Abstract
Introduction
More than half of painless solid swellings of the body of the testis are malignant, with a peak incidence in men aged 30 to 34 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 overview, aiming to answer the following clinical question: What are the effects of treatments following orchidectomy in men diagnosed with stage 1 germ cell tumours (confined to testis)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).
Results
At this update, 76 records were screened for inclusion. Appraisal of titles and abstracts led to the exclusion of 47 studies and the further review of 29 full publications. Of the 29 full articles evaluated, two systematic reviews and one RCT, were added at this update. Data from long-term follow-up of an already reported study were also added. We performed a GRADE evaluation for seven PICO combinations.
Conclusions
In this systematic overview, we categorised the efficacy for seven interventions based on information about the effectiveness and safety of adjuvant chemotherapy (including different drugs and the number of cycles), adjuvant radiotherapy (including different regimens), adjuvant surgery, and surveillance/observation.
Key Points
More than half of painless solid swellings of the body of the testis are malignant, with a peak incidence in men aged 30 to 34 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 germ cell tumours confined to the testis (stage 1), standard treatment is orchidectomy followed by radiotherapy (seminoma only), chemotherapy, surgery/retroperitoneal lymph node dissection (non-seminoma only), or surveillance. All management options are associated with cure rates approaching 100% because of successful salvage therapy.
There may be no difference between adjuvant chemotherapy and adjuvant radiotherapy in relapse rates at 2 to 5 years for stage 1 seminoma, with adjuvant chemotherapy causing acute side effects that were short lived compared to adjuvant radiotherapy.
We don't know which is the most effective chemotherapy regimen or what is 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 para-aortic and ipsilateral pelvic nodes in men who have undergone orchidectomy for stage 1 seminoma.
Adjuvant surgery (retroperitoneal lymph node dissection) is less effective at reducing risk of relapse at 2 years after orchidectomy compared with chemotherapy in men with non-seminomatous testicular cancer.
No adjuvant therapy has been demonstrated to improve survival compared with surveillance after orchidectomy. The choice of treatment following orchidectomy is influenced by factors such as the pattern of toxicity, the inconvenience and complexity of treatment, and patient preference, particularly the person's attitude to relapse.
Clinical context
General background
Testicular cancer represents only 1% of all cancers, with germ cell tumours being by far the most common pathology. This disease is the most common form of cancer in men aged under 40 years, and is curable in a large majority of cases. However, it may be a significant burden to some men in the prime of their lives either due to the disease or to its treatment, or both. The primary treatment for testicular germ cell tumours is radical orchidectomy; this allows diagnosis and definitive histological subtyping. Further management depends on the histological subtype, extent of disease at diagnosis, and also the presence of elevated tumour markers, which is more likely in non-seminoma with loco-regional and/or distant metastases.
Focus of the review
The majority of men present with disease clinically confined to the testis (stage 1) and may be offered surveillance (observation with treatment at relapse), adjuvant chemotherapy, adjuvant radiotherapy (seminoma), or retroperitoneal lymph node dissection (non-seminoma). Despite the multiple available options for the management of stage 1 tumours, the optimal management is controversial. This overview focuses on the evidence for the various options and may help individual decision-making for patients and clinicians.
Comments on evidence
For a rare disease, several RCTs have been successfully completed to guide evidence-based decision making. However, one of the main options, surveillance, has been developed empirically over time.
Search and appraisal summary
The update literature search for this overview was carried out from the date of the last search, June 2010, to October 2014. A back search from 1966 was performed at this update to capture studies on non-seminomatous testicular germ-cell cancers, which were added at this update. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. After deduplication and removal of conference abstracts, 76 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 47 studies and the further review of 29 full publications. Of the 29 full articles evaluated, two systematic reviews and one RCT were added at this update. Data from long-term follow-up of an already reported study were also added.
Additional information
The management philosophy for determining individual treatment strategy of germ cell tumours has changed from a general approach where cure was the main concern, to one where the potential toxicity of active treatment is now very much taken into account. The best example of this is in stage 1 disease, where cure is almost universal regardless of the initial management route. The toxicity of adjuvant treatment is increasingly becoming recognised to be of much importance in the clinical decision-making about individual treatment choice.
