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Treatment outcome and patterns of relapse following adjuvant carboplatin for stage I testicular seminomatous germ-cell tumour: results from a 17-year UK experience
Annals of Oncology Advance Access published June 2, 2015
1 Treatment outcome and patterns of relapse following adjuvant carboplatin for stage I testicular seminomatous germ cell tumour: Results from a 17 year UK experience C. Chau1,2,3, R. Cathomas4, M. Wheater3, D. Klingbiel5, M. Fehr6, J. Bennett7, H. Markham8, C. Lee1,3, S.J. Crabb1,3, T. Geldart7 1
Cancer Sciences Unit, University of Southampton Faculty of Medicine,
Southampton, UK 2
NIHR Wellcome Trust Clinical Research Facility, University of Southampton,
Southampton, UK Department of Medical Oncology, University Hospital Southampton NHS Foundation
Trust, Southampton, UK 4
Medical Oncology, Kantonsspital Graubünden, Chur, Switzerland
5
Swiss Group for Clinical Cancer Research Coordinating Center, Bern, Switzerland
6
Medical Oncology, Kantonsspital St. Gallen Hospital, St. Gallen, Switzerland
7
Dorset Cancer Centre, Poole Hospital NHS Foundation Trust, Poole, UK
8
Department of Histopathology, University Hospital Southampton NHS Foundation
Trust, Southampton, UK
Corresponding Author: Dr. Thomas Geldart, Dorset Cancer Centre, Poole Hospital NHS Foundation Trust, Poole BH15 2JB, UK, Tel: 44-1202-665511, Email: [email protected]
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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3
2 Abstract Background: Following inguinal orchidectomy, management options for patients with stage I seminoma include initial surveillance or treatment with adjuvant radiotherapy or chemotherapy. The anticipated relapse rate for patients followed by surveillance alone is approximately 15%, with adjuvant treatment this risk is reduced to approximately 4-5% at five years. After carboplatin treatment, follow up strategies vary and there are no validated, predictive markers of relapse. Patients and methods: We conducted a retrospective analysis of all patients presenting with stage I seminoma who received a single cycle of adjuvant carboplatin
results of univariate and multivariate analysis evaluating possible risk factors for post carboplatin relapse. Results: 517 eligible patients were identified. All underwent nuclear medicine estimation of GFR prior to treatment with carboplatin (dosed at AUC 7). With a median follow up of 47.2 months (range 0.4 – 214), 21/517 patients have relapsed resulting in a 5 year estimated relapse-free survival of 95.0% (95%CI; 92.8–97.3%). Median time to relapse was 22.7 months (range 12.5 – 109.5). Relapse beyond 3 years was rare (4/517; 0.8%). 20 of 21 (95%) relapsed patients had retroperitoneal lymph node metastases. The majority (16/21; 76%) of patients had elevated tumour markers at relapse. 20/517 (3.9%) patients developed a new contralateral testicular germ cell cancer. There were no seminoma related deaths. Tumour size was the only variable significantly associated with an increased risk of relapse. Conclusions: Overall results for this large cohort of patients confirm an excellent prognosis for these patients with outcomes equivalent to those seen in prospective clinical trials. Increasing tumour size alone appears to be associated with an increased risk of post chemotherapy relapse.
Key words: Stage I seminoma, relapse pattern, adjuvant carboplatin, chemotherapy, treatment outcome
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in South Central England between 1996 - 2013. We report on outcome and the
3 Key message: We looked at the outcomes and relapse pattern of stage I seminoma patients treated with adjuvant chemotherapy in a large UK population. Approximately 5% of patients treated by this approach will relapse. Larger tumour size appeared to be associated with an increasing risk of relapse. The overall prognosis is excellent with no seminoma related deaths.
Introduction Seminoma accounts for 60% of testicular germ cell tumours (GCTs) with 80% of
with computed tomography (CT) of chest, abdomen and pelvis along with measurement of tumour markers: alpha-fetoprotein (AFP), β-human chorionic gonadotropin (β-HCG), and lactate dehydrogenase (LDH), represents standard initial management.
Following orchidectomy, management options for stage I seminoma comprise of active surveillance or adjuvant treatment. Regardless of approach, virtually all patients with seminoma are cured given the effectiveness of salvage chemotherapy at relapse (2).
For patients managed with active surveillance, a recent pooled international retrospective study of 1344 patients reported a relapse rate of 13% after a median follow up of 52 months, with no seminoma related deaths (3). A separate retrospective analysis suggested tumour size greater than 40mm in combination with rete testis invasion was associated with a significantly higher relapse rate (up to 32%), although prospective analyses have not confirmed these risk categories (4-5)
The MRC TE19/EORTC 30982 clinical trial evaluated adjuvant therapy in 1447 patients treated with a single dose of carboplatin AUC 7 (area under the curve x 7; n= 573) compared to para-aortic radiotherapy (n= 904). The trial demonstrated noninferiority of carboplatin with an overall relapse rate of 5.3% vs 4% after a median follow up of 6.5 years. Given the favourable toxicity profile and the avoidance of risk of radiotherapy-induced secondary malignancies, carboplatin has become the preferred adjuvant treatment (6-9).
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patients presenting with stage I disease (1). Radical inguinal orchidectomy, staging
4 Several trials have used a combined, risk-adapted approach in which patients with tumour size >40mm and rete testis invasion were offered adjuvant carboplatin, and low risk patients managed with surveillance (10,11). Within the TE19 trial, no results relating to possible risk factors of relapse were reported. It therefore remains unclear to what extent adjuvant chemotherapy reduces the risk in patients at higher risk of relapse as compared to lower risk patients.
Methods
Detailed methods are available in supplementary material. All consecutive patients with stage I seminoma treated with a single dose of adjuvant carboplatin AUC7 within a single supra-network regional team between July 1996 and October 2013 were identified. Carboplatin dose was calculated on radioisotope measured GFR uncorrected for body surface area using the Calvert formula (12).
Tumour characteristics, time to adjuvant chemotherapy, clinical outcomes, incidence of contralateral GCT and secondary malignancies, pattern of relapse and salvage treatment given at relapse were recorded. Cut off for follow-up was April 28th 2014.
Follow-up and treatment at relapse 29/517 (5.6%) patients within the cohort were treated within the TE19 trial and were followed-up 3 monthly for the first two years, 6 monthly in year 3 – 5 and annually thereafter for up to 10 years. At each visit, patients underwent clinical examination, chest x-ray and measurement of AFP, β-HCG, +/- LDH. Patients outside the clinical trial were followed-up similarly for a minimum of three years (3 monthly in year 1, 4 monthly in year 2, 6 monthly in year 3). CT abdomen was performed routinely at one year post orchidectomy and if clinically indicated thereafter. After discharge, followup was taken over by the general practitioner (GP). GPs were provided with written guidance requiring referral back to the regional specialist team on suspicion of relapse.
