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MERSEYSIDE AND CHESHIRE CANCER NETWORK: GUIDELINES FOR THE MANAGEMENT OF UROLOGICAL CANCER Testicular Tumour Treatment Guidelines Authors: Professor Peter Clark Dr Judith Carser Mr Mark Fordham Review Date: August 2013 Testicular Guidelines Review Date: August 2013 CONTENTS 1. 2. 3. 4. 5. 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10 5.11 5.12 5.13 5.14 5.15 5.16 6. 6.1 6.2 6.3 6.4 6.5 7. 8. 8.1 8.2 9. 10. 10.1 10.2 10.3 10.4 10.5 11. 12. 13. 14. Introduction Details of the Testis MDT GP referral guidelines Initial management of a suspected testicular tumour and local MDT referral guidelines Pathology guidelines Clinical Information Required on the Specimen Request Form Preparation of Specimens before Dissection Specimen Handling and Block Selection Gross Examination of Orchidectomy Specimens Primary Lymphadenectomy Specimens Excision of Residual Masses after Chemotherapy Block Selection Orchidectomy Specimens for Clinically Localised Disease Retroperitoneal Lymph Node Dissections and Postchemotherapy Residual Masses Classification of Testicular Tumours Pathological Prognostic Factors in Stage 1 Disease Metastatic Disease and Post-chemotherapy Residual Masses Reporting of Biopsy Specimens Macroscopic Items Microscopic Items Reporting of Frozen Sections Radiology guidelines Clinical background Who Should be Managed? Recommendations for Cross-Sectional Imaging in Cancer Management August 2006 Staging Objectives Staging Nodal and Metastatic Disease Guidelines on Fertility Support Services Treatment protocols Seminoma NSGCT Pre-chemotherapy preparation of the patient Follow up protocols Stage 1 seminoma Metastatic seminoma Stage 1 NSGCT Metastatic NSCGT Management of residual masses post chemotherapy Management of Metachronous Contralateral Testis Tumour Specialist Palliative Care Clinical Trials Patient Information Page 4 5 5 5-6 6-11 6-7 7 7 7-8 8 8 8 8 8-9 9 9-10 10 10-11 11 11 11 11-12 11 11 11 12 12 13 14-16 14-15 15-16 17 18-22 18-19 19 19-20 20 21-22 22 22 23 24 2 APPENDICES Appendix A - Pathway Appendix B - Histology: Handling and Cut-up of Surgical Specimens Appendix C - TNM Pathological Staging Appendix D - Treatment Algorithm Appendix E – Chemotherapy protocols 25 26-29 REFERENCES 34-38 30 31 32-33 3 1. INTRODUCTION The majority of solid neoplasms that develop within the testis are malignant of which 95% are germ cell tumours (GCT). These GCTs are classified by their histological appearance into seminoma (60% - 70% incidence; age range 20 – 50 years) and nonseminomatous germ cell tumours (NSGCTs), which in the UK are often referred to as teratomas, (incidence 30% - 40%; age range 15 – 40 years). Those tumours with mixed elements (15%- 30%) are managed as for NSGCTs. This histological classification correlates well with the natural history of the tumour types and also their response rates to modern treatment modalities. Seminoma is radiosensitive but both seminoma and NSGCT respond well to cisplatin based chemotherapy regimens with 5 year survival rates of 90% for all GCTs and >95% for all seminomas. Prognosis is most favourable in low volume disease with a 99% 5 year survival rate for all stage I tumours but less favourable (~60%) for the rarer cases of advanced tumours with visceral metastases. Although testicular tumours are rare with an incidence of about 3/100,000 in the UK and account for only 1% of all male cancers, it is the commonest solid malignancy in men in the age range 15 – 35 years and incidence is increasing. In Mersey and Cheshire Cancer Network approximately 80 - 90 new tumours are diagnosed each year. No specific aetiological factors have been identified but there is an increased relative risk in first degree relatives (father/brother) (1) in patients with a history of testicular maldescent (2) and patients with primary infertility (3). In addition, men who have been successfully treated for testis cancer have a 2% - 5% incidence of developing a further tumour in the remaining testis, in some cases many years later (4). The remaining 5% non-germ cell tumours comprise mainly lymphoma presenting in adult men (age range 50 – 70 years); other tumours include sex cord tumours (sertoli cell tumours, leydig cell tumours) in adults and paratesticular tumours (rhabdomyosarcoma in infants and leiomyosarcoma in adults). A particular feature of some GCTs is the presence of the serum tumour markers beta Human Chorionic Gonadotrophin (bHCG), alpha feto-protein (AFP), and lactate dehydrogenase (LDH). Although not uniquely specific for GCT, they provide important information when they are present about tumour burden, tumour type and response to treatment and possible relapse. The presence of a raised serum AFP indicates a teratomatous element