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. 2011 Jan 25;2011:1807.

Testicular cancer: seminoma

Peter Chung 1,#, Padraig Warde 2,#
PMCID: PMC3217763  PMID: 21477387

Abstract

Introduction

More than half of painless solid swellings of the body of the testis are malignant, with a peak incidence in men aged 25 to 35 years. Most testicular cancers are germ cell tumours and half of these are seminomas, which tend to affect older men and have a good prognosis.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in men with stage 1 seminoma (confined to testis) who have undergone orchidectomy? What are the effects of treatments in men with good-prognosis non-stage 1 seminoma who have undergone orchidectomy? What are the effects of maintenance chemotherapy in men who are in remission after orchidectomy and chemotherapy for good-prognosis non-stage 1 seminoma? What are the effects of treatments in men with intermediate-prognosis seminoma who have undergone orchidectomy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 29 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review, we present information relating to the effectiveness and safety of the following interventions: chemotherapy (maintenance, adjuvant, single-agent carboplatin, 3 or 4 cycles, different number of cycles of adjuvant, using bleomycin added to vinblastine plus cisplatin, using etoposide plus cisplatin with or without bleomycin, adding higher doses to a 2-drug chemotherapy regimen using cisplatin or vinblastine); radiotherapy (different adjuvant regimens [20 Gy in 10 fractions to para-aortic area, 30 Gy in 15 fractions to para-aortic area and iliac nodes], different drug combinations, 30–36 Gy in 15–18 fractions); and surveillance.

Key Points

More than half of painless solid swellings of the body of the testis are malignant, with a peak incidence in men aged 25 to 35 years.

  • Most testicular cancers are germ cell tumours and about half of these are seminomas, which tend to affect older men and have a good prognosis.

In men with seminoma confined to the testis (stage 1), standard treatment is orchidectomy followed by radiotherapy, chemotherapy, or surveillance. All 3 management options are associated with cure rates approaching 100% because of successful salvage therapy.

  • Adjuvant chemotherapy reduces the risk of relapse after orchidectomy compared with surveillance, but is associated with short-term adverse effects (nausea, diarrhoea, and indigestion) and possible long-term risks of reduced fertility and development of second malignancies.

  • We don't know which is the most effective chemotherapy regimen, or the optimum number of cycles to use. The high cure rate with standard therapy makes it difficult to show which alternative therapy is superior.

  • Toxicity is lower, but efficacy the same, with adjuvant irradiation of 20 Gy in 10 fractions compared with 30 Gy in 15 fractions, or with irradiation to para-aortic nodes compared with ipsilateral iliac nodes.

In men with good-prognosis non-stage 1 seminoma who have had orchidectomy, radiotherapy may improve survival and be less toxic than chemotherapy, except in men with large-volume disease, in whom chemotherapy may be more effective.

  • Combined chemotherapy may be more effective than single agents, but 3 cycles seem to be as effective as 4 and with less toxicity.

  • A standard radiotherapy treatment comprises 30 to 36 Gy in 15 to 18 fractions (2 Gy per fraction), although we don't know whether this is more effective than other regimens.

In men who are in remission after orchidectomy plus chemotherapy for good-prognosis, non-stage 1 seminoma, further chemotherapy is unlikely to reduce relapse rates or increase survival.

  • Chemotherapy increases survival in men with intermediate-prognosis seminomas who have had orchidectomy; although evidence for this is derived mostly from treatment of intermediate-prognosis non-seminoma, it is likely to be generalisable to intermediate-prognosis seminoma.

Clinical context

About this condition

Definition

Although testicular symptoms are common, testicular cancer is relatively rare. Solid swellings affecting the body of the testis have a high probability (>50%) of being due to cancer. The most common presenting symptom of cancer is a painless lump or swelling (>85%). About 10% of men present with acute pain and 20% to 30% experience a heavy dragging feeling or general ache. These symptoms may lead the cancer to be initially wrongly diagnosed as epididymitis or acute testicular torsion. A small percentage present with symptoms of metastatic disease and infertility. Testicular germ cell tumours are divided into seminomas, which make up about half of all testicular tumours and which occur in older patients; and non-seminomatous tumours, comprising teratomas, mixed tumours, and other cell types, which tend to occur in younger patients. Several staging systems for testicular cancer have been developed (see table 1 ). The most commonly used system for metastatic disease in current practice is the International Germ Cell Consensus Classification, which classifies testicular tumours as good prognosis, intermediate prognosis, or poor prognosis.[1] This system is less useful in seminoma, as 90% are classified as good prognosis and the majority of men with seminoma present with disease confined to the testis. Thus we have further divided good-prognosis seminoma into stage 1 (confined to testis) and non-stage 1, based on the Royal Marsden and TNM staging systems.

Table 1.

Staging systems for testicular cancer (see text).

  Royal Marsden TNMS (broad categories only) IGCCC
Confined to the testis, no evidence of metastases I Stages 0–1B Good prognosis
Confined to testis with rising serum markers IM Stage 1S Good prognosis
Abdominal node metastases II Stage II Good prognosis
2 cm diameter or less IIA IIA Good prognosis
2–5 cm diameter IIB IIB Good prognosis
5 cm diameter or less IIC IIC Good prognosis
Supradiaphagmatic nodal metastases III Stage III covers these stages differently, but includes all those with nodes and distant metastases, converging again below Good prognosis
Mediastinal IIIM   Good prognosis
Supraclavicular, cervical, or axillary IIIN   Good prognosis
No abdominal node metastases IIIO   Good prognosis
Node size/disease volume III MNO/ABC   Good prognosis
Extralymphatic metastases IV   Good prognosis
Lung IV L1, 2, or 3, depending on number of metastases Stage IIIB M1A and B Good prognosis
Liver, brain, bone Liver H+, Bone Bo+, Brain Br+ Stage IIIC Intermediate prognosis + non-pulmonary visceral metastases
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IGCCC, International Germ Cell Consensus Classification.

Incidence/ Prevalence

There are about 1400 new cases of testicular cancer (seminomas, non-seminomas) in the UK annually, with the peak incidence in men aged 25 to 35 years.[2] This cancer comprises 1% of all cancers in men and is the most common tumour in young men. Incidence varies markedly with geography; a study among 10 cancer registries in northern Europe identified a 10-fold variation, with the highest incidence rate in Denmark (7.8 per 100,000) and lowest in Lithuania (0.9 per 100,000).[3] Recent reviews of the incidence of testicular cancer have reported a clear trend towards increased incidence during the past 30 years in the majority of industrialised countries in North America, Europe, and Oceania.[4] [5]

Aetiology/ Risk factors

There seem to be both individual and environmental risk factors for testicular cancer.[2] Having a close relative who has had testicular cancer increases the risk of getting the disease. Inherited genetic factors may play a role in up to 1 in 5 cancers. Men are more at risk of developing testicular cancer if they have a history of developmental abnormality (e.g., maldescent or gonadal dysgenesis); previous cancer in the opposite testis; HIV infection, AIDS, or both; torsion; trauma (although this may be coincidental); and Klinefelter's syndrome.[2] The wide geographical variation and changes over time in incidence rates imply that there are likely to be important environmental factors, because the individual risk factors described above do not explain global disease patterns.[3]

Prognosis

Testicular tumours generally have a good prognosis. The International Germ Cell Consensus Classification (see table 1 ) classifies 90% of all seminomas as "good prognosis". These include tumours confined to the testis (stage 1 of the Royal Marsden or TNM system) as well as tumours with nodal but no non-pulmonary visceral metastases. The remaining 10% of seminomas, including those with non-pulmonary visceral metastases, are classified as "intermediate prognosis". No seminomas are classified as "poor prognosis". Untreated disease will progress over time, leading to large local tumours and distant spread. The first site of spread is the lymphatic system, particularly the para-aortic and pelvic lymph nodes. Haematological spread leading to lung, liver, and brain metastases is less common in seminomas; 75% of men present with stage 1 disease. Overall survival in the "good prognosis" category is expected to be in the order of 86% at 5 years, and of the 10% who present as "intermediate prognosis", 5-year survival is in the order of 72%. However, these data are based mainly on people with non-seminomas.[1] Seminoma is a radio-sensitive tumour, and the standard treatment for stage 1 seminoma is orchidectomy followed by adjuvant radiotherapy, adjuvant chemotherapy, or surveillance.[6] Clinical observation suggests that, with these approaches, cure rates are nearly 100%.

Aims of intervention

To reduce morbidity, mortality, and relapse rates, while minimising adverse effects.

Outcomes

Mortality; cure rates; relapse rates, including relapse-free survival; quality of life; adverse effects of treatment.

Methods

Clinical Evidence search and appraisal June 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2010, Embase 1980 to June 2010, and The Cochrane Database of Systematic Reviews, June 2010 [online] (1966 to date of issue). When editing this review we used The Cochrane Database of Systematic Reviews 2010, issue 2. An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and observational studies and RCTs in any language, with any level of blinding, no minimum size, and with any maximum loss to follow-up. There was no minimum length of follow-up required to include studies. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. Wherever possible we have adhered to the TNM staging system and International Germ Cell Consensus Classification (IGCCC) when assessing the evidence. However, for the purposes of this review, we have chosen to describe the evidence in 2 broad groups, which consist of data applicable to those with seminomas clinically confined to the testis (stage I) and all others with evidence of disease beyond the testis (non-stage I). In the latter group, wherever possible, we have differentiated data specific to good-prognosis and intermediate-prognosis seminomas from data on all testicular tumours (in keeping with the International Germ Cell Consensus Classification [IGCCC]).To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Testicular cancer: seminoma.