At relapse, patients with stage IIA relapse underwent dog-leg radiotherapy. Patients of good prognosis disease according to IGCCCG (International Germ Cell Cancer
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Patients and adjuvant treatment
5 Collaborative Group) classification, with stage IIB or higher relapse, had 3 cycles of standard dose BEP (bleomycin, etoposide, cisplatin) chemotherapy (13). Patients with intermediate prognosis received 4 cycles BEP. All salvage chemotherapy was co-ordinated via a single regional specialist centre.
Statistical methods Detailed statistical methods are available in supplementary material. The primary endpoint was 5-year relapse-free survival rate. Secondary objectives included overall survival, cancer-specific survival, incidence of contralateral GCT, risk factors predictive of relapse and incidence of secondary malignancies.
region referred back to participating centres, and all systemic treatment co-ordinated from a single regional centre (UHS), follow up is effectively much longer. To account for this we calculated “virtual” follow up as time from date of orchidectomy to data cut-off date (April 28th 2014) or death. Virtual follow up was used to calculate a “real world” follow up time but was not used for Kaplan Meier analysis of relapse. Time-toevent endpoints were analysed by Cox regression models and Kaplan-Meier methods.
Results Patient characteristics 517 eligible patients were identified (Table 1). Median age at diagnosis was 38 years (range 18 – 73). Hospital median follow-up was 3.9 years (range 0 – 17.8). Virtual median follow up was 6.5 years (range 0.3 – 17.8 years).8 years).0.3 – 17.8 years). Relapse rate and assessment of risk factors 21/517 (4%) patients have relapsed giving an estimated RFS of 97.4% (95% CI 96.0–98.9%) at 2 years and 95.0% (92.8–97.3%) at 5 years (Figure 1). 20/21 (95%) with good prognosis metastatic disease (IGCCCG classification) and 1/21 (4.8%) with intermediate prognosis disease (Table 2). The median time from orchidectomy to relapse was 22.7 months (range 12.5 – 109.5). 12/21 (57%) relapses occurred within 2 years and 17/21 (80%) within 3 years. The relapse rate for the whole
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Since all deaths are reported back to NHS records, all relapses occurring within
6 population after three years was 0.8% (4/517; after 49, 50, 53 and 108 months). There were no seminoma related deaths.
Three quarters of relapsing patients, 16/21 (76%) had elevated tumour markers at relapse (9 raised βHCG and LDH, 4 raised βHCG alone and 3 raised LDH alone) and / or an abnormal protocol scheduled CT. The main site of relapse was in the retroperitoneum (19/21; 90%) with 100% of patients with abdominal/ pelvic involvement at relapse.
13/21 (62%) patients were asymptomatic at relapse. 12/21 (57%) asymptomatic
during follow-up of a gastro-intestinal stromal tumour (GIST). 8/22 (36%) patients (including all relapses beyond 3 years) were symptomatic at relapse, with the most common presentation being abdominal pain (6/22; 27%). One patient (1/22; 5%) presented with a deep vein thrombosis and one (1/22; 5%) with a pulmonary embolus.
When continuous values for tumour size were used, we found some evidence that larger size was associated with higher risk of relapse. For each cm increase in primary tumour size, there was an increase in risk of relapse (univariate 19%, 95% CI 0-43%, p=0.05; multivariate 24%, 95% CI 1-52%, p=0.04; Table 3). Using a 4cm cut off, 5 year RFS was nearly double (5.9 v 3.3%) in those patients with larger primary tumours. There was no statistically significant association between relapse rate and the other variables assessed. Treatment of Relapse Treatment at relapse is summarized in Figure 2. 4/21 (19%) patients (those with stage IIA/B relapse) were treated with dog-leg radiotherapy, the remainder with salvage chemotherapy. 18/21 (86%) remain alive and disease free following initial salvage treatment alone.
3/21 (14%) relapsing patients suffered a second relapse (time from first to second relapse: 7.6, 11.2, and 12 months). One first relapsed with stage IIA disease and was treated with salvage radiotherapy to complete response. His 1-year planned CT scan identified a second relapse with disease in the abdomen and mediastinum. He received successful salvage EP chemotherapy but died from a myocardial infarction 7 years later.
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patients were detected in routine follow up, and one was discovered incidentally
7
The remaining 2 patients had stage IIC disease at first relapse and received standard dose, salvage BEP chemotherapy. Within 12 months, both had a second relapse, one identified by planned CT at 1 year, one identified by PET/CT at 11 months). The former patient received 3 cycles of TIP chemotherapy and remains alive and well without further relapse after a follow up of 11 years. The latter received salvage treatment with involved field retroperitoneal radiotherapy to a dose of 40Gy in 20 fractions, but suffered a third relapse within 3 months of treatment with enlarging pelvic nodal disease outside his radiotherapy field. He was treated with TIP chemotherapy and remains alive and disease free after a follow up of 5 years. .
20/517 (3.9%) patients were diagnosed with a separate contralateral testicular germ cell tumour (CTGCT). None of these patients relapsed from their initial seminoma.
3/517 (0.6%) patients were diagnosed with synchronous bilateral seminoma (treated with bilateral orchidectomy followed by one cycle of adjuvant carboplatin). 17/517 (3.3%) patients developed a new, metachronous CTGCT (9 seminoma, 8 nonseminoma) during follow up, with a median time to CTGCT of 8.8 years (range 0.8 – 22 years). Two patients developed CTGCT more than 20 years after their first diagnosis.
In the 9/517 (2%) patients who developed contralateral seminoma (all stage 1 disease), 2 underwent orchidectomy alone without additional adjuvant therapy (diagnosed within 2 years of the first GCT), 3 received another single dose of adjuvant carboplatin, and 4 received adjuvant radiotherapy (the diagnosis of these GCT were made prior to 2000). In the 8/517 (1.5%) patients who developed contralateral non-seminoma, 4 with stage 1 disease underwent orchidectomy alone and 4 with metastatic disease received BEP chemotherapy.
Secondary malignancies and overall survival As of April 28th 2014, 512/517 (99%) patients are alive and six patients have died. There were no seminoma related deaths. All deaths occurred after 5 years and the five-year cancer-specific survival rate was 100%. One patient (0.2%) died from metastatic disease from a second, contralateral non-seminomatous GCT primary, the other five patients died of causes unrelated to GCT (one suicide, one myocardial infarction, two bronchopneumonia and one rectal cancer).
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Contralateral testicular germ cell tumour
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6/517 (1.2%) patients were diagnosed with non germ cell secondary malignancy during follow up. 3/6 within 12 months of receiving their adjuvant carboplatin chemotherapy (plasmacytoma, renal cell carcinoma, GIST) and 3/6 between 6 – 8 years after their adjuvant chemotherapy (rectal cancer, malignant melanoma, mantle cell lymphoma). Discussion
To our knowledge, we present the largest published series describing the clinical
cycle of post-operative adjuvant carboplatin chemotherapy dosed exclusively according to nuclear medicine estimation of GFR. We report real-world experience and confirm the low relapse rate and highly favourable prognosis for this large cohort of patients. Outcome overall is excellent with all relapsing patients responding to salvage treatment and no seminoma related deaths.