within the tumour even if this is not identified on histology. Although bHCG may be moderately raised in seminoma, high values are associated with NSGCT and indicate tumour burden and activity. The serum marker LDH is non specific but can indicate tumour burden and be a sign of tumour relapse. The post-orchidectomy rate of fall of bHCG (half-life 2-3 days) and AFP (half-life 5-7 days) will indicate if the tumour has been removed or if metastases are present. Because most patients presenting with a testicular tumour are young adults often at the stage of considering starting a family, the potential effects on their fertility of both surgery and chemotherapy need to inform the planning of any management regime. These guidelines should be read in conjunction with the European Association of Urology Guidelines (2011), the European Society of Medical Oncology Clinical Recommendations (2010) and the National Comprehensive Cancer Network Guidelines (2011) (5-8). 4 2. DETAILS OF THE TESTIS MDT Core members: Peter Clark Judith Carser Doug Errington Mark Fordham Vijay Aachi Jane Belfield Iwan Lewis-Jones Nicola Wilson Carmela Parisi / Claire Richards Consultant Medical Oncologist Consultant Medical Oncologist Consultant Clinical Oncologist Consultant Urological Surgeon Consultant Histopathologist Consultant Radiologist Consultant Andrologist Clinical Nurse Specialist MDT Coordinators This group meets every Thursday at 8.30am before the testis tumour clinic. Extended members who are available when needed are:Doug Errington Iwan Lewis-Jones Richard Page Professor J Vora Consultant Clinical Oncologist Consultant Andrologist Consultant Thoracic Surgeon Consultant Endocrinologist The Network Pathway for testicular tumours is outlined in Appendix A. 3. GP REFERRAL GUIDELINES A fast track fax referral form is available to GPs for all patients with suspected testicular tumour and all patients are seen urgently. GPs have the facility to request scrotal ultrasound scan and tumour marker estimation. 4. INITIAL MANAGEMENT OF A SUSPECTED TESTICULAR TUMOUR AND LOCAL MDT REFERRAL GUIDELINES In the majority of cases, when the intra-testicular mass has been confirmed, management consists of a radical orchidectomy performed via the groin and dividing and transfixing the spermatic cord at the deep inguinal ring. The patient is counselled that the operation is being performed to remove what is suspected to be a malignant tumour but this will not be confirmed until the testis has been examined histologically (unless the tumour markers are raised or there is evidence of metastatic disease). As part of the pre-operative preparation it is essential for serum tumour markers to be measured. If elevated, then sequential post-operative measurements will indicate whether they fall to normal, indicating a stage I tumour that has been completely removed, or if they remain elevated indicating metastatic disease even if the CT scan is normal. Some men will express anxiety at the change in their body image when an orchidectomy is discussed. The use of a silicone testicular implant placed at the time of the surgery produces a satisfactory prosthesis in most patients but some find that there is an unnatural feel or appearance which they can find difficult to accept. All men should have the option of having a prosthesis inserted at the time of radical orchidectomy. In the rare cases where a patient presents with a testicular tumour in a solitary testis, or if sub fertility is suspected, sperm banking should be offered before any surgery is 5 performed and in the former case, to consider performing a testis sparing excision of the tumour. Although testis sparing surgery runs the risk of incompletely removing any tumour, there is evidence to suggest that in some cases chemotherapy may eradicate any remaining malignant cells within the testis (9, 10). Such patients can be referred to the specialist MDT for further assessment. In cases where the patient has presented with advanced GCT and extensive distant metastases, surgery for the primary may be regarded of secondary importance to commencing urgent chemotherapy treatment (11). In cases of patients with heavy tumour burden and high tumour markers it is important to exclude cerebral metastases as neurosurgical treatment may be indicated prior to starting chemotherapy. These patients should be referred urgently to Professor P. Clark or Dr J. Carser at Clatterbridge Centre for Oncology. Following orchidectomy, the patient should be referred directly to Professor P. Clark or Dr J. Carser where the patient will be seen in the next weekly clinic or on an ad hoc basis if assessment is urgently required. The Specialist MDT co-ordinator contacts the local pathologist who will inform Dr Aachi and send the slides or