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 or 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, of which there are multiple subtypes, such as choriocarcinoma, embryonal carcinoma, yolk sac tumour, teratoma, and mixed tumours among others, and which tend to occur in younger men. Several staging systems for testicular cancer have been developed. The most commonly used system is the UICC/AJCC TNM classification, which divides patients into categories of localised, regional metastatic, and distant metastatic disease. For metastatic disease, the International Germ Cell Consensus Classification divides patients with metastatic testicular tumours into good prognosis, intermediate prognosis, or poor prognosis groups and is most frequently used to prognosticate and direct treatment after orchidectomy.[1] This system is less useful in seminoma, as 90% are classified as good prognosis. The majority of men with testicular germ cell tumours (TGCT) present with disease confined to the testis and thus are stage 1.
Incidence/ Prevalence
There are about 2200 new cases of testicular cancer (seminomas, non-seminomas) in the UK annually, with the peak incidence in men aged 30 to 34 years.[2] [3] 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).[4] Reviews of the incidence of testicular cancer have reported a clear trend towards increased incidence in the majority of industrialised countries in North America, Europe, and Oceania.[5] [6]
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 developing 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.[4]
Prognosis
Testicular tumour patients generally have an excellent prognosis, particularly those with localised disease at diagnosis, where survival exceeds 99%. Of men with testicular tumours, 75% present with stage 1 disease. Seminoma is a radio-sensitive tumour, and the standard treatment after orchidectomy for stage 1 seminoma may include adjuvant radiotherapy, adjuvant chemotherapy, or surveillance.[7] For non-seminoma, standard treatment after orchidectomy may consist of adjuvant chemotherapy, retroperitoneal lymph node dissection, or surveillance. For those with metastatic disease, the first site of spread is often via the lymphatic system, particularly the para-aortic and, less frequently, the pelvic lymph nodes for seminoma. Haematological spread leading to lung, liver, and brain metastases is less common in seminomas than in non-seminomas. For those with metastatic disease, the International Germ Cell Consensus Classification indicates that overall survival figures in the 'good prognosis' category, 'intermediate prognosis' category, and 'poor prognosis' category are expected to be in the order of 86%–92%, 72%–80%, and 48%, respectively, at 5 years.
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.
Methods
Search strategy BMJ Clinical Evidence search and appraisal date October 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to October 2014, Embase 1980 to October 2014, The Cochrane Database of Systematic Reviews 2014, issue 10 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews and RCTs published in English, with any level of blinding, no minimum size, and with any maximum loss to follow-up. There was no minimum length of follow-up. Wherever possible we have adhered to the TNM staging system and International Germ Cell Consensus Classification (IGCCC) when assessing the evidence. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the overview. In addition, information that did not meet our pre-defined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update, we have removed the following previously reported questions: 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 non-stage 1 seminomas who have undergone orchidectomy? Data and quality To aid readability of the numerical data in our overviews, 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). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. 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: germ cell tumours.
| Important outcomes | Cure rates, Mortality, Quality of life, Relapse rates | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments following orchidectomy in men diagnosed with stage 1 germ cell tumours (confined to testis)? | |||||||||
| 1 (1477) | Mortality | Adjuvant radiotherapy versus adjuvant chemotherapy | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for methodological flaws (lack of statistical assessment and lack of power) |
| 1 (1477) | Relapse rates | Adjuvant radiotherapy versus adjuvant chemotherapy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological flaws (exclusion of some men from analysis) |
| 1 (382) | Mortality | Adjuvant surgery versus adjuvant chemotherapy | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for open-label design of study; directness point deducted for low event rate, which leads to uncertainty as to whether there is a true difference in effect between treatments |
| 1 (382) | Relapse rates | Adjuvant surgery versus adjuvant chemotherapy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for open-label design of study |
| 1 (156) | Relapse rates | Surveillance versus adjuvant radiotherapy | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and lack of statistical analysis of between-group difference |
| 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 | |
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)[21] [22] recommend follow-up for 5 years after initial treatment. However, relapse can occur after this, and others recommend follow-up for 10 years.[23]
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, Assistant Professor, Radiation Oncology, University of Toronto Toronto, Canada.
Padraig Warde, Professor, Radiation Oncology, University of Toronto, Toronto, Canada.
