Non Risk-Adapted Surveillance in Clinical Stage I Nonseminomatous Germ Cell Tumors: The Princess Margaret Hospital s Experience

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1 EUROPEAN UROLOGY 59 (2011) available at journal homepage: Platinum Priority Testis Cancer Editorial by Arthur I. Sagalowsky on pp of this issue Non Risk-Adapted Surveillance in Clinical Stage I Nonseminomatous Germ Cell Tumors: The Princess Margaret Hospital s Experience Jeremy F. Sturgeon, Malcolm J. Moore, David M. Kakiashvili, Ignacio Duran, Lynn C. Anson-Cartwright, Dominik R. Berthold, Padraig R. Warde, Mary K. Gospodarowicz, Ruth E. Alison, Justin Liu, Clement Ma, Greg R. Pond, Michael A. Jewett * Departments of Medical, Surgical, and Radiation Oncology, Princess Margaret Hospital, University Health Network and Department of Surgery (Urology), University of Toronto, Toronto, Ontario, Canada Article info Article history: Accepted December 10, 2010 Published online ahead of print on December 22, 2010 Keywords: Non risk adapted Nonseminomatous germ cell tumors Stage I surveillance Abstract Background: Since 1981 Princess Margaret Hospital has used initial active surveillance (AS) with delayed treatment at relapse as the preferred management for all patients with clinical stage I nonseminomatous germ cell tumors (NSGCT). Objective: Our aim was to report our overall AS experience and compare outcomes over different periods using this non risk-adapted approach. Design, setting, and participants: Three hundred and seventy-one patients with stage I NSGCT were managed by AS from 1981 to For analysis by time period, patients were divided into two cohorts by diagnosis date: initial cohort, (n = 157), and recent cohort, (n = 214). Intervention: Patients were followed at regular intervals, and treatment was only given for relapse. Measurements: Recurrence rates, time to relapse, risk factors for recurrence, diseasespecific survival, and overall survival were determined. Results and limitations: With a median follow-up of 6.3 yr, 104 patients (28%) relapsed: 53 of 157 (33.8%) in the initial group and 51 of 214 (23.8%) in the recent group. Median time to relapse was 7 mo. Lymphovascular invasion ( p < ) and pure embryonal carcinoma ( p = 0.02) were independent predictors of recurrence; 125 patients (33.7%) were designated as high risk based on the presence of one or both factors. In the initial cohort, 66 of 157 patients (42.0%) were high risk and 36 of 66 patients (54.5%) relapsed versus 17 of 91 low-risk patients (18.7%) ( p < ). In the recent cohort, 59 of 214 patients (27.6%) were high risk and 29 of 59 had a recurrence (49.2%) versus 22 of 155 low-risk patients (14.2%) ( p < ). Three patients (0.8%) died from testis cancer. The estimated 5-yr disease-specific survival was 99.3% in the initial group and 98.9% in the recent one. Conclusions: Non risk-adapted surveillance is an effective, simple strategy for the management of all stage I NSGCT. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Division of Urology, Department of Surgical Oncology, Princess Margaret Hospital, University Health Network, 610 University Avenue, Suite 3-130, Toronto, Ontario M5G 2M9, Canada. Tel ; Fax: address: m.jewett@utoronto.ca (M.A. Jewett) /$ see back matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 EUROPEAN UROLOGY 59 (2011) Introduction Almost half of patients diagnosed with a nonseminomatous testicular germ cell tumor (NSGCT) present with disease confined to the testis with no evidence of distant metastases (clinical stage I) [1]. Treatment options after orchiectomy include retroperitoneal lymph node dissection (RPLND), adjuvant chemotherapy, or active surveillance (AS) with treatment on relapse. Five-year survivals are approximately 100% for all three approaches [2 5]. The current focus is to diminish treatment-related morbidities while maintaining efficacy. Since the first report by Peckam et al, >3500 patients have been reported in surveillance programs worldwide [6,7]. Lymphovascular invasion (LVI) and the presence of embryonal carcinoma (EC) in the primary are the most consistently identified independent prognostic factors for recurrence. This has led to stratification by risk of relapse with immediate treatment of those defined as high risk, reserving surveillance for those at low risk [8 11]. However, at least a third of so-called high-risk patients are rendered disease free by orchiectomy and do not require further therapy [12]. Since 1981 the Princess Margaret Hospital Testis Cancer Group has offered AS as the preferred management option for all men with clinical stage I NSGCT. We report our results with this non risk-adapted AS policy over the last 25 yr. Comparisons over different time points have been made to evaluate the impact of changing diagnostic and therapeutic tools. 