Management of Stage 1 Seminoma

Introduction

Management decision making after orchidectomy for stage 1 seminoma is a common urological dilemma. It requires an understanding of the disease’s natural history, treatment options, outcomes and risks. Options for post-orchidectomy management (surveillance, adjuvant chemotherapy, adjuvant radiotherapy) are explored in this module.

After orchidectomy and CT imaging confirms CS1 seminoma, a decision needs to be made by patient and clinician about subsequent management. The first decision is for surveillance or adjuvant treatment. Attempts have been made to stratify the patient for risk of relapse. Although this dogma has crept into urological practice, it is not based on high-level evidence. Section 1 outlines the rationale and evidence for risk stratification. Section 2 describes surveillance protocols and outlines advantages/disadvantages of this approach.

If adjuvant treatment is decided on, the next step is to explore the options of single agent carboplatin or radiotherapy. Sections 3 and 4 outline the use of adjuvant carboplatin and radiotherapy, respectively. Finally, section 5 briefly outlines potential strategies for reducing ionising radiation exposure during follow up, whichever management option is used for CS1 seminoma.

1. Should we risk stratify CS1 seminoma to help decide on surveillance or adjuvant treatment?

Following orchidectomy, patients with stage 1 seminoma can be managed by surveillance or treated with adjuvant therapy in the form of either single agent carboplatin chemotherapy or radiotherapy. The aim of management is cure, and cure rates are very high (>99%) with all treatment options, even after relapse of stage 1 seminoma (Cullen, 2012). Contemporary series demonstrate that between 15-30% of patients with stage 1 seminoma will relapse if they receive no adjuvant treatment. These are patients with sub-clinical metastatic disease in the retroperitoneum. Essentially, the aim of adjuvant treatment is to reduce relapse rates, which reduces the number of men that require BEP (bleomycin, etoposide, cisplatin) chemotherapy as treatment for relapse.

If all men with stage 1 seminoma receive adjuvant treatment, the overtreatment rate is high. Is it possible to risk stratify these men, to identify those at higher risk of relapse (those who would be most likely to benefit from adjuvant treatment), and to identify those men at low risk of relapse and avoid adjuvant overtreatment for them?

Two factors have been considered potential risk predictors to stratify patients when deciding on post-orchidectomy management.

• Tumour size >4cm and presence of rete testis invasion may be predictors of relapse (Aparicio, 2011)

Note that these factors have not been comprehensively, prospectively validated in the setting of surveillance versus one dose of carboplatin. Aparicio et al. (2011) have reported early findings (five-year results) of a prospective study of surveillance versus two doses of carboplatin based on presence of risk factors, but longer follow-up is need before risk-adaptation can accepted as standard of care.

The available data (Aparicio, 2011. Aparicio, 2005) on outcomes based on these two risk factors are as follows:

• Neither risk factor present, no adjuvant treatment: 6 –12% relapse
• Both risk factors present, no adjuvant treatment: 32% relapse

It is helpful to review the EAU guideline comments on stage 1 seminoma risk stratification, which are reproduced verbatim here:

"Using tumour size > 4 cm and rete testis invasion, patients with seminoma stage I may be subdivided into a low-and high-risk group of occult metastatic disease. Patients with and without both risk factors have a risk of occult disease of 32% and 12%, respectively. These risk factors were introduced by an analysis of retrospective trials. A prospective trial based on these risk factors (no risk factors: surveillance; both risk factors: two courses of carboplatin AUC 7) showed the feasibility of a risk-adapted approach. Early data with limited follow-up indicate that patients without either risk factor have a 6.0% risk of relapse at 5 years. Patients in the high-risk group treated with carboplatin experienced a 1.4% relapse rate at mean follow up of 34 months.

However, given the fact that cure is achieved in ~100% in patients with stage I seminoma whatever therapy used (adjuvant radiotherapy, adjuvant chemotherapy, or surveillance) and that the relapse rate in large surveillance series not using risk factors is about 15-20% indicates a risk of over-treatment. Therefore, the therapeutic decision should be shared with an informed patient” (Albers, 2011).

This EAU statement does not actually give us a recommendation on the use of risk-adaptation, but rather it summarises the evidence and concludes that patients should be involved in the decision making process, which of course should be standard practice. If patients can understand the implications of this retrospective data, they may be able to draw their own conclusions and reach a treatment decision. Some, however, will rely on the treating physician to make the decision for them; in which case current expert opinion emphasises the weakness evidence for utility of risk-adaptation, and it probably should not be used unless higher-level evidence becomes available.

2. Surveillance in CS1 Seminoma

2.1 Should we use surveillance?

If patients under surveillance relapse, there is 99% cure rate with subsequent bleomycin, etoposide and cisplatin chemotherapy. This point is used as an argument for putting all patients on surveillance; the cancer specific survival is identical whichever management option (surveillance, adjuvant radiotherapy, adjuvant carboplatin) is chosen. The relapse figures indicate that default adjuvant treatment with either radiotherapy or carboplatin will over-treat 70%-85% of patients. If this ‘surveillance for all’ strategy is used, the majority of patients (the non-relapsing 70%-85%) will avoid unnecessary adjuvant treatment.