tissue for review. The histopathology is then discussed in the next Testis MDT. Any radiology will be amended by Dr Belfield or arranged subsequently at the RLBUHT and reviewed by Dr Belfield. Patient presents with Testis Tumour If too ill – Peter Clark/Judith Carser (PIC/JEC) IMMEDIATELY If physically fit – pre-op markers Radical Orchidectomy Advice about body image & Testis Prosthesis Within 24 hours Refer directly to PIC/JEC Post op markers Key: Local Urology Team 5. Histology and radiology reviewed for SMDT PATHOLOGY GUIDELINES Histopathological examination of the radical orchidectomy specimen assesses the primary for both the type of testicular tumour, evidence of lymphovascular invasion and the extent of spread of the tumour within the scrotum ie the pT stage. Where a tumour exhibits both seminoma and teratoma elements the tumour is managed according to the teratoma element. The presence of differentiated teratoma is also noted. 5.1 Clinical Information Required On The Specimen Request Form This includes laterality, the type of specimen (biopsy, simple or radical orchidectomy, lymphadenectomy or post-chemotherapy residual mass), the anatomical origin of lymph 6 nodes and history of prior testicular tumours and treatment. Information concerning serum tumour markers is useful, although results may not always be available at the time the clinicians submit the specimen. Pathology specimens should be dissected and reported in accordance with the latest dataset for testicular tumours and post chemotherapy residual masses reports published by the Royal College of Pathologists. Standards and datasets can be found at www.rcpath.org.uk 5.2 Preparation of Specimens before Dissection Orchidectomy and lymphadenectomy specimens generally require fixation in formalin for 24 hours at least. Fixative can be slow to penetrate the thick testicular coverings, and therefore careful incision into the capsule can be useful for tumour preservation. It should be noted that ‘bivalving’ of the fresh specimen can lead to bulging of the cut surfaces and the distortion can make assessment of the relationship between the tumour and the rete and tunica difficult. Because germ cell tumours are particularly poorly cohesive, there may also be artifactual contamination of relevant resection margins. This spread of tumour can also mimic vascular invasion. 5.3 Specimen Handling and Block Selection A synoptic reporting proforma has been added as an aide memoire for the main features of these neoplasms (Appendix B). The proforma extracts the dataset currently used in diagnosis and staging. This would usually be supplemented by a more detailed written report. Aspects of best practice in handling testicular tumour specimens have recently been reviewed (12). 5.4 Gross Examination of Orchidectomy Specimens Most patients with a clinical diagnosis of testicular tumour undergo a radical orchidectomy, whereby the testis is removed with the tunica, epididymis and a length of spermatic cord via an inguinal approach. Organ-sparing surgery, to preserve a degree of natural hormonal production, is an option in specific cases, for instance in patients with bilateral testicular tumours (13). Excision margins are inked in these cases. Radical testicular specimens should be orientated by identifying the cord, the slightly more bulbous head of epididymis tapering to the tail of the epididymis, separated from the testis proper by the epididymal sinus. Specimens are measured in three dimensions and the length of spermatic cord recorded. The terms of proximal and distal are best avoided when referring to the cord as they can cause confusion. A block is taken from the cord resection margin prior to incision of the tumour to avoid contamination. Sections from the midpoint and the base of cord can also be taken at this time, as they more commonly reveal vascular invasion than the cord resection margin. Direct invasion into the cord, whether into the lower cord or the surrounding fibro adipose tissue outside the tunica, should be noted for staging purposes (pT3). The parietal tunica vaginalis can then be reflected and the presence of a hydrocele and/or adhesions noted. Unless there is invasion through the tunica albuginea into the vaginalis, the vaginalis is often not well represented in tissue sections as it separates from the testis. The absence of invasion should therefore be recorded at 7 this time for staging purposes. Breaches in the tunica are also noted. The specimen can then be bivalved through the rete and epididymis. In summary, the following are noted: Tumour location (upper pole, mid-section or lower pole) The appearance (solid or cystic) and colour of the tumour The maximum tumour size The relationship of the tumour to the tunicas, rete testis, epididymis and cord The presence of abnormalities in the residual normal testis. 