Our results are in keeping with the majority of patients (355/573; 62% patients in the chemotherapy arm) treated prospectively in the TE19 trial whose carboplatin dose was determined by nuclear medicine estimation of GFR and prospectively followed for up to 10 years. Our group and subgroup analysis of TE19 have previously highlighted the importance of accurate estimation of GFR and the potential for underdosing and higher relapse rate when GFR estimation formulae and lower doses of carboplatin are used (7,12).
In contrast to the very low rates of CTGCT seen in the pivotal phase III TE19 trial, the development of a contralateral primary in our series; 20/517 (3.9%), was as common as the development of systemic disease relapse following adjuvant carboplatin (21/517, 4%), but with a notably longer median time to event (median 8.8 v 1.9 years). In keeping with contemporary published series, our findings do not support the conclusion drawn by the TE19 trial that the risk of developing contralateral testicular tumours is reduced by adjuvant carboplatin (14,15). It should be noted however, that patients in our series did not routinely undergo biopsy of their contralateral testis at initial diagnosis unless there were clear risk factors for contralateral intratubular germ cell neoplasia (ITGCN); namely age < 30, testicular atrophy, raised follicle stimulating hormone (FSH), oliogspermia. Our findings emphasis the need for General Practitioners and patients to be aware of the risk and
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outcome and relapse data of patients with stage I seminoma treated with a single
9 long potential interval between initial orchidectomy and the development of a new, metachronous, contralateral primary following discharge from routine hospital surveillance..
Increasing primary tumour size was associated with a higher risk of relapse, and at a cut off of 4cm, 5 year RFS was nearly doubled in those patients with larger primary tumours (5.9 v 3.3%) although this cut-off did not reach statistical significance in uniand multivariable Cox regression analysis, possibly due to lack of events. Invasion of rete testis (p=0.75) or a combination of size and rete testis invasion (p=0.67) was not found to be a prognostic factor for relapse. Time to adjuvant chemotherapy did
60 days of surgery. This is in contrast to colorectal and breast cancer, whereby a longer time to adjuvant chemotherapy is associated with poorer outcome (16,17).
The fact that no other markers appear prognostic in our series have been influenced by the relatively low sample size and relapse rate seen in our cohort, in contrast to higher relapse rates seen in series evaluating surveillance.
The vast majority of relapses were first identified by per-protocol CT imaging +/blood tumour marker elevation, whilst CXR did not diagnose any recurrence. The presence of elevated markers in the majority of relapsing patients is in marked contrast to findings from the international active surveillance cohort, where only a small minority of patients had elevated markers at relapse (76 v 3%) (3). These findings may relate to the less intensive CT surveillance schedule adopted following adjuvant chemotherapy or inherent differences in tumour biology in patients relapsing following adjuvant chemotherapy. For patients followed according to our schedule, CXR appears to add little value whilst estimation of serial tumour markers remains important (18).
The median time to relapse was 22.7 months with no relapses detected before 12.5 months (range 12.5 – 109.5), a figure considerably longer than in the international surveillance series (14 months; range 2 – 84 months) (3). Although direct comparisons are difficult, adjuvant carboplatin chemotherapy may not only reduce the risk of relapse, but may also delay the time to relapse although again, this may be partially explained by our less intensive CT surveillance schedule.
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not appear to influence outcome although 75% of patient received treatment within
10 Regardless of follow up protocol and management approach, patient outcome following relapse after adjuvant treatment or surveillance strategies can be considered as essentially equivalent. Despite more intensive imaging and longer hospital follow up in the international surveillance series, the proportion of patients in each prognostic group at relapse were extremely similar, (20/21; 95% v 171/173; 99% presenting with good prognosis disease). Late relapse (beyond 3 years; 1% vs 0.8%) was rare in both groups and there was 100% disease specific survival.
Given equivalent outcomes, our results and the results of surveillance strategies feed into the ongoing debate around optimal management for stage I seminoma.
exposure, treatment related toxicity, and risk of / time to relapse all have a bearing on patient and clinician management choice and the design of any given follow up schedule.
Although our study is limited by the inherent weaknesses of any retrospective analysis, treatment was delivered within a single NHS with central supra-regional review for all patients. All consecutively eligible patients were included and all salvage chemotherapy delivered in a single centre. While median hospital follow-up appears rather short (3.9 years) due to the fact that many patients had to be censored at the time of discharge, the effective or “virtual” median follow up (6.5 years) is significantly longer.
In conclusion, adjuvant carboplatin is firmly established as a safe and effective adjuvant treatment. The risk of systemic relapse is low and similar to the risks of developing a new contralateral germ cell primary cancer. Systemic relapse beyond 3 years of follow-up was rare whilst median time to development of a new contralateral primary was over 8 years; clinicians and patients should remain alert to the possibility of a new primary occurring many years after initial diagnosis. Tumour size appears to be associated with a small but significant increase in risk of systemic relapse. We continue to recommend that all patients managed with adjuvant carboplatin undergo nuclear medicine calculation of GFR and that surveillance schedules include routine CT imaging and tumour markers.
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Healthcare costs, patient compliance and anxiety, surveillance CT radiation
11
No funding/ grant was received.
The authors have declared no conflicts of interest.
References: 1. Powles TB, Bhardwa J, Shamash J et al. The changing presentation of germ cell tumours of the testis between 1983 and 2002. BJU Int 95:1197-1200, 2005
3. Kollmannsberger C, Tandstad T, Jewett MA, et al. Patterns of Relapse in Patients With Clinical Stage I Testicular Cancer Managed With Active Surveillance. J Clin Oncol 2014; 56.2116 4. Tandstad T, Smaaland R, Laurell A, et al. Management of seminomatous testicular cancer: a binational prospective population-based study from the Swedish norwegian testicular cancer study group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(6):719-25. 5. Aparicio J, Maroto P, Margeli M, et al. Prognostic factors for relapse in stage i seminoma: a new nomogram derived from three consecutive, riskadapted studies from the spanish germ cell cancer group (SGCCG). Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2014. 6. Oliver RT, Mason MD, Joffe JK, et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet. 2005;366(9482):293-300. 7. Oliver RT, Mead GM, Coleman R, et al. Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214). Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(8):957-62. 8. Mead GM, Fossa SD, Roberts JT, et al. Randomized trials in 2466 patients with stage I seminoma: patterns of relapse and follow-up. Journal of the National Cancer Institute. 2011;103(3):241-9. 9. Richiardi L, Scelo G, Olsen JH, et al. Second malignancies among survivors of germ-cell testicular cancer: a pooled analysis between 13 cancer registries. International journal of cancer Journal international du cancer. 2007;120(3):623-31.
