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Testis

1. Predisposing Factors/Prevention

Revised 08 May 2013​

Predisposing Factors

Cancer of the testis is relatively uncommon in B.C., but the incidence rate has almost quadrupled in the past 40 years. Mortality has fallen during the same period as effective treatments have evolved.

Patients with testicular atrophy of any cause such as cryptorchism, mumps orchitis, or ectopic testis have an increased risk for developing testis cancer. Vasectomy has been ruled out as a cause of testicular cancer. There is also a 3-5% risk for testis cancer patients to develop a contralateral testis cancer. First degree relatives of a testis cancer patient have a 3-10 fold increase in risk for developing a testis cancer.

References:

  1. Canadian Cancer Society/National Cancer Institute of Canada: Canadian Cancer Statistics 2005. Toronto, Canada, 2005.

  2. Adami H-O, Hunter D, Trichopoulos D. Textbook of Cancer Epidemiology. Oxford University Press, New York, 2002; P429-445.

  3. Moller H, Prener A, Skakkebaek NE. Testicular cancer, cryptorchidism, inguinal hernia, testicular atrophy, and genital malformations: case-control studies in Denmark. Cancer Causes Control 1996; 7: 264-274.

  4. Van der-Maase H, Rorth M, Walbom-Jorgensen S et al. Carcinoma in situ of contralateral testis in patients with testicular germ cell cancer: study of 27 cases in 500 patients. Br Med J (Clin Res Ed) 1986; 293: 1398-1401.

  5. Westergaard T, Olsen JH, Frisch M et al. Cancer risk in fathers and brothers of testicular cancer patients in Denmark. A population-based study. Int J Cancer 1996; 66: 627-631.

  6. Sonneveld DJ, Sleijfer DT, Schrafford-Koops H et al. Familial testicular cancer in a single-centre population. Eur J Cancer 1999; 35: 1368-1373.

  7. Kollmansberger C, Tyldesley S, Moore C et al. Evolution in management of testicular seminoma: population-based outcomes with selective utilization of active therapies. Annals of Oncology 2011, 22: 808-814.


Prevention:

Testicular self-examination is the recommended method of early detection for testicular cancer but no evidence is available as to its efficiency. Due to the overall low incidence and high cure rate of testis cancer there is no need for additional preventive measures besides self examination for first-degree relatives.

Reference: 

  1. Schottenfeld D. Testicular cancer. In: Schottenfeld D, Fraumeni JF Jr. (Eds). Cancer Epidemiology and Prevention. 2nd Ed. 1996. Oxford University Press, Oxford. Pp 1207-1219.

2. Screening/Early Detection

Revised 08 May 2013​

Screening is advised in individuals who are deemed at high risk of testis tumours, e.g. affected first degree relative (especially an identical twin), history of a delayed or undescended testis, and particularly patients who have had a prior malignancy in the contralateral testicle. These individuals should perform monthly testicular self-examination. In addition, patients with a previous malignancy of the opposite testis should be examined by clinicians at regular intervals.

3. Diagnosis

Revised 08 May 2013

3.1 Clinico-pathologic considerations

Presentation is often as a painless mass or swelling in the testis (70-80% of cases). Pain can occur if there is torsion, hemorrhage, and swelling. In rare cases, there may be simultaneous bilateral tumours. Spread occurs by either vascular or lymphatic routes. Metastatic disease leads to presenting complaints in approximately 15% of cases overall with testicular tumours, with metastatic presentation being more frequent with non seminoma than with seminoma. This will lead to symptoms specific to the affected organ or adjacent tissues. Patients may develop back pain due to large retroperitoneal lymphadenopathy, gynecomastia due to elevation of HCG (germ cell tumours), and other hormonal functional elements may be present (stromal tumours).

3.2 Diagnostic pathology

Basic diagnostic Work Up for patients with suspected or confirmed testis cancer

  • History and physical examination
  • CT Chest/abdomen/pelvis
  • Chest X-ray may be sufficient in patients with early stage disease
  • CBC, LDH, bHCG, AFP, creatinine (both prior to , and after, orchiectimy)
  • Testicular ultrasound (pre-orchiectomy)

Pathological diagnosis is then obtained by a radical inguinal orchiectomy with high ligation of the spermatic cord. Needle or incisional biopsy through the scrotum is contraindicated. An orchiectomy can be delayed until after chemotherapy in patients with metastatic disease with a clinical (marker positive) diagnosis of germ cell tumour and an urgent need for systemic therapy.

Gross Description

Gross description of radical orchiectomy specimens should include:

  • The length of spermatic cord attached
  • The external dimensions of the testis
  • The preservation or loss of normal testicular contour
  • The presence or absence of a mass
  • Size of the mass(es)
  • The presence of satellite nodules or not
  • The texture of all nodules
  • The relationship of all nodules to the tunical albuginea, the tunica vaginalis, rete testis, epididymis and cord

Microscopic Description

The following features should be included:

  • Tumor size
  • Enumeration of the cell type(s) present: if more than once cell type is present, some indication should be given of the proportions
  • A statement should be made regarding the relationship to the tunica albuginea, tunica vaginalis, rete testis, the epididymis and the spermatic cord
  • The presence or absence of lymphatic and/or venous invasion within the testes and within the cord should be commented upon
  • The presence of in-situ germ cell neoplasia should be noted
  • The presence/absence of spermatogenesis and Leydig cell hyperplasia in the residual testis should be commented upon
  • Margin status.

Because of its clinical importance, it is highly recommended that all histological specimens are assessed by a reference pathologist experienced in testis cancer pathology.

The BC Cancer Agency employs the TNM system (UICC 2009) and the Classification of the International Germ Cell Collaborative Group (J Clin Oncol 1997).