2. Patients and methods Three hundred and seventy-one patients with clinical stage I NSGCT were managed by AS, reserving treatment for relapse, from January 1981 until the end of An additional 27 patients underwent treatment for a variety of reasons including patient preference. Records were reviewed with Research Ethics Board approval and entered in our ecancercare testis database. Pathology was reviewed for all patients who underwent orchiectomy elsewhere. Tumor size, stage (T1 T4), and predominant histologic subtype with percentage of EC if present were recorded. Pure choriocarcinoma patients were excluded. Staging included physical examination (PE), chest x-ray (CXR), and computed tomography of abdomen and pelvis (CT-AP) with contrast. All imaging studies done elsewhere were reviewed or repeated. Elevated tumor markers (TM), b-chorionic gonadotropin, and a-fetoprotein were followed to nadir in the normal range. Our follow-up protocol has been reported: Patients were followed for at least 5 yr [13]. TM and CXR were repeated every 2 mo for 2 yr, every 4 mo in year 3, every 6 mo in year 4, and annually in year 5 with CT-AP every 4 mo for the first 2 yr of surveillance. Disease progression was defined as imaging or physical examination evidence of metastases and/or elevated TM. Indications for treatment have not changed over the years. Patients with limited retroperitoneal nodal disease on CT, that is, equivalent to stage 2A/N1, who had <100 ng/ml TM levels, underwent bilateral RPLND (after November 1984 with nerve sparing). Progressors equivalent to stage 2B and S1 were managed with chemotherapy. Adjuvant chemotherapy was given if multiple nodes were involved (stage 2A/N1, generally with more than two nodes) or there was extranodal microscopic disease or persistent marker elevation. Chemotherapy was given for relapse. Initially, three cycles of the VAB regimen (vinblastine, dactinomycin, bleomycin, and cisplatin) was used [14]. Subsequently, BEP (cisplatin, etoposide, and bleomycin) was used [15]. From 1981 to 1983, patients with a retroperitoneal recurrence and positive TM were treated with radiation to the retroperitoneum, receiving 2500 rads in 20 fractions over 4 5 wk. The use of radiation therapy was discontinued in Analysis Recurrence rates, time to relapse, risk factors predictive for recurrence, disease-specific survival, and overall survival were determined. Summary statistics were used to describe the patient population. The Kaplan-Meier method was used to estimate overall and recurrencefree survival (RFS). Survival was calculated from the date of orchiectomy until death (recurrence for RFS) or from the last known date the patient was alive. Univariate Cox proportional hazards regression was applied to each characteristic as a predictor of RFS. Histology was categorized as pure, predominant (>50% defined by a single histology), and any presence (ie, if the histology was present). An optimal multivariate model was constructed using forward stepwise selection. Differences between high-risk and low-risk patients, as well as between early and late cohorts, were tested using an exact x 2 test. All tests were two sided, and a p value of 0.05 was considered statistically significant. We compared our results over two different time ranges. Those diagnosed between 1981 and 1992 (n = 157) were analyzed as an initial cohort; those diagnosed between 1993 and 2005 (n = 214) were analyzed as a recent cohort. 3. Results Table 1 summarizes the patient characteristics. Overall, 365 (98.4%) were stage T1 2, LVI was detected in 92 (24.8%), 56 (15.1%) had pure EC, and teratoma was found in 250 (67.3%). Twenty-three (6.2%) had both risk factors. Fifteen (4.0%) developed a second contralateral primary (median: 9.3 yr; range: yr). Relapse occurred in 104 patients (28.0%) with a median time to relapse of 7.1 mo. Eighty-two (78.9%) relapsed in the first year of follow-up and 18 (17.3%) in the second. Four (3.8%) experienced late relapses (2.5, 5.1, 9.5, and 12.4 yr), and all were salvaged. CT-AP, TM, PE, and CXR were positive at relapse in 80 (76.9%), 67 (64.4%), 18 (17.3%), and 17 (16.3%), respectively (Table 2). CXR was never the only modality to identify disease progression (Fig. 1). In