Important outcomes Cure rates, Mortality, Relapse rates
Studies (Participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of treatments in men with stage 1 seminoma (confined to testis) who have undergone orchidectomy?
1 RCT and 1 cohort study (1604) Relapse rates Adjuvant radiotherapy versus adjuvant chemotherapy 4 0 0 0 0 High
3 cohort studies (845) Relapse rates Surveillance versus adjuvant radiotherapy in men who have undergone orchidectomy 2 –1 0 0 0 Very low Quality point deducted for incomplete reporting of results
3 cohort studies (741) Relapse rates Surveillance versus adjuvant chemotherapy in men who have undergone orchidectomy 2 0 0 0 0 Low
1 (478) Relapse rates Para-aortic strip adjuvant radiotherapy versus para-aortic plus ipsilateral adjuvant radiotherapy 4 0 0 0 0 High
1 (625) Relapse rates 20 Gy adjuvant radiotherapy versus 30 Gy adjuvant radiotherapy 4 0 0 0 0 High
2 (324) Relapse rates Different numbers of cycles of adjuvant chemotherapy versus each other 2 0 0 0 0 Low
1 cohort study (199) Mortality Different numbers of cycles of adjuvant chemotherapy versus each other 2 –1 0 0 0 Very low Quality point deducted for sparse data
What are the effects of treatments in men with good-prognosis non-stage 1 seminoma who have undergone orchidectomy?
1 (270) Relapse rates Etoposide plus cisplatin versus etoposide plus carboplatin 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting. Directness point deducted for inclusion of men with mixed tumours
1 (270) Mortality Etoposide plus cisplatin versus etoposide plus carboplatin 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of men with non-seminomas
1 (156) Relapse rates Etoposide plus cisplatin plus bleomycin versus etoposide plus cisplatin 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of men with non-seminomas
1 (156) Mortality Etoposide plus cisplatin plus bleomycin versus etoposide plus cisplatin 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of men with non-seminomas
1 (164) Relapse rates Two-drug regimen versus five-drug regimen 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of men with non-seminomas
1 (164) Mortality Two-drug regimen versus five-drug regimen 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of men with non-seminomas
1 (212) Relapse rates Bleomycin plus vinblastine plus cisplatin versus cisplatin plus vinblastine 4 0 0 –1 0 Moderate Directness point deducted for inclusion of men with non-seminomas
1 (212) Mortality Bleomycin plus vinblastine plus cisplatin versus cisplatin plus vinblastine 4 0 0 –1 0 Moderate Directness point deducted for inclusion of men with non-seminomas
1 (114) Cure rates Adding higher versus lower doses of cisplatin to two-drug regimens 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of men with teratoma
1 (134) Cure rates Adding higher versus lower doses of vinblastine to two-drug regimens 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of men with teratoma
2 (350) Relapse rates Three versus four cycles of chemotherapy 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of men with teratoma
2 (978) Mortality Three versus four cycles of chemotherapy 4 –1 –1 –1 0 Very low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for inclusion of men with teratoma
2 (361) Relapse rates Single-agent versus combined chemotherapy 4 –1 –1 –1 0 Very low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for few comparators
2 (361) Mortality Single-agent versus combined chemotherapy 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for few comparators
What are the effects of maintenance chemotherapy in men who are in remission after orchidectomy and chemotherapy for good-prognosis non-stage 1 seminoma?
2 (296) Relapse rates Maintenance chemotherapy versus no maintenance chemotherapy 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of men with teratoma
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We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Adjuvant treatment

Anticancer treatment given after surgical removal of the primary tumour and in the absence of any detectable residual tumour in order to prevent or reduce the risk of subsequent relapse.

Gonadal dysgenesis

A condition in which primordial germ cells reach the testes but are progressively destroyed so that few remain by the time of puberty. It is clinically characterised by small testicular size, poor testicular function, and infertility.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Orchidectomy

Total surgical removal of the affected testicle; also known as orchiectomy. When it is done for suspected malignancy, orchidectomy is often done via the trans-inguinal route in order to minimise the risk of tumour spillage and consequent local recurrence.

Surveillance

A policy of systematic clinical, biochemical, and radiological follow-up undertaken with the aim of detecting relapse at an early stage so that effective therapy can be given promptly. Current guidelines (European Society for Medical Oncology)[28] [29] recommend follow-up for 5 years after initial treatment. However, relapse can occur after this, and others recommend follow-up for 10 years.[30]

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Peter Chung, Radiation Medicine Program, Princess Margaret Hospital, Assistant Professor, Radiation Oncology, University of Toronto Toronto, Canada.

Padraig Warde, Princess Margaret Hospital, Professor, Radiation Oncology, University of Toronto, Toronto, Canada.

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BMJ Clin Evid. 2011 Jan 25;2011:1807.

Adjuvant chemotherapy

Summary

Adjuvant chemotherapy reduces the risk of relapse after orchidectomy compared with surveillance, but is associated with short-term adverse effects (nausea, diarrhoea, and indigestion) and possible long-term risks of reduced fertility and development of second malignancies.

Benefits and harms

Adjuvant chemotherapy versus surveillance:

See option on surveillance.

Adjuvant chemotherapy versus adjuvant radiotherapy:

See option on adjuvant radiotherapy.

Different drug combinations for adjuvant chemotherapy:

See option on adjuvant chemotherapy using different drug combinations.

Different number of cycles of adjuvant chemotherapy:

See option on different number of cycles of adjuvant chemotherapy.

Comment

Observational harms data

Sexual dysfunction:

We found 2 systematic reviews (search dates 1999) assessing sexual dysfunction after treatment for testicular cancer.[7] [8] The first review did not report results for different treatments separately (see option on surveillance).[7] The second review identified 7 prospective and 28 retrospective observational studies (2786 men with seminoma, teratoma, or mixed tumours).[8] The prospective studies provided insufficient data to compare directly the effects on sexual function of orchidectomy plus surveillance, radiotherapy, or chemotherapy. The review found that, in men with teratoma or mixed tumours, orchidectomy plus chemotherapy was associated with loss of desire in 25% of men, reduced or absent orgasm in 28%, erectile dysfunction in 11%, and sexual dissatisfaction in 15%. Sexual dissatisfaction might not have been caused by treatment. The review found limited evidence, from indirect comparisons of data from retrospective studies, that orchidectomy plus chemotherapy was associated with less erectile dysfunction than orchidectomy plus radiotherapy, but was associated with more loss of desire. Rates of erectile dysfunction and loss of desire were similar between adjuvant chemotherapy and surveillance.

Development of second malignancies and other late effects associated with chemotherapy:

Secondary malignancies develop more commonly in survivors of seminoma than in the general population, partly as a result of chemotherapy. One review identified 13 studies, including in people who were treated for (any) testicular cancer with a variety of chemotherapy regimens, including regimens containing alkylating agents.[9] The largest of these studies examined 40,576 survivors of testicular cancer with at least 1 year follow-up, some of whom had data from more than 35 years of follow-up. The review reported that, overall, the use of chemotherapy treatment alone was associated with an increased risk of second cancer (RR 1.8, 95% CI 1.3 to 2.5). However, the review found that, among the relatively small number of seminoma patients treated with chemotherapy alone (808 people), there was no significant statistical increase in risk of second cancer (RR 1.6, 95% CI <1 to 4.3). Other studies included in the review examining risk of secondary leukaemia found low incidence but excess risk (RR 3 to 7), compared to the general population, during the first 10 years after treatment. The risk, however, seemed to return to near normal after 10 to 20 years.[9] More recently, chemotherapy use has been estimated to be similar, in terms of cancer induction risk, to smoking. Other potentially harmful effects include hearing loss and reduced renal function associated with cisplatin, Raynaud's phenomenon associated with combined chemotherapy with etoposide plus cisplatin plus bleomycin, and pulmonary fibrosis associated with bleomycin. However, adjuvant chemotherapy for stage 1 seminoma is almost exclusively single-agent carboplatin, and long-term data with regard to second malignancy in this setting are not yet available. Thus it is unknown whether the same risks apply.

Clinical guide:

Orchidectomy plus surveillance, adjuvant chemotherapy, or adjuvant radiotherapy all produce equally high cure rates in people with stage 1 seminoma. The choice of treatment is determined by factors such as the pattern of toxicity, the inconvenience and complexity of treatment, and patient preference, particularly the person's attitude to relapse. With surveillance, most people can avoid the toxicity of adjuvant treatment, but they must face the uncertainty of relapse as well as regular hospital follow-up for as long as 10 years. Adjuvant radiotherapy and adjuvant chemotherapy can both substantially reduce the risk of relapse, but both are associated with mild short-term toxicity. Radiotherapy is also associated with a low but definite long-term risk of second malignancy and reduced fertility. The long-term risks associated with adjuvant chemotherapy are as yet not quantified. The pattern of relapse also differs after adjuvant radiotherapy or chemotherapy. After radiotherapy, relapse in the pelvic nodes (in those treated with para-aortic radiotherapy), mediastinum, or supraclavicular area is most common. After chemotherapy, relapse is most common in the para-aortic nodes. The cohort study comparing surveillance, adjuvant radiotherapy, and adjuvant chemotherapy has been reported separately both here and under adjuvant radiotherapy.[10]

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jan 25;2011:1807.

