG). The criteria for inclusion into CSI were normal val­ues of all these examinations. Informed consent was obtained from all patients. Patients with choriocarcinoma component were not included in the study.

All performed dia­gnostic and therapeutical approaches were done accord­ing to actual guideline recommendations for patients with testicular cancer [14,15], without intervention by reason of clinical trials; results of examinations and outcome were consecutively recorded and evaluated.

Patients selection

Group A consisted of 287 patients with LVI negative CSI NSGCTT, who were man­aged by the rules of surveillance, which consisted of a regular follow‑up after orchiectomy with tumor markers (AFP, hCG) measurement and abdominal CT scans performed in 3- month‑ intervals in the first year, 6- month‑ intervals for the next 2– 5 years, and annually thereafter. Patients, who relapsed during follow‑up, were treated with platinum‑based combination chemotherapy –  BEP regimen (bleomycin 30 U IV on days 1, 8, and 15 plus etoposide 100 mg/ m² IV on days 1– 5 plus cisplatin 20 mg/ m² IV on days 1– 5; every 21days).

Group B consisted of 167 patients with CS I NSGCT with LVI and/ or > 50% embryonal cell carcinoma in the orchiectomy specimen, who received two cycles of adjuvant BEP chemotherapy.

Statistical analysis

The age‑ specific characteristics of all patients were analyzed by using descriptive statistics. Data analysis was car­ried out in an R project setting. Normality of data distribution of age at the time of dia­gnosis in each study group was tested by Kolmogorov‑ Smirnov test. Continuous variables were compared by independent sample t‑tests. Statistical significance of differences was tested according to the variables by Kruskal‑ Wallis test, chi‑ square test of independence and Wilcoxon test. Survival curves were generated using the Kaplan‑ Meier method, and they were compared by the Log Rank test. All statistical tests were two‑sided and statistical significance was set at p < 0.05.

Results

Group A

The mean age of 287 LVI negative CSI NSGCTT patients at the time of dia­gnosis was 30 (median 29.1 years, 25– 75% quantile was 24.4 and 34.2 years).

Relapse occurred in 48 (16.7%) patients after a mean follow‑up of 11.2 months(median 7.0 months, 25– 75% quantile was 5.15 and 12.5 months, range 2.1– 86.1 months). Thirty‑ five patients (72.9%) relapsed within the first year of fol­low‑up, 18 patients (37.5%) from them relapsed within six months after dia­gnosis.

Six patients (2.1%) from this group died after a mean follow‑up of 42.8 months(median 34.3 months, range 11.4 to 179.7 months). Progression‑free survival (PFS) was 83.3% with a median fol­low‑up of 113.9 months. Overall surviv­­al (OS) rate of CSI NSGCTT patients in group A was 281/ 287 (97.9%) with median follow‑up of 142 months (mean 148.1 months) following orchiectomy.

Group B

The mean age of 167 patients with LVI positive CSI NSGCTT was 31.2 (median 30.1 years, 25– 75% quantile was 24.7 and 35.9 years).

Relapse was recorded in two (1.2%) patients after a mean time of 56.2 months(42.2 and 49.4 months). One of them (0.6%) died 139.4 months after primary treatment. PFS was 98.8% with a median follow‑up of 134 months. OS rate of CSI NSGCTT patients in group B was 166/ 167 (99.4%) with median follow‑up of 135.7 months (mean 120.3 months).

Comparing these two groups of patients, statistically significant difference in proportion of patients without progression (83.3% vs. 98.8%) was found (p < 0.001) (Graph 1) with no significant difference in the median of progression free follow‑up. No significant difference in OS was recorded.

Discussion

Over the last 35 years, the distribution of stage in initial dia­gnosis of NSGCTT has changed, with more patients being dia­g-nosed at earlier stages. Approximately 30– 50% of patients with NSGCTT pres­ent with CSI disease [15,16].

The management of CSI NSGCTT fol­lowing orchiectomy is controversial and generates the most debate. Optionsinclude surveillance (with salvage treat-ment for relapse), adjuvant cisplatin‑based combination chemotherapy, or retroperitoneal lymph node dissection (RPLND). All options provide cure rates of approximately 99% [17]. In the USA, a standard postorchiectomy approach has been nerve‑ sparing RPLND, while mainly in Europe, primary surgical ap­proaches have fallen out of favor and nonsurgical approaches now predominate. Recent guidelines of the European Germ Cell Cancer Consensus Group (EGCCCG) [14] recommend active sur­veillance for low‑ risk CSI NSGCTT patients and adjuvant chemotherapy with two cycles of BEP for high‑risk CSI NSGCTT.

