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BMJ Clin Evid. 2007; 2007: 1807.
Published online 2007 February 1.
PMCID: PMC2943781

Testicular cancer: seminoma

Dr Richard David Neal, Senior Lecturer in General Practice,# Nicholas Stuart, Professor of Cancer Studies,# and Clare Wilkinson, Professor#

Abstract

Introduction

More than half of painless solid swellings of the body of the testis are malignant, with a peak incidence in men aged 25-35 years. About half of testicular cancers 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 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 April 2006 (BMJ 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 27 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: adjuvant irradiation (20 Gy in 10 fractions to paraaortic area, 30 Gy in 15 fractions to paraaortic area and iliac nodes), chemotherapy (maintenance, adjuvant, single-agent carboplatin, three or four 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 two-drug chemotherapy regimen using cisplatin or vinblastine), radiotherapy (adjuvant, different drug combinations, 30-36 Gy in 15-18 fractions), 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 25-35 years.

  • About half of testicular cancers 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 to infradiaphragmatic lymph nodes, which is associated with cure rates approaching 100%.

  • Adjuvant chemotherapy and radiotherapy reduce the risk of relapse after orchidectomy compared with surveillance, but both reduce fertility and may increase the risk of secondary malignancy in the long term.
  • We do not 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 that any 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 three cycles seem to be as effective as four and with less toxicity.
  • Standard radiotherapy treatment comprises 30-36 Gy in 15-18 fractions, although we do not 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.

  • We do not know whether chemotherapy increases survival in men with intermediate prognosis seminomas who have had orchidectomy.

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 20-30% 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 cancers 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 in current practice is the International Germ Cell Consensus Classification, which classifies testicular tumours as good prognosis, intermediate prognosis, or poor prognosis. Because 90% of seminomas are classified as good prognosis, this system is less useful for seminomas, and so we have further divided good prognosis seminoma into stage 1 (confined to testis) and non-stage 1 (with nodal but no non-visceral metastases), based on the Royal Marsden and TNM staging systems.

Table 1
Staging systems for testicular cancer (see text).

Incidence/ Prevalence

There are about 1400 new cases of testicular cancer (seminona, teratoma, or mixed seminoma/teratoma) in the UK annually, with the peak incidence in men aged 25-35 years. It 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). Recent reviews of the incidence of testicular cancer have reported a clear trend toward increased incidence during the past 30 years in the majority of industrialised countries in North America, Europe, and Oceania.

Aetiology/ Risk factors

There appear to be both individual and environmental risk factors for testicular cancer. 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 one in five 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 and/or AIDS, torsion, trauma (although this may be coincidental), and Klinefelter's syndrome. 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.

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 those 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 pelvic and para-aortic lymph nodes. Haematological spread leading to lung, liver, and brain metastases is less common in seminomas; 75% of men present with stage 1 disease. From the perspective of the International Germ Cell Cancer Collaborative Group prognostic classification, 90% of seminomas present as "good prognosis" with a 5 year survival of 86%, and 10% present as "intermediate prognosis" with a 5 year survival of 73%. Seminoma is a radio-sensitive tumour, and the standard treatment for stage 1 seminoma is orchidectomy followed by infradiaphragmatic lymph node irradiation. Clinical observation suggests that, with this approach, 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, quality of life, adverse effects of treatment.

Methods

BMJ Clinical Evidence search and appraisal April 2006. For this review various sources were used for the identification of studies: Medline 1966 to April 2006, Embase 1980 to April 2006, and The Cochrane Library Issue 1 2006. Additional searches were carried out on the NHS Centre for Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and the National Institute of Health and Clinical Excellence guidance (NICE) websites. Abstracts of studies retrieved in the search were assessed independently by two information specialists. The contributors also performed hand searches of their own files. Predetermined criteria were used to identify relevant studies. Study design criteria included systematic reviews, RCTs, and observational studies identified by systematic reviews. We included open label trials. The minimum number of individuals in each trial was 20.There was no minimum percentage of people to be followed up. There was no minimum length of follow up. There are very few RCTs published on treatments for seminoma, and we have therefore included RCTs published only as abstracts and observational studies if they were identified by systematic reviews. The main systematic review on treatment of seminoma on which this review is based does not use a single staging system when describing data. However, it divides treatment options into stage 1 seminoma (in keeping with the Royal Marsden and TNM staging) and into other good prognosis, intermediate prognosis, and poor prognosis testicular tumours (in keeping with the International Germ Cell Consensus Classification [IGCCC] staging). We have therefore chosen to do the same. Wherever possible, we have differentiated data specific to good and intermediate prognosis seminomas from data on all testicular tumours. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table
GRADE evaluation of interventions for testicular cancer: seminoma

Glossary

Adjuvant treatment
is 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
is used to describe those situations 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
Also known as orchiectomy, orchidectomy means total surgical removal of the affected testicle. 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
is 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) recommend follow up for 5 years after initial treatment. However, relapse can occur after this, and others recommend follow up for 10 years.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

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

Dr Richard David Neal, North Wales Clinical School, Cardiff University Wales College of Medicine, Wrexham, Wales.

Nicholas Stuart, University of Bangor, Bangor, Wales.

Clare Wilkinson, North Wales Clinical School, Cardiff University Wales, College of Medicine, Wrexham, Wales.

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2007; 2007: 1807.
Published online 2007 February 1.