However, if a patient does relapse, he will need three full cycles of BEP chemotherapy. This regimen is associated with significant risk of treatment side effects. We do not know what the long term side effects of a single dose of carboplatin are, but if there are any, they are likely to be very significantly less than those associated with three cycles of BEP. This is an argument for using adjuvant carboplatin rather than surveillance in all patients; although there will be a significant overtreatment rate, the relapse rate is reduced from 10-30% to ~2%, i.e. only ~2% of patients will require BEP chemotherapy, compared to 15-30%.

2.2 Surveillance Criteria

Traditional thinking on suitability for surveillance aimed to identify those at lower risk of relapse by considering risk factors (size of primary tumour and rete testis invasion). If risk factor stratification is accepted as valid, traditional protocols have only included patients with 1 risk factor.

Likewise, traditionally, only patients deemed ‘motivated’ (i.e. a man that will reliably attend for surveillance visits, which are more frequent than for those who have had adjuvant treatment) were accepted for surveillance.

These criteria become invalid with the current drive to accept all patients with stage 1 seminoma for surveillance.

2.3 Surveillance Protocols

There is no single agreed or validated surveillance protocol. The aim of surveillance is to detect disease recurrence at an early stage, whilst limiting unnecessary investigation and CT-associated radiation exposure.

Minimum recommendations are: first 24 months: six visits and four CT scans, next 36 months, six visits and three CT scans, followed by yearly visits with zero or one annual CT scan up to 10 years (van As et al., 2008, Albers et al., 2011, NCCN 2009).

How long should surveillance be continued for? Modern surveillance programs (i.e. for patients who have not received adjuvant treatment) indicate an overall relapse rate of 12–15% in the first three- four years, with a 10-year overall relapse rate of approximately 18%–20%. Therefore, the vast majority of relapses will occur in the first four years. However, most surveillance programs suggest follow-up for ten years.

3. Adjuvant carboplatin chemotherapy in CS1 Seminoma

3.1 Should we use carboplatin?

Historically, adjuvant radiation therapy was the treatment option of choice in stage 1 seminoma. The MRC (TE19) / EORTC (30982) ran and reported the seminal, randomised trial of adjuvant carboplatin versus radiotherapy (Oliver et al., 2005). Relapse rates were similar in the two arms of the study, and true non-inferiority of carboplatin was confirmed in the 2011 update of the trial (Oliver et al., 2011) along with statistical confirmation of a reduction in contralateral GCT. Interestingly, the pattern of relapse varied; patients treated with carboplatin were more likely to relapse in sub-diaphragmatic lymph nodes, while patients treated with radiotherapy typically relapsed in nodes outside the treatment field (supra-diaphragmatic). Acute toxicities were less for patients receiving carboplatin.

Adjuvant carboplatin reduces relapse compared to surveillance. The table below shows relapse figures from various studies. Recall that relapse rates without adjuvant treatment are 20-30%.

Authors	No of cases	Cycles of carboplatin	Mean FU (months)	Relapses (%)
Krege et al.	43	2	28	0
Dieckmann	93	1	48	8.6
et al.	32	2	52	0
Oliver et al.	146	1		0.7
Reiter et al.	107	2	74	0

Figure 2. Relapse rates after adjuvant carboplatin for CS1 seminoma

3.2 One or two doses of adjuvant carboplatin?

Historically, two doses of carboplatin were used for adjuvant treatment. With the move to AUC(7) dosing, Oliver et al (1994) demonstrated one cycle was as effective as two, and this has generally been adopted.

Some still advocate two cycles; there are no high-level data proving that two cycles have improved efficacy, although there are suggestions that dose intensity may be important.

3.3 What is the toxicity of adjuvant carboplatin?

Powles et al. (2008) reported a retrospective single institution series of 20 years’ experience with adjuvant carboplatin. Two doses were used in the first five years of the study and subsequently a single dose. Nearly 200 patients were included, and at 9 years median follow-up there was neither evidence of increased cardiovascular toxicity nor an increase in second malignancies (haematological or solid organ) These data are still immature, and longer follow-up is required to confirm absence of toxicity.

Steiner et al. (2011) reported a retrospective multicentre experience of two cycles of carboplatin, which were generally well tolerated; bone marrow suppression was common, but other acute complications were rare. Long term, there were five second malignancies and 3 three cardiovascular events in 276 patients in this study.

4. Adjuvant radiotherapy in CS1 Seminoma

Adjuvant radiotherapy was the gold standard adjuvant treatment for CS1 seminoma many years. Radiotherapy is effective in reducing relapse; risk of relapse at 10 and 20 years is 1% and 2%, respectively (Hallemeier, 2013). However, adjuvant radiotherapy may be associated with long-term toxicity (cardiovascular events and second malignancy). Many centres do not now offer radiotherapy as adjuvant treatment, and some consider it an outdated adjuvant treatment fro CS1 on account of toxicity. For example, a recent survey of 52 medical oncologists in Australia documented the management for 470 CS1 seminoma patients. Management was in the form of surveillance in 33%, radiotherapy in 5% and adjuvant carboplatin in 62% of patients (Grimison et al., 2013).

