Surveillance in Stage I Seminoma Patients: A Long-Term Assessment

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1 EUROPEAN UROLOGY 57 (2010) available at journal homepage: Testis Cancer Surveillance in Stage I Seminoma Patients: A Long-Term Assessment Sebastian Cummins a, Thomas Yau b, Robert Huddart c, David Dearnaley c, Alan Horwich c, * a The Royal Surrey County Hospital NHS Trust, Egerton Road, Guildford, UK b University Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong c Institute of Cancer Research & Royal Marsden Hospital, Downs Road, Sutton, UK Article info Article history: Accepted June 8, 2009 Published online ahead of print on June 16, 2009 Keywords: Management Outcomes Seminoma Testis cancer Abstract Background: Following orchidectomy patients with stage I seminoma of the testis may be managed by either surveillance or adjuvant treatment. In view of the very high cure rate, it is important to analyse long-term outcomes. Objective: : To provide data to advise patients on treatment burden and risk of recurrence associated with surveillance. Design, setting, and participants: We audited the case records of 164 stage I seminoma patients registered at the Royal Marsden Hospital who were managed with a surveillance policy between 1980 and 2004 and followed for 1 20 yr (median: 13.5 yr). Measurements: All treatments and patterns of relapse were documented. Results and limitations: Twenty-two of 164 (13%) patients had relapsed at a median of 15.5 mo (range: 6 55 mo) from orchidectomy. Eighteen relapses appeared to be confined to the para-aortic nodes, but 6 of the 13 (46%) men treated with only para-aortic radiotherapy suffered a further relapse at another site. The disease-specific mortality was 1.3%. In the complete series of 164 patients, a total of 50 cycles of chemotherapy and 26 courses of radiotherapy was administered, representing an average of 0.46 treatment units per patient or an average of 3.45 treatment units per relapsing patient. The total number of treatment days was 390 d for radiotherapy and 133 d for chemotherapy, representing an average of 3.2 d per patient or 23.8 d per relapsing patient. This was a single-centre series extending back to the 1980s. Imaging and treatment protocols have advanced since then. Conclusions: Surveillance postorchidectomy is a safe practice in the long term, and the majority of patients can avoid further treatment. There is the risk that those who do relapse face a higher burden of treatment than would be required if adjuvant treatment had been given. # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Institute of Cancer Research & Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel ; Fax: address: alan.horwich@icr.ac.uk, Chris.Martin@icr.ac.uk (A. Horwich) /$ see back matter # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 674 EUROPEAN UROLOGY 57 (2010) Introduction Testicular germ cell tumours represent only around 1% of all male cancer but they are the most common malignancy in young adult men, and the median age of presentation of seminoma is 35 yr. Just over half of these tumours are pure seminoma, and around 75% of seminoma patients present with stage I disease, that is, no clinical evidence of metastasis. Inguinal orchidectomy is the mainstay of treatment. The patient may then be managed by surveillance or adjuvant therapy, consisting of either radiotherapy (RT) or chemotherapy [1,2]. RT is usually administered as a course of 20 Gy in 10 fractions over 14 d to the para-aortic nodes [3], although in the past higher doses and larger fields were used [4]. RTis associated with both short- and long-term morbidities, which is of particular import given the young age and good prognosis of this group of cancer patients [5]. Peptic ulceration, bowel disturbance, cardiovascular disease, second malignancies, fertility problems, and quality-of-life changes have all been reported in the context of adjuvant therapy for stage I seminoma [6 12]. Adjuvant chemotherapy with carboplatin has also been assessed [2], but it is too early to be confident that the long-term toxicities of this approach are known. Surveillance policies offer the opportunity to detect relapsing patients early whilst avoiding the morbidities and risks of treatment for most [13,14]. Reports have demonstrated the feasibility of surveillance protocols, particularly when aligned with effective salvage regimens. Series from the Royal Marsden Hospital, from the Princess Margaret Hospital, Toronto, and from a national collaboration in Denmark all concluded that surveillance is a reasonable policy, albeit with some practical difficulties in view of the lack of sensitivity of specific serum markers [15 17]. An overview analysis of these series together with patients from the Royal London Hospital showed that the significant prognostic factors predicting relapse on surveillance were rete testis invasion and primary tumour size [18]; however, these factors have not yet been validated in an alternative series. Consensus guidelines accept surveillance as an option which can be offered to stage I seminoma patients following orchidectomy [19]. This retrospective analysis assesses the treatment burden and long-term outcomes seen in patients managed by surveillance for stage I seminoma of the testis at the Royal Marsden Hospital. The series of patients has a median follow-up of more than 13 yr following orchidectomy. 