Adjuvant chemotherapy

Summary

RELAPSE RATES Compared with adjuvant radiotherapy: Adjuvant chemotherapy does not increase the rate of relapse-free survival at 2–3 years in men with stage 1 seminoma compared with adjuvant radiotherapy ( high-quality evidence ). Compared with surveillance: Adjuvant chemotherapy may reduce relapse rates in men who have undergone orchidectomy for stage 1 seminoma compared with surveillance ( low-quality evidence ). NOTE We found no clinically important results about adjuvant chemotherapy compared with surveillance in the treatment of men who had undergone orchidectomy for stage 1 seminoma. Consensus suggests that adjuvant chemotherapy reduces the risk of relapse compared with surveillance, but that it is associated with immediate adverse effects (nausea, diarrhoea, and indigestion) and possible long-term risks of reduced fertility and development of secondary malignancies.

Benefits

Adjuvant chemotherapy versus surveillance:

See glossary. See benefits of surveillance.

Adjuvant chemotherapy versus adjuvant radiotherapy:

See benefits of adjuvant radiotherapy.

Different drug combinations for adjuvant chemotherapy:

See benefits of adjuvant chemotherapy using different drug combinations.

Different number of cycles of adjuvant chemotherapy:

See benefits of different number of cycles of adjuvant chemotherapy.

Harms

Adjuvant chemotherapy versus surveillance:

See harms of surveillance.

Adjuvant chemotherapy versus adjuvant radiotherapy:

See harms of adjuvant radiotherapy.

Different drug combinations for adjuvant chemotherapy:

See harms of adjuvant chemotherapy using different drug combinations.

Different number of cycles of adjuvant chemotherapy:

See harms of different number of cycles of adjuvant chemotherapy.

Sexual dysfunction:

We found two systematic reviews (search dates 1999) that assessed sexual dysfunction after treatment for testicular cancer. The first review did not report results for different treatments separately (see harms of surveillance). The second review identified seven prospective and 28 retrospective observational studies (2786 men with seminoma, teratoma, or mixed tumours). 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 secondary malignancies associated with chemotherapy:

Secondary malignancies develop more commonly in survivors of seminoma than the general population, partly as a result of chemotherapy. One non-systematic review identified nine studies, each including 300 people or more, who were treated for (any) testicular cancer with a variety of chemotherapy regimens, including regimens containing alkylating agents. Follow up was for 6 years or longer. None of the studies identified by the review found a significant increase in the risk of secondary solid tumours or leukaemias in people who had received chemotherapy (RRs ranging from 0.7 to 3.4 for solid tumours, and from 2.0 to 5.2 for leukaemias, all with wide confidence intervals). However, the review suggested that there may be a significant increase in the risk of secondary leukaemia in people treated for (any) testicular cancer with etoposide, although these data are difficult to interpret given the rarity of leukaemia, the variation of risk from time of exposure, and the varying doses of etoposide given in the studies. Three studies cited in the review found a significant increase in secondary leukaemia in people receiving etoposide (RR 2.4, 95% CI 1.4 to 3.7; RR 5.1, 95% CI 1.4 to 130; RR 5.2, 95% CI 2.3 to 10). 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.

Comment

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 immediate toxicity. Radiotherapy is also associated with a low but difficult to quantify long term risk of second malignancy and reduced fertility. The pattern of relapse also differs after adjuvant radiotherapy or chemotherapy. After radiotherapy, relapse in pelvic nodes, mediastinum, or supraclavicular area is most common. After chemotherapy, relapse is most common in the para-aortic nodes. Seminoma is a radio-sensitive tumour, and the current standard treatment for stage 1 seminoma is orchidectomy followed by infradiaphragmatic lymph node irradiation. The cohort study comparing surveillance, adjuvant radiotherapy, and adjuvant chemotherapy has been reported separately in both here and under adjuvant radiotherapy.

Substantive changes

No new evidence

2007; 2007: 1807.
Published online 2007 February 1.

Adjuvant radiotherapy

Summary

RELAPSE RATES Compared with adjuvant chemotherapy: Adjuvant radiotherapy does not increase the rate of relapse-free survival at 2–3 years in men with stage 1 seminoma compared with adjuvant chemotherapy ( high-quality evidence ). Compared with surveillance: Adjuvant radiotherapy may reduce relapse rates at 5 years in men who have undergone orchidectomy compared with surveillance ( very low-quality evidence ). NOTE We found no clinically important results about adjuvant radiotherapy compared with surveillance or adjuvant chemotherapy in the treatment of men who had undergone orchidectomy for stage 1 seminoma. Seminoma is a radio-sensitive tumour, and the current standard treatment for stage 1 seminoma is orchidectomy followed by infradiaphragmatic lymph node irradiation. Consensus suggests that, although some men relapse and need salvage chemotherapy, final cure rates with orchidectomy plus radiotherapy approach 100%. Adjuvant radiotherapy is associated with immediate adverse effects (nausea, diarrhoea, and indigestion) and with possible long-term risks of reduced fertility and development of secondary malignancies.

Benefits

Adjuvant radiotherapy versus surveillance:

See benefits of surveillance.