References
- 1.International Germ Cell Cancer Collaborative Group. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997;15:594–603. [DOI] [PubMed] [Google Scholar]
- 2.Dearnaley DP, Huddart RA, Horwich A. Regular review: managing testicular cancer. BMJ 2001;322:1583–1588. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Cancer Research UK. Testicular cancer statistics. 2015. Available at http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/testicular-cancer (last accessed 17 September 2015). [Google Scholar]
- 4.Adami HO, Bergström R, Möhner M, et al. Testicular cancer in nine northern European countries. Int J Cancer 1994;59:33–38. [DOI] [PubMed] [Google Scholar]
- 5.Huyghe E, Matsuda T, Thonneau P. Increasing incidence of testicular cancer worldwide: a review. J Urol 2003;170:5–11. [DOI] [PubMed] [Google Scholar]
- 6.Parkin DM, Whelan SL, Ferlay J, et al. (eds). Cancer incidence in five continents, vols I–VIII. IARC CancerBase No. 7. Lyon, France: IARC, 2005. [Google Scholar]
- 7.Shelley MD, Burgon K, Mason MD. Treatment of testicular germ-cell cancer: a Cochrane evidence-based systematic review. Cancer Treat Rev 2002;28:237–253. [DOI] [PubMed] [Google Scholar]
- 8.Nazareth I, Lewin J, King M. Sexual dysfunction after treatment for testicular cancer. A systematic review. J Psychosom Res 2001;51:735–743. [DOI] [PubMed] [Google Scholar]
- 9.Jonker-Pool G, Van de Wiel H, Hoekstra HJ, et al. Sexual functioning after treatment for testicular cancer – review and meta-analysis of 36 empirical studies between 1975–2000. Arch Sex Behav 2001;30:55–74. [DOI] [PubMed] [Google Scholar]
- 10.Feldman DR, Bosl GJ, Sheinfeld J, et al. Medical treatment of advanced testicular cancer. JAMA 2008;299:672–684. [DOI] [PubMed] [Google Scholar]
- 11.Fung C, Fossa SD, Milano MT, et al. Solid tumors after chemotherapy or surgery for testicular nonseminoma: a population-based study. J Clin Oncol 2013;31:3807–3814. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Cullen MH, Stenning SP, Parkinson MC, et al. Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report. J Clin Oncol 1996;14:1106–1113. [DOI] [PubMed] [Google Scholar]
- 13.Oliver RT, Mason MD, Mead GM, et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: randomised trial. Lancet 2005;366:293–300. [DOI] [PubMed] [Google Scholar]
- 14.Oliver RT, Mead GM, Rustin GJ, et al. Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214). J Clin Oncol 2011;29:957–962. [DOI] [PubMed] [Google Scholar]
- 15.Chung P, Mayhew LA, Warde P, et al. Management of stage I seminomatous testicular cancer: a systematic review. Clin Oncol (R Coll Radiol) 2010;22:6–16. [DOI] [PubMed] [Google Scholar]
- 16.Hotte SJ, Mayhew LA, Jewett M, et al; Genitourinary Cancer Disease Site Group of the Cancer Care Ontario Program in Evidence-based Care. Management of stage I non-seminomatous testicular cancer: a systematic review and meta-analysis. Clin Oncol (R Coll Radiol) 2010;22:17–26. [DOI] [PubMed] [Google Scholar]
- 17.Albers P, Siener R, Krege S, et al; German Testicular Cancer Study Group. Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group. J Clin Oncol 2008;26:2966–2972. [DOI] [PubMed] [Google Scholar]
- 18.Rørth M, Jacobsen GK, von der Maase H, et al. Surveillance alone versus radiotherapy after orchiectomy for clinical stage I nonseminomatous testicular cancer. Danish Testicular Cancer Study Group. J Clin Oncol 1991;9:1543–1548. [DOI] [PubMed] [Google Scholar]
- 19.Fosså SD, Horwich A, Russell JM, et al. Optimal planning target volume for stage 1 testicular seminoma: a Medical Research Council randomised trial. Medical Research Council Testicular Tumor Working Party. J Clin Oncol 1999;17:1146. [DOI] [PubMed] [Google Scholar]
- 20.Jones WG, Fossa SD, Mead GM, et al. Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I testicular seminoma: a report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial 30942 (ISRCTN18525328). J Clin Oncol 2005;23:1200–1208. [DOI] [PubMed] [Google Scholar]
- 21.Pileri SA, Milani M, Fraternali-Orcioni G, et al. ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of testicular seminoma. Ann Oncol 2001;12:1217–1218. [PubMed] [Google Scholar]
- 22.ldenburg J, Fosså SD, Nuver J, et al; ESMO Guidelines Working Group. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24 Suppl 6:vi125–vi132. [DOI] [PubMed] [Google Scholar]
- 23.Dieckmann KP, Albers P, Classen J, et al. Late relapse of testicular germ cell neoplasms: a descriptive analysis of 122 cases. J Urol 2005;173:824–829. [DOI] [PubMed] [Google Scholar]