the initial cohort, 53 of 157 (33.8%) relapsed compared with 51 of 214 (23.8%) in the recent cohort ( p = 0.06). When predictors of recurrence were analyzed, only LVI (hazard ratio [HR]: 3.22; 95% confidence interval [CI], ; p < ) and the presence of pure EC (HR: 1.74; 95% CI, ; p = 0.02) were significant using the multivariate Cox proportional hazards model. Overall, 125 patients (34%) were designated as high risk based on the presence of at least one of these two factors, and 65 of 125 (52%) (LVI alone: 54%) of them recurred, as opposed to 39 of 246(15.8%) who were considered low risk. In the initial cohort, 66 of 157 patients (42%) were high risk, and 36 (54.5%) relapsed versus 17 of 91(18.7%) at low risk. In the

3 558 EUROPEAN UROLOGY 59 (2011) Table 1 Patient characteristics Table 2 Diagnostic tools and sites at relapse Patients n = 371 % Age, yr Mean (SD) 30.5 (8.6) Range, yr * Primary tumor stage T T T T Tumor histology y >50% Embryonal carcinoma Immature teratoma Mature teratoma Seminoma Yolk sac tumor Mixed tumors (no histology >50%) Mixed tumors (unknown %) Tumor histology with teratoma component LVI z Yes No Unknown Pure EC, 100% Yes No Both LVI: Yes and 100% EC Second primary tumor in contralateral testis Patients Median time to diagnosis, yr 9.3 Range, yr Tumor histology of second primary Seminoma Nonseminoma Embryonal carcinoma (1) Mixed germ cell (3) Sertoli cell Leydig cell EC = embryonal carcinoma; LVI = lymphovascular invasion; SD = standard deviation. * A total of 13 men (3.5%) were <18 yr of age. y Orchiectomy was performed in our institution in 19% of cases, and slides for the remainder (81%) were requested from outside hospitals. The pathology review result is recorded here as our reference pathology. z By cohort, LVI was as follows: initial cohort ( ): LVI, yes, no, unknown (32%, 57%, and 11%, respectively) with 52% LVI, yes relapsed. Recent cohort ( ): LVI, yes, no, unknown (20%, 70%, and 10%, respectively) with 57% LVI, yes relapsed. Our institution s orchiectomy specimens ( ): LVI, yes, no, unknown (15%, 72%, and 13%, respectively). recent cohort, 59 of 214 (27.6%) were high risk, and 29 (49.2%) recurred versus 22 of 155 low-risk patients (14.2%). Median follow-up was 6.3 yr ( yr); 343 patients (95.0%) for at least 2 yr, 250 (69.3%) for >5 yr, and 125 (34.6%) for >10 yr. Twenty (5.4%) were lost to follow-up during the first 2 yr. Progression occurred in the retroperitoneum in 78 patients (75.0%), 8 of whom had other sites of relapse (Table 2). Nine (8.7%) relapsed only in the lung, six of them with elevated TM; another seven had disease elsewhere. Four (3.8%) relapsed with nodal disease outside of the retroperitoneum. Another 10 (9.6%) had elevated markers as the sole indication of relapse. Overall, 70.2% relapsed with low-volume stage IS-2B disease. Chemotherapy was At relapse First relapse % in 104 relapses Diagnostic tools CT abdomen and pelvis Tumor markers Physical exam Chest x-ray CT chest Other Ultrasound abdomen and pelvis, 5 MRI abdomen and pelvis, 4 X-ray pelvis and hips, 1 Total 203 Sites RP RP only, 70 RP plus other sites, 8 Tumor markers Lung Other (see below) Total Tumor marker elevation only 10 Single site RP 70 Lung 9 Supraclavicle 3 Inguinal 1 Multiple sites RP plus lung 3 RP plus spleen 1 RP plus liver 1 RP plus supraclavicle 1 RP plus mediastinum plus inguinal 1 RP plus lung plus supraclavicle 1 Lung plus mediastinum 1 Lung plus femur 1 Lung plus supraclavicle 1 Total 104 CT = computed tomography; MRI = magnetic resonance imaging; RP = retroperitoneum. the primary treatment at progression in 57 patients (54.8%; Table 3). Twenty patients (35.1%) had surgery for residual disease including 13 RPLNDs (residual cancer: 3, teratoma: 5, necrosis/fibrosis: 5). The primary treatment at relapse was surgery in 40 including 1 lung resection and 39 RPLNDs. The pathology was cancer in 35 including the lung lesion, teratoma in 1, and 4 had no tumor. Two of the four with no tumor went on to develop recurrence elsewhere, and the other two were considered nonprogressors for analysis. In the initial cohort, six (5.8%) received initial abdominal radiation therapy for relapse. One in the recent cohort refused treatment and was lost to follow-up at 15 mo. Of the 104 patients who required treatment for recurrence of disease, 3 (0.8%) died from testicular cancer, 1 in the initial cohort and 2 in the recent group. By International Germ Cell Cancer Consensus Group classification, two had a good and one had a poor prognosis. The remaining 101 patients have been followed a median of 7.4 yr (range: yr) from relapse. After completion of treatment, 99 of 100 patients remain disease free, and 1 is alive with disease. An additional patient refused treatment