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2. Boujelbene N, Cosinschi A, Bhagwati S et al. Pure seminoma: A review and update. Radiation Oncology 2011, 6:90.
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10. Beyer J, Albers P, Busch J, et al. Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2013;24(4):878-88. 11. Aparicio J, Maroto P, del Muro XG et al. Risk-adapted treatment in clinical stage I testicular seminoma: the third Spanish Germ Cell Cancer Group study. J Clin Oncol 2011: 29:4677-4681.
13. International Germ Cell Cancer Collaborative Group (IGCCCG). The International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancer. J Clin Oncol 1997; 15: 594-603. 14. Dieckmann KP, Kulejewski M, Pichlmeier U et al. Diagnosis of contralateral testicular intraepithelial neoplasia (TIN) in patients with testicular germ cell cancer: Systematic two-site biopsies are more sensitive than a single random biopsy. Eur Urol 51:175–185 (2007) 15. Powles T, Robinson D, Oliver T et al. The long-term risks of adjuvant carboplatin treatment for stage I seminoma of the testis. Ann Oncol. 2008 Mar;19(3):443-7. Epub 2007 Nov 28 16. Biagi JJ, Raphael MJ, Mackillop WJ et al. Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systemic review and meta-analysis. JAMA 2011 Jun 8; 305 (22): 2335-42 17. de Melo Gagliato D, Gonzalez-Angulo AM, Lei X et al. Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer. Journal of Clinical Oncology 2013. 49.7693. 18. Tolan S, Vesprini D, Panzarella T, et al. No role for routine chest radiography in stage I seminoma surveillance. European urology. 2010;57(3):474-9.
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12. Cathomas R, Klingbiel D, Geldart TR, Wheater M, et al. Relevant risk of carboplatin underdosing in cancer patients with normal renal function using estimated GFR: lessons from a stage I seminoma cohort. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2014;25(8):1591-7.
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Figure 2. Treatment at relapse
517 patients
21 patients relapsed First relapse
17 chemotherapy
1
Second relapse
1 radiotherapy
Third relapse
1 chemotherapy (TIP)
18 alive and disease free
1
2 chemotherapy (TIP, EP)
2 alive and disease free, 1 died of myocardial infarction
1 alive and disease free
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1
4 radiotherapy
Table 1. Patient Characteristics, n=517 Age (years) Median (range)
38 (18–73)
Tumour size (mm) ≤40mm
333 (64%)
>40mm
169 (33%)
Unknown
15 (3%)
Rete testis invasion 331 (64%)
Yes
166 (32%)
Unknown
20 (4%)
Tumour >40mm and rete invasion No
427 (82%)
Yes
65 (13%)
Unknown
25 (5%)
Extratesticular invasion No
397 (77%)
Yes
67 (13%)
Unknown
53 (10%)
Time to adjuvant carboplatin (days) ≤30
103 (20%)
31–60
284 (55%)
> 60
112 (22%)
Unknown
18 (3%)
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No
Table 2. Patient characteristics at relapse; n=21 Setting of relapse detection Detected at routine follow up
13 (62%)
Unplanned
8 (38%)
First indicator of relapse in asymptomatic patients (N=14) Abnormal CT
11 (79%)
Elevated tumour markers
2 (14%)
Other abnormal imaging
1 (7%) (PET – unplanned & asymptomatic)
Yes
16 (76%)
No
4 (19%)
Unknown
1 (5%)
Site of relapse Retroperitoneal LN only
17 (81%)
Iliac LN only
1 (5%)
Multiple nodal sites
2 (9%) 1x retroperitoneal + mediastinal 1x inguinal + iliac
Multiple nodal and visceral sites
1 (5%) Retroperitoneal, mediastinal, liver
Salvage therapy at 1st relapse Chemotherapy
17 (81%)
Dog leg radiotherapy
4 (19%)
Salvage chemotherapy regime at 1st relapse BEP x 3
7 (41%)
BEP x 4
7 (41%)
Modified BEP
3 (18%)
IGCCCG classification Good prognosis
20 (95%)
Intermediate prognosis
1 (5%)
Response to salvage therapy Complete response, marker negative
6 (29%)
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Elevated LDH or β-HCG at relapse
Partial response, marker negative
14 (66%) Unknown
1 (5%)
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5-year RFS 95.0%
HR (95% CI), p-value univariable
All patients
No of Relapse relapse rate 21/517 4%
Tumour size ≤ 4cm >4cm unknown
11/333 3.3% 10/169 5.9% 0/15 0%
95.5% 93.6%
1 (ref) 1.9 (0.8–4.6), p=0.13
1 (ref) 2.2 (0.9–5.8), p=0.10
1.2 (1.0–1.4), p=0.05
1.2 (1.0–1.5), p=0.04
1 (ref) 0.9 (0.3–2.6), p=0.89
Tumour size (continuous*) Rete testis invasion No Yes Unknown
13/331 3.9% 7/166 2.2% 1/20 5.0%
95.1% 94.9%
1 (ref) 1.2 (0.5–2.9), p=0.75
Size >4cm AND rete testis invasion No Yes unknown
17/427 4.0% 3/65 4.6% 1/25 4.0%
95.1% 94.0%
1 (ref) 1.3 (0.4–4.5), p=0.67
Age ≤ 29 30–59
6/86 7.0% 14/418 3.3%
89.9% 96.1%
2.2 (0.9–5.9), p=0.10 1 (ref)
HR (95% CI), p multivariable** Table 3. Uni- and multivariate analysis of possible risk factors for relapse
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≥ 60
1/11
9.1%
88.9%
2.9 (0.4–22.0), p=0.30
Lymphovascular invasion No Yes Excess Smear artefact Unknown
15/378 3/52 2/50 1/37
4.0% 5.8% 4.0% 2.7%
95.2% 93.5% 94.3%
1.0 (ref) 1.4 (0.4–4.9), p=0.58 0.9 (0.2–4.0), p=0.90
1 (ref) 0.7 (0.1–3.4), p=0.65 0.7 (0.2–3.2), p=0.64
Extratesticular invasion No Yes Unknown
15/397 3.8% 3/67 4.5% 3/53 5.7%
95.4% 94.7%
1 (ref) 1.2 (0.3–4.0), p=0.82
1 (ref) 1.1 (0.3–4.0), p=0.88
Time to adjuvant carboplatin ≤ 30 days 31–60 days >60 days unknown
4/103 14/284 3/112 0/18
95.4% 93.9% 96.4%
1 (ref) 1.4 (0.4–4.1), p=0.59 0.7 (0.2–3.1), p=0.63
3.9% 4.9% 2.7% 0.0%
per cm increase of tumour size ** Variables without HR have not been included; tumour size has been included either continuous or with the 40 mm cutoff. The values shown are from the model with the continuous version of tumour size, but are similar in the model with the 40 mm cutoff.