3.3 Classification c​riteria

Histologic Subtypes (partial list):

Germ Cell tumours:
  • Intratubular germ cell neoplasia, unclassified
Seminoma
  •  Seminoma, NOS (9061)
  •  Spermatocytic (9063)
Non-seminoma
  • Embryonal carcinoma (9070)
  • Endodermal sinus - yolk sac carcinoma (9071)
  • Teratoma - mature (9080/0)
  • Malignant Teratoma-undiff. (9082)
  • or intermediate (9083)
  • Choriocarcinoma combined with teratoma (9101)
  • Malignant teratoma trophoblastic (9102)
  •  Mixed Seminoma/ Non-seminoma
Sex Cord/ gonadal stroma tumours :

Leydig cell tumour

Malignant Leydig cell tumour

Sertoli cell tumour

Malignant Sertoli cell tumour

Granulosa cell tumour

Thecoma

Tumours of collecting system and Rete testis

4. Staging

​Revised 08 May 2013 

The BC Cancer Agency employs the TNM system (UICC 7th Edition, 2009) and the Classification of the International Germ Cell Collaborative Group (J Clin Oncol 1997).

4.1 

Testis Staging Diagram
UICC 7th Edition, 2009  (Pls note: pM0 and pMx are no longer valid categories)

To define the clinical stage of a patient with gonadal germ cell tumour the TNM classification of the UICC should be used (1). In addition, most patients with metastatic disease are classified according to the classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) (2) which is based on prognostic factors rather than anatomical distribution of metastases. The individual treatment strategy is based on both the TNM classification and the IGCCCG-prognostic factor-based classification which includes histology, location of primary tumour, location of metastases and level of AFP, ß-HCG and LDH as prognostic markers to categorize patients into "good", "intermediate" and "poor" prognosis. Patients with a mixed seminomatous/ non-seminomatous tumor are considered and treated as non-seminoma.

IGCCCG prognostic grouping classification for metastatic Germ Cell Tumours:

Prognosis

5-year-survival

Non-Seminoma

Seminoma

good

90%

Testis or primary extragonadal retroperitoneal tumour 
and low markers: AFP <1.000 ng/ml
and ß-HCG <5.000 IU/l (<1.000 ng/ml)
and LDH <1.5 x normal level
and no non-pulmonary visceral metastases

Any primary localisation
Any marker level 
and no non-pulmonary visceral metastases

intermediate

75%

Testis or primary extragonadal retroperitoneal tumour
and intermediate markers
AFP 1.000-10.000 ng/ml
and/or ß-HCG 5.000-50.000 IU/l (1.000-10.000 ng/ml)
and/or LDH 1,5 – 10 x normal level
and no presence of non-pulmonary visceral metastases

Any primary localisation
and presence of non-pulmonary visceral metastases (liver, CNS, bone, intestinum)
Any marker level

poor

50%

Primary mediastinal germ cell tumour with or without testis or primary retroperitoneal tumour
and presence of non-pulmonary visceral metastases (liver, CNS, bone, intestinum)
and/or "high markers"
AFP >10.000 ng/ml,
ß-HCG >50.000 IU/l 
(10.000 ng/ml)
or LDH >10 x normal level

4.2 Investigations for Staging

In order to allow accurate staging, all staging investigations should be done within 4 weeks pre- or 4-6 weeks post orchiectomy (in particular for the determination of stage I disease).

CBC, creatinine, liver function tests, bHCG, AFP, LDH. Markers should be followed weekly until normal after initiation of treatment

  • CXR if not done preoperatively (sufficient for stage I seminoma)
  • CT scan of chest (not necessary for stage I seminoma), abdomen and pelvis
  • Additional imaging may be required for specific sites of disease and to localize kidneys (if radiotherapy is being considered).
  • Sperm count (with or without banking as appropriate) if fertility is a concern
  • Pituitary gonadotropins may be measured in patients where there is concern over oligospermia
  • Bone scans should be obtained in patients with elevated levels of alkaline phosphatase or if bone metastases are clinically suspected
  • Imaging of the brain by CT or preferably by MRI is required in patients with clinical signs potentially indicating brain metastases and in patients with extensive lung involvement and/or poor prognosis criteria NSGCT
  • Note: PET scan or CT PET scans ARE NOT RECOMMENDED as part of routine staging.

References:

  1. Testis. In Sobin L, Gospodarowicz M, Wittekind C et al. (eds): UICC Classification of Malignant Tumours, Seventh Edition. Wiley-Blackwell 2009.

  2. Mead G,. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 1997; 15: 594-603.

5. Management


Revised 08 May 2013 

All testicular tumours at any stage must be treated for cure. Testicular tumours are rare, but it is the most common solid tumour in men between 15-34 years of age. The majority of tumours are of germ cell origin and approximately equally divided between seminoma and non-seminoma. It is very unusual to see a malignant non-seminoma in a patient over 40 years of age. Whilst only 10% of seminoma cases have overt dissemination at diagnosis, some 30% of patients with embryonal carcinoma have spread when seen initially. Other pathologies include stromal tumours, and lymphoma is the commonest cause of a malignant testicular mass in the elderly. 

Pathology review is strongly recommended.

A large body of evidence from clinical trials exists for initial management that allows physicians and patients to choose between different first-line treatments which offer the best curative option with the least amount of toxicity. However, due to the multitude of available treatment options, decision making regarding the optimal management of a patient has become more complicated and complex. This applies in particular to patients with early stage disease who are often cured with minimal interventions and who are at risk of being overtreated. Likewise, patients with advanced, relapsed or refractory disease are difficult to treat.

Germ cell cancer is a rare and highly curable disease that needs expert treatment. Clear evidence has evolved that in particular patients with advanced germ cell cancer benefit from the expertise of their managing physician with significantly improved survival and less toxicity. There is a correlation between the experience of the physician and the number of patients treated per year. A large patient volume resulting in competence and experience even with rare clinical scenarios is crucial, and it is strongly recommended by all existing guidelines to refer patients, in particular patien​ts with metastatic or even relapsed disease to experienced tertiary centers with special experience in the field of germ cell cancer. 

Discussion of patients at the weekly multidisciplinary GU Tumour Case Conference is also highly recommended.

Rare histologic subtypes such as malignant lymphoma of the testicle, and primary sarcomas of the testicle are dealt with in the lymphoma and sarcoma sections of the cancer management manual.