4 [()TD$FIG] EUROPEAN UROLOGY 59 (2011) Fig. 1 Diagnostic tools at detection of relapse. and is alive with disease. There were seven deaths unrelated to testicular cancer. The estimated 5-yr disease-specific survival was 99.3% in the initial group and 98.9% in the recent one; overall it was 99.1%. At 5 yr the estimated recurrence-free survival overall Table 3 Initial treatment at first relapse Initial treatment No. of patients 1 Chemotherapy, n =57 Chemotherapy only 37 Chemotherapy plus surgery (RPLND: 12; 18 lung resection: 5; mediastinum resection: 1) Chemotherapy plus RPLND plus further chemotherapy * Chemotherapy plus femoral resection plus 1 chemotherapy plus radiation Subtotal 57 Surgery n = 40 (RPLND, n = 39; lung resection, n =1) RPLND only 36 RPLND plus chemotherapy 3 Lung resection plus chemotherapy * 1 Subtotal 40 Radiation, n =6 Radiation only 4 Radiation plus RPLND 1 Radiation plus chemotherapy * 1 Subtotal 6 No treatment, n = 1 Refused treatment 1 Subtotal 1 Total 104 * These patients died from testis cancer. was 72.5%, and in the initial and recent cohorts, it was 67.3% and 76.3%, respectively (Fig. 2). 4. Discussion Numerous studies have confirmed that initial AS after orchiectomy is a safe treatment option for patients with clinical stage I NSGCT [2,6]. Prognostic factors for relapse have been identified, and many have advocated riskadapted treatment policies [2,8,10,11,16 18]. However, even with the best combination of available prognostic factors, at least a third of so-called high-risk patients are treated unnecessarily with a risk-adapted policy [11,12]. Our series of 371 patients with a median follow-up of 6.3 yr represents the largest reported surveillance cohort from a single institution. Our experience confirms that AS is an effective and safe strategy that is generalizable to all patients with clinical stage I NSGCT. Overall, 104 (28.0%) relapsed; disease progression was recognized within 1 yr in most of the cases, and proper treatment resulted in the successful salvage of all but three patients (0.8%). These findings are consistent with other published data that have reported relapse rates of 26 35% and mortality rates of 0 3% (Table 4) [2,6,7,13]. To assess the possible impact of improved imaging over time, we divided the patients into initial and recent cohorts. The relapse rate was higher from 1981 to 1992 compared with 1993 to 2005(33.8% vs 23.8%), but the estimated 5-yr disease-specific survival was similar (99.3% vs 98.9%). The lower relapse rate observed recently is likely explained by stage migration due to better diagnostic evaluation.

5 560 [()TD$FIG] EUROPEAN UROLOGY 59 (2011) Fig. 2 Survival curves. Our data confirm the prognostic significance of primary tumor LVI ( p < ) but suggest that pure EC (not percentage ranges) is as important ( p = 0.02) [2,12,16]. We had 125 patients with one or both and thus considered them high risk; 65 (52%) relapsed, and 60 remain disease free. Of patients with LVI, only 50 (54%) relapsed. Recurrence without any risk factors was noted in only 39 of 246 patients (15.8%). We are concerned there may be interobserver and tumor sampling differences when measuring the extent of EC, so the use of EC predominant as a prognostic factor may not be generalizable. More than 70% of the patients had small-volume disease on relapse, indicating that an appropriately conducted surveillance program can detect recurrence early and diminish the burden of treatment. Late relapses (>2 yr) were infrequent (four, or 1%), and all were salvaged. CT-AP was the follow-up modality most likely to detect recurrence, and the combined use of TM and CT-AP was the Table 4 Studies of surveillance in clinical stage I nonseminomatous germ cell tumors Study (publication year) No. of patients Median follow-up, yr No. of relapses (%) Median time to relapse, mo (range) No. of deaths (%) Overall survival rate, % Read (1992) [6] (27) NR 5 (2) 98 Daugaard (2003) [6] (29) 5 (1 171) 0 (0) 98.6 Colls (1999) [6] (28) NR 3 (2) 97 Kollmannsberger (2010) [7] (26) 4 (1 49) 0 (0) 100 Francis (2000) [6] (28) 6 (1 122) 2 (1) 99 Sharir (1999) [13] (28) (1) 99 Gels (1995) [6] (27) 4 (2 24) 2 (1) 99 Sogani (1998) [6] (26) 5 (2 24) 3 (3) 97 Roeleveld (2001) [6] (26) 7 (3 44) 1 (1) 98.9 Nicolai (1995) [6] (29) 7 (2 68) 3 (3.5) 96 NR = not recorded.