Adjuvant radiotherapy

Summary

In men with seminoma confined to the testis (stage 1), orchidectomy followed by radiotherapy to infradiaphragmatic lymph nodes reduces risk of relapse compared to surveillance. Adjuvant radiotherapy is associated with short-term adverse effects (nausea, diarrhoea, and indigestion) and possible long-term risks of reduced fertility and development of second malignancies.

Benefits and harms

Adjuvant radiotherapy versus surveillance:

See option on surveillance.

Adjuvant radiotherapy versus adjuvant chemotherapy:

We found one RCT[11] and one cohort study.[10]

Relapse rates

Adjuvant radiotherapy compared with adjuvant chemotherapy Adjuvant radiotherapy does not increase the rate of relapse-free survival at 2 to 5 years in men with stage 1 seminoma, compared with adjuvant chemotherapy (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Relapse rates
[11]
RCT		 1447 men with stage 1 seminoma, 5:3 randomisation Relapse-free survival 2 years
97% with adjuvant radiotherapy
98% with adjuvant chemotherapy using carboplatin
P = 0.32
HR 1.28
90% CI 0.85 to 1.93
The 90% CI excludes an increase in relapse rates in men taking carboplatin of >3% at 2 years 		Not significant
[11]
RCT		 1447 men with stage 1 seminoma, 5:3 randomisation Relapse-free survival 3 years
96% with adjuvant radiotherapy
95% with adjuvant chemotherapy using carboplatin
P = 0.32
HR 1.28
90% CI 0.85 to 1.93
The 90% CI excludes an increase in relapse rates in men taking carboplatin of >4% at 3 years 		Not significant
[10]
Cohort study
3-armed trial 		224 men Relapse rates 5 years
5/79 (5%) with adjuvant radiotherapy
1/78 (2%) with adjuvant chemotherapy
P value for adjuvant chemotherapy v adjuvant radiotherapy reported as not significant
CI not reported 		Not significant
Open in a new tab

Cure rates

No data from the following reference on this outcome.[11] [10]

Mortality

No data from the following reference on this outcome.[11] [10]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[11]
RCT		 1447 men with stage 1 seminoma, 5:3 randomisation Proportion of men unable to do normal work 25 days
38% with adjuvant radiotherapy
19% with adjuvant chemotherapy using carboplatin
Absolute results reported graphically
P <0.0001 		Effect size not calculated adjuvant chemotherapy
[11]
RCT		 1447 men with stage 1 seminoma, 5:3 randomisation Proportion of men with moderate or severe lethargy 25 days
24% with adjuvant radiotherapy
7% with adjuvant chemotherapy using carboplatin
Absolute results reported graphically
P <0.0001 		Effect size not calculated adjuvant chemotherapy
[11]
RCT		 1447 men with stage 1 seminoma, 5:3 randomisation New second primary germ cell tumours 5 years
10/904 (1.1%) with adjuvant radiotherapy
2/573 (0.4%) with adjuvant chemotherapy using carboplatin
P = 0.04 		Effect size not calculated adjuvant chemotherapy
[11]
RCT		 1447 men with stage 1 seminoma, 5:3 randomisation Proportion of men with thrombocytopenia grades 1 or 2
12/904 (2%) with adjuvant radiotherapy
58/573 (12%) with adjuvant chemotherapy using carboplatin
P <0.0001 		Effect size not calculated adjuvant radiotherapy
[11]
RCT		 1447 men with stage 1 seminoma, 5:3 randomisation Thrombocytopenia grades 3 or 4
0/904 (0%) with adjuvant radiotherapy
17/573 (4%) with adjuvant chemotherapy using carboplatin
P <0.0001 		Effect size not calculated adjuvant radiotherapy
[11]
RCT		 1447 men with stage 1 seminoma, 5:3 randomisation Dyspepsia
127/904 (17%) with adjuvant radiotherapy
40/573 (8%) with adjuvant chemotherapy using carboplatin
P <0.0001 		Effect size not calculated adjuvant chemotherapy
[10]
Cohort study
3-armed trial 		224 men Sickness
36% with adjuvant radiotherapy
35% to 50% with adjuvant chemotherapy
[10]
Cohort study
3-armed trial 		224 men Diarrhoea
60% with adjuvant radiotherapy
0% to 12% with adjuvant chemotherapy
[10]
Cohort study
3-armed trial 		224 men Indigestion
30% with adjuvant radiotherapy
24% with adjuvant chemotherapy
[10]
Cohort study
3-armed trial 		224 men Fertility problems
14% with adjuvant radiotherapy
6% with adjuvant chemotherapy
[10]
Cohort study
3-armed trial 		224 men Proportion off work over 12 weeks
21% with adjuvant radiotherapy
23% with adjuvant chemotherapy
Absolute numbers not reported
Open in a new tab

Different adjuvant radiotherapy regimens versus each other:

See option on different adjuvant radiotherapy regimens.

Comment

Observational harms data

Sexual dysfunction:

We found 2 systematic reviews (search dates 1999) assessing sexual dysfunction after treatment for testicular cancer.[7] [8] The first review did not report results for different treatments separately (see option on surveillance).[7] The second review identified 7 prospective and 28 retrospective observational studies (2786 men with seminoma, teratoma, or mixed tumours) assessing sexual dysfunction after surveillance, radiotherapy, or chemotherapy.[8] The prospective studies provided insufficient data to compare directly the effects of orchidectomy plus surveillance, adjuvant radiotherapy, or adjuvant chemotherapy on sexual function. The review pooled data on sexual dysfunction after radiotherapy from 9 studies (417 men), chemotherapy from 6 studies (160 men), and chemotherapy plus surgery from 9 studies (404 men). It found a loss of desire in 14% of men with radiotherapy, 25% with chemotherapy, and 13% with chemotherapy plus surgery; reduced or absent orgasm in 23% of men with radiotherapy, 29% with chemotherapy, and 22% with chemotherapy plus surgery; ejaculatory problems in 40% of men with radiotherapy, 28% with chemotherapy, and 62% with chemotherapy plus surgery; and sexual dissatisfaction in 16% of men with radiotherapy, 15% with chemotherapy, and 20% with chemotherapy plus surgery. The review found limited evidence, from indirect comparisons of data from retrospective studies, that radiotherapy, chemotherapy, and chemotherapy plus surgery were associated with more erectile dysfunction than surveillance.

Development of secondary malignancies associated with radiotherapy:

Second malignancies develop more commonly in survivors of seminoma than in the general population, partly as a result of radiotherapy. One systematic review identified 12 studies, each including 400 people or more, who were treated for (any) testicular cancer with radiotherapy, chemotherapy, or both.[12] There was overlap between some of these studies; however, the largest of these examined 40,576 1-year survivors of testicular cancer treated between 1943 and 2001, some of whom had data from more than 35 years of follow-up. The use of radiotherapy treatment alone was associated with increased risk of second solid cancer (RR 2.0, 95% CI 1.9 to 2.2), and these risks remained elevated even to 35 years after treatment. The risks seemed to be slightly higher for men treated from 1975 onwards (RR 2.5) than for those treated before 1975 (RR 1.7), but it is unclear as to the cause of this finding. Cancers of the pleura, oesophagus, lung, colon, bladder, pancreas, and stomach accounted for about 60% of sites involved. A similar study included in the review (28,843 men treated between 1935 and 1993) examining risk of secondary leukaemia found low incidence but excess risk (RR 3.28, 95% CI 1.69 to 5.72 before 1975 and RR 2.53, 95% CI 0.93 to 5.52 from 1975 onwards) compared to the general population.[12]

Clinical guide:

Orchidectomy plus surveillance, adjuvant chemotherapy, or adjuvant radiotherapy all produce equally high cure rates in people with stage 1 seminoma. The choice of treatment is determined by factors such as the pattern of toxicity, the inconvenience and complexity of treatment, and patient preference, particularly the individual's attitude to relapse. With surveillance, most people can avoid the toxicity of adjuvant treatment, but they must face the uncertainty of relapse as well as regular hospital follow-up for as long as 10 years. Adjuvant radiotherapy and adjuvant chemotherapy can both substantially reduce the risk of relapse, but both are associated with mild immediate short-term toxicity. Radiotherapy is also associated with a low but definite long-term risk of second malignancy and reduced fertility. The pattern of relapse also differs after adjuvant radiotherapy or chemotherapy. After radiotherapy, relapse in the pelvic nodes (in those treated with para-aortic radiotherapy), mediastinum, or supraclavicular area is most common. After chemotherapy, relapse is most common in the para-aortic nodes. The cohort study comparing surveillance, adjuvant radiotherapy, and adjuvant chemotherapy has been reported separately both here and under adjuvant radiotherapy.[10]

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jan 25;2011:1807.