Reference:

  1. Collette L, Sylvester RJ, Stenning SP, Fossa SD, Mead GM, de Wit R, de Mulder PHM, Neymark N, Lallemand E, Kaye SB. Impact of the treating institution on survival of patients with „poor-prognosis" metastatic nonseminoma. European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group and the Medical Research Council Testicular Cancer Working Party. J Natl Cancer Inst 1999;91: 839-846.

5.1 Pure Seminomas

 Revised 08 May 2013 

AFP negative, moderate elevations of LDH or bHCG acceptable (any AFP elevation in a “pure” seminoma would prompt treatment according to nonseminoma guidelines).


N0 M0 (clinical stage I)

Despite normal CT scans, a 20% risk of clinical occult metastatic disease in locoregional lymph nodes with subsequent disease progression remains, if no adjuvant treatment is applied after orchiectomy. Nevertheless, the cure rate in CS I seminoma patients is almost 100% after salvage of relapse. The primary management strategy after inguinal orchiectomy is surveillance with administration of irradiation or chemotherapy at time of relapse. Adjuvant radiation treatment, or adjuvant chemotherapy with single agent carboplatin are options , but are rarely the best option and surveillance is almost always the preferred strategy .


Surveillance is the current standard management strategy after an orchiectomy, but initial assessment at a cancer center is strongly recommended. The potential advantage of surveillance is that patients are spared acute and late radiation toxicity and possibly an associated increased risk of secondary malignancies. Surveillance is labour-intensive and requires long-term follow-up in highly motivated patients. The exceptional patient that is not available or unwilling to undergo prolonged and close follow-up are not candidates for a surveillance strategy. Reported relapse rate on surveillance are approximately 20%. Almost all relapses should be salvageable with further therapy (either chemotherapy or radiotherapy). As a result, adjuvant radiotherapy and adjuvant chemotherapy are very rarely the recommended management.


Adjuvant radiotherapy of the para-aortic or para-aortic plus pelvic region was historically the most frequently used adjuvant treatment resulting in a relapse rate of 3-4% at 10 years. Almost all of these recurrences are located outside the irradiated area, mostly in the pelvis (1.7%) (if only para-aortic fields are used) or close to the border of the radiation fields. Total radiation dose is 20-25 Gy in 10 to 20 fractions. When used the standard fractionation is 25 Gy in 15 fractions to the para-aortic nodes alone. Due to the risk for secondary malignancies and the increased risk for cardiotoxicity, adjuvant radiation is no longer recommended as a standard management option and should be reserved for the exceptional patients with contraindications for active surveillance or adjuvant carboplatin.


Adjuvant chemotherapy with single agent Carboplatin is an alternative to radiation therapy or surveillance for stage I seminoma. A large phase III trial comparing one cycle of adjuvant carboplatin with adjuvant radiation demonstrated non-inferiority of Carboplatin to adjuvant radiation. Relapses in the Carboplatin arm, however, occurred mainly in the retroperitoneum. In the rare event that adjuvant carboplatin is chosen, one cycle at a dose of AUC (Area under the curve) 7 is considered standard of care.


Consultation with a specialized center regarding the optimal treatment strategy in an individual patient is strongly recommended.


Studies of surveillance have identified tumour size (4 cm vs. >4 cm, hazard ratio 2.0) and rete testis invasion (hazard ratio 1.7) as important predictors of relapse in multivariate analysis. Other factors which may increase relapse rates include younger age (<34 years), lymphatic or vascular invasion, and undifferentiated histology. However, strategies to stratify patients into high and low risk groups to decide on surveillance or adjuvant therapies based on these risk factors (ie a risk adapted approach) have not been consistently validated (5,6). Even those patients with high risk features (eg size greater than 4 cm) can be managed with surveillance. In general, the majority of STAGE I SEMINOMA PATIENTS SHOULD BE OFFERED SURVEILLANCE AS THE PRIMARY RECOMMENDATION after inguinal orchiectomy regardless of these risk factors. Other groups have recently made similar recommendations for primary management (7,8). Adjuvant chemotherapy or adjuvant radiotherapy may be appropriate options in exceptional circumstances.


References:

  1. Jones WG, Fossa SD, Mead GM, et al. A randomised trial of 30 versus 20 Gy in the adjuvant treatment of stage I testicular seminoma: A report on Medical Research Councel Trial TE 18, EORTC 30942. J Clin Onc 2005, 23: 1200-1208.

  2. Fossa A, Jones WG, Stenning S, Collaborateurs ftT. Quality of life (QL) after radiotherapy (RT) for stage I seminoma : results from a randomized trial of two RT schedules (MRC TE18). Proc Am Soc Clin Oncol 2002; 21: abstract # 750.

  3. Warde P, Specht L, Horwich A, Oliver T, Panzarella T, Gospodarowicz M, von der Maase H.; Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. J Clin Oncol. 2002, 20: 4448-4452.

  4. Oliver RT, Mead GM, Rustin G, et al: Randomized trial of Carboplatin versus radiotherapy for stage I seminoma: . J Clin Onc 2011, 29: 957-962.

  5. Aparicio J, Maroto P, Garcia del Muro X. Risk-adapted treatment in Clnical stage I testicular seminoma: The third Spanish Germ Cell Cancer Group study. J Clin Onc 2011, 29: 4677-4681.

  6. Chung P, Daugard G, Tyldesley S et al. Prognostic factors for relapse in stage I seminoma managed with surveillance: A validation study. J Clin Onc 2010, 28 (15s) abst: 4535.

  7. Wood L, Kollmannsberger C, Jewett M, et al . Canadian consensus guidelines for the management of testicular germ cell cancer. Can Urol Assoc J. 2010, 4(2):e19-38.