Adjuvant radiotherapy versus adjuvant chemotherapy:

We found one RCT and one cohort study. The RCT (1447 men with stage 1 seminoma, 5 : 3 randomisation) compared adjuvant radiotherapy (904 men) versus adjuvant chemotherapy using carboplatin (543 men). It found no significant difference in rates of relapse-free survival at 2 or 3 years between adjuvant radiotherapy and adjuvant carboplatin (relapse-free survival, at a median of 4 years: 96.7% with radiotherapy v 97.7% with carboplatin; at 3 years: 95.9% with adjuvant radiotherapy v 94.8% with 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 more than 3% at 2 years and more than 4% at 3 years). Irradiation involved 20 Gy in 10 fractions or 30 Gy in 15 fractions; 13% of men had irradiation of the ipsilateral iliac and inguinal lymph nodes (dogleg field) and 87% had irradiation to the para-aortic strip. The cohort study (224 men) compared three interventions: adjuvant radiotherapy, adjuvant chemotherapy, and surveillance. It found that relapse rates were significantly lower with adjuvant radiotherapy or adjuvant chemotherapy than with surveillance (5% with radiotherapy v 2% with chemotherapy v 27% with surveillance; P < 0.01 for either treatment v surveillance). It found no significant difference in relapse rates over 5 years between adjuvant radiotherapy and adjuvant chemotherapy (5/79 [5%] with radiotherapy v 1/78 [2%] with chemotherapy; P value reported as non-significant, CI not reported).

Different adjuvant radiotherapy regimens versus each other:

See benefits of different adjuvant radiotherapy regimens.

Harms

Adjuvant radiotherapy versus surveillance:

See harms of surveillance.

Adjuvant radiotherapy versus adjuvant chemotherapy:

The RCT found that a higher proportion of men in the radiotherapy group were unable to do normal work or had moderate or severe lethargy compared with the chemotherapy group at 25 days (men unable to do normal work: 38% with adjuvant radiotherapy v 19% with adjuvant chemotherapy; P < 0.0001; men with moderate or severe lethargy: 24% with adjuvant radiotherapy v 7% with adjuvant chemotherapy; P < 0.0001; absolute data presented graphically). Men in the radiotherapy group had a significantly higher number of new second primary germ cell tumours (10/904 [1.1%] with adjuvant radiotherapy v 2/573 [0.4%] with adjuvant chemotherapy; 5 year event rate: 1.96% with adjuvant radiotherapy v 0.54% with adjuvant chemotherapy; P = 0.04), significantly less thrombocytopenia, although no bleeding was reported (thrombocytopenia grades 1 or 2: 12/904 [2%] v 58/573 [12%]; grades 3 or 4: 0/904 [0%] v 17/573 [4%]; P < 0.0001), and significantly more dyspepsia (127/904 [17%] v 40/573 [8%]; P < 0.0001). The cohort study found a similar amount of adverse effects between radiotherapy and chemotherapy, although chemotherapy using carboplatin was associated with less nausea and an earlier return to work than radiotherapy.

Sexual dysfunction:

We found two systematic reviews (search dates 1999) that assessed sexual dysfunction after treatment for testicular cancer. The first review did not report results for different treatments separately (see harms of surveillance). The second review identified seven prospective and 28 retrospective observational studies (2786 men with seminoma, teratoma, or mixed tumours) assessing sexual dysfunction after surveillance, radiotherapy, or chemotherapy. 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 nine studies (417 men), chemotherapy from six studies (160 men), and chemotherapy plus surgery from nine 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:

Secondary malignancies develop more often in survivors of seminoma than in the general population. A cohort study conducted in Scotland followed up 897 men who had received radiotherapy for (any) testicular tumours between 1950 and 1969. The study found a significant increase in subsequent malignancies in the unirradiated sites after 15–19 years compared with the expected rate (subsequent malignancies in unirradiated sites: 28/547 [5%] observed v 14 expected; P < 0.0), mainly occurring in the urinary or lower gastrointestinal system.

Different adjuvant radiotherapy regimens versus each other:

See harms of different adjuvant radiotherapy regimens.

Comment

Clinical guide:

Seminoma is a radio-sensitive tumour, and the standard treatment for stage I seminoma is orchidectomy followed by infradiaphragmatic lymph node irradiation. Observational evidence suggests that cure rates with this approach are nearly 100%. The cohort study comparing surveillance, adjuvant radiotherapy, and adjuvant chemotherapy is reported separately both here and under surveillance. 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 immediate toxicity. Radiotherapy is also associated with a low but difficult to quantify long term risk of second malignancy and reduced fertility. The pattern of relapse also differs after adjuvant radiotherapy or chemotherapy. After radiotherapy, relapse in pelvic nodes, mediastinum, or supraclavicular area is most common. After chemotherapy, relapse is most common in the para-aortic nodes. Seminoma is a radio-sensitive tumour, and the current standard treatment for stage 1 seminoma is orchidectomy followed by infradiaphragmatic lymph node irradiation.

Substantive changes

No new evidence

2007; 2007: 1807.
Published online 2007 February 1.

Surveillance

Summary

RELAPSE RATES Compared with adjuvant radiotherapy: Surveillance may be less effective at 5 years than adjuvant radiotherapy at reducing relapse rates in men who have undergone orchidectomy for stage 1 seminoma ( very low-quality evidence ). 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 ). NOTE We found no clinically important results about surveillance compared with adjuvant radiotherapy or chemotherapy in men who had undergone orchidectomy for stage 1 seminoma. Seminoma is a radio-sensitive tumour, and the standard treatment for stage 1 seminoma is orchidectomy followed by infradiaphragmatic lymph node irradiation. Consensus suggests that surveillance avoids the adverse effects associated with adjuvant radiotherapy or chemotherapy, but may increase the risk of delayed relapse. Therefore, it requires follow-up for as long as 10 years.