Since only 30% of patients relapse dur­ing surveillance, 70% of patients who are cured by orchiectomy alone could be unnecessary exposed to adjuvant treatment‑related toxicity. To reduce this overtreatment, the EAU 2009 guidelines [18] advise a ’risk‑adapted treatment approach’ recommending adjuvant treat­ment only for high‑risk cases. The EAU 2009 guidelines [18] propose two cycles of adjuvant BEP chemotherapy to those high‑risk patients with pT2N0M0 (LVI positive) or pT3- 4N0M0, while those low‑ risk cases (pT1N0M0, LVI negative) are recom­mended to undergo surveillance.

Given that all current strategies for CSI NSGCTT, when carried out well, lead to nearly uniform cure, diminishing treatment‑related morbidity has become the primary concern.

Few large European or USA series of non‑risk adapted treatment utilizing primary active surveillance for all patients with CSI NSGCTT irrespective to risk profile have been reported [19– 21]. There were 221/ 1, 139 (19%) relapses with median follow‑up of 62 months described in the recent Kollmansberger et al [19] study with median time to relapse 6.0 months. Canadian study [20] using non‑risk‑-adapted approach described two cohorts. In the initial cohort (1981– 1992), 53/157 (33.8%) relapsed compared with 51/214 (23.8%) in the recent cohort (1993– 2005). In our previous study [13], there were 52/ 145 (35.9%) relapses fol­lowing surveillance only with a median follow‑up of 6.5 months. Non‑ risk‑adapted surveillance provides excellent survival and reduces the overall treatment burden and potentially the longer‑term toxicities of treatment [20]. Nichols et al [21] argue that adjuvant chemotherapy results in unnecessary treatment for approximately 50% of these patients with increasing awareness of the long‑term risk for cardiovascular diseases and second malignancies attributable to platinum‑based chemotherapy. On the other hand, based on the historical literature, active surveillance of all patients with CSI NSGCTT, i.e. without risk stratification, will result in delayed treatment of relapse in up to 30% of patients, usually with multiple cycles of chemotherapy and surgical resection of residual masses [22].

The European current guidelines [14,15] recommend risk‑adapted ap­proach in CSI NSGCTT. The results of large prospective SWENOTECA study [23] showed LVI negative patients who chose surveillance relapse rate 39/ 228 (13.5%) at a median follow‑up of 5.0 years. In our pres­ent prospective study, we observed the relapse rate 48/ 287 (16.7%) at a median follow‑up of 7.0 months. Recent results of the SWENOTECA study [24] showed258 LVI positive patients (follow‑up 8.0 years) receiving one course of BEP 8 (3.2%) relapse with median time to relapse 1.1 years. Albers et al [25] reported results of the largest randomized trial (German Testicular Cancer Study Group) investigating adjuvant treatment strategies in CSI NSGCTT which showed2/ 174 (1.2%) relapses following one course of BEP chemotherapy. In our present cross‑ sectional longitudinal study, we observed LVI positive patients receiving two courses of BEP regimen 2/ 167 (1.2%) relapses at a median fol­low‑up of 56.2 months. Administration of adjuvant chemotherapy after orchiectomy on CSI NSGCTT nearly eliminates the risk of relapse. A pooled analysis of 13 studies involving 1,043 patients revealed a relapse rate of 1.6% with six patients (0.6%) dying of disease [26]. Given the two cycles of BEP, only 3% of patients relapsed; therefore, the risk reduction of relapse is 90%. According to EGCCCG in Europe, two cycles of BEP chemotherapy are considered the standard treatment option [14,27,28]. Considering very similar outcomes of active surveillance and adjuvant chemotherapy (OS), individual patient preferences should be a strong factor in management decision [29].

Conclusions

Our recent experience confirms that surveillance policy is recommended only in low‑ risk CSI NSGCTT patients (LVI negative). Patients at high risk of relapse (LVI positive) may be cured with adjuvant chemotherapy. Further studies with long‑term follow‑up are necessary, they will give answer for controversies between non‑risk‑adapted and risk‑adapted treatment approach in the future.

This publication is the result of the imple­mentation of project APVV-0016-11 supported by the Slovak Research and Development Agency.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Submitted: 4. 3. 2015

Accepted: 8. 3. 2015

prof. Dalibor Ondrus, MD, DSc.

1^st Department of Oncology

Comenius University Faculty of Medicine

St. Elisabeth Cancer Institute

Heydukova 10

812 50 Bratislava

Slovak Republic

e-mail: dalibor.ondrus@ousa.sk