  8. Albers P, Albrecht W, Algaba F et al. EUA guidelines on testicular cancer: 2011 update. Eur Urol 2011, 60(2):304-319.

N1-3 M0 (Clincal stage II A/B/C)
Relapse-free survival for patients with stage II A / B seminoma is approximately 95% and 90% at 6 years, respectively. Post inguinal orchidectomy, radiation treatment to the para-aortic and ipsilateral pelvic area (25 Gy in 20 fractions, with a boost to the involved nodes to a further 10 Gy in 5 fractions) is the standard treatment option for stage II A and a treatment option for stage IIB. Where fertility is an issue, the remaining testicle is shielded in conjunction with sperm banking. ​​

Chemotherapy with three cycles of standard-dose cisplatin, etoposide and bleomycin (BEP), or four cycles of etopside, cisplatin (EP, in case of contraindication for bleomycin) represent an alternative treatment for patients and is emerging as the standard treatment option for stage IIB seminoma in order to avoid potential long-term complications of radiation therapy.


Practical considerations for the use of BEP and other chemotherapy regimens:


1) When considering the use of any chemotherapy, including bleomycin, the treating physician should balance the relative risks and benefits of the particular regimens available, relative to the patient’s comorbidities and tolerance of that regimen.


2) Relative contraindications to the use of bleomycin include: age over 40, poor renal function, high cumulative bleomycin dose, severe pre-exisiting lung disease, and anaphylactic reaction to prior bleomycin exposure.


3) All patients should be informed that they should notify their oncologist if they develop pulmonary symptoms (shortness of breath, dry cough, etc).


4) Patients should be asked if they have developed any of the aforementioned pulmonary symptoms regularly while on chemotherapy.


5) Patients should be examined for respiratory signs (such as inspiratory lag, or rales) regularly while on chemotherapy.


6) BEP should be abandoned in favour of EP or VIP when respiratory symptoms and signs of toxicity develop even in the absence of normal pulmonary function testing or lung imaging is normal.


7) Pumonary function tests are usually performed prior to commencing BEP and at the beginning of the 4th cycle.


8) For those who are going onto post chemotherapy surgery, the 11th and 12th doses of bleomycin are usually held.


9) If there has been a significant decline in the diffusion capacity (>30-40 %), bleomycin is held.


10) Arbitrary neutrophil recovery should not delay the initiation of chemotherapy. Cycles should start every 21 days without dose adjustment or delay. Prophylactic GCS-F is recommended for all ifosfamide containing regimens, patients with intermediate or poor risk disease and patients with a previous episode of neutropenic fever and/or a significant delay in neutrophil recovery. In patients with good risk disease and treatment with BEP or EP, neutropenic fever is rare and the prophylactic use of GCS-F is at the discretion of the treating physician.


11) To minimize the risks of cisplatin-based chemotherapy on renal function, aggressive pre and post chemotherapy hydration is required. At least 1 liter of normal saline should be given prior to initiation of cisplatin and 1.5 to 2 additional liters after cisplatin daily. Patients should be encouraged to drink liquids aggressively and report significant vomiting immediately to their oncologist. Patients often gain a significant weight over the course of each five day session related to water intake, but this mobilizes rapidly and does not require diuretics for management.


12) Bleomycin is an essential drug for optimal treatment of patients with testicular cancer, and can be given safely in the vast majority of patients and should not be withheld without clear cut contraindications to its use.


Advanced Seminoma - N3 >10 cm or M1 (Clinical stage IIC or III; "good" or "intermediate" prognosis acc. To the IGCCCG classification)

These patients will be treated with chemotherapy according to the IGCCCG classification. The standard approach is three cycles of BEP for patients with good risk disease, and 4 cycles of BEP for those with intermediate risk disease. When there are contraindications to bleomycin 4 cycles of EP is an alterative for patients with good risk disease, and 4 cycles of VIP is an alterative for patients with intermediate risk disease. A multi-disciplinary assessment is preferred before instigating therapy. These patients should have their evaluation and therapy expedited (visceral metastases from seminoma is rare).


Post treatment residual masses

Post-chemotherapy, as well as post-radiotherapy, the approach used at BCCCA for residual masses in seminoma patients is to closely follow by imaging investigations and tumour marker determinations rather than immediate resection, irrespective of the size of the mass. If close observation is not possible, residuals larger than 3 cm can be resected. PET scanning appears to be a promising tool in defining patients with residual lesions, in particular for lesions > 3 cm. It is important to perform the PET scan not earlier than 8 weeks after completion of chemotherapy in order to minimize false positive findings. This is the ONLY standard indication for PET scanning in testicular cancer management. The negative predictive value of PET-CT scans is high, and seminoma patients with PET-negative residuals should be followed irrespective of the size of the residual lesion. The positive predictive value of a PET-CT scan is less reliable (6). In PET-CT positive patients after chemotherapy either biopsy, close observation with serial CT scans, or, possibly, repeat PET-CT scans are recommended. If observed, residual masses are observed after therapy until there is definitive evidence of growth. Biopsy positive residual lesions or growing residual lesions should be resected whenever possible. The resection of growing residual seminoma lesions should be done in an experienced center and by a surgeon experienced with this procedure. The resection of seminoma residual lesions is technically more difficult and associated with a higher complication rate as compared to the resection of nonseminoma lesions.


Routine use of radiotherapy for residual masses is not recommended (5), however, in the setting of clear isolated progression in a residual mass after chemotherapy, in a patient unable to undergo a resection, radiotherapy should be considered. Patients with residual masses after initial therapy should be discussed at the weekly multidisciplinary GU Tumour Case Conference.


References:

  1. Herr HW, Sheinfeld J, Puc HS et al. Surgery for a post-chemotherapy residual mass in seminoma. J Urol 1997; 157: 860-862.

  2. Puc HS, Heelan R, Mazumdar M et al. Management of residual mass in advanced seminoma: results and recommendations from the Memorial Sloan-Kettering Cancer Center. J Clin Oncol 1996; 14: 454-460.

  3. Albers P, Weissbach L, Krege S et al. Predictions of necrosis after chemotherapy of advanced germ cell tumors: results of a prospective multicenter trial of the German Testicular Cancer Study Group. J Urol 2004; 171: 1835-1838.