Surveillance

Summary

Adjuvant chemotherapy and radiotherapy reduce the risk of relapse after orchidectomy compared with surveillance. Surveillance avoids the adverse effects associated with adjuvant radiotherapy or chemotherapy.

Benefits and harms

Surveillance versus adjuvant radiotherapy in men who have undergone orchidectomy:

We found no RCTs comparing surveillance versus adjuvant radiotherapy in men who have undergone orchidectomy for stage 1 seminoma. An RCT assessing survival is unlikely to be conducted; it would be difficult to detect differences in mortality between groups because of the excellent prognosis and small differences in long-term outcomes. We found one systematic review[12] (search date 2009) that identified 4 prospective cohort studies assessing surveillance in men following orchidectomy.

Relapse rates

Surveillance compared with adjuvant radiotherapy Surveillance may be less effective than adjuvant radiotherapy at 5 years at reducing relapse rates in men who have undergone orchidectomy for stage 1 seminoma (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Relapse rates
[12]
Systematic review		 471 men with stage 1 seminoma who had undergone orchidectomy Proportion of relapse-free men 5 years
231/245 (94%) with adjuvant radiotherapy
189/226 (84%) with surveillance
Significance assessment and P value not reported
[12]
Systematic review
3-armed trial 		224 men Relapse rates 5 years
5% with adjuvant radiotherapy
27% with surveillance
Absolute numbers not reported
P <0.01 for either treatment (radiotherapy or chemotherapy) v surveillance 		Effect size not calculated adjuvant radiotherapy
[12]
Systematic review		 150 men with stage 1 seminoma who had undergone orchidectomy Proportion of relapse-free men 5 years
107/107 (100%) with adjuvant radiotherapy
37/43 (79%) with surveillance
P <0.01 for radiotherapy v surveillance 		Effect size not calculated adjuvant radiotherapy
Open in a new tab

Cure rates

No data from the following reference on this outcome.[12]

Mortality

No data from the following reference on this outcome.[12]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[10]
Cohort study
3-armed trial 		224 men Sickness
36% with adjuvant radiotherapy
6% with surveillance
Absolute numbers not reported
[10]
Cohort study
3-armed trial 		224 men Diarrhoea
60% with adjuvant radiotherapy
4% with surveillance
Absolute numbers not reported
[10]
Cohort study
3-armed trial 		224 men Indigestion
30% with adjuvant radiotherapy
11% with surveillance
Absolute numbers not reported
[10]
Cohort study
3-armed trial 		224 men Fertility problems
14% with adjuvant radiotherapy
6% with surveillance
Absolute numbers not reported
[10]
Cohort study
3-armed trial 		224 men Proportion off work over 12 weeks
21% with adjuvant radiotherapy
3% with surveillance
Absolute numbers not reported
[12]
Systematic review		 204 men Sickness
27.5% with adjuvant radiotherapy
with
Absolute numbers not reported
Open in a new tab

Surveillance versus adjuvant chemotherapy in men who have undergone orchidectomy:

We found no RCTs comparing surveillance versus adjuvant chemotherapy in men who have undergone orchidectomy for stage 1 seminoma. An RCT assessing survival is unlikely to be conducted; it would be difficult to detect differences in mortality between groups because of the excellent prognosis and small differences in long-term outcomes. We found one systematic review (search date 2009),[12] which identified 3 prospective cohort studies comparing surveillance versus adjuvant chemotherapy.

Relapse rates

Surveillance compared with adjuvant chemotherapy Surveillance may be less effective than adjuvant chemotherapy at reducing relapse rates in men who have undergone orchidectomy for stage 1 seminoma (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Relapse rates
[12]
Systematic review
3-armed trial 		224 men Relapse rates 5 years
2% with adjuvant chemotherapy
27% with surveillance
Absolute numbers not reported
P <0.01 for either treatment (chemotherapy or radiotherapy) v surveillance 		Effect size not calculated adjuvant chemotherapy
[12]
Systematic review		 203 men Relapse rate 5 years
3% with adjuvant chemotherapy
17% with surveillance
Absolute numbers not reported
P = 0.01 for chemotherapy v surveillance 		Effect size not calculated adjuvant chemotherapy
[12]
Systematic review		 314 men Relapse rate 5 years
4% with adjuvant chemotherapy
7% with surveillance
Absolute numbers not reported
Significance assessment and P value not reported
Open in a new tab

Cure rates

No data from the following reference on this outcome.[12]

Mortality

No data from the following reference on this outcome.[12]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[12]
Systematic review
3-armed trial 		224 men Sickness
35% to 50% with adjuvant chemotherapy
6% with surveillance
Absolute numbers not reported
[12]
Systematic review
3-armed trial 		224 men Diarrhoea
0% to 12% with adjuvant chemotherapy
4% with surveillance
Absolute numbers not reported
[10]
Systematic review
3-armed trial 		224 men Indigestion
24% with adjuvant chemotherapy
11% with surveillance
Absolute numbers not reported
[12]
Systematic review
3-armed trial 		224 men Fertility problems
6% with adjuvant chemotherapy
6% with surveillance
Absolute numbers not reported
[12]
Systematic review
3-armed trial 		224 men Proportion off work over 12 weeks
23% with adjuvant chemotherapy
3% with surveillance
Absolute numbers not reported
[12]
Systematic review		 314 men Sickness
47% with adjuvant chemotherapy
with
Absolute numbers not reported
[12]
Systematic review		 314 men Diarrhoea
3% with adjuvant chemotherapy
with
Absolute numbers not reported
Open in a new tab

Comment

Observational harms data

Sexual dysfunction:

We found 2 systematic reviews (search dates 1999) that assessed sexual dysfunction after treatment for testicular cancer.[7] [8] The first review (79 observational studies: 66 retrospective studies, 6 controlled studies in 709 men, and 7 uncontrolled studies in 337 men, all with seminoma, teratoma, or mixed tumours) found that men undergoing any treatment (orchidectomy plus surveillance, radiotherapy, or chemotherapy) for testicular cancer had significantly reduced or absent orgasm (13 controlled and uncontrolled studies: OR 4.62, 95% CI 2.47 to 8.63) and erectile dysfunction (OR 2.47, 95% CI 1.54 to 3.96) at up to 2 years after treatment. However, the review did not report results for individual treatments, so it does not help in determining which treatment is least likely to cause sexual dysfunction. The second review identified 7 prospective and 28 retrospective observational studies (2786 men with seminoma, teratoma, or mixed tumours) assessing sexual dysfunction after surveillance, radiotherapy, or chemotherapy.[8] The prospective studies provided insufficient data to compare directly the effects of orchidectomy plus surveillance, radiotherapy, or chemotherapy on sexual function. The review found that orchidectomy plus surveillance was associated with loss of desire in 25% of people, reduced or absent orgasm in 24%, erectile dysfunction in 7%, and sexual dissatisfaction in 8%. Sexual dissatisfaction may not be caused by treatment. The review found limited evidence, from indirect comparisons of data from retrospective studies, that orchidectomy plus surveillance was associated with less erectile dysfunction but more loss of desire than orchidectomy plus radiotherapy. Rates of erectile dysfunction and loss of desire were similar with surveillance and adjuvant chemotherapy.

Clinical guide:

Orchidectomy plus surveillance, adjuvant chemotherapy, or adjuvant radiotherapy all produce equally high cure rates in people with stage 1 seminoma. The choice of treatment is determined by factors such as the pattern of toxicity, the inconvenience and complexity of treatment, and patient preference, particularly the person's attitude to relapse. With surveillance, most people can avoid the toxicity of adjuvant treatment, but they must face the uncertainty of relapse as well as regular hospital follow-up for as long as 10 years. Adjuvant radiotherapy and adjuvant chemotherapy can both substantially reduce the risk of relapse, but both are associated with mild short-term toxicity. Radiotherapy is also associated with a low but definite long-term risk of second malignancy and reduced fertility. The pattern of relapse also differs after adjuvant radiotherapy or chemotherapy. After radiotherapy, relapse in the pelvic nodes (in those treated with para-aortic radiotherapy), mediastinum, or supraclavicular area is most common. After chemotherapy, relapse is most common in the para-aortic nodes. The cohort study comparing surveillance, adjuvant radiotherapy, and adjuvant chemotherapy has been reported separately both here and under adjuvant radiotherapy.[10]

Substantive changes

Surveillance New evidence added. Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2011 Jan 25;2011:1807.

Different adjuvant radiotherapy regimens

Summary

Toxicity is lower, but efficacy the same, with adjuvant irradiation of 20 Gy in 10 fractions compared with 30 Gy in 15 fractions, or with restricted irradiation (to para-aortic nodes only) compared with irradiation to both para-aortic and ipsilateral iliac nodes.

Benefits and harms

Para-aortic strip adjuvant radiotherapy versus para-aortic plus ipsilateral adjuvant radiotherapy:

We found one systematic review (search date 2009),[12] which identified one RCT comparing para-aortic strip adjuvant radiotherapy versus para-aortic plus ipsilateral adjuvant radiotherapy.[13]

Relapse rates

Para-aortic strip compared with para-aortic plus ipsilateral iliac lymph node irradiation Para-aortic strip (restricted) irradiation is as effective as para-aortic plus ipsilateral iliac lymph node irradiation at 3 years in men who have undergone orchidectomy for stage 1 seminoma (high-quality evidence). Note: Toxicity increases with increases in irradiation field.