5.5 Primary Lymphadenectomy Specimens Although retroperitoneal lymph node dissections can be performed as an alternative to surveillance or chemotherapy in patients with stage I disease, this is unusual in the UK. Any such specimens are measured in three dimensions. Lymph nodes are identified and described as either macroscopically normal or involved by tumour. 5.6 Excision of Residual Masses after Chemotherapy A complete retroperitoneal lymph node dissection may be performed in these cases but often only the involved lymph nodes are removed (‘lumpectomy’). Specimens are measured in three dimensions. It is useful to ink the surgical resection margins as completeness of excision is a determinant of outcome. The masses usually consist of single or multiple lymph nodes but occasionally visceral metastases may be resected. 5.7 Block Selection Comprehensive sampling is essential for both primary resections and residual masses as the identification of even small areas of a different subtype can alter patient management and impact on prognosis. Although the recommendation of one block per centimetre of tumour is usual, more may be required to adequately represent all the macroscopically different areas of tumour as well as the interface with surrounding structures for staging and management purposes. Conversely, large but homogeneous tumours may require less. 5.8 Orchidectomy Specimens for Clinically Localised Disease Blocks are selected to represent: • The cord resection margin, midpoint and base of cord at least (prior to sectioning the tumour to avoid contamination) • The relationship of the tumour(s) to the rete testis, epididymis and cord • The minimum distance of the tumour to the nearest inked resection margin for partial orchidectomies • All areas of the tumour(s) with different macroscopic appearances (solid, cystic, pale or haemorrhagic) • Adjacent testis including the capsule, a common site for vascular invasion • Uninvolved testis. 8 5.9 Retroperitoneal Lymph Residual Masses Node Dissections and Post-chemotherapy Blocks are selected to represent: • All areas of the positive node(s) with different macroscopic appearances (solid, cystic, pale or haemorrhagic) • The minimum distance of the tumour to the nearest inked resection margin • All macroscopically negative nodes to search for micrometastatic disease. For post-chemotherapy residual masses, particularly in the absence of a biopsy diagnosis prior to treatment, it is often useful to include areas of necrosis as ghost outlines of the tumour often remain and allow the distinction between seminoma and teratoma. 5.10 Classification of Testicular Tumours There are two major classifications of germ cell tumours, the British Testicular Tumour Panel (BTTP) (14-16) and the World Health Organization (WHO) (17) The BTTP classification was based on a review of over 1000 cases with clinical outcome, prior to the introduction of platinum based therapy. Whereas the WHO classification lists tumour subtypes individually, the BTTP tends to group different patterns of differentiation into categories that were clinically relevant at the time. The BTTP approach led to the early recognition of the malignant potential of testicular tumours entirely composed of differentiated, somatic elements in the adult male (16) and the use of teratoma differentiated rather than mature teratoma to distinguish them from their ovarian counterparts, which are essentially benign. The malignant nature of these tumours in adult (18, 19) but not prepubertal males (20, 21) was subsequently confirmed. Unfortunately, the category of teratoma in the WHO classification contains both benign and malignant tumours. Dermoid cysts are classified as teratomas, yet are considered to be benign (17, 22), although only a very small number of malignant cases have been reported. It is essential for clinical management purposes that it is clear that tumours composed entirely of differentiated somatic elements can metastasise and the term of teratoma differentiated appears to convey that understanding. Furthermore, these tumours are refractory to germ cell type chemotherapy, and can undergo secondary transformation towards a somatic malignancy. This was only clearly recognised and characterised relatively recently (23) and was not described in the BTTP classification. Equally, the BTTP only catalogued trophoblastic tumours with a biphasic pattern equivalent to choriocarcinoma. The few cases of cystic trophoblastic tumour were described subsequently, usually in post-chemotherapy residual masses, and they appear to be associated with good prognosis (24, 25). Placental site trophoblastic tumours are even rarer (26, 27). Correlations between the major