Benefits

Surveillance versus adjuvant radiotherapy or adjuvant chemotherapy in men who have undergone orchidectomy:

We found no systematic review or RCTs comparing surveillance versus adjuvant radiotherapy or 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. Cohort studies suggest that surveillance may be as effective in preventing relapse as adjuvant radiotherapy or adjuvant chemotherapy. We found one systematic review (search date 2002), which identified three prospective cohort studies assessing surveillance in 956 men following orchidectomy between 1981 and 1994. The first cohort study (261 men with stage I seminoma) assessed surveillance alone for a median of 48 months after orchidectomy and found that 49/261 (19%) men relapsed over 4 years. The second cohort study (471 men with stage I seminoma who had undergone orchidectomy) compared outcomes in 245 men receiving adjuvant radiotherapy versus those in 226 men receiving surveillance (examined 4 monthly in years 1–3, 6 monthly in years 4–7, and yearly in years 8–10). It found higher relapse rates with surveillance than with radiotherapy at 5 years (proportion relapse-free: 189/226 [84%] with surveillance v 231/245 [94%] with adjuvant radiotherapy; significance assessment and P value not reported). Only one person (in the surveillance group) died of seminoma over 5 years. The third cohort study (224 men) compared three interventions in men who had undergone orchidectomy: surveillance, adjuvant radiotherapy, and adjuvant chemotherapy. It found that relapse rates were significantly higher with surveillance than with adjuvant radiotherapy or adjuvant chemotherapy (27% with surveillance v 5% with radiotherapy v 2% with chemotherapy; P < 0.01 for either treatment v surveillance). It found no significant difference in relapse rates over 5 years between adjuvant radiotherapy and adjuvant chemotherapy (5/79 [5%] with radiotherapy v 1/78 [2%] with chemotherapy; P value reported as non-significant, CI not reported).

Harms

Surveillance versus adjuvant radiotherapy or adjuvant chemotherapy in men who have undergone orchidectomy:

Two of the cohort studies gave no information on adverse effects. The third cohort study found that fewer men receiving surveillance than radiotherapy or chemotherapy had sickness (6% with surveillance v 36% with radiotherapy v 35–50% with chemotherapy), diarrhoea (4% v 60% v 0–12%), indigestion (11% v 30% v 24%), and fertility problems (6% v 14% v 6%), and that men returned to work earlier (proportion off work for over 12 weeks: 3% v 21% v 23%).

Sexual dysfunction:

We found two systematic reviews (search dates 1999) that assessed sexual dysfunction after treatment for testicular cancer. 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, and so it does not help in determining which treatment is least likely to cause sexual dysfunction. The second review identified seven prospective and 28 retrospective observational studies (2786 men with seminoma, teratoma, or mixed tumours) assessing sexual dysfunction after surveillance, radiotherapy, or chemotherapy. 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.

Comment

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 immediate toxicity. Radiotherapy is also associated with a low but difficult to quantify long term risk of second malignancy and reduced fertility. The pattern of relapse also differs after adjuvant radiotherapy or chemotherapy. After radiotherapy, relapse in pelvic nodes, mediastinum, or supraclavicular area is most common. After chemotherapy, relapse is most common in the para-aortic nodes. Seminoma is a radio-sensitive tumour, and the current standard treatment for stage 1 seminoma is orchidectomy followed by infradiaphragmatic lymph node irradiation. The cohort study comparing surveillance, adjuvant radiotherapy, and adjuvant chemotherapy has been reported separately in both here and under adjuvant radiotherapy.

Substantive changes

No new evidence

2007; 2007: 1807.
Published online 2007 February 1.

Different adjuvant radiotherapy regimens

Summary

RELAPSE RATES Para-aortic strip compared with para-aortic plus ipsilateral: Para-aortic strip (restricted) irradiation is as effective (or does not increase relapse rates) when compared to para-aortic plus ipsilateral iliac lymph node irradiation at 3 years in men who have undergone orchidectomy for stage 1 seminoma ( high-quality evidence ). 20 Gy compared with 30 Gy: 20 Gy in 10 fractions does not reduce relapse rates at 37–61 months in men who have undergone orchidectomy for stage 1 seminoma compared with 30 Gy in 15 fractions (high-quality evidence). NOTE Para-aortic irradiation has been associated with less nausea, vomiting, and leukopenia compared with ipsilateral iliac lymph node irradiation, and 20 Gy irradiation has been associated with less lethargy compared with 30 Gy.