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Relapse rates
[13]
RCT		 478 men
In review [12] 		Rates of relapse-free survival 3 years
227/236 (96%) with para-aortic strip (restricted field) irradiation (30 Gy in 15 fractions for 3 weeks)
233/242 (97%) with para-aortic strip plus ipsilateral iliac lymph node (traditional field) irradiation (30 Gy in 15 fractions for 3 weeks)
Mean difference +0.6%
95% CI –3.4 to +4.6
P value not reported 		Not significant
Open in a new tab

Cure rates

No data from the following reference on this outcome.[13]

Mortality

No data from the following reference on this outcome.[13]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[13]
RCT		 478 men
In review [12] 		Adverse effects
with para-aortic strip (restricted field) irradiation (30 Gy in 15 fractions for 3 weeks)
with para-aortic strip plus ipsilateral iliac lymph node (traditional field) irradiation (30 Gy in 15 fractions for 3 weeks)
[13]
RCT		 478 men
In review [12] 		Secondary malignancies (adenocarcinoma or non-seminomatous testicular tumours)
2/478 (0.4%) with para-aortic strip (restricted field) irradiation (30 Gy in 15 fractions for 3 weeks)
1/478 (0.2%) with para-aortic strip plus ipsilateral iliac lymph node (traditional field) irradiation (30 Gy in 15 fractions for 3 weeks)
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20 Gy adjuvant radiotherapy versus 30 Gy adjuvant radiotherapy:

We found one systematic review (search date 2009),[12] which identified one RCT comparing 20 Gy adjuvant radiotherapy versus 30 Gy adjuvant radiotherapy.[14]

Relapse rates

20 Gy compared with 30 Gy irradiation 20 Gy irradiation in 10 fractions is as effective as 30 Gy irradiation at reducing relapse rates at 61 months in men who have undergone orchidectomy for stage 1 seminoma (high-quality evidence). Note: Toxicity increases as dose increases.

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Relapse rates
[14]
RCT		 625 men with stage 1 seminoma who had received orchidectomy in the previous 8 weeks
In review [12] 		Relapse rates median of 61 months
11/312 (4%) with irradiation to the para-aortic strip of 20 Gy in 10 fractions over 2 weeks
10/313 (3%) with irradiation to the para-aortic strip of 30 Gy in 15 fractions over 3 weeks
HR 1.11
90% CI 0.54 to 2.28 		Not significant
Open in a new tab

Cure rates

No data from the following reference on this outcome.[14]

Mortality

No data from the following reference on this outcome.[14]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[14]
RCT		 625 men with stage 1 seminoma who had received orchidectomy in the previous 8 weeks
In review [12] 		Moderate or severe lethargy 4 weeks
5% with 20 Gy in 10 fractions over 2 weeks
20% with 30 Gy in 15 fractions over 3 weeks
Absolute numbers not reported
P <0.01
CI values not reported 		Effect size not calculated 20 Gy in 10 fractions over 2 weeks
[14]
RCT		 625 men with stage 1 seminoma who had received orchidectomy in the previous 8 weeks
In review [12] 		Moderate or severe lethargy 12 weeks
with 20 Gy in 10 fractions over 2 weeks
with 30 Gy in 15 fractions over 3 weeks
Absolute results not reported
Reported as not significant
CI values not reported 		Not significant
[14]
RCT		 625 men with stage 1 seminoma who had received orchidectomy in the previous 8 weeks
In review [12] 		Inability to return to work 4 weeks
28% with 20 Gy in 10 fractions over 2 weeks
46% with 30 Gy in 15 fractions over 3 weeks
Absolute numbers not reported
P <0.01
CI values not reported 		Effect size not calculated 20 Gy in 10 fractions over 2 weeks
[14]
RCT		 625 men with stage 1 seminoma who had received orchidectomy in the previous 8 weeks
In review [12] 		Inability to return to work 12 weeks
with 20 Gy in 10 fractions over 2 weeks
with 30 Gy in 15 fractions over 3 weeks
Absolute results not reported
Reported as not significant
CI values not reported 		Not significant
[14]
RCT		 625 men with stage 1 seminoma who had received orchidectomy in the previous 8 weeks
In review [12] 		World Health Organization grade 3 to 4 nausea and vomiting
57/313 (18%) with 20 Gy in 10 fractions over 2 weeks
61/312 (20%) with 30 Gy in 15 fractions over 3 weeks
P = 0.06 		Not significant
[14]
RCT		 625 men with stage 1 seminoma who had received orchidectomy in the previous 8 weeks
In review [12] 		Development of non-germ cell tumours 61 months
with 20 Gy in 10 fractions over 2 weeks
with 30 Gy in 15 fractions over 3 weeks
Absolute results not reported
The RCT found that 6 men, all in the 30-Gy irradiation group (6/313 [2%]), developed non-germ cell tumours over 61 months. Of these, 3 may have been associated near or within the radiotherapy fields
Open in a new tab

Comment

Clinical guide:

Adjuvant radiotherapy continues to be a treatment option used for stage 1 disease. Equally good results can be achieved using lower doses of radiation to smaller treatment volumes, thus leading to less toxicity and quicker recovery. It should be noted that while radiotherapy to a para-aortic strip results in similar overall relapse rates to that with para-aortic and ipsilateral iliac field, there may be a change in the relapse pattern such that there is an increased number of iliac node relapses in those treated with para-aortic strip.

Substantive changes

Different adjuvant radiotherapy regimens New evidence added. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011 Jan 25;2011:1807.

Different adjuvant chemotherapy drug combinations

Summary

We don't know which is the most effective chemotherapy regimen. The high cure rate with standard therapy makes it difficult to show that any alternative therapy is superior.

Benefits and harms

Different adjuvant chemotherapy drug combinations versus each other:

We found one systematic review (search date 2009), which identified no RCTs or observational studies of sufficient quality.[12]

Comment

Clinical guide:

Given the modest toxicity and high efficacy of adjuvant radiotherapy, any adjuvant chemotherapy would also need to be simple and relatively non-toxic as well as being effective. Single-agent carboplatin fits these criteria. However, other more complex or toxic regimens would not, so there is no reason for RCTs assessing such regimens to be conducted.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jan 25;2011:1807.

Different number of cycles of adjuvant chemotherapy

Summary

We don't know the optimum number of cycles of adjuvant chemotherapy to use. The high cure rate with standard therapy makes it difficult to show that any alternative therapy is superior.

Benefits and harms

Different numbers of cycles of adjuvant chemotherapy versus each other:

We found one systematic review (search date 2009), which identified no RCTs comparing different chemotherapy regimens in men who had undergone orchidectomy for stage 1 seminoma.[12] The review identified 2 prospective cohort studies comparing 1 cycle of carboplatin versus 2 cycles.

Relapse rates

One cycle compared with two cycles of carboplatin One cycle of carboplatin may be as effective as 2 cycles at reducing relapse rates at 2 years (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Relapse rates
[12]
Systematic review		 125 men who had undergone orchidectomy for stage 1 seminoma Rates of relapse 2 years
8/93 (9%) with 1 cycle of carboplatin 400 mg/m2 (93 men)
0/32 (0%) with 2 cycles of carboplatin 400 mg/m2 (32 men)
P > 0.08 		Not significant
[12]
Systematic review		 199 men who had undergone orchidectomy for stage 1 seminoma Relapse rate
3/171 (2%) with 1 cycle of carboplatin
1/28 (4%) with 2 cycles of carboplatin
P value not reported
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Mortality

One cycle compared with two cycles of carboplatin We don't know whether 1 cycle of carboplatin reduces mortality rates at 9 years compared with 2 cycles (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality
[12]
Systematic review		 199 men who had undergone orchidectomy for stage 1 seminoma All-cause mortality 9 years
with 1 cycle of carboplatin
with 2 cycles of carboplatin
Absolute results not reported
SMR for all-cause mortality 0.89
95% CI 0.36 to 1.83 		Not significant
Open in a new tab

Cure rates

No data from the following reference on this outcome.[12]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[12]
Systematic review		 125 men who had undergone orchidectomy for stage 1 seminoma Myelotoxicity
with 1 cycle of carboplatin 400 mg/m2
with 2 cycles of carboplatin 400 mg/m2
Absolute results not reported
Open in a new tab

Further information on studies

In the first study included in the review, the relapse-free survival at 5 years was 91% for both groups combined; the study did not directly compare 2 cycles versus 1 cycle of carboplatin for the outcome of mortality.

Comment

Clinical guide:

It is unclear whether the relapse rate is lower after 2 cycles of carboplatin, especially with the difference in calculation of the dose both between and within studies. Given that 2 cycles of chemotherapy are likely to produce more toxicity than 1 cycle, most oncologists would recommend a single cycle of adjuvant carboplatin.

Substantive changes

Different number of cycles of adjuvant chemotherapy New evidence added. Categorisation unchanged (Unknown effectiveness), as there remains insufficient evidence to define the optimum number of cycles of adjuvant chemotherapy to use.