categories of BTTP and the WHO classifications are easy to draw. 5.11 Pathological Prognostic Factors in Stage I Disease For classical seminomas, tumour size (up to 40 mm versus over 40 mm), invasion of the rete testis and vascular invasion (lymphatic and/or venous) have been identified as risk factors for relapse and are used in some centres to identify patients who may benefit from adjuvant treatment rather than surveillance (28, 29). Invasion into the rete testis 9 was defined as direct spread into the stroma of the rete testis and not tubular involvement (pagetoid spread of intratubular germ cell neoplasia or luminal invasion) in the pooled analysis of large surveillance studies (28). It should be emphasised that the assessment of vascular invasion can be particularly difficult in seminomas due to the extremely friable nature of the tumour, hence the need for careful handling as emphasised earlier. For teratomas/nonseminomatous germ cell tumours, vascular invasion (lymphatic and/or venous) has consistently been identified as a risk factor and is used to guide management (30-33). The presence and extent of undifferentiated teratoma has also been shown to be predictive, but not always on multivariate analysis (32, 33). In teratoma differentiated, the presence of immature elements is not a prognostic factor but the development of secondary malignant transformation, characterised by an invasive growth pattern, is associated with poor prognosis unless complete surgical excision is achievable (23). 5.12 Metastatic Disease and Post-chemotherapy Residual Masses The role of pathology in metastatic disease is to confirm the diagnosis of a germ cell tumour if there is clinical uncertainty. However, prognosis and treatment decisions are then based on the International Consensus Classification (9). Serum markers and imaging are used to assess response to chemotherapy. Residual masses may persist after completion of treatment. Patients with seminoma do not generally require resection of a persistent mass, as the presence of residual viable seminoma and the development of recurrence are rare (34, 35). On the other hand, in patients with teratoma, over half of resections contain viable disease, and it is not possible to identify preoperatively those with fibrosis or necrosis only (34, 36). The presence of malignant germ cell elements (10%) other than teratoma differentiated, (50% of cases), and incomplete resection are independent risk factors for progression (36-38). The presence of undifferentiated teratoma has been identified as the single most significant risk factor for progression in patients with complete resections (38). Patients with teratoma differentiated in their primary orchidectomy are more likely to have an incomplete response and are at higher risk of harbouring teratoma differentiated in residual masses, and therefore viable persistent tumour (39). However the absence of teratoma differentiated from the primary tumour does not preclude its presence in metastases (40, 41). The presence of cytologically atypical epithelial or mesenchymal elements in teratoma differentiated is not uncommon in post-chemotherapy specimens and does not alter prognosis. However, if the somatic cells show invasive pattern this is indicative of secondary transformation towards a somatic malignancy, which is associated with a higher risk than teratoma differentiated alone (42). 5.13 Reporting of Biopsy Specimens Testicular biopsies are most commonly performed in the context of infertility and intratubular germ cell neoplasia (TIN) may be an incidental finding. If untreated, invasive testicular tumour develops in 70% of cases within 7 years (43). The rationale for performing contralateral biopsies in patients with germ cell tumours is to consider offering the option of low-dose irradiation to prevent the development of an invasive germ cell tumour and the need for a second orchidectomy and therefore complete androgen ablation. However, the value of routine biopsies is controversial as 10 the overall prevalence is low (5%) and up to 25% of patients treated for TIN develop androgen insufficiency requiring testosterone supplementation (44-46). Nevertheless, patients with an atrophic contralateral testis and who present before the age of 30 appear to be at higher risk and may be offered biopsy (45). Generally three levels are taken. It is useful to retain spare sections of immunocytochemistry in case of doubt about the diagnosis of TIN. A Feulgen stain can be useful for the rapid identification of spermatozoa as they are bright red in a blue background. Opinions are divided concerning the value of Bouin's fixation (12, 47). It offers better cytological detail and allows a better assessment of spermatogenesis but can adversely affect the results of immunocytochemistry. Formalin fixation can induce artefact with ballooning of the cytoplasm, mimicking neoplasia, but most cases can be resolved with the use of markers. 