  4. Mosharafa AA, Foster RS, Leibovich BC et al. Is post-chemotherapy resection of seminomatous elements associated with higher acute morbidity? Journal of Urology 2003; 169: 2126-2128.

  5. Duchesne GM, Stenning SP, Aass N et al. Radiotherapy after chemotherapy for metastatic seminoma--a diminishing role. MRC Testicular Tumour Working Party. Eur J Cancer 1997; 33: 829-835.

  6. De Santis M, Becherer A, Bokemeyer C et al. 2-18fluoro-deoxy-D-glucose Positron Emission Tomography Is a Reliable Predictor for Viable Tumor in Postchemotherapy Seminoma: An Update of the Prospective Multicentric SEMPET Trial. J Clin Oncol 2004; 22: 1034-1039.

5.2 Nonseminomatous Germ Cell Tumours (With or Without Seminoma)

Revised 08 May 2013

​T1-3 N0 M0 S0-S3 (clinical stage I and IS)

The cure rate of patients with non-seminoma clinical stage I is 99%. Vascular invasion (VI) of the primary tumour is the most important prognostic indicator for relapse. Patients with VI have a risk of 48% to develop metastatic disease, whereas only 14–22% of patients without VI will relapse. The evidence and percentage of embryonal carcinoma of the total tumour volume is the second most relevant prognostic factor, with an increase in risk correlating to the proportion of embryonal carcinoma within the primary tumour.

Treatment Options:

Three treatment options exist for clinical stage I patients:

Surveillance, which is the preferred treatment option irrespective of the risk status. Adjuvant chemotherapy or retroperitoneal lymph node dissection (RPLND) are alternate options, but only for patients unwilling or unable to undergo surveillance,

Management details:

  1. Surveillance (preferred treatment option)
    • All staging is unequivocally normal;
    • patient is considered reliable and available for close follow up including serial CT scans of the retroperitoneum; and
    • surveillance is acceptable to the referring urologist, the patient and the oncologist.
  2. Retroperitoneal lymph node dissection (nerve-sparing).This surgical technique is intended to preserve the contralateral sympathetic nerves which allows ejaculation in most patients. However, where lymphadenopathy is encountered intraoperatively, a full bilateral block dissection should be performed. Relapses after RPLND occur mainly in the lungs (approximately 10%). Discussion in the multidisciplinary GU tumor conference and referral to an experienced centre is strongly recommended for consideration of RPLND and for the operation itself when indicated.
  3. Adjuvant chemotherapy with one (or two cycles of BEP) may be considered in selected high risk patients unwilling or unable to undergo surveillance. There is no randomized comparison or 1 versus 2 cycle of BEP in this setting. Both strategies are associated with a low relapse rate of approximately 4-5% (8,9,10). These patients should therefore be discussed at the multidisciplinary conference. Referral to an experienced centre is advised.

For patients with clearly elevated and rising tumour markers after orchiectomy (ie T1N0 S 1-3 disease), BEP for 3 cycles is recommended. Such cases should be discussed at multi-disciplinary tumour board before commencing chemotherapy.

T0-4 N1-2 M0 S0 (clinical stage II and "good prognosis" according to the IGCCCG classification)

The cure rate for CS IIA and IIB non-seminoma is close to 98%.

Treatment should be selected to provide the best chance of cure with a single modality, as this will minimize morbidity. Early referral for assessment is preferred.

  1. Primary chemotherapy according to the IGCCCG classification is recommended. For patients with "good prognosis" disease according to IGCCCG criteria, standard treatment is three cycles BEP. In case of contraindications to bleomycin, four cycles of cisplatin and etoposide (EP) can be given. Patients with a retroperitoneal mass ≥ 2 cm (stage IIB) and/or positive markers should receive primary chemotherapy followed by resection of residual lesions of ≥ 1 cm. Patients with residual mass < 1 cm after chemotherapy are considered low risk of relapse and routine resection is not warranted.
  2. The treatment of patients with marker-negative stage IIA remains controversial. Up to 50% of patients (ref: Stephenson et al) have false positive lymph nodes and are pathological stage I disease. For these patients, an observation period with short-term CT follow up (e.g. repeat CT after 6-8 weeks) is recommended in order to allow the disease to declare itself. Growing lesions as well as positive tumor markers will be treated according to the IGCCCG classification. Regressing lymph nodes should be observed. If lymph nodes remain unchanged but suspicious a primary retroperitoneal lymph node dissection may be indicated. All RPLNDs should be done in an expert center.

References:

  1. Vergouwe Y, Steyerberg EW, Eijkemans MJ, et al: Predictors of occult metastasis in clinical stage I nonseminoma: a systematic review.[see comment]. Journal of Clinical Oncology 21:4092-9, 2003

  2. Albers P, Siener R, Kliesch S, et al: Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial. Journal of Clinical Oncology 21:1505-12, 2003

  3. Donohue JP, Foster RS, Rowland RG, et al: Nerve-sparing retroperitoneal lymphadenectomy with preservation of ejaculation. J Urol. 144:287-291, 1990

  4. Donohue JP, Thornhill JA, Foster RS, et al: The role of retroperitoneal lymphadenectomy in clinical stage B testis cancer: the Indiana University experience (1965 to 1989). J Urol 153:85-89, 1995

  5. Weissbach L, Bussar MR, Flechtner H, et al: RPLND or primary chemotherapy in clinical stage IIA/B nonseminomatous germ cell tumors? Results of a prospective multicenter trial including quality of life assessment. Eur Urol 37:582-594, 2000

  6. Pont J, Holtl W, Kosak D, et al: Risk-adapted treatment choice in stage I nonseminomatous testicular germ cell cancer by regarding vascular invasion in the primary tumor: a prospective trial. Journal of Clinical Oncology 8:16-20, 1990

  7. Amato RJ, Ro JY, Ayala AG, et al: Risk-adapted treatment for patients with clinical stage I nonseminomatous germ cell tumor of the testis. Urology 63:144-8; discussion 148-9, 2004

  8. Albers P et al. 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 Jun 20;26(18):2966-72.

  9. Tansdstad T et al. Risk-adapted treatment in clinical stage I nonseminomatous germ cell testicular cancer: the SWENOTECA management program. J Clin Oncol. 2009 May 1;27(13):2122-8.