BMJ Clin Evid. 2011 Jan 25;2011:1807.

Chemotherapy using etoposide plus cisplatin (with or without bleomycin)

Summary

RCTs indicate that cisplatin is superior to carboplatin, and the addition of bleomycin to cisplatin and etoposide improves effectiveness. Overall, seminoma seems more sensitive to chemotherapy than non-seminoma, and, since bleomycin may occasionally cause fatal toxicity, many oncologists recommend cisplatin plus etoposide to treat good-prognosis non-stage 1 seminoma.

Benefits and harms

Etoposide plus cisplatin versus etoposide plus carboplatin:

We found one systematic review (search date 2007),[9] which identified one RCT comparing etoposide plus cisplatin versus etoposide plus carboplatin in men with non-stage 1 good-prognosis tumours (seminoma or non-seminoma; see comment below).[15]

Relapse rates

Etoposide plus cisplatin compared with etoposide plus carboplatin Etoposide plus cisplatin may increase relapse-free survival rates at about 2 years in men with good-prognosis non-stage 1 seminoma or non-seminoma, compared with etoposide plus carboplatin (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Relapse rates
[15]
RCT		 270 men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Relapse-free survival
with etoposide plus cisplatin
with etoposide plus carboplatin
Absolute results reported graphically
P <0.05 		Effect size not calculated etoposide plus cisplatin
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Cure rates

No data from the following reference on this outcome.[15]

Mortality

Etoposide plus cisplatin compared with etoposide plus carboplatin Etoposide plus cisplatin and etoposide plus carboplatin may be equally effective for increasing overall survival in men with good-prognosis non-stage 1 seminoma or non-seminoma (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality
[15]
RCT		 270 men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Overall survival median 22.4 months
with etoposide plus cisplatin
with etoposide plus carboplatin
Absolute results reported graphically
P = 0.52 		Not significant
Open in a new tab

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[15]
RCT		 270 men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Adverse effects
with
Open in a new tab

Etoposide plus cisplatin plus bleomycin versus etoposide plus cisplatin:

We found one systematic review (search date 2007),[9] which identified one RCT comparing etoposide plus cisplatin plus bleomycin versus etoposide plus cisplatin alone in men with non-stage 1 good-prognosis tumours (seminoma or non-seminoma; see comment below).[16]

Relapse rates

Etoposide plus cisplatin plus bleomycin compared with etoposide plus cisplatin Etoposide plus cisplatin plus bleomycin may reduce relapse rates at about 4 years in men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours, compared with etoposide plus cisplatin alone (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Relapse rates
[16]
RCT		 178 men with good-prognosis non-stage 1 seminoma (33 men), teratoma, or mixed tumours
In review [9] 		Relapse rates median 4.1 years
8/81 (10%) with etoposide plus cisplatin plus bleomycin
17/75 (23%) with etoposide plus cisplatin
P value not reported
Open in a new tab

Cure rates

No data from the following reference on this outcome.[16]

Mortality

Etoposide plus cisplatin plus bleomycin compared with etoposide plus cisplatin Etoposide plus cisplatin plus bleomycin may increase survival rates at 3 years in men with good-prognosis non-stage 1 seminoma and non-seminoma, compared with etoposide plus cisplatin alone (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality
[16]
RCT		 178 men with good-prognosis non-stage 1 seminoma (33 men), teratoma, or mixed tumours
In review [9] 		Survival 3 years
95% with etoposide plus cisplatin plus bleomycin
86% with etoposide plus cisplatin
P = 0.01 		Effect size not calculated etoposide plus cisplatin plus bleomycin
Open in a new tab

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[16]
RCT		 178 men with good-prognosis non-stage 1 seminoma (33 men), teratoma, or mixed tumours
In review [9] 		Drug-related mortality
with
Open in a new tab

Two-drug regimen versus five-drug regimen :

We found one systematic review (search date 2007),[9] which identified one RCT comparing a 2-drug regimen versus a 5-drug regimen in men with non-stage 1 good-prognosis tumours (seminoma or teratoma; see comment below).[17]

Relapse rates

Two-drug compared with five-drug regimen A 2-drug regimen of etoposide plus cisplatin may be as effective as a 5-drug regimen of cisplatin plus vinblastine plus bleomycin plus cyclophosphamide plus dactinomycin in reducing relapse rates at 5 years in men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours, and may reduce toxicity (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Relapse rates
[17]
RCT		 164 men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Relapse-free survival mean of 5 years
with etoposide plus cisplatin (2-drug regimen)
with cisplatin plus vinblastine plus bleomycin plus cyclophosphamide plus dactinomycin (5-drug regimen)
Absolute results reported graphically
Reported as not significant
P value not reported 		Not significant
Open in a new tab

Cure rates

No data from the following reference on this outcome.[17]

Mortality

Two-drug compared with five-drug regimen A 2-drug regimen of etoposide plus cisplatin may be as effective as a 5-drug regimen of cisplatin plus vinblastine plus bleomycin plus cyclophosphamide plus dactinomycin in increasing overall survival at 5 years in men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours, and may reduce toxicity (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality
[17]
RCT		 164 men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Overall survival mean of 5 years
with etoposide plus cisplatin (2-drug regimen)
with cisplatin plus vinblastine plus bleomycin plus cyclophosphamide plus dactinomycin (5-drug regimen)
Absolute results reported graphically
Reported as not significant
P value not reported 		Not significant
Open in a new tab

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[17]
RCT		 164 men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Adverse effects
with etoposide plus cisplatin (2-drug regimen)
with cisplatin plus vinblastine plus bleomycin plus cyclophosphamide plus dactinomycin (5-drug regimen)
Open in a new tab

Comment

Clinical guide:

The data from these trials indicate that cisplatin is superior to carboplatin and the addition of bleomycin to cisplatin and etoposide improves effectiveness. However, the majority of people in these RCTs had non-seminoma and a smaller proportion had seminoma, and it is unclear if these conclusions apply equally to both patient groups. Unfortunately it is not feasible to repeat these studies in seminoma alone. Overall, seminoma seems more sensitive to chemotherapy than non-seminoma, and, since bleomycin may occasionally cause fatal toxicity, many oncologists recommend cisplatin plus etoposide to treat good-prognosis non-stage 1 seminoma.

Substantive changes

Chemotherapy using etoposide plus cisplatin (with or without bleomycin) One systematic review updated; no new evidence added. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Jan 25;2011:1807.

Chemotherapy using vinblastine plus cisplatin plus bleomycin

Summary

Vinblastine is now rarely used in the treatment of testicular cancer, and has largely been replaced by etoposide, which has superior effectiveness.

Benefits and harms

Bleomycin plus vinblastine plus cisplatin versus cisplatin plus vinblastine:

We found one systematic review (search date 2007),[9] which identified one RCT comparing adding bleomycin to vinblastine plus cisplatin versus cisplatin plus vinblastine alone in men with non-stage 1 good-prognosis tumours (seminoma or non-seminoma; see comment for chemotherapy using etoposide plus cisplatin [with or without bleomycin]).[18]

Relapse rates

Bleomycin plus vinblastine plus cisplatin compared with cisplatin plus vinblastine alone Adding bleomycin to 2-drug regimens containing vinblastine plus cisplatin seems more effective at 4 years at reducing relapse rates, in men with non-stage 1 good-prognosis tumours, than cisplatin plus vinblastine alone (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Relapse rates
[18]
RCT		 222 men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Relapse rates 4 years
5/110 (5%) with adding bleomycin to vinblastine plus cisplatin
8/108 (7%) with cisplatin plus vinblastine alone
P = 0.12 		Not significant
Open in a new tab

Cure rates

No data from the following reference on this outcome.[18]

Mortality

Bleomycin plus vinblastine plus cisplatin compared with cisplatin plus vinblastine alone Adding bleomycin to 2-drug regimens containing vinblastine plus cisplatin reduces tumour-related mortality at 4 years, in men with non-stage 1 good-prognosis tumours, compared with cisplatin plus vinblastine alone (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality
[18]
RCT		 222 men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Tumour-related mortality 4 years
6/110 (5%) with adding bleomycin to vinblastine plus cisplatin
16/108 (15%) with cisplatin plus vinblastine alone
P = 0.02 		Effect size not calculated adding bleomycin to vinblastine plus cisplatin
Open in a new tab

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[18]
RCT		 222 men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Treatment-related mortality
6/110 (5%) with adding bleomycin to vinblastine plus cisplatin
1/108 (1%) with cisplatin plus vinblastine alone
P = 0.06 		Not significant
Open in a new tab

Comment

Clinical guide:

Vinblastine is now rarely used in the treatment of testicular cancer, and has largely been replaced by etoposide, which has superior effectiveness. RCTs of vinblastine plus cisplatin therefore have little relevance to current medical practice.

Substantive changes

Chemotherapy using vinblastine plus cisplatin plus bleomycin One systematic review updated. No new evidence added. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Jan 25;2011:1807.

Adding higher compared with lower doses of cisplatin or vinblastine to a two-drug chemotherapy regimen

Summary

Adding higher-dose cisplatin to vinblastine-plus-bleomycin regimens may increase cure rates at 1 year in men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours compared with adding lower doses of cisplatin. However, vinblastine is now rarely used in the treatment of testicular cancer, and has largely been replaced by etoposide, which has superior effectiveness.