5.14 Macroscopic Items Biopsies are measured and completely embedded. 5.15 Microscopic Items • Approximate number of tubular cross-sections present. • Assessment of spermatogenesis. • Presence or absence of TIN. 5.16 Reporting of Frozen Sections Frozen sections of testicular lesions are rarely required as ultrasound diagnosis is extremely reliable. However, they may be requested to confirm the diagnosis prior to orchidectomy in patients with bilateral tumours or if clinical findings are equivocal. The identification of undifferentiated teratoma is usually straightforward but the distinction between seminoma with a prominent granulomatous reaction and a reactive process may be difficult. Similarly, the distinction between teratoma differentiated and an epidermal cyst is compromised by the problem of sampling as the diagnosis of teratoma differentiated is made on the demonstration of skin appendages, non-squamous somatic elements or TIN. Urologists and their patients must be made aware of the inherent difficulties of the technique and these potential pitfalls. TNM Staging – see Appendix C. 6. RADIOLOGY GUIDELINES 6.1 Clinical Background The patterns of spread of testicular tumours are predictable. NSGCT typically spreads initially to the retroperitoneal lymph nodes, but pulmonary metastatic disease may be seen at first presentation. Seminoma metastasises to lymph nodes in the retroperitoneum, and eventually mediastinum, rarely involving lung and other organs. 6.2 Imaging Following orchidectomy and an established diagnosis of a testicular germ cell tumour, all patients should be staged with CT. For NSGCT, this should include chest, abdomen and 11 pelvis. Follow-up depends on disease stage at presentation, and some patients may be suitable for surveillance programmes. 6.3 Recommendations for Cross-Sectional Imaging in Cancer Management August 2006 All patients with seminoma should be staged with CT of abdomen and pelvis at presentation. It is an option to include thoracic CT in the initial assessment, as the discovery of retroperitoneal nodal enlargement would necessitate thoracic CT. 6.4 Staging objectives • • • • To detect lymph node metastases in abdomen, thorax and supraclavicular fossa. To identify lung metastases. To identify disseminated blood-borne metastatic disease, e.g., liver. To identify brain metastases in selected patients. Note that the primary tumour is not assessed by CT or MRI. 6.5 Staging Nodal and Metastatic disease 6.5.1 CT CT is the preferred investigation, as it remains the most sensitive modality for identifying small (less than 1 cm) pulmonary metastases. For NSGCT, because of the relatively high incidence of chest deposits, CT scanning of whole body is preferred. At initial staging of all germ cell tumours contrast-enhanced CT of the thorax, abdomen and pelvis should be obtained although subsequently the pelvis may be omitted particularly in patients who have no prior history of inguinal-scrotal surgery. However, in patients who have had a scrotal incision, inguinal hernia repair, or developed testis cancer in an ectopic / undescended testis, the pelvis should be imaged on follow-up examinations. • • • • • • Oral administration of 1 litre of water or iodinated contrast medium. 100-150 ml of intravenous iodinated contrast medium injected at 3-4 ml/sec. MDCT is commenced at 25-30 seconds post-injection to assess the thorax and 70-80 seconds post-injection to assess the abdomen and pelvis. Alternative protocol for 16-slice MDCT: commence scanning at 50 seconds post-injection to include chest, abdomen and pelvis. A maximum slice thickness of 5 mm is required using spiral technique. Using MDCT, slice thickness will depend on scanner capability. In general, sections are acquired at 1.25-2.5 mm and reformatted at 5 mm for viewing. Values of CTDIvol should normally be below the relevant national reference dose for the region of scan and patient group. 6.5.2 MRI 12 MRI has similar sensitivity to CT for detection of nodes in the retroperitoneum but in general is not used for this purpose. MRI is the technique of choice for detecting brain metastases. If a patient presents with more than 20 pulmonary metastases or HCG level greater than 100,000 or other IGCCCG poor prognostic features brain deposits are sufficiently likely that MRI is indicated. The trophoblastic subtype of NSGCT is also associated with a high incidence of brain deposits. The brain may act as a “sanctuary site” for NSGCT deposits during treatment with chemotherapy. 