  10. Pont J et al. Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long-term results of a prospective trial. J Clin Onc. 14(2):441-8, 1996

Any T any N1-3 M0 S2,3; T any N any M1 S0-3 (Clinical stage III or "good", "intermediate" or "poor" prognosis according to the IGCCCG classification)

Induction chemotherapy followed by resection of residual masses is the standard approach for these patients. Because of the complexity and specialized nature of this treatment, referral to the BC Cancer Agency for opinion is strongly recommended.

For patients with "good prognosis" disease according to IGCCCG criteria, standard treatment is three cycles BEP. In case of contraindications against bleomycin, four cycles of cisplatin and etoposide (EP) can be given. Four cycles of BEP are the standard treatment for patients with intermediate or poor prognosis. Four cycles of etoposide, ifosfamide and cisplatin (VIP) are equally effective compared to BEP, but cause more acute myelotoxicity without offering additional benefits. VIP should however be considered in patients with contraindications for bleomycin or patients who are at high risk for bleomycin induced toxicity (age > 40 years; poor renal function; wide-spread metastastic disease; high cumulative bleomycin dose). VIP should also be considered for patients with extensive pulmonary metastases in whom secondary post-chemotherapy resections of residual lung lesions is expected.

In patients with a residual mass ≥1 cm and normalization of tumour markers, the residual masses have to be resected. Histological findings in subsequent surgery for residual masses after first line chemotherapy will reveal necrosis in about 50-60%, mature teratoma in 20-30% and vital cancer in 10-15%. The incidence of vital cancer is even higher after salvage chemotherapy. If technically feasible, all residual masses should be resected ( ie a full bilateral RPLND). In patients with residual masses at multiples sites, an individual decision should be made regarding number and extension of resections. If malignancy is evident in the resected specimen, two further cycles of intensive chemotherapy may be required.

Patients with brain metastases at initial presentation are still potentially curable and require multimodality therapy including neurosurgery, radiation oncology and medical oncology. Asymptomatic patients with brain metastases can be started on chemotherapy while the benefit of initial cranial irradiation remains unclear in these patients. The role of consolidating radiation in patients with good response in the brain to chemotherapy remains unclear and requires individualized treatment decision. All patients with brain metastases should be referred to a specialized center.

Patients in whom brain metastases are discovered after an otherwise complete extracranial response to systemic chemotherapy, or persist after an otherwise complete extracranial response to chemotherapy, should have resectable lesions removed and proceed with curative intent cranial irradiation thereafter. When crainial irradiation is given with curative intent for non-seminoma the dose of radiation to the whole brain should be in the range of 40 to 45 Gy in 1.8 to 2 Gy fractions with a boost to gross disease to higher dose (typically a further 10 Gy). Brain metastases with seminoma is rare but more radiosensitive, and doses in the 30 to 40 Gy range are appropriate. Such cases should be discussed at multidisciplinary tumour board prior to cranial radiotherapy. Patients who relapse or progress with extracranial disease and brain metastases after previous chemotherapy have a poor prognosis. Treatment should include palliative cranial irradiation.

To maintain the highest chances for curability, all "poor-prognosis" patients should be transferred to a specialized centre without any delay to benefit from optimal interdisciplinary management and supportive care.

Reference:

  1. O'Sullivan JM, Huddart RA, Norman AR, et al: Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours. Annals of Oncology 14:91-6, 2003

5.3 Recurrent Germ Cell Tumour

Revised 08 May 2013 

Relapses of early stage germ cell tumours are uncommon, but even with widespread disease patients are potentially curable.

Tumour markers should be repeated and a pathological diagnosis obtained when necessary to confirm the diagnosis. Systemic relapse in patients previously treated with chemotherapy are potentially curable and should be assessed at the Cancer Agency for a multidisciplinary opinion. Usually chemotherapy will be the primary treatment for recurrent germ cell tumours, but surgery and/or radiotherapy may also be required.


Due to the complexity of the disease of these patients, referral to experienced high volume centers is strongly recommended.

The recently published IGCCCG-2 prognostic score for relapsed disease includes 7 factors (histology; presence of liver, lung or brain metastases; progression-free interval; AFP and HCG level at relapse; location of primary tumor) which differentiate 5 risk groups with significant differences in progression – and overall survival rates. This classification allows much improved prognostication of patients.


Seminoma

Paraaortic nodal recurrences on surveillance are managed as for N1-3 patients, as described above for clinical stage II. The majority of patients with relapse after first-line radiotherapy will have a cure rate >90% and should receive cisplatin-based chemotherapy comparable to the treatment strategy in advanced chemonaive seminoma. Conventional-dose cisplatin-based salvage chemotherapy after first-line therapy with BEP will result in long-term remissions in up to 50% of patients. Regimens of choice are four cycles of VIP, VeIP or TIP.


Non-seminoma


Systemic relapse in chemotherapy naive patients are potentially curable and are treated as for de novo M1 patients.


Salvage treatment after first-line chemotherapy for metastatic disease consists of four cycles of VIP, VeIP or TIP. Conventional-dose cisplatin-based salvage chemotherapy can achieve long-term remissions in 15-40% of patients.


A subsequent retrospective comparison of patients treated with conventional and high dose chemotherapy suggested a significant advantage of high dose chemotherapy over conventional dose chemotherapy for almost all IGCCCG-2 risk groups. A single high dose chemotherapy cycle, as consolidation after three conventional cisplatin-based cycles as second line therapy, has been demonstrated not to be superior to four conventional cisplatin-based chemotherapy cycles in patients w​ith favourable prognostic criteria (gonadal primary; complete or marker-negative response to first-line therapy). Sequential high does chemotherapy appears to offer a benefit and is currently tested in randomized studies.


The chemotherapy approach of standard or high dose chemotherapy in relapsed patients must be discussed with the multidisciplinary team and should include consideration of the patient’s risk factors prognosis, and co-morbidities.