Benefits and harms

Adding higher versus lower doses of cisplatin to two-drug regimens:

We found one systematic review (search date 2002),[6] which identified one RCT comparing adding higher versus lower doses of cisplatin to vinblastine plus bleomycin in men with non-stage 1 good-prognosis tumours (seminoma or non-seminoma; see comment on chemotherapy using etoposide plus cisplatin [with or without bleomycin]).[19]

Relapse rates

No data from the following reference on this outcome.[19]

Cure rates

Higher-dose cisplatin compared with lower-dose cisplatin Adding higher-dose cisplatin to vinblastine-plus-bleomycin regimens may increase cure rates at 1 year in men with good-prognosis non-stage 1 seminoma, teratoma, or non-seminoma, compared with adding lower-dose cisplatin (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Cure rates
[19]
RCT		 114 people with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours
In review [6] 		Complete response rates 1 year
63% with higher-dose cisplatin plus vinblastine plus bleomycin
43% with lower-dose cisplatin plus vinblastine plus bleomycin
P = 0.03 		Effect size not calculated higher-dose cisplatin plus vinblastine plus bleomycin
[19]
RCT		 People with maximal disease
In review [6]
Subgroup analysis		 Complete response rates 1 year
57% with higher-dose cisplatin plus vinblastine plus bleomycin
34% with lower-dose cisplatin plus vinblastine plus bleomycin
P = 0.02 		Effect size not calculated higher-dose cisplatin plus vinblastine plus bleomycin
Open in a new tab

Mortality

No data from the following reference on this outcome.[19]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[19]
RCT		 114 people with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours
In review [6]
Subgroup analysis		 Thrombocytopenia 1 year
51% with higher-dose cisplatin plus vinblastine plus bleomycin
38% with lower-dose cisplatin plus vinblastine plus bleomycin
Significance not reported
Open in a new tab

Adding higher versus lower doses of vinblastine to two-drug regimens:

We found one RCT comparing adding higher versus lower doses of vinblastine to cisplatin plus bleomycin in men with non-stage 1 good-prognosis tumours (seminoma or non-seminoma; see comment on chemotherapy using etoposide plus cisplatin [with or without bleomycin]).[20]

Relapse rates

No data from the following reference on this outcome.[20]

Cure rates

Higher-dose vinblastine compared with lower-dose vinblastine Adding higher-dose vinblastine to cisplatin-plus-bleomycin regimens may not increase complete remission rates at 1 year in men with good-prognosis non-stage 1 seminoma, teratoma, or non-seminoma, compared with adding lower-dose vinblastine (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Cure rates
[20]
RCT		 203 men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours Complete remission 1 year
71% with 4 courses of higher-dose vinblastine (0.20 mg/kg) plus cisplatin plus bleomycin for 12 weeks
71% with 4 courses of lower-dose vinblastine (0.15 mg/kg) plus cisplatin plus bleomycin for 12 weeks
CI not reported
Open in a new tab

Mortality

No data from the following reference on this outcome.[20]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[20]
RCT		 203 men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours Leukocytopenia
36% with 4 courses of higher-dose vinblastine (0.20 mg/kg) plus cisplatin plus bleomycin for 12 weeks
13% with 4 courses of lower-dose vinblastine (0.15 mg/kg) plus cisplatin plus bleomycin for 12 weeks
P = 0.001 		Effect size not calculated lower-dose vinblastine plus cisplatin plus bleomycin
[20]
RCT		 203 men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours Granulocytopenic fever
55% with 4 courses of higher-dose vinblastine (0.20 mg/kg) plus cisplatin plus bleomycin for 12 weeks
30% with 4 courses of lower-dose vinblastine (0.15 mg/kg) plus cisplatin plus bleomycin for 12 weeks
CI not reported
Open in a new tab

Comment

Clinical guide:

Vinblastine is now rarely used in the treatment of testicular cancer, having been largely replaced by etoposide, which has superior effectiveness, although higher doses of cisplatin may compensate for the inferiority of vinblastine in 3-drug combinations of cisplatin plus vinblastine plus bleomycin. Studies of vinblastine plus cisplatin therefore have little relevance to current medical practice.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jan 25;2011:1807.

Radiotherapy (30–36 Gy in 15–18 fractions)

Summary

We found no direct information about different radiotherapy regimens in men who had undergone orchidectomy for good-prognosis non-stage 1 seminoma. Consensus and current practice support the use of radiotherapy at 30 Gy to 36 Gy in 15 to 18 fractions, but cannot confirm that this is the optimum dose. Lower doses of irradiation were as effective as 30 Gy to 36 Gy with stage 1 seminoma, but this may not necessarily apply to men with non-stage 1 seminoma.

Benefits and harms

Radiotherapy (30–36 Gy in 15–18 fractions):

We found one systematic review (search date 2002), which identified no RCTs of radiotherapy in men who had undergone orchidectomy for good-prognosis non-stage 1 seminoma (see comment below).[6] See harms of different radiotherapy regimens for stage 1 seminoma (different adjuvant radiotherapy regimens).

Comment

The dose of radiotherapy has traditionally been 30 Gy to 36 Gy in 15 to 18 fractions, based on consensus and observational evidence of effectiveness. However, we found no RCT evidence to confirm that this is the optimum dose. Although one RCT (reported in 3 papers)[14] found that lower doses of irradiation (20 Gy) were as effective as 30 Gy with stage 1 seminoma, this evidence does not necessarily apply to men with non-stage 1 seminoma.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jan 25;2011:1807.

Radiotherapy versus chemotherapy

Summary

We found no clinically important results from RCTs about radiotherapy compared with chemotherapy in men who had undergone orchidectomy for good-prognosis non-stage 1 seminoma. Consensus suggests that the immediate toxicity of radiotherapy is less than that of chemotherapy, but that the risk of relapse after radiotherapy is higher with larger-volume disease (>5 cm disease, stage IIC). Therefore, radiotherapy is preferred for small-volume disease (stage IIA) and chemotherapy for larger-volume disease (stage IIC).

Benefits and harms

Radiotherapy versus chemotherapy:

We found one systematic review (search date 2002), which identified no RCTs of radiotherapy versus chemotherapy in men who had undergone orchidectomy for good-prognosis non-stage 1 seminoma (see comment below).[6] See harms of different radiotherapy regimens for stage 1 seminoma (different adjuvant radiotherapy regimens, different adjuvant chemotherapy drug combinations, and different number of cycles of adjuvant chemotherapy).

Comment

The immediate toxicity of radiotherapy is less than that of chemotherapy, but the risk of relapse after radiotherapy is higher with larger-volume disease (>5 cm disease, stage IIC). Therefore, radiotherapy is preferred for small-volume disease (stage IIA) and chemotherapy for larger-volume disease (stage IIC). For intermediate-volume disease (>2 cm <5 cm, stage IIB), either radiotherapy or chemotherapy may be used.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jan 25;2011:1807.

Three versus four cycles of chemotherapy

Summary

Three cycles of chemotherapy seem to be as effective as 4 cycles, and with less toxicity.

Benefits and harms

Three versus four cycles of chemotherapy:

We found one systematic review (search date 2007),[9] which identified 3 RCTs comparing different numbers of cycles of chemotherapy.[21] [22] [23]

Relapse rates

Three cycles compared with four cycles of chemotherapy We don’t know whether 3 cycles of chemotherapy increases relapse rates or relapse-free survival in men with both seminomas and non-seminomas compared with 4 cycles, but 3 cycles may cause less toxicity (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Relapse rates
[21]
RCT		 184 men with non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Relapse rates
5/88 (6%) with 3 cycles over 9 weeks of cisplatin plus etoposide plus bleomycin
5/96 (5%) with 4 cycles over 12 weeks of cisplatin plus etoposide plus bleomycin
Significance assessment not reported
[22]
RCT		 166 men with non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Relapse-free survival
16/83 (19%) with 3 cycles over 9 weeks of cisplatin plus etoposide plus bleomycin
19/83 (23%) with 4 cycles over 12 weeks of cisplatin plus etoposide plus bleomycin
HR 0.84
95% CI 0.43 to 1.63 		Not significant
Open in a new tab

No data from the following reference on this outcome.[23]

Cure rates

No data from the following reference on this outcome.[21] [22] [23]

Mortality

Three cycles compared with four cycles of chemotherapy We don’t know whether 3 cycles of chemotherapy may increase progression-free or overall survival rates in men with both seminomas and non-seminomas compared with 4 cycles, but 3 cycles may cause less toxicity (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality
[22]
RCT		 166 men with non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Overall mortality median 3 years
3/83 (4%) with 3 cycles over 9 weeks of cisplatin plus etoposide plus bleomycin
13/83 (16%) with 4 cycles over 12 weeks of cisplatin plus etoposide plus bleomycin
HR 0.22
95% CI 0.06 to 0.77 		Moderate effect size 3 cycles of chemotherapy
[23]
RCT
4-armed trial 		812 men with non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Progression-free survival 2 years
90% with 3 cycles of chemotherapy (2 arms combined)
89% with 4 cycles of chemotherapy (2 arms combined)
Absolute numbers not reported
HR 0.93
80% CI 0.71 to 1.24
CI was set at 80% to allow for 2-sided comparison (4-armed trial) 		Not significant
[23]
RCT
4-armed trial 		812 men with non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Overall survival 2 years
97% with 3 cycles of chemotherapy (2 arms combined)
97% with 4 cycles of chemotherapy (2 arms combined)
Absolute numbers not reported
HR 1.02
80% CI 0.61 to 1.73
CI was set at 80% to allow for 2-sided comparison (4-armed trial) 		Not significant
Open in a new tab