Benefits

Different adjuvant radiotherapy regimens compared with each other:

We found one systematic review (search date 2002, 2 RCTs). The second included RCT was a preliminary report, published only as an abstract in several publications at the time of the review. It was later reported in full after the search date of the review. The review did not perform a meta-analysis because of heterogeneity among the trials in dose, schedule of radiotherapy, and treatments compared. Neither of the RCTs assessed effects on mortality. The first RCT (478 men) included in the review compared para-aortic strip (restricted field) irradiation versus para-aortic strip plus ipsilateral iliac lymph node (traditional field) irradiation (30 Gy in 15 fractions for 3 weeks in both groups). It found that both regimens reduced relapse over 3 years with no significant difference in rates of relapse-free survival between groups (227/236 [96%] with para-aortic v 233/242 [96.6%] with iliac lymph node; mean % difference 0.6, 95% CI –3.4 to +4.6; P value not reported). The second included RCT (published as an abstract, 625 men with stage I seminoma who had received orchidectomy in the previous 8 weeks) compared irradiation to the para-aortic strip of 20 Gy in 10 fractions over 2 weeks versus 30 Gy in 15 fractions over 3 weeks. It found no significant difference in relapse rates over a mean of 37 months between 30 Gy and 20 Gy (8 with 30 Gy v 10 with 20 Gy; HR 1.27, 90% CI 0.58 to 2.8; absolute number of men in each group not reported). The subsequent full report of the RCT found no significant difference in relapse rates between 30 Gy and 20 Gy over a median of 61 months (10/313 [3%] with 30 Gy v 11/312 [4%] with 20 Gy; HR 1.11, 90% CI 0.54 to 2.28). One man in the 20 Gy group had died at 61 months.

Harms

Different adjuvant radiotherapy regimens compared with each other:

The first included RCT found that men receiving para-aortic irradiation had less severe and less frequent acute toxicities such as nausea, vomiting, and leucopenia than did men also receiving ipsilateral iliac lymph node irradiation, and had higher sperm counts at 18 months (no further data reported). It found that 3/478 (0.6%) men developed secondary malignancies (adenocarcinoma or nonseminomatous testicular tumours); 2/478 (0.4%) had also received para-aortic irradiation, and 1/478 (0.2%) had also received ipsalateral irradiation. The second included RCT assessed quality of life and found that 20 Gy significantly increased both moderate or severe lethargy and inability to return to work compared with 30 Gy irradiation at 4 weeks (lethargy: 20% with 30 Gy v 5% with 20 Gy; inability to return to work: 46% with 30 Gy v 28% with 20 Gy; both outcomes reported as significant; CIs not reported). It found no significant difference in these outcomes at 12 weeks (reported as non-significant, CI not reported). The subsequent full report of the second RCT found that a similar proportion of men had World Health Organization grade 3–4 nausea and vomiting in both groups (61/313 [20%] with 30 Gy v 57/312 [18%] with 20 Gy; P = 0.06). It found that six men, all in the 30 Gy irradiation group (6/313 [2%]), developed non-germ cell tumours over 61 months.

Comment

Clinical guide:

Adjuvant radiotherapy is widely used for stage I disease. It is now clear that equally good results can be achieved using lower doses of radiation to smaller treatment volumes, thus leading to less toxicity and quicker recovery.

Substantive changes

No new evidence

2007; 2007: 1807.
Published online 2007 February 1.

Different adjuvant chemotherapy drug combinations

Summary

We found no clinically important results comparing different chemotherapy drug combinations in men who had undergone orchidectomy for good-prognosis stage 1 seminoma.

Benefits

We found one systematic review (search date 2002), which identified no RCTs or observational studies of sufficient quality.

Harms

We found no RCTs or observational studies of sufficient quality.

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, and so there is no reason for RCTs assessing such regimens to be conducted.

Substantive changes

No new evidence

2007; 2007: 1807.
Published online 2007 February 1.

Different number of cycles of adjuvant chemotherapy

Summary

RELAPSE RATES One cycle compared with two cycles: One cycle of carboplatin may not reduce relapse rates at 2 years compared with two cycles of carboplatin ( very low-quality evidence ).

Benefits

We found one systematic review (search date 2002), which identified no RCTs comparing different chemotherapy regimens in men who had undergone orchidectomy for stage 1 seminoma. The review identified one prospective cohort study (125 men) that compared one cycle of carboplatin 400 mg/m2 (93 men) versus two cycles (32 men). It found higher rates of relapse over 2 years after one cycle of carboplatin than after two cycles, although the difference was not significant (relapse rates over 2 years: 8/93 [9%] with one cycle v 0/32 [0%] with two cycles; P > 0.08), and the relapse-free survival in both groups combined at 5 years was 91%.

Harms

The cohort study found a low myelotoxicity rate and suggested that carboplatin was associated with low gonadal toxicity. It did not compare rates of myelotoxicity between one and two cycles.

Comment

Clinical guide:

The relapse rate may be lower after two cycles of carboplatin than after one, but in the absence of a randomised comparison this is not certain. Given that two cycles of chemotherapy produce more than twice the toxicity of one cycle, most oncologists would recommend a single cycle of adjuvant carboplatin.

Substantive changes

No new evidence

2007; 2007: 1807.
Published online 2007 February 1.

Chemotherapy using etoposide plus cisplatin (with or without bleomycin)

Summary

MORTALITY Etoposide plus cisplatin compared with etoposide plus carboplatin: Etoposide plus cisplatin may increase relapse-free survival rates at about 2 years (but not overall survival rates) in men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours compared with etoposide plus carboplatin ( low-quality evidence ). 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, teratoma, or mixed tumours compared with etoposide plus cisplatin ( very low-quality evidence ). Two-drug compared with five-drug regimen: Etoposide plus cisplatin may not increase overall survival rates at 5 years in men with good-prognosis non-stage 1 seminoma, teratoma, or mixed tumours, but may reduce toxicity, compared with a five-drug regimen of cisplatin, vinblastine, bleomycin, cyclophosphamide and dactinomycin (very low-quality evidence). 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 (very low-quality evidence). Two-drug compared with five-drug regimen: Etoposide plus cisplatin may not reduce relapse rates at 5 years in men with good prognosis non-stage 1 seminoma, teratoma, or mixed tumours compared with a five-drug regimen of cisplatin, vinblastine, bleomycin, cyclophosphamide, and dactinomycin, but may reduce toxicity (very low-quality evidence).