Residual masses after salvage chemotherapy should be resected as soon as possible after the end of chemotherapy. In case of progressive tumour markers, after salvage treatment and lack of other chemotherapeutic options, surgical resection of residual tumours should be considered if complete resection of all tumour manifestations seems feasible.


Late Relapse

Patients with late relapse (> 2 years after first-line therapy) should be referred to the next specialized center for further management. If technically feasible, patients with late relapse and negative tumour markers should undergo immediate radical surgery to completely resect all mature teratoma or secondary non-germ cell cancer. Due to the poor results of chemotherapy in patients with late relapses, patients with small and completely resectable lesions should undergo surgery even in case of elevated tumour markers. If the lesions are not completely resectable, biopsies should be obtained for histological assessment and salvage chemotherapy should be initiated. If the patient responds to salvage chemotherapy, secondary surgery should be conducted whenever possible. 


5.4 Non-Germ Cell Tumours

Revised 08 May 2013

​Gonadostromal tumours of the testis comprise about 6% of adult testis tumours, but 20% of gonadostromal tumours occur in children. Because of the rare nature of these tumours, their pathology should be reviewed. Patients will be seen at BC Cancer Agency on request. Patients may present with a painless testis mass, but almost 20% will present with symptoms referable to endocrine imbalance. Leydig (interstitial cell) tumours are particularly prone to produce androgen (but may produce estrogen, progesteron, corticosteroids) and therefore in children can cause precocity or later in life masculinization. Gynecomastia can also occur. Up to 8% of Leydig cell tumours are bilateral.

Lymphomas and paratesticular rhabdomyosarcomas are dealt with in other sections of the policy manual.​

5.5 Sertoli and Leydig Cell Tumours

​Revised 08 May 2013

Sertoli (sex cord) cell tumours are more prone to produce estrogens than androgens and typical markers AFP, bHCG are normal. Again, gynecomastia can occur or decreased libido.

Some 10% of both Sertoli and Leydig cell tumours are malignant, but prediction of behavior can be difficult from pathology. Gonadoblastomas are gonadostromal cell tumours with a mixed germ cell population and may also be hormonally functional. These are particularly associated with dysgenetic testicles and should therefore be reviewed by the urologist.

Initial work up (see diagnosis) should be along the lines of any testicular mass. In addition, patients may benefit from a baseline evaluation of serum testosterone, dehydroepiandrosterone, androstenediol, 17-hydroxyprogesterone, 11-desoxycortisol and urinary 17-ketosteroids. A few patients may have secondary alterations in LH/FSH.

The treatment of choice is radical inguinal orchidectomy ± retroperitoneal lymph node dissection. These tumors are only moderately chemotherapy sensitive and surgery remains the mainstay of treatment for these patients whenever feasible.

Follow-Up

​Revised 08 May 2013

Following the completion of treatment, all patients need to be monitored for potential recurrence of cancer and complications of therapy. This is needed both for management of the individual patient (where early detection would improve outcome), and to permit periodic review and improvement of current treatment policy.

Often it is felt appropriate to share follow up with the family doctor (and/or the urologist), in which case it is important for the patient to be clear who is responsible for certain aspects of the disease, e.g. symptom control by the family doctor, with advice from the BC Cancer Agency at the doctor's request.

Notification is requested in the event of any of the following:

  • Local recurrence at the primary site (particularly in patients with clinically localized disease treated with surgery and/or radiotherapy)
  • Metastasis at regional or distant sites
  • Complications of therapy, especially if acute requiring hospitalization, or chronic and symptomatic
  • Death with primary cause and whether cancer or treatment contributed

The event, date, and evidence, where appropriate, should be sent to the Agency chart where it will come to the attention of the oncologist, and will be available for periodic review by the tumour group. This information is requested annually for patients no longer followed at the BC Cancer Agency.

Germ Cell Tumours

The BC Cancer Agency chooses to particularly follow:

Patients with useful future treatment options (most testis tumours), especially if the relapse is difficult to detect and/or timing of treatment is important.

At each visit patients require, as a minimum, history and physical examination, plus the investigations outlined in the schedule below. All patients require annual blood pressure measurement. Post-chemotherapy patients will require annual creatinine, Mg, fasting lipid levels, fasting glucose levels as well as testosterone. Sperm counts may be measured at the patient's or physician's request and if necessary, related investigations may need pursuing.

The following guidelines are recommendations which may have to be adjusted in selected patients based upon the individual clinical situation.

Seminoma – CS I

Stage

Treatment performed

Clinical examination and diagnostics

Frequency of examination (i.e. every x months) * except when indicated by footnote

   

Year 1

Year 2

Year 3

Year 4

Year 5

Years 6-10

CS I

 



Surveillance

 

Or

Adjuvant chemotherapy

LDH, AFP, HCG, clinical examination

3,

6

6

6

12

12*

X-ray of the chest

3, 6*

6

12

12

12

-

CT scan of the abdomen/pelvis**

3,6*

6

12

-

12

-*


**The dose of radiation from each CT scan should be minimized. When a CT scan is used, for surveillance ideally the lowest dose CT should be used that allows the radiologist reasonable ability to delineate a 2 cm or greater retroperitoneal node. The role of MRI as an alternative to CT is being investigated and may become standard. For those with acceptable ultrasound assessment of the retroperitoneum (dependent on patients body habitus), alternating CT and ultrasound is an option to reduce radiation exposure.

* In year one, the first CT scan should be at 3 months, then every 6 months for the next 20 months, so that 4 CT scans are done over the first 2 years, followed by one CT in year 3, and one CT in year 5. There was a lack of consensus on whether to do a scan between year 7 and 8, but the majority opinion was that no scans were needed after year 5. Overall 6 CT scans will be done as part of surveillance over the entire 5 year period. There was no consensus on the need for tumour markers beyond 5 years.