1 Treatment outcome and patterns of relapse following adjuvant carboplatin for stage I testicular seminomatous germ cell tumour: Results from a 17 year UK experience C. Chau1,2,3, R. Cathomas4, M. Wheater3, D. Klingbiel5, M. Fehr6, J. Bennett7, H. Markham8, C. Lee1,3, S.J. Crabb1,3, T. Geldart7 1
Cancer Sciences Unit, University of Southampton Faculty of Medicine,
Southampton, UK 2
NIHR Wellcome Trust Clinical Research Facility, University of Southampton,
Southampton, UK Department of Medical Oncology, University Hospital Southampton NHS Foundation
Trust, Southampton, UK 4
Medical Oncology, Kantonsspital Graubünden, Chur, Switzerland
5
Swiss Group for Clinical Cancer Research Coordinating Center, Bern, Switzerland
6
Medical Oncology, Kantonsspital St. Gallen Hospital, St. Gallen, Switzerland
7
Dorset Cancer Centre, Poole Hospital NHS Foundation Trust, Poole, UK
8
Department of Histopathology, University Hospital Southampton NHS Foundation
Trust, Southampton, UK
Corresponding Author: Dr. Thomas Geldart, Dorset Cancer Centre, Poole Hospital NHS Foundation Trust, Poole BH15 2JB, UK, Tel: 44-1202-665511, Email: [email protected]
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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3
2 Abstract Background: Following inguinal orchidectomy, management options for patients with stage I seminoma include initial surveillance or treatment with adjuvant radiotherapy or chemotherapy. The anticipated relapse rate for patients followed by surveillance alone is approximately 15%, with adjuvant treatment this risk is reduced to approximately 4-5% at five years. After carboplatin treatment, follow up strategies vary and there are no validated, predictive markers of relapse. Patients and methods: We conducted a retrospective analysis of all patients presenting with stage I seminoma who received a single cycle of adjuvant carboplatin
results of univariate and multivariate analysis evaluating possible risk factors for post carboplatin relapse. Results: 517 eligible patients were identified. All underwent nuclear medicine estimation of GFR prior to treatment with carboplatin (dosed at AUC 7). With a median follow up of 47.2 months (range 0.4 – 214), 21/517 patients have relapsed resulting in a 5 year estimated relapse-free survival of 95.0% (95%CI; 92.8–97.3%). Median time to relapse was 22.7 months (range 12.5 – 109.5). Relapse beyond 3 years was rare (4/517; 0.8%). 20 of 21 (95%) relapsed patients had retroperitoneal lymph node metastases. The majority (16/21; 76%) of patients had elevated tumour markers at relapse. 20/517 (3.9%) patients developed a new contralateral testicular germ cell cancer. There were no seminoma related deaths. Tumour size was the only variable significantly associated with an increased risk of relapse. Conclusions: Overall results for this large cohort of patients confirm an excellent prognosis for these patients with outcomes equivalent to those seen in prospective clinical trials. Increasing tumour size alone appears to be associated with an increased risk of post chemotherapy relapse.
Key words: Stage I seminoma, relapse pattern, adjuvant carboplatin, chemotherapy, treatment outcome
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in South Central England between 1996 - 2013. We report on outcome and the
3 Key message: We looked at the outcomes and relapse pattern of stage I seminoma patients treated with adjuvant chemotherapy in a large UK population. Approximately 5% of patients treated by this approach will relapse. Larger tumour size appeared to be associated with an increasing risk of relapse. The overall prognosis is excellent with no seminoma related deaths.
Introduction Seminoma accounts for 60% of testicular germ cell tumours (GCTs) with 80% of
with computed tomography (CT) of chest, abdomen and pelvis along with measurement of tumour markers: alpha-fetoprotein (AFP), β-human chorionic gonadotropin (β-HCG), and lactate dehydrogenase (LDH), represents standard initial management.
Following orchidectomy, management options for stage I seminoma comprise of active surveillance or adjuvant treatment. Regardless of approach, virtually all patients with seminoma are cured given the effectiveness of salvage chemotherapy at relapse (2).
For patients managed with active surveillance, a recent pooled international retrospective study of 1344 patients reported a relapse rate of 13% after a median follow up of 52 months, with no seminoma related deaths (3). A separate retrospective analysis suggested tumour size greater than 40mm in combination with rete testis invasion was associated with a significantly higher relapse rate (up to 32%), although prospective analyses have not confirmed these risk categories (4-5)
The MRC TE19/EORTC 30982 clinical trial evaluated adjuvant therapy in 1447 patients treated with a single dose of carboplatin AUC 7 (area under the curve x 7; n= 573) compared to para-aortic radiotherapy (n= 904). The trial demonstrated noninferiority of carboplatin with an overall relapse rate of 5.3% vs 4% after a median follow up of 6.5 years. Given the favourable toxicity profile and the avoidance of risk of radiotherapy-induced secondary malignancies, carboplatin has become the preferred adjuvant treatment (6-9).
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patients presenting with stage I disease (1). Radical inguinal orchidectomy, staging
4 Several trials have used a combined, risk-adapted approach in which patients with tumour size >40mm and rete testis invasion were offered adjuvant carboplatin, and low risk patients managed with surveillance (10,11). Within the TE19 trial, no results relating to possible risk factors of relapse were reported. It therefore remains unclear to what extent adjuvant chemotherapy reduces the risk in patients at higher risk of relapse as compared to lower risk patients.
Methods
Detailed methods are available in supplementary material. All consecutive patients with stage I seminoma treated with a single dose of adjuvant carboplatin AUC7 within a single supra-network regional team between July 1996 and October 2013 were identified. Carboplatin dose was calculated on radioisotope measured GFR uncorrected for body surface area using the Calvert formula (12).
Tumour characteristics, time to adjuvant chemotherapy, clinical outcomes, incidence of contralateral GCT and secondary malignancies, pattern of relapse and salvage treatment given at relapse were recorded. Cut off for follow-up was April 28th 2014.
Follow-up and treatment at relapse 29/517 (5.6%) patients within the cohort were treated within the TE19 trial and were followed-up 3 monthly for the first two years, 6 monthly in year 3 – 5 and annually thereafter for up to 10 years. At each visit, patients underwent clinical examination, chest x-ray and measurement of AFP, β-HCG, +/- LDH. Patients outside the clinical trial were followed-up similarly for a minimum of three years (3 monthly in year 1, 4 monthly in year 2, 6 monthly in year 3). CT abdomen was performed routinely at one year post orchidectomy and if clinically indicated thereafter. After discharge, followup was taken over by the general practitioner (GP). GPs were provided with written guidance requiring referral back to the regional specialist team on suspicion of relapse.