Benefits

We found one systematic review (search date 2002, 3 RCTs) in men with non-stage 1 good prognosis tumours (seminoma or teratoma; see comment below).

Etoposide plus cisplatin versus etoposide plus carboplatin:

The first RCT (270 men with good prognosis non-stage 1 seminoma, teratoma, or mixed tumours) included in the review compared etoposide plus cisplatin versus etoposide plus carboplatin. It found that etoposide plus cisplatin significantly increased relapse-free survival compared with etoposide plus carboplatin (P < 0.05), but it found no significant difference in overall survival over a median 22.4 months (P = 0.52, absolute results presented graphically).

Etoposide plus cisplatin versus etoposide plus carboplatin:

The second RCT (178 men with good prognosis non-stage 1 seminoma [33 men], teratoma, or mixed tumours) included in the review compared etoposide plus cisplatin plus bleomycin versus etoposide plus cisplatin alone. It found that men receiving additional bleomycin had lower relapse rates over a median 4.1 years than did men receiving etoposide plus cisplatin (8/81 [10%] with adding bleomycin v 17/75 [23%] with cisplatin plus etoposide; P value not reported). It found that adding bleomycin significantly increased survival rates over 3 years (95% with adding bleomycin v 86% with cisplatin plus etoposide; P = 0.01). The third RCT (164 men with good prognosis non-stage 1 seminoma, teratoma, or mixed tumours) included in review compared etoposide plus cisplatin versus cisplatin plus vinblastine plus bleomycin plus cyclophosphamide plus dactinomycin. It found no significant difference in relapse-free or overall survival over a mean of 5 years between groups (reported as non-significant, absolute results presented graphically, P value not reported). RCTs specifically including only patients with good prognosis non-stage 1 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.

Harms

Etoposide plus cisplatin versus etoposide plus carboplatin:

The first RCT found that etoposide plus cisplatin was associated with significantly less anaemia (P = 0.005), thrombocytopenia (P < 0.005), and neutropenia (P = 0.004) than etoposide plus carboplatin.

Etoposide plus cisplatin plus bleomycin versus etoposide plus cisplatin:

The second RCT assessed the combined outcome of drug related mortality and found that two people receiving additional bleomycin and one person receiving etoposide plus cisplatin had these outcomes. The third RCT found that etoposide plus cisplatin reduced toxicity compared with cisplatin plus vinblastine plus bleomycin plus cyclophosphamide plus dactinomycin (emesis: P = 0.05; mucositis: P = 0.06).

Comment

Clinical guide:

These RCTs indicate that cisplatin is superior to carboplatin and that adding bleomycin to cisplatin and etoposide improves effectiveness. However, all of the studies included both seminomas and teratomas, and it is not clear whether these conclusions apply equally to both. Nonetheless, the RCTs will never be repeated with seminoma alone, and so a pragmatic view must be taken. Given that seminoma is known to be more sensitive to chemotherapy than teratoma, and given that bleomycin occasionally causes fatal toxicity, many oncologists recommend cisplatin plus etopside to treat good prognosis non-stage 1 seminoma.

Substantive changes

No new evidence

2007; 2007: 1807.
Published online 2007 February 1.

Chemotherapy using vinblastine plus cisplatin plus bleomycin

Summary

RELAPSE RATES Bleomycin plus vinblastine plus cisplatin compared with cisplatin plus vinbastine: Adding bleomycin to two-drug regimens containing vinblastine plus cisplatin seems to be more effective at 4 years than vinblastine plus cisplatin at reducing relapse rates in men with non-stage 1 good-prognosis tumours ( moderate-quality evidence ). MORTALITY Bleomycin plus vinblastine plus cisplatin compared with cisplatin plus vinbastine: Adding bleomycin to two-drug regimens containing vinblastine plus cisplatin reduces tumour-related mortality at 4 years in men with non-stage 1 good-prognosis tumours compared with vinblastin plus cisplatin (moderate-quality evidence).

Benefits

Adding bleomycin to vinblastine plus cisplatin:

We found one systematic review (search date 2002, 1 RCT) in men with non-stage 1 good prognosis tumours (seminoma or teratoma; see comment for chemotherapy using etoposide plus cisplatin [with or without bleomycin]). The RCT (222 men with good prognosis non-stage 1 seminoma, teratoma, or mixed tumours) included in the review compared adding bleomycin to vinblastine plus cisplatin versus cisplatin plus vinblastine alone. It found no significant difference in relapse rates over 4 years between regimens, although fewer men receiving bleomycin relapsed (5/110 [5%] with adding bleomycin v 8/108 [7%] with cisplatin plus vinblastine; P = 0.12). It found that adding bleomycin significantly reduced tumour related mortality over 4 years (6/110 [5%] with adding bleomycin v 16/108 [15%] with cisplatin plus vinblastine; P = 0.02).

Harms

Adding bleomycin to vinblastine plus cisplatin:

The RCT found no significant difference in mortality related to treatment, although this was higher in people receiving bleomycin (6/110 [5%] with added bleomycin v 1/108 [1%] with vinblastine plus cisplatin; P = 0.06).