Seminoma – CS I

Stage

Treatment performed

Clinical examination and diagnostics

Frequency of examination (i.e. every x months) * except when indicated by footnote

   

Year 1

Year 2

Year 3

Year 4

Years 5-6

Years 7-10



CS I

 



Post Radiotherapy

 

 

LDH, AFP, HCG, clinical examination

6

6

12

12

12

12

X-ray of the chest

6

12

12

12

24

-

CT scan of the pelvis
+/- abdomen

12

12

-

24*

24*

-

 

* One CT scan in year 1,2, 4, and 6, then stop. Total of 4 CT scans over 6 years.


Nonseminoma – CS I/ II

Stage

Treatment performed

Clinical examination and diagnostics

Frequency of examination (i.e. every x months) * except when indicated by footnote

   

Year 1

Year 2

Year 3

Year 4

Year 5

Years 5-10

 

CS I – Low risk and tumour marker positive

 



 

Surveillance

 



LDH, AFP, HCG, clinical examination

3

3

6

6

6

12

X-ray of the chest

3,6

6

6

6

6

12

CT scan of the abdomen/pelvis*

3rd and 12th months

24th month

-

-

56th month

-



CSI– High risk or tumour marker negative /unknown

 

 



Surveillance

 

 

LDH, AFP, HCG, clinical examination

2

2

6

6

6

12

X-ray of the chest

3

3

6

6

6

12

CT scan of the abdomen/pelvis*

3rd, 6th and 12th months

6

12

12

12

-

 

 

PS I (Pathologic stage I)

 

 



Primary RPLND

 

LDH, AFP, HCG, clinical examination

3

3

3

6

6

12

X-ray of the chest

6

6

6

12

12

-

CT scan of the abdomen/pelvis*

3rd and 12th months

24th month

-

-

56th month

-



CS I

 

 



adj. chemotherapy

 

 

LDH, AFP, HCG, clinical examination

3

3

6

6

6

12

X-ray of the chest

6

12

12

12

12

-

CT scan of the abdomen/pelvis*

6

24th month

-

-

56th month

-

*the CT of the pelvis can be omitted in patients who have not had scrotal or pelvic surgery that could alter the normal lymphatic drainage of the testicles.

Reference:

  1. Rustin, G. J., G. M. Mead, et al. (2007). "Randomized trial of two or five computed tomography scans in the surveillance of patients with stage I nonseminomatous germ cell tumors of the testis: Medical Research Council Trial TE08, ISRCTN56475197--the National Cancer Research Institute Testis Cancer Clinical Studies Group." Journal of clinical oncology 25(11): 1310-5.


Seminoma– advanced stages

Prognostic group

Clinical examination and diagnostics

Frequency of examination (i.e. every x months) * except when indicated by footnote

 
  

Year 1

Year 2

Year 3

Year 4

Year 5

Years 5-10

 

 

"good/

intermediate prognosis"

 



LDH, AFP, HCG, clinical examination

3

6

6

12

12

12+

 

X-ray of the chest or CT scan of the chest (if supradiaph. disease)+

3 then 6*

6

6

-

24*

  

CT scan of the abdomen/pelvis

3, then 6

6

12

-

24*

  


* depending on the presence of intrathoracic disease. For stage II seminoma, or after salvage radiotherapy for recurrence of stage I seminoma. CT scan should be done at 3 months then every 6 months for the first two years, then once in year 3, followed by a final scan at 5 years, then CT scans can be stopped. + After completion of 5 years of follow-up, patients can be discharged to their family physician for ongoing follow-up for relapse and late complications.


Nonseminoma – advanced stages

Prognostic group

Clinical examination and diagnostics

Frequency of examination (i.e. every x months) * except when indicated by footnote

 
  

Year 1

Year 2

Year 3

Year 4

Year 5

Years 5-10

 

 

 

"good prognosis"

 



LDH, AFP, HCG, clinical examination

3

3

6

6

6

12

 

X-ray of the chest or CT scan of the chest (if supradiaph. disease)+

3 then 6*

6

6

-

-

  

CT scan of the abdomen/pelvis

3, then 6

6

12

-

24*

  


"intermediate/poor prognosis

 

 

LDH, AFP, HCG, clinical examination

3

3

6

6

6

12

 

X-ray of the chest or CT scan of the chest (if supradiaph. disease)

3, then 6*

6*

6*

6

24*

  

CT scan of the abdomen/ pelvis

3, then 6

6

12

-

24*

  

* depending on the presence of intrathoracic disease. For stage II seminoma, or after salvage radiotherapy for recurrence of stage I seminoma. CT scan should be done at 4 months intervals x 2, then 6 months intervals x 2, then annually until 3 years, followed by a final scan at 5 years, then can be stopped.

Long Term Follow-Up

Follow-up after five years should be done once a year and can be done by the family doctor. The follow-up program should include the following: tumour marker AFP and HCG; examination of the remaining testicle; monitoring for potential cardiac risk factors (e.g. cholesterol, triglycerides, hypertension, microalbumenia, hypogonadism, etc). After radiotherapy, patients remain at higher risk for second malignancy, and appropriate screening for colon cancer should be initialed according to standard colorectal screening guidelines (see colorectal cancer section). After chemotherapy patients should be monitored for effects of pulmonary, renal and oto-toxicity. A higher index of suspicious for avascular necrosis of the hip should be maintained for those with ongoing hip pain, and hypogonadism for those with symptoms of fatigue and low sex drive.

References:

  1. Meinardi MT, Gietema JA, van der Graaf WT, et al: Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18:1725-1732, 2000

  2. Strumberg D, Bruegge S, Korn MW, et al: Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer. Ann Oncol 13:229-236, 2002

  3. Hauges HS, Bosl GJ, Boer H et al. Long-term and late effects of germ cell testicular cancer treatments and impications for follow-up. J Clin Onc 2012, 30:3752-3763.

Non-Germ Cell Tumours

A definitive follow up program cannot be specified. Most Sertoli cell tumours with metastatic potential will relapse within six months of diagnosis. The pattern of relapse is similar to nonseminomatous germ cell tumours. It is suggested these patients be followed for a minimum of two years. Urinary or serum androgens and estrogen assays can be helpful.

SOURCE: Testis ( )
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