4.1 Adjuvant radiotherapy protocol

The standard irradiation dose is 20 Gy in 10 daily (2 Gy) fractions, below the diaphragm, to include para-aortic lymph nodes. The ipsilateral ilio-inguinal nodes should be included in the following scenarios:

• previous orchidopexy
• previous pelvic surgery
• previous hernia surgery
• scrotal violation at orchidectomy.

Prophylaxis to the mediastinum is unnecessary, as relapse rarely occurs at this site.

4.3 Adjuvant radiotherapy long-term toxicity

The main concerns for DXT long-term toxicity are:

• increased risk of second cancers
• Increased risk of cardiovascular events

The mechanism for second cancer induction is straightforward – the carcinogenic effect of radiotherapy. Traditionally, a higher radiation dose has been used, and the follow up reports now being published are of a cohort of patients exposed to greater doses than currently used. For example, in Horwich et al. (2014), doses between 30-40Gy were the most commonly used, compared to 20Gy in contemporary practice.

There is very little data indicating an increased risk of cardiovascular events after treatment for CS 1 seminoma with radiotherapy. Indeed, a theoretical causal mechanism with subdiaphragmatic radiotherapy is hard to construct.

Despite this, Fossa et al. (2007) reported that testicular cancer patients who were younger than 35 years at diagnosis and were treated with radiotherapy alone in 1975 or later had higher mortality from all circulatory diseases (SMR = 1.70, 95% CI = 1.21 to 2.31) compared with the general population.

The Mayo Clinic reported that long term risks of major cardiac events and second malignancies at 20 years after adjuvant radiotherapy for CS1 seminoma were 12% and 19%, respectively (Hallemeier, 2013). A recent SEER registry review of over 9000 patients treated for stage 1 seminoma, followed for a median of 12 years, demonstrated excess morbidity associated with adjuvant radiotherapy, linked to second malignant neoplasms but not to cardiovascular mortality (Beard et al. 2013).

Horwich et al (2014) recently reported follow up of 2629 CS1 seminoma patients treated with adjuvant radiotherapy between 1960 and 1992, contributing 51 151 person-years of follow-up. The standardised incidence ratio (SIR) for second cancer incidence (excluding non-melanoma skin cancer and second testicular cancer) was 1.53 (P>0.0001) giving an absolute excess risk of 29.4 cancers per 10000 person-years. Despite the highly significant SIR, the absolute numbers of second cancers are relatively low.

Site	Number observed	Number expected	SIR	P	95%CI
Pancreas	26	8.3	3.14	0.0001	2.13-4.60
Bladder	49	19.9	2.46	0.0001	1.86-3.25
Stomach	26	13.5	1.93	0.01	1.31-2.83
Prostate	80	60.3	1.33	<0.05	1.07-1.65
Colorectal	55	41.6	1.32	<0.05	1.02-1.72

Figure 4 – Second cancers that were significantly more frequent in patients treated with adjuvant radiotherapy than expected in the general population. SIR – standardised incidence ratio. Adapted from Horwich et al. (2014).

5. Can we reduce or avoid CT-associated ionising radiation in stage 1 seminoma follow-up?

Imaging techniques involving ionising radiation confer a risk of second malignancy, and repeat exposure confers additive risk (Berrington de Gonzalez, 2004).

Chest CT delivers a radiation dose equivalent to 400 chest radiographs (8mSv vs 0.02mSv). Adding abdominal to chest CT increases exposure to 20mSv. It has been suggested that this 20mSv exposure results in a 1:1000 lifetime risk of second cancer/leukaemia over the subsequent 40 years (Dalal et al, 2006). A chest X-ray is a low-cost and low-exposure (0.02mSV) investigation, which is likely to pick up nodules of 1cm or greater in the lungs, pleurally based lesions or mediastinal masses (Dalal et al, 2006). It is reasonable, therefore to consider chest X-ray as an alternative to chest CT where indicated.

There has been recent interest in the potential for MRI to replace CT for cross-sectional imaging follow up of testis cancer. There is no current systematic comparison of CT to MR in this setting (Hanson, 2009), and MR should only be used in clinical trials, as sequences and interpretation have not be fully elucidated. A randomized MRC trial is currently investigating the frequency and modality of imaging in stage 1 seminoma. It compares abdominal imaging in four arms using a 2x2 trial structure; seven CTs, three CTs, seven MRIs, or three MRIs (MRC Clinical Trials Unit, 2008).

Summary

• Risk stratification to guide management has not been prospectively validated, and may not be a useful approach
• Post-orchidectomy relapse rates can be reduced by adjuvant treatment, but this confers a high level of overtreatment compared to surveillance
• Increasing evidence suggests there is late toxicity associated with adjuvant radiotherapy, and some groups have abandoned this as a treatment option.
• Single dose carboplatin is as effective as radiotherapy in reducing relapse. The long-term toxicity of single dose carboplatin is not known.

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