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

No new evidence

2007; 2007: 1807.
Published online 2007 February 1.

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

Summary

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

Benefits

We found one systematic review (search date 2002, 1 RCT) and one additional RCT in men with non-stage 1 good prognosis tumours (seminoma or teratoma; see comment for chemotherapy using etoposide plus cisplatin [with or without bleomycin]).

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

The RCT (114 people with good prognosis non-stage 1 seminoma, teratoma, or mixed tumours) identified by the review compared higher versus lower dose cisplatin, both combined with vinblastine plus bleomycin. It found that higher dose cisplatin significantly increased complete response rates at 1 year compared with lower dose (63% with higher dose v 43% with lower dose; P = 0.03), with a clear advantage for the subgroup with maximal disease (57% with higher dose v 34% with lower dose; P = 0.02).

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

The additional RCT (203 men with good prognosis non-stage 1 seminoma, teratoma, or mixed tumours) compared four courses of higher (0.20 mg/kg) versus lower (0.15 mg/kg) dose vinblastine, both combined with cisplatin plus bleomycin for 12 weeks. Only 134/203 (66%) people were followed up. The RCT found that 71% of people in each group had complete remission at 1 year (CI not reported).

Harms

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

The RCT included in the review found that 51% of men receiving higher dose cisplatin compared with 38% of people receiving lower dose cisplatin had severe thrombocytopenia (significance of the difference between groups not reported). It found that less than 10% of people in both groups had severe thrombocytopenia.

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

The additional RCT found that adding high dose vinblastine to cisplatin plus bleomycin significantly increased leucocytopenia compared with adding low dose (36% with high dose v 13% with low dose; P = 0.001). It also found higher rates of granulocytopenic fever in people taking high dose vinblastine (55% with high dose v 30% with low dose; CI not reported).

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 three 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

2007; 2007: 1807.
Published online 2007 February 1.

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 30–36 Gy in 15–18 fractions, but cannot confirm that this is the optimum dose. Lower doses of irradiation were as effective as 30–36 Gy in people with stage 1 seminoma, but this may not necessarily apply to people with non-stage 1 seminoma.

Benefits

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).

Harms

We found no RCTs. See harms of different radiotherapy regimens for stage I seminoma (different adjuvant radiotherapy regimens.)

Comment

The dose of radiotherapy has traditionally been 30–36 Gy in 15–18 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 three papers) found that lower doses of irradiation (20–30 Gy) were as effective as 30–36 Gy in people with stage 1 seminoma, this evidence does not necessarily apply to people with non-stage 1 seminoma.

Substantive changes

No new evidence

2007; 2007: 1807.
Published online 2007 February 1.

Radiotherapy versus chemotherapy

Summary

We found no clinically important results 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 (greater than 2 cm disease, stage IIB). Therefore, radiotherapy is often preferred for small-volume disease (stage IIA), and chemotherapy for larger-volume disease (stage IIB).

Benefits

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).

Harms

We found no RCTs. See harms of different radiotherapy regimens for stage I 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 (>2 cm disease, stage IIB). Therefore, radiotherapy often preferred for small volume disease (stage IIA) and chemotherapy for larger volume disease (stage IIB).

Substantive changes

No new evidence

2007; 2007: 1807.
Published online 2007 February 1.

Three versus four cycles of chemotherapy

Summary

MORTALITY Three cycles compared with four cycles: We don’t know whether three cycles of chemotherapy may increase progression-free or overall survival rates in men with both seminomas and non-seminomas compared with four cycles, but three cycles may be more effective at reducing toxicity ( low-quality evidence ).

Benefits

We found one systematic review (search date 2002), which identified three RCTs comparing different numbers of cycles of chemotherapy. The first RCT (184 men with non-stage 1 seminoma, teratoma, or mixed tumours) compared three cycles over 9 weeks versus four cycles over 12 weeks of cisplatin plus etoposide plus bleomycin. It found similar relapse rates between three and four cycles of chemotherapy (5/88 [6%] with three cycles v 5/96 [5%] with four cycles; significance assessment not reported). The second RCT (166 men with non-stage 1 seminoma, teratoma, or mixed tumours) also compared three cycles over 9 weeks versus four cycles over 12 weeks of cisplatin plus etoposide plus bleomycin. It found that three cycles significantly reduced overall mortality at a median 3 years compared with four cycles (3/83 [4%] with three cycles v 13/83 [16%] with four cycles; HR 0.22, 95% CI 0.06 to 0.77). It found no significant difference in relapse-free survival (16/83 [19%] v 19/83 [23%]; HR 0.84, 95% CI 0.43 to 1.63). The third RCT (812 men with non-stage 1 seminoma, teratoma, or mixed tumours) compared four interventions: three cycles of combination chemotherapy (cisplatin plus etoposide plus bleomycin) for 3 days, three cycles of combination chemotherapy for 5 days, four cycles of combination chemotherapy (cisplatin plus etoposide plus bleomycin for 3 cycles, etoposide for 1 cycle) for 3 days, and four cycles of combination chemotherapy for 5 days. It found no significant difference in progression free or overall survival over 2 years between three and four cycles cycles of chemotherapy (progression free survival: 90% with three cycles v 89% with four cycles; HR 0.93, 80% CI 0.71 to 1.24; overall survival: 97% with three cycles v 97% with four cycles; HR 1.02, 80% CI 0.61 to 1.73).