2. Patients and methods In total, 164 stage I seminoma patients who registered between 1980 and 2004 were treated with inguinal orchidectomy followed by surveillance. In all cases, the pathological diagnosis was confirmed by review; however, details of pathologic risk factors such as tumour size, rete testis invasion, or vascular invasion were not consistently recorded. Patients were staged according to the Royal Marsden Hospital staging classification, with stage I disease defined as tumour confined to the testis, with no evidence of metastases. Staging was confirmed by computed tomography (CT) of the chest, abdomen, and pelvis and by blood tests including full blood count; biochemistry; tumour markers, namely a-fetoprotein; the b subunit of human chorionic gonadotrophin (b-hcg); and, since 1998, lactic dehydrogenase (LDH). Surveillance involved outpatient visits every 3 mo for the first 2 yr, every 4 mo for year 3, every 6 mo for years 4 and 5, and annually thereafter. At each follow-up, the patients underwent physical examination, chest x-ray, and analysis of tumour markers. CT scanning of the abdomen was performed every 6 mo for 2 yr and then annually until 5 yr postorchidectomy. In the early years of the study, alternate CT scans were replaced by abdominal ultrasound. A CT scan was not repeated after 5 yr, unless relapse was suspected. Retrospectively reviewed data included age, date of first presentation, pathologic features of the tumour, date of developing relapsed disease, sites of relapse, tumour markers, radiologic investigations at time of relapse, salvage treatment for relapsed disease, subsequent clinical course, and survival status. 3. Results After a median follow-up of 13.5 yr (range: 1 20 yr), 22 of 164 (13%) clinical stage I seminoma patients on surveillance were found to have relapsed (Fig. 1, Table 1). The median Fig. 1 Stage I seminoma surveillance: relapse-free rate.

3 EUROPEAN UROLOGY 57 (2010) Table 1 Characteristics of relapsed patients. Patient no. Age, yr Interval to relapse, mo Sites of relapse Treatment Subsequent relapses Survival Cause of death PAN RT No relapse S PAN RT No relapse S PAN + lung Carbo 4 No relapse D Lymphoma PAN Carbo 4 + RT No relapse S PAN RT No relapse S PAN RT Left SCF S PAN Carbo 4 PAN S PAN RT Mediastinum S PAN + inguinal scar Carbo 3 + RT No relapse D Small cell carcinoma PAN + external iliac Carbo 1 + RT No relapse S PAN + left groin EP 4 + RT Peritoneal cavity D Seminoma PAN Carbo 4 + RT No relapse S PAN RT Intra-abdominal D Seminoma PAN RT No relapse S PAN RT Mediastinum D TCC bladder PAN RT Mediastinum S PAN RT Mediastinum S PAN RT No relapse D Aortic aneurysm PAN RT No relapse S PAN RT No relapse S PAN Carbo 1 + RT No relapse S PAN BEP 4 No relapse S BEP = bleomycin, etoposide, and cisplatin; Carbo = carboplatin; D = died; EP = etoposide and cisplatin; PAN = para-aortic nodes; RT = radiotherapy; S = survived; TCC = transitional cell carcinoma. Table 2 Treatment summary of initial relapse on surveillance. Site of initial relapse n Treatment of initial relapse (no.) Further relapse (seminoma mortality) PAN 18 RT (13) 6 (1) Carbo + RT (3) 0 Carbo (1) 1 BEP (1) 0 PAN + pelvic node 2 Carbo + RT (1) 0 EP + RT (1) 1 (1) PAN + lung 1 Carbo (1) 0 PAN + scar 1 Carbo + RT (1) 0 BEP = bleomycin, etoposide, and cisplatin; Carbo = carboplatin; EP = etoposide and cisplatin; PAN = para-aortic nodes; RT = radiotherapy. time from primary presentation of seminoma to first relapse was 15.5 mo (range: 6 55 mo). Clinically, only four (18%) patients were symptomatic at time of relapse. Abnormal physical-examination findings were detected in two (9%) patients. CT scans confirmed the diagnosis of relapsed disease in all 22 patients (100%). Eighteen of 22 patients had isolated relapses in the para-aortic lymph nodes. Four patients had relapses in additional sites: one in the lung, two in the external iliac nodes, and one (with previous inguinal surgery) in the orchidectomy scar. Treatment of relapse is detailed in Table 2. Thirteen patients with small-volume abdominal lymphadenopathy at relapse were treated with local RT to retroperitoneum to a dose of 35 Gy in fractions. Six of these patients relapsed again (four just in the mediastinum) and were treated with chemotherapy. Five initial recurrences were treated with a single dose of carboplatin followed by local RT [20], and none relapsed. The other four initial recurrences were treated with four cycles of chemotherapy; the relapse rates were one of two for single agent carboplatin, one of one for etoposide and cisplatin (EP) and none of one for bleomycin, etoposide, and cisplatin (BEP). All 22 patients had a good initial response to salvage treatment, although only 14 remained continuously disease free; eight second relapses occurred 4 48 mo from first relapse and 2 patients ultimately died of biopsy-proven recurrent seminoma. The first of these was a 33-yr-old man on surveillance who relapsed in the left para-aortic and external iliac lymph nodes. He received four cycles of EP followed by involved-field RT. He then relapsed in the peritoneal cavity. Despite initially responding to further chemotherapy, he eventually died following surgery for persisting intra-abdominal disease. The second patient was a 27-yr-old man who received local RT for a relapse in the para-aortic lymph nodes. He developed further bulky paraaortic disease 2 yr later and died of abdominal progression, despite further salvage chemotherapy. The other four deaths in the series were from unrelated causes. Three died from other solid tumours, follicular lymphoma, metastatic small cell carcinoma of the tonsil, and bladder cancer (not an irradiated site); one patient died of an abdominal aortic aneurysm. These results show diseasespecific mortality of 1.3% in this series. To estimate the overall burden of treatment for germ cell cancer following orchidectomy (excluding treatment of other conditions and palliative care), the individual case records were reviewed and units of treatment, either a cycle of chemotherapy or a course of RT, were recorded, as were number of treatment days. In the total series of 164 patients, a total of 50 cycles of chemotherapy and 26 courses of RT was administered, representing an average of 0.46 treatment unit per patient or an average of 3.45

4 676 EUROPEAN UROLOGY 57 (2010) treatment units per relapsing patient. The figures for an analysis of number of treatment days were a total of 390 d for RT and 133 d for chemotherapy, representing an average of 3.2 d per patient or 23.8 d per relapsing patient. 4. Discussion This study updates our previous reports [14,15,21] on surveillance for stage I testicular seminoma patients at the Royal Marsden Hospital. The majority of the patients were registered in the 1980 s and early 1990 s; now, there is mature data on long-term safety of this policy. After a median follow-up period of 13 yr, the recurrence and disease-specific mortality rates were 13% and 1.3%, respectively. This recurrence rate is lower than our previously reported result of 18% [15] and lower than results reported by other groups (18 20%) [16,17,22], possibly because of the selective use of adjuvant treatment. Of the 22 patients who were treated for relapse in our series, 8 (36%) suffered a second relapse. With the caveat that the patient numbers in this situation in our series are small, it appears that the recurrences treated with RT alone behaved more aggressively than the typical stage II seminoma, for which high control rates are reported [23,24]. There were no second relapses in the five patients whose first recurrence was treated with carboplatin and RT; however, experience with this practice is largely limited to our centre, and it is not a standard approach for smallvolume stage II seminoma. There was one relapse in the two patients treated with carboplatin monotherapy, and this approach is no longer recommended [25]. In the 22 patients who relapsed out of the total of 164 on surveillance, the actual treatment burden was 26 courses of RT and 18 courses (50 cycles) of chemotherapy. These treatments lasted a total of 523 treatment days. In our series, however, there appeared to be an excess of further recurrences after RT for small-volume retroperitoneal relapse. Additionally, we treated two relapsing patients with carboplatin monotherapy. For purposes of comparison with current adjuvant treatments, if our series were idealised, assuming only 2 of 13 recurrences after RT and a standard chemotherapy approach of BEP 3, the treatment burden of surveillance would be much reduced to an estimated 37 cycles of chemotherapy, 14 courses of RT, and a total of 156 treatment days. These figures can be compared with an estimate of treatment burden following adjuvant RT, assuming 4 5% relapse and 85% disease-free survival of relapsing patients with combination chemotherapy; 164 courses of RT and 9 courses of chemotherapy (29 cycles, 7 3 cycles of 3-d BEP and 2 4 cycles of 5-d BEP). The estimated number of treatment days would be An approximate treatment burden after carboplatin can be estimated, assuming a 5% relapse risk after a single adjuvant cycle and further treatments including five courses of RT 2 3 cycles of 3- d BEP and 1 4 cycles of 5-d BEP, 174 cycles of chemotherapy, and five courses of RT. Of course in this setting, the majority of chemotherapy courses would be of low toxicity, as they would comprise a single dose of carboplatin. These courses would take an estimated 277 treatment days, less even than surveillance. An estimate can also be made of treatment burden associated with a selective policy, as published by the Spanish Germ Cell Cancer Cooperative Group [26]. In this study of 314 patients with stage I seminoma, 100 patients were regarded as low risk and were managed by surveillance; of those, 6% relapsed. Another 214 patients were higher risk and received two cycles of adjuvant carboplatin; of those, 3.3% relapsed. The estimated treatment burden in this series is 24 chemotherapy cycles in the surveillance patients and 428 cycles of carboplatin monotherapy, 28 cycles of EP, and one course of RT in the higher risk patients, leading to a total of about 688 treatment days in 314 patients (or an expected 360 treatment days in our 164 patients). Although the measure of treatment burden based on number of treatment cycles or courses favours surveillance in the entire population, those individuals who relapsed on surveillance had a relatively high treatment burden. The tempo of relapse is relatively slow compared to that noted in stage I nonseminomatous germ cell tumours on surveillance, with 20% of seminoma relapses occurring >3 yr after orchidectomy. In the Medical Research Council prospective surveillance trial [27], 75% of 396 patients with stage I nonseminoma were relapse free at 2 yr and 73% were relapse free at 5 yr. For seminoma, long-term follow-up is important in the monitoring of stage I patients; however, none of our 98 patients known to be relapse free 5 yr after orchidectomy suffered a later relapse. We did not undertake routine CT scans after 5 yr, but the substantial further follow-up data would suggest that late relapse is very uncommon. The combined series analysis of prognostic factors [18] reported a 3.6% difference in relapse-free rates between5yrand10yr,basedonamedianfollow-upof7yr, but imaging protocols were variable and investigations after 2 3 yr were described simply as less frequent. If regular annual CT scans of the abdomen had been performed, these relapses might have been detected earlier. With regard to detection of relapse, it is notable that only 18% of the patients were symptomatic, with 9% demonstrating physical signs at relapse. Blood tests were of limited value; b-hcg was elevated in one-third of patients at relapse (LDH was not analysed in follow-up in the majority of our patients). The incorporation of both LDH and placental alkaline phosphatase measurement [28,29] into a surveillance programme may enhance its sensitivity, although there are concerns about specificity. Chest x-ray detected recurrence in only one patient. This result is similar to results found when exploring the use of routine chest x-ray in surveillance for nonseminomatous germ cell tumour [29] and suggests that there is little benefittoroutinechestx-rayinthefollow-upofstagei seminomas. The majority of relapses were diagnosed on CT scanning, and it is likely that recent imaging improvements have increased the sensitivity of the technique compared to the early years of this series. The optimal protocol for routine surveillance CT scanning in this group

5 EUROPEAN UROLOGY 57 (2010) of patients has yet to be defined. Positron emission tomography (PET) with 18 fluorodeoxyglucose has been assessed in high-risk stage I nonseminoma but appears to lack sensitivity, as 33 of 87 PET-negative patients relapsed on surveillance [30]. 5. Conclusions Patients with stage I seminoma have a long life expectancy, and considerations of late treatment-related toxicities are important. Our analysis supports the safety of surveillance compared to adjuvant therapy postorchidectomy. The surveillance programme, however, does come at a cost to the subset of patients who relapse, since they generally face an increased burden of treatment compared to the adjuvant setting. It also requires high levels of physician and patient motivation, and compliance with medical advice is difficult to predict [31]. Nonattenders risk presenting with largevolume disease recurrence and subsequent difficulties with salvage. Therefore, the decision regarding surveillance or adjuvant therapy should be made with an understanding of the context of both the individual and the treatment centre. Author contributions: Alan Horwich 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: Horwich, Huddart, Dearnaley. Acquisition of data: Cummins, Yau. Analysis and interpretation of data: Horwich. Drafting of the manuscript: Horwich, Cummins, Yau. Critical revision of the manuscript for important intellectual content: Dearnaley, Huddart. Statistical analysis: Yau, Cummins. Obtaining funding: none. Administrative, technical, or material support: none. Supervision: Horwich. 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: This work was undertaken at The Royal Marsden NHS Foundation Trust, which received a proportion of its funding from the NHS Executive; we acknowledge NHS funding to the NIHR Biomedical ResearchCentre. The viewsexpressed inthispublicationarethose of the authors and not necessarily those of the NHS Executive. This work was supported by the Institute of Cancer Research (ICR), and Cancer Research UK (CUK) grant number C46/A3970 to the ICR Section of Radiotherapy. References [1] Hamilton CAH, Easton A, Peckham MJ. 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