6 EUROPEAN UROLOGY 59 (2011) most useful method of detection. There is a lack of consensus about the best combination and frequency of imaging tests in surveillance programs [19]. Concern has been expressed about a possible increased cancer risk from diagnostic radiation exposure in patients with a normal life expectancy [20,21]. We did not perform CT-AP beyond the second year of follow-up but now do at discharge at 5 yr [13,22]. The key determinants of optimal therapy for stage I NSGCT are overall survival and burden of treatment. All approaches provide equivalent and excellent outcomes so that the morbidity and burden of therapy becomes more important. Surveillance is recommended for low-risk patients in all guidelines. The current controversy is whether to treat or observe high-risk men. In our series, surveillance restricts this burden to those patients who need therapy, with >50% only requiring a single treatment modality. A calculation of the treatment that our patients would have received if we had used a risk-adapted policy demonstrates that the overall burden of treatment has been reduced in our non risk-adapted approach. Overall, 28% of our patients required treatment of any sort, and our most recent cohort with a relapse of 23.8% is the lowest rate of any surveillance experience. The German Testicular Cancer Study Group has recently reported their trial comparing RPLND with one course of adjuvant BEP in all patients with clinical stage I NSGCT [23]. The use of laparoscopic RPLND in high-risk patients has also been studied [24]. However, the burden of treatment was greater than with our non riskadapted universal surveillance. The most significant factor was the number of cycles of chemotherapy. A multicenter report from northwest North America provides additional evidence [7]. In a recently reported decision analysis, Nguyen et al. concluded that active treatment is only preferred over surveillance when the risk of relapse is >46 54% [25]. Physicians need to fully inform patients of all treatment options [26]. Cullen et al. have observed patient preferences when informed about the risk of chemotherapy for relapse (about 50% with our definition of high risk) [26]. Regardless of patient occupation and other characteristics, a 30 50% risk range was the perceived average threshold for treatment selection. The incidence of contralateral tumors in our sample is higher than in other published series. This could be related to the longer follow-up in our group because the median time to develop a second tumor was >7 yr. 5. Conclusions Our experience confirms that non risk-adapted AS is a valid option for all patients with stage I NSGCT. Our data have contributed to the Canadian recommendation that it is the preferred treatment option, and the recent European Society of Medical Oncology clinical practice guidelines support this option as equivalent to adjuvant chemotherapy [27,28]. It is a treatment option in the European Association of Urology guidelines [29] and the recently updated European guidelines [30]. It provides excellent survival and reduces the overall treatment burden and potentially the longer-term toxicities of treatment. Author contributions: Michael A. Jewett had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Jewett, Moore, Kakiashvili, Duran. Acquisition of data: Sturgeon, Jewett, Alison, Moore, Gospodarowicz, Warde, Duran, Berthold. Analysis and interpretation of data: Jewett, Moore, Gospodarowicz, Warde, Duran, Kakiashvili, Berthold, Anson-Cartwright. Drafting of the manuscript: Kakiashvili, Duran, Jewett, Anson-Cartwright. Critical revision of the manuscript for important intellectual content: Jewett, Moore, Duran, Kakiashvili, Berthold, Warde, Gospodarowicz, Pond, Anson-Cartwright. Statistical analysis: Ma, Pond. Obtaining funding: None. Administrative, technical, or material support: Anson-Cartwright, Liu. Supervision: Jewett. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Bhardwa JM, Powles T, Berney D, Baithun S, Nargund VH, Oliver RTD. 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