7. GUIDELINES ON FERTILITY SUPPORT SERVICES All patients are referred for sperm banking if they are to undergo chemotherapy. Any patients with suspected infertility or solitary testes will also be invited to carry out sperm banking pre-orchidectomy. 13 8. TREATMENT PROTOCOLS 8.1 Seminoma Stage I Approximately 75% of patients have stage 1 disease and survival rates are >99% regardless of the management strategy chosen. Surveillance In surveillance following radical orchidectomy recurrences can occur late (up to 2 - 5 years) necessitating long term CT based follow up. The main advantage to surveillance is that most patients do not require any further treatment. The disadvantages to surveillance are the need for longer follow-up, the requirement for a greater number of CT scans (and thus the increased amount of irradiation) and the psychological morbidity of living with a significant chance of relapse (15%) which requires relatively tough chemotherapy. (48, 49) Adjuvant chemotherapy A single cycle of carboplatin AUC 7 reduces the risk of relapse to <5% if an EDTA creatinine clearance is used to direct the dosing of carboplatin and also reduces the risk of a contralateral GCT at least in the medium term with 6.5 years of study follow up reported (50, 51) Adjuvant radiotherapy This is as effective as adjuvant carboplatin but has more side effects, a worse quality of life after treatment and has a small, but significant chance of inducing a second malignancy in the long term and therefore is rarely used (50, 52). All options for the management of stage I seminoma of the testis result in a very high cure rate as salvage chemotherapy is effective for relapse. Patients are offered the choice of surveillance or adjuvant chemotherapy and the advantages and disadvantages of both discussed. 14 Stage II Although abdominal radiotherapy remains an option (especially for stage IIA disease) combination cisplatin-based combination chemotherapy is commonly used (BEP for 3 cycles or EP for 4 cycles if contraindications to bleomycin). Stage III - IV Standard 3-day BEP chemotherapy for 3 cycles (good prognosis) or EP for 4 cycles if contraindications to bleomycin. Intermediate prognosis patients receive 4 cycles of BEP on a 5-day schedule (see Table 1). Table 1: IGCCCG International prognostic classification for Seminoma (9) Good prognosis group Proportion of patients 90% 5-year survival 86% Intermediate prognosis group Proportion of patients 10% Seminoma Any primary site No non-pulmonary visceral metastases Normal AFP, any bHCG or LDH Seminoma Testis or retro-peritoneal primary site Non-pulmonary visceral metastases Normal AFP, any bHCG or LDH 5-year survival 72% 8.2 NSGCT Stage I Serum tumour markers should be monitored weekly until normal. Markers which fail to normalise are treated as per metastatic NSCGT. The majority of relapses occur within the first 12 months and patients are divided into low (15-20% risk) and high risk groups (40-50% risk) for recurrence according to whether or not lympho-vascular invasion is present. It is especially important that all cases have detailed histological review at the MDT. For the high risk group, 2 cycles of adjuvant BEP chemotherapy are recommended (unless patients agree to enter the III study which is examining the role of a single cycle of adjuvant chemotherapy) (53) Patients in the low risk group are offered surveillance after radical orchidectomy. The follow up is intense and it is important that they have a high level of compliance (see 10.3.1) (32). Some patients with low risk disease however still opt for adjuvant chemotherapy, mainly for the knowledge that after such treatment risk of relapse is remote. 15 Stages IM - IV Combination cisplatin based chemotherapy for 3-4 cycles, depending on the prognostic group (table 2). Treatment algorithm - see Appendix D. Table 2: IGCCCG International prognostic classification for NSGCT (9) Good prognosis group Proportion of patients 56% 5-year survival 90% Intermediate prognosis group Proportion of patients 28% 5-year survival 80% Poor prognosis group Proportion of patients 16% 5-year survival 50% NSGCT – ALL of: Testis or retroperitoneal primary site No nonpulmonary visceral metastases AFP < 1000 ng/ml, beta HCG < 5000IU/L, LDH < 1.5 x ULN NSGCT – ALL of: Testis or retroperitoneal primary site No non-pulmonary visceral metastases Any of: AFP ≥ 1000 and ≤ 10,000 ng/ml bHCG ≥ 5000 and ≤ 50,000 IU/L LDH ≥ 1.5 ≤ 10 x ULN NSGCT – ANY of: Mediastinal primary site Non-pulmonary visceral metastases AFP > 10,000 ng/ml; bHCG > 50,000 IU/L; or LDH >10 x ULN. For management purposes the extent of tumour spread is divided into four stages based on the Royal Marsden Hospital staging system (table 3). Table 3 STAGE I IM II III IV ANATOMICAL EXTENT Tumour confined to the testis. No evidence of distant spread As above but persistently elevated markers