No data from the following reference on this outcome.[21]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[21]
RCT		 184 men with non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Toxicity
with 3 cycles over 9 weeks of cisplatin plus etoposide plus bleomycin
with 4 cycles over 12 weeks of cisplatin plus etoposide plus bleomycin
Absolute results not reported
[22]
RCT		 166 men with non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Nausea and vomiting
47/83 (57%) with 3 cycles over 9 weeks of cisplatin plus etoposide plus bleomycin
62/83 (74%) with 4 cycles over 12 weeks of cisplatin plus etoposide plus bleomycin
P = 0.02 		Effect size not calculated 3 cycles of chemotherapy
[22]
RCT		 166 men with non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Haematological grade III or IV toxicity
1% to 59% with 3 cycles over 9 weeks of cisplatin plus etoposide plus bleomycin
7% to 65% with 4 cycles over 12 weeks of cisplatin plus etoposide plus bleomycin
Absolute numbers not reported
P >0.2
The study was probably underpowered to detect significant differences 		Not significant
[22]
RCT		 166 men with non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Renal grade II to IV toxicity
1/79 (1%) with 3 cycles over 9 weeks of cisplatin plus etoposide plus bleomycin
0/79 (0%) with 4 cycles over 12 weeks of cisplatin plus etoposide plus bleomycin
P = 1.0
The study was probably underpowered to detect significant differences 		Not significant
[22]
RCT		 166 men with non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Pulmonary grade II to IV toxicity
10/79 (12%) with 3 cycles over 9 weeks of cisplatin plus etoposide plus bleomycin
7/79 (8%) with 4 cycles over 12 weeks of cisplatin plus etoposide plus bleomycin
P = 0.6
The study was probably underpowered to detect significant differences 		Not significant
[23]
RCT
4-armed trial 		812 men with non-stage 1 seminoma, teratoma, or mixed tumours
In review [9] 		Leukopenic fever
60/406 (15%) with 3 cycles of chemotherapy (2 arms combined)
62/406 (15%) with 4 cycles of chemotherapy (2 arms combined)
P value not reported
Open in a new tab

Comment

Clinical guide:

RCTs specifically including only good-prognosis seminoma are relatively rare. Most studies of chemotherapy for testicular germ cell tumours include both seminomas and non-seminomas, but it is likely that the results are generalisable to men with good-prognosis seminoma.

Substantive changes

Three versus four cycles of chemotherapy One systematic review updated. No new evidence added. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Jan 25;2011:1807.

Chemotherapy using single-agent carboplatin versus combined chemotherapy regimens

Summary

Combined chemotherapy may be more effective than single agents, but may be associated with more adverse effects.

Benefits and harms

Single-agent versus combined chemotherapy:

We found one systematic review (search date 2007),[9] which identified 2 RCTs, the second of which was reported initially as an abstract.[25] [26] The review reported a pooled analysis of individual patient data.[9]

Relapse rates

Single-agent compared with combined chemotherapy We don't know whether single-agent carboplatin reduces relapse rates compared with combined chemotherapy regimens (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Relapse rates
[9]
Systematic review		 361 men with good- (90%) and intermediate-prognosis (10%) non-stage 1 seminomas
2 RCTs in this analysis		 Relapse rates
52/177 (29%) with single-agent carboplatin chemotherapy
17/184 (9%) with combined chemotherapy
P value not reported
[9]
Systematic review		 361 men with good- (90%) and intermediate-prognosis (10%) non-stage 1 seminomas
2 RCTs in this analysis		 Progression-free survival 2 years
72% with single-agent carboplatin chemotherapy
92% with combined chemotherapy
Absolute numbers not reported
P <0.01 		Effect size not calculated combined chemotherapy
Open in a new tab

Cure rates

No data from the following reference on this outcome.[9]

Mortality

Single-agent compared with combined chemotherapy We don't know whether single-agent carboplatin reduces mortality compared with combined chemotherapy regimens at 2 years (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality
[9]
Systematic review		 361 men with good- (90%) and intermediate-prognosis (10%) non-stage 1 seminomas
2 RCTs in this analysis		 Overall survival 2 years
89% (95% CI 85% to 95%) with single-agent carboplatin chemotherapy
94% (95% CI 91% to 98%) with combined chemotherapy
Absolute numbers not reported
P = 0.09 		Not significant
Open in a new tab

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[25]
RCT		 130 men with good-prognosis non-stage 1 seminomas
In review [9] 		Neutropenia
3% with single-agent carboplatin chemotherapy
32% with combined chemotherapy with etoposide plus cisplatin
Absolute numbers not reported
P <0.001 		Effect size not calculated single-agent carboplatin chemotherapy
[25]
RCT		 130 men with good-prognosis non-stage 1 seminomas
In review [9] 		Haematological toxicity
with single-agent carboplatin chemotherapy
with combined chemotherapy with etoposide plus cisplatin
Absolute results not reported
[26]
RCT		 251 men with good-prognosis non-stage 1 seminomas
In review [9] 		Leukopenia and thrombocytopenia (WHO grade 3–4)
7/89 (8%) with single-agent carboplatin chemotherapy
67/93 (72%) with combined chemotherapy with etoposide plus cisplatin plus ifosfamide
P value not reported
Open in a new tab

Comment

Clinical guide:

The evidence suggests that carboplatin is inferior to combination chemotherapy in terms of relapse rates, with a possibility of a small reduction in overall survival, and should preclude its use for non-stage 1 seminoma.

Substantive changes

Chemotherapy using single-agent carboplatin versus combined chemotherapy regimens One systematic review updated, pooled data added. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Jan 25;2011:1807.

Maintenance chemotherapy

Summary

In men who are in remission after orchidectomy plus chemotherapy for good-prognosis non-stage 1 seminoma, further chemotherapy is unlikely to reduce relapse rates or increase survival.

Benefits and harms

Maintenance chemotherapy versus no maintenance chemotherapy:

We found no systematic review, but found 2 RCTs, comparing maintenance chemotherapy versus no maintenance chemotherapy.[24] [27]

Relapse rates

Maintenance chemotherapy compared with no maintenance chemotherapy Maintenance chemotherapy may not reduce relapse rates at 1 to 5 years in men with complete remission after initial chemotherapy, compared to no maintenance chemotherapy (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Relapse rates
[24]
RCT		 113 men with seminoma, teratoma, or mixed tumours who had complete remission after combined chemotherapy for 12 weeks Relapse rates 12 months
5/58 (9%) with maintenance chemotherapy using vinblastine
4/55 (7%) with no maintenance chemotherapy
P value not reported
[27]
RCT
3-armed trial 		183 men with seminoma, teratoma, or mixed tumours who had complete remission after combined chemotherapy for 12 weeks; of these men, 88 were randomised Relapse rates 5 years
11/43 (26%) with maintenance chemotherapy with vinblastine for 6 months
7/45 (16%) with no maintenance chemotherapy for 6 months
7/95 (7%) with no randomisation to treatment
P = 0.08 for relapse among all 3 groups 		Not significant
Open in a new tab

Cure rates

No data from the following reference on this outcome.[24] [27]

Mortality

No data from the following reference on this outcome.[24] [27]

Adverse effects

No data from the following reference on this outcome.[24] [27]

Comment

Clinical guide:

RCTs specifically including only good-prognosis seminoma are rare. Most studies of chemotherapy for testicular germ cell tumours include both seminomas and non-seminomas, but it is likely that the results are generalisable to men with good-prognosis seminoma.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jan 25;2011:1807.

Chemotherapy

Summary

Although there are no trials that include only this category of people, results in intermediate-prognosis non-seminoma are likely to be generalisable to men with seminoma, and thus chemotherapy increases survival in men with intermediate-prognosis seminomas who have had orchidectomy.

Intermediate-prognosis tumours represent only 10% of seminomas, and no seminomas are classified as worse than this category.

Benefits and harms

Chemotherapy in men with intermediate-prognosis seminomas:

We found one systematic review (search date 2002), which identified no RCTs (see comment below).[6]

Comment

Clinical guide:

Intermediate-prognosis tumours represent only 10% of seminomas, and no seminomas are classified as worse than this category. There are no RCTs specifically including only intermediate-prognosis seminoma alone. Most studies of chemotherapy for testicular germ cell tumours include both intermediate-prognosis non-seminomas and seminomas, but it is likely that the results are generalisable to men with intermediate-prognosis seminoma.

Relapse:

Seminoma relapses very rarely after adequate chemotherapy. If seminoma relapses, it has a poor prognosis and does not respond well to further chemotherapy. The optimum treatment is unknown, although most would treat in the same way as for relapsed non-seminoma.

Substantive changes

No new evidence

Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group

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