Harms

The first RCT reported that giving three rather than four cycles of chemotherapy “significantly reduces toxicity”, but gave no information on toxicity in either group. The second RCT found that three cycles of chemotherapy significantly reduced nausea and vomiting compared with four cycles (47/83 [57%] with three v 62/83 [74%] with four cycles; P = 0.02). It found no significant difference in toxicity between groups (haematological grade III or IV: 1–59% v 7–65%; P > 0.2; renal grade II–IV: 1/79 [1%] v 0/79 [0%]; P = 1.0; pulmonary grade II–IV: 10/79 [12%] v 7/79 [8%]; P = 0.6), although the study was probably underpowered to detect significant differences. The third RCT found a similar incidence of haematological toxicity between four and three cycles of chemotherapy (leucopenic fever: 60/406 [15%] with 3 cycles v 62/406 [15%] with 4 cycles; P value not reported).

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

No new evidence

2007; 2007: 1807.
Published online 2007 February 1.

Chemotherapy using single agent carboplatin versus combined chemotherapy regimens

Summary

RELAPSE RATES Single-agent compared with combined chemotherapy: Single agent carboplatin may not reduce relapse rates at 52 months to 3 years compared with combined chemotherapy regimens ( very low-quality evidence ). MORTALITY RATES Single-agent compared with combined chemotherapy: Single-agent carboplatin may not reduce mortality rates at 52 months to 3 years compared with combined chemotherapy regimens ( low-quality evidence ).

Benefits

We found one systematic review (search date 2002), which identified two RCTs. The first RCT (130 men with good prognosis non-stage 1 seminomas) compared single agent carboplatin chemotherapy versus combined chemotherapy with etoposide plus cisplatin. It found no significant difference in relapse-free or overall survival at 3 years between single agent carboplatin and combined chemotherapy (relapse-free survival: HR 0.64, 95% CI 0.32 to 1.28; overall survival: HR 0.85, 95% CI 0.35 to 2.10; absolute results presented graphically). The RCT may have been underpowered to detect a clinically important difference between groups. The second RCT (published only as an abstract, 251 men with good prognosis non-stage 1 seminomas) compared single agent carboplatin chemotherapy versus combined chemotherapy with etoposide plus cisplatin plus ifosfamide. It found that single agent carboplatin was significantly less effective than combined chemotherapy in increasing relapse-free survival over a median 52 months, but found no significant difference in overall survival (relapse-free survival: 74% with single agent v 95% with combined chemotherapy, P < 0.01; overall survival: 87% with single agent v 95% with combined; P value reported as non-significant, CI not reported; absolute data not reported).

Harms

The first RCT found that carboplatin was associated with significantly less neutropenia than combined chemotherapy with etoposide plus cisplatin (3% with carboplatin v 32% with etoposide plus cisplatin; P < 0.001). It found similar haematological toxicity between groups (5 men in each group had World Health Organization grade 3 or 4 thrombocytopenia). The second RCT found that leucopenia and thrombocytopenia were lower in men taking carboplatin than in men taking cisplatin plus etoposide plus ifosfamide (World Health Organization grade 3–4: 7/89 [8%] with carboplatin v 67/93 [72%] with cisplatin + etoposide + ifosfamide; P value not reported).

Comment

Clinical guide:

There is sufficient evidence that carboplatin may be inferior to combination chemotherapy to preclude its use for non-stage I seminoma.

Substantive changes

No new evidence

2007; 2007: 1807.
Published online 2007 February 1.

Maintenance chemotherapy

Summary

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

Benefits

We found no systematic review but found two RCTs. The first RCT (171 men with seminoma, teratoma, or mixed tumours) compared maintenance chemotherapy using vinblastine versus no maintenance chemotherapy in 113 men who had complete remission after combined chemotherapy for 12 weeks. It found similar relapse rates over 12 months between groups (5/58 [9%] with maintenance chemotherapy v 4/55 [7%] without; P value not reported). The second RCT (253 men with seminoma, teratoma, or mixed tumours also compared maintenance chemotherapy with vinblastine versus no maintenance chemotherapy for 6 months, in men who had complete remission after combined chemotherapy for 12 weeks. Of the 183 men who had complete remission, 88 were randomised maintenance chemotherapy or no maintenance chemotherapy, but the RCT assessed outcomes in all 183 men. The RCT found no significant difference in relapse rates over about 5 years between men who had received maintenance chemotherapy and those that had not (proportion of people randomised who relapsed: 11/43 [26%] with maintenance chemotherapy v 7/45 [16%] without; proportion of people not randomised but followed up who relapsed: 7/95 [7%]; P = 0.08 for relapse among all three groups).

Harms

The RCTs gave no information on adverse effects of maintenance chemotherapy compared with no maintenance; they assessed only adverse effects of initial combined chemotherapy regimens.

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

2007; 2007: 1807.
Published online 2007 February 1.

Chemotherapy

Summary

We found no direct information about chemotherapy in men with intermediate-prognosis seminomas. Intermediate-prognosis tumours represent only 10% of seminomas, and no seminomas are classified as worse than this category.

Benefits

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

Harms

We found no RCTs. See harms of adjuvant chemotherapy for stage I seminoma.

Comment

Clinical guide:

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

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 relapsed teratoma.

Substantive changes

No new evidence


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