At relapse, patients with stage IIA relapse underwent dog-leg radiotherapy. Patients of good prognosis disease according to IGCCCG (International Germ Cell Cancer
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Patients and adjuvant treatment
5 Collaborative Group) classification, with stage IIB or higher relapse, had 3 cycles of standard dose BEP (bleomycin, etoposide, cisplatin) chemotherapy (13). Patients with intermediate prognosis received 4 cycles BEP. All salvage chemotherapy was co-ordinated via a single regional specialist centre.
Statistical methods Detailed statistical methods are available in supplementary material. The primary endpoint was 5-year relapse-free survival rate. Secondary objectives included overall survival, cancer-specific survival, incidence of contralateral GCT, risk factors predictive of relapse and incidence of secondary malignancies.
region referred back to participating centres, and all systemic treatment co-ordinated from a single regional centre (UHS), follow up is effectively much longer. To account for this we calculated “virtual” follow up as time from date of orchidectomy to data cut-off date (April 28th 2014) or death. Virtual follow up was used to calculate a “real world” follow up time but was not used for Kaplan Meier analysis of relapse. Time-toevent endpoints were analysed by Cox regression models and Kaplan-Meier methods.
Results Patient characteristics 517 eligible patients were identified (Table 1). Median age at diagnosis was 38 years (range 18 – 73). Hospital median follow-up was 3.9 years (range 0 – 17.8). Virtual median follow up was 6.5 years (range 0.3 – 17.8 years).8 years).0.3 – 17.8 years). Relapse rate and assessment of risk factors 21/517 (4%) patients have relapsed giving an estimated RFS of 97.4% (95% CI 96.0–98.9%) at 2 years and 95.0% (92.8–97.3%) at 5 years (Figure 1). 20/21 (95%) with good prognosis metastatic disease (IGCCCG classification) and 1/21 (4.8%) with intermediate prognosis disease (Table 2). The median time from orchidectomy to relapse was 22.7 months (range 12.5 – 109.5). 12/21 (57%) relapses occurred within 2 years and 17/21 (80%) within 3 years. The relapse rate for the whole
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Since all deaths are reported back to NHS records, all relapses occurring within
6 population after three years was 0.8% (4/517; after 49, 50, 53 and 108 months). There were no seminoma related deaths.
Three quarters of relapsing patients, 16/21 (76%) had elevated tumour markers at relapse (9 raised βHCG and LDH, 4 raised βHCG alone and 3 raised LDH alone) and / or an abnormal protocol scheduled CT. The main site of relapse was in the retroperitoneum (19/21; 90%) with 100% of patients with abdominal/ pelvic involvement at relapse.
13/21 (62%) patients were asymptomatic at relapse. 12/21 (57%) asymptomatic
during follow-up of a gastro-intestinal stromal tumour (GIST). 8/22 (36%) patients (including all relapses beyond 3 years) were symptomatic at relapse, with the most common presentation being abdominal pain (6/22; 27%). One patient (1/22; 5%) presented with a deep vein thrombosis and one (1/22; 5%) with a pulmonary embolus.
When continuous values for tumour size were used, we found some evidence that larger size was associated with higher risk of relapse. For each cm increase in primary tumour size, there was an increase in risk of relapse (univariate 19%, 95% CI 0-43%, p=0.05; multivariate 24%, 95% CI 1-52%, p=0.04; Table 3). Using a 4cm cut off, 5 year RFS was nearly double (5.9 v 3.3%) in those patients with larger primary tumours. There was no statistically significant association between relapse rate and the other variables assessed. Treatment of Relapse Treatment at relapse is summarized in Figure 2. 4/21 (19%) patients (those with stage IIA/B relapse) were treated with dog-leg radiotherapy, the remainder with salvage chemotherapy. 18/21 (86%) remain alive and disease free following initial salvage treatment alone.
3/21 (14%) relapsing patients suffered a second relapse (time from first to second relapse: 7.6, 11.2, and 12 months). One first relapsed with stage IIA disease and was treated with salvage radiotherapy to complete response. His 1-year planned CT scan identified a second relapse with disease in the abdomen and mediastinum. He received successful salvage EP chemotherapy but died from a myocardial infarction 7 years later.
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patients were detected in routine follow up, and one was discovered incidentally
7
The remaining 2 patients had stage IIC disease at first relapse and received standard dose, salvage BEP chemotherapy. Within 12 months, both had a second relapse, one identified by planned CT at 1 year, one identified by PET/CT at 11 months). The former patient received 3 cycles of TIP chemotherapy and remains alive and well without further relapse after a follow up of 11 years. The latter received salvage treatment with involved field retroperitoneal radiotherapy to a dose of 40Gy in 20 fractions, but suffered a third relapse within 3 months of treatment with enlarging pelvic nodal disease outside his radiotherapy field. He was treated with TIP chemotherapy and remains alive and disease free after a follow up of 5 years. .
20/517 (3.9%) patients were diagnosed with a separate contralateral testicular germ cell tumour (CTGCT). None of these patients relapsed from their initial seminoma.
3/517 (0.6%) patients were diagnosed with synchronous bilateral seminoma (treated with bilateral orchidectomy followed by one cycle of adjuvant carboplatin). 17/517 (3.3%) patients developed a new, metachronous CTGCT (9 seminoma, 8 nonseminoma) during follow up, with a median time to CTGCT of 8.8 years (range 0.8 – 22 years). Two patients developed CTGCT more than 20 years after their first diagnosis.
In the 9/517 (2%) patients who developed contralateral seminoma (all stage 1 disease), 2 underwent orchidectomy alone without additional adjuvant therapy (diagnosed within 2 years of the first GCT), 3 received another single dose of adjuvant carboplatin, and 4 received adjuvant radiotherapy (the diagnosis of these GCT were made prior to 2000). In the 8/517 (1.5%) patients who developed contralateral non-seminoma, 4 with stage 1 disease underwent orchidectomy alone and 4 with metastatic disease received BEP chemotherapy.
Secondary malignancies and overall survival As of April 28th 2014, 512/517 (99%) patients are alive and six patients have died. There were no seminoma related deaths. All deaths occurred after 5 years and the five-year cancer-specific survival rate was 100%. One patient (0.2%) died from metastatic disease from a second, contralateral non-seminomatous GCT primary, the other five patients died of causes unrelated to GCT (one suicide, one myocardial infarction, two bronchopneumonia and one rectal cancer).
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Contralateral testicular germ cell tumour
8
6/517 (1.2%) patients were diagnosed with non germ cell secondary malignancy during follow up. 3/6 within 12 months of receiving their adjuvant carboplatin chemotherapy (plasmacytoma, renal cell carcinoma, GIST) and 3/6 between 6 – 8 years after their adjuvant chemotherapy (rectal cancer, malignant melanoma, mantle cell lymphoma). Discussion
To our knowledge, we present the largest published series describing the clinical
cycle of post-operative adjuvant carboplatin chemotherapy dosed exclusively according to nuclear medicine estimation of GFR. We report real-world experience and confirm the low relapse rate and highly favourable prognosis for this large cohort of patients. Outcome overall is excellent with all relapsing patients responding to salvage treatment and no seminoma related deaths.
Our results are in keeping with the majority of patients (355/573; 62% patients in the chemotherapy arm) treated prospectively in the TE19 trial whose carboplatin dose was determined by nuclear medicine estimation of GFR and prospectively followed for up to 10 years. Our group and subgroup analysis of TE19 have previously highlighted the importance of accurate estimation of GFR and the potential for underdosing and higher relapse rate when GFR estimation formulae and lower doses of carboplatin are used (7,12).
In contrast to the very low rates of CTGCT seen in the pivotal phase III TE19 trial, the development of a contralateral primary in our series; 20/517 (3.9%), was as common as the development of systemic disease relapse following adjuvant carboplatin (21/517, 4%), but with a notably longer median time to event (median 8.8 v 1.9 years). In keeping with contemporary published series, our findings do not support the conclusion drawn by the TE19 trial that the risk of developing contralateral testicular tumours is reduced by adjuvant carboplatin (14,15). It should be noted however, that patients in our series did not routinely undergo biopsy of their contralateral testis at initial diagnosis unless there were clear risk factors for contralateral intratubular germ cell neoplasia (ITGCN); namely age < 30, testicular atrophy, raised follicle stimulating hormone (FSH), oliogspermia. Our findings emphasis the need for General Practitioners and patients to be aware of the risk and
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outcome and relapse data of patients with stage I seminoma treated with a single
9 long potential interval between initial orchidectomy and the development of a new, metachronous, contralateral primary following discharge from routine hospital surveillance..
Increasing primary tumour size was associated with a higher risk of relapse, and at a cut off of 4cm, 5 year RFS was nearly doubled in those patients with larger primary tumours (5.9 v 3.3%) although this cut-off did not reach statistical significance in uniand multivariable Cox regression analysis, possibly due to lack of events. Invasion of rete testis (p=0.75) or a combination of size and rete testis invasion (p=0.67) was not found to be a prognostic factor for relapse. Time to adjuvant chemotherapy did
60 days of surgery. This is in contrast to colorectal and breast cancer, whereby a longer time to adjuvant chemotherapy is associated with poorer outcome (16,17).
The fact that no other markers appear prognostic in our series have been influenced by the relatively low sample size and relapse rate seen in our cohort, in contrast to higher relapse rates seen in series evaluating surveillance.
The vast majority of relapses were first identified by per-protocol CT imaging +/blood tumour marker elevation, whilst CXR did not diagnose any recurrence. The presence of elevated markers in the majority of relapsing patients is in marked contrast to findings from the international active surveillance cohort, where only a small minority of patients had elevated markers at relapse (76 v 3%) (3). These findings may relate to the less intensive CT surveillance schedule adopted following adjuvant chemotherapy or inherent differences in tumour biology in patients relapsing following adjuvant chemotherapy. For patients followed according to our schedule, CXR appears to add little value whilst estimation of serial tumour markers remains important (18).
The median time to relapse was 22.7 months with no relapses detected before 12.5 months (range 12.5 – 109.5), a figure considerably longer than in the international surveillance series (14 months; range 2 – 84 months) (3). Although direct comparisons are difficult, adjuvant carboplatin chemotherapy may not only reduce the risk of relapse, but may also delay the time to relapse although again, this may be partially explained by our less intensive CT surveillance schedule.
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not appear to influence outcome although 75% of patient received treatment within
10 Regardless of follow up protocol and management approach, patient outcome following relapse after adjuvant treatment or surveillance strategies can be considered as essentially equivalent. Despite more intensive imaging and longer hospital follow up in the international surveillance series, the proportion of patients in each prognostic group at relapse were extremely similar, (20/21; 95% v 171/173; 99% presenting with good prognosis disease). Late relapse (beyond 3 years; 1% vs 0.8%) was rare in both groups and there was 100% disease specific survival.
Given equivalent outcomes, our results and the results of surveillance strategies feed into the ongoing debate around optimal management for stage I seminoma.
exposure, treatment related toxicity, and risk of / time to relapse all have a bearing on patient and clinician management choice and the design of any given follow up schedule.
Although our study is limited by the inherent weaknesses of any retrospective analysis, treatment was delivered within a single NHS with central supra-regional review for all patients. All consecutively eligible patients were included and all salvage chemotherapy delivered in a single centre. While median hospital follow-up appears rather short (3.9 years) due to the fact that many patients had to be censored at the time of discharge, the effective or “virtual” median follow up (6.5 years) is significantly longer.
In conclusion, adjuvant carboplatin is firmly established as a safe and effective adjuvant treatment. The risk of systemic relapse is low and similar to the risks of developing a new contralateral germ cell primary cancer. Systemic relapse beyond 3 years of follow-up was rare whilst median time to development of a new contralateral primary was over 8 years; clinicians and patients should remain alert to the possibility of a new primary occurring many years after initial diagnosis. Tumour size appears to be associated with a small but significant increase in risk of systemic relapse. We continue to recommend that all patients managed with adjuvant carboplatin undergo nuclear medicine calculation of GFR and that surveillance schedules include routine CT imaging and tumour markers.
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Healthcare costs, patient compliance and anxiety, surveillance CT radiation
11
No funding/ grant was received.
The authors have declared no conflicts of interest.
References: 1. Powles TB, Bhardwa J, Shamash J et al. The changing presentation of germ cell tumours of the testis between 1983 and 2002. BJU Int 95:1197-1200, 2005
3. Kollmannsberger C, Tandstad T, Jewett MA, et al. Patterns of Relapse in Patients With Clinical Stage I Testicular Cancer Managed With Active Surveillance. J Clin Oncol 2014; 56.2116 4. Tandstad T, Smaaland R, Laurell A, et al. Management of seminomatous testicular cancer: a binational prospective population-based study from the Swedish norwegian testicular cancer study group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(6):719-25. 5. Aparicio J, Maroto P, Margeli M, et al. Prognostic factors for relapse in stage i seminoma: a new nomogram derived from three consecutive, riskadapted studies from the spanish germ cell cancer group (SGCCG). Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2014. 6. Oliver RT, Mason MD, Joffe JK, et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet. 2005;366(9482):293-300. 7. Oliver RT, Mead GM, Coleman R, et al. Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214). Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(8):957-62. 8. Mead GM, Fossa SD, Roberts JT, et al. Randomized trials in 2466 patients with stage I seminoma: patterns of relapse and follow-up. Journal of the National Cancer Institute. 2011;103(3):241-9. 9. Richiardi L, Scelo G, Olsen JH, et al. Second malignancies among survivors of germ-cell testicular cancer: a pooled analysis between 13 cancer registries. International journal of cancer Journal international du cancer. 2007;120(3):623-31.
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2. Boujelbene N, Cosinschi A, Bhagwati S et al. Pure seminoma: A review and update. Radiation Oncology 2011, 6:90.
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10. Beyer J, Albers P, Busch J, et al. Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2013;24(4):878-88. 11. Aparicio J, Maroto P, del Muro XG et al. Risk-adapted treatment in clinical stage I testicular seminoma: the third Spanish Germ Cell Cancer Group study. J Clin Oncol 2011: 29:4677-4681.
13. International Germ Cell Cancer Collaborative Group (IGCCCG). The International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancer. J Clin Oncol 1997; 15: 594-603. 14. Dieckmann KP, Kulejewski M, Pichlmeier U et al. Diagnosis of contralateral testicular intraepithelial neoplasia (TIN) in patients with testicular germ cell cancer: Systematic two-site biopsies are more sensitive than a single random biopsy. Eur Urol 51:175–185 (2007) 15. Powles T, Robinson D, Oliver T et al. The long-term risks of adjuvant carboplatin treatment for stage I seminoma of the testis. Ann Oncol. 2008 Mar;19(3):443-7. Epub 2007 Nov 28 16. Biagi JJ, Raphael MJ, Mackillop WJ et al. Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systemic review and meta-analysis. JAMA 2011 Jun 8; 305 (22): 2335-42 17. de Melo Gagliato D, Gonzalez-Angulo AM, Lei X et al. Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer. Journal of Clinical Oncology 2013. 49.7693. 18. Tolan S, Vesprini D, Panzarella T, et al. No role for routine chest radiography in stage I seminoma surveillance. European urology. 2010;57(3):474-9.
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12. Cathomas R, Klingbiel D, Geldart TR, Wheater M, et al. Relevant risk of carboplatin underdosing in cancer patients with normal renal function using estimated GFR: lessons from a stage I seminoma cohort. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2014;25(8):1591-7.
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Figure 2. Treatment at relapse
517 patients
21 patients relapsed First relapse
17 chemotherapy
1
Second relapse
1 radiotherapy
Third relapse
1 chemotherapy (TIP)
18 alive and disease free
1
2 chemotherapy (TIP, EP)
2 alive and disease free, 1 died of myocardial infarction
1 alive and disease free
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1
4 radiotherapy
Table 1. Patient Characteristics, n=517 Age (years) Median (range)
38 (18–73)
Tumour size (mm) ≤40mm
333 (64%)
>40mm
169 (33%)
Unknown
15 (3%)
Rete testis invasion 331 (64%)
Yes
166 (32%)
Unknown
20 (4%)
Tumour >40mm and rete invasion No
427 (82%)
Yes
65 (13%)
Unknown
25 (5%)
Extratesticular invasion No
397 (77%)
Yes
67 (13%)
Unknown
53 (10%)
Time to adjuvant carboplatin (days) ≤30
103 (20%)
31–60
284 (55%)
> 60
112 (22%)
Unknown
18 (3%)
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No
Table 2. Patient characteristics at relapse; n=21 Setting of relapse detection Detected at routine follow up
13 (62%)
Unplanned
8 (38%)
First indicator of relapse in asymptomatic patients (N=14) Abnormal CT
11 (79%)
Elevated tumour markers
2 (14%)
Other abnormal imaging
1 (7%) (PET – unplanned & asymptomatic)
Yes
16 (76%)
No
4 (19%)
Unknown
1 (5%)
Site of relapse Retroperitoneal LN only
17 (81%)
Iliac LN only
1 (5%)
Multiple nodal sites
2 (9%) 1x retroperitoneal + mediastinal 1x inguinal + iliac
Multiple nodal and visceral sites
1 (5%) Retroperitoneal, mediastinal, liver
Salvage therapy at 1st relapse Chemotherapy
17 (81%)
Dog leg radiotherapy
4 (19%)
Salvage chemotherapy regime at 1st relapse BEP x 3
7 (41%)
BEP x 4
7 (41%)
Modified BEP
3 (18%)
IGCCCG classification Good prognosis
20 (95%)
Intermediate prognosis
1 (5%)
Response to salvage therapy Complete response, marker negative
6 (29%)
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Elevated LDH or β-HCG at relapse
Partial response, marker negative
14 (66%) Unknown
1 (5%)
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5-year RFS 95.0%
HR (95% CI), p-value univariable
All patients
No of Relapse relapse rate 21/517 4%
Tumour size ≤ 4cm >4cm unknown
11/333 3.3% 10/169 5.9% 0/15 0%
95.5% 93.6%
1 (ref) 1.9 (0.8–4.6), p=0.13
1 (ref) 2.2 (0.9–5.8), p=0.10
1.2 (1.0–1.4), p=0.05
1.2 (1.0–1.5), p=0.04
1 (ref) 0.9 (0.3–2.6), p=0.89
Tumour size (continuous*) Rete testis invasion No Yes Unknown
13/331 3.9% 7/166 2.2% 1/20 5.0%
95.1% 94.9%
1 (ref) 1.2 (0.5–2.9), p=0.75
Size >4cm AND rete testis invasion No Yes unknown
17/427 4.0% 3/65 4.6% 1/25 4.0%
95.1% 94.0%
1 (ref) 1.3 (0.4–4.5), p=0.67
Age ≤ 29 30–59
6/86 7.0% 14/418 3.3%
89.9% 96.1%
2.2 (0.9–5.9), p=0.10 1 (ref)
HR (95% CI), p multivariable** Table 3. Uni- and multivariate analysis of possible risk factors for relapse
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≥ 60
1/11
9.1%
88.9%
2.9 (0.4–22.0), p=0.30
Lymphovascular invasion No Yes Excess Smear artefact Unknown
15/378 3/52 2/50 1/37
4.0% 5.8% 4.0% 2.7%
95.2% 93.5% 94.3%
1.0 (ref) 1.4 (0.4–4.9), p=0.58 0.9 (0.2–4.0), p=0.90
1 (ref) 0.7 (0.1–3.4), p=0.65 0.7 (0.2–3.2), p=0.64
Extratesticular invasion No Yes Unknown
15/397 3.8% 3/67 4.5% 3/53 5.7%
95.4% 94.7%
1 (ref) 1.2 (0.3–4.0), p=0.82
1 (ref) 1.1 (0.3–4.0), p=0.88
Time to adjuvant carboplatin ≤ 30 days 31–60 days >60 days unknown
4/103 14/284 3/112 0/18
95.4% 93.9% 96.4%
1 (ref) 1.4 (0.4–4.1), p=0.59 0.7 (0.2–3.1), p=0.63
3.9% 4.9% 2.7% 0.0%
per cm increase of tumour size ** Variables without HR have not been included; tumour size has been included either continuous or with the 40 mm cutoff. The values shown are from the model with the continuous version of tumour size, but are similar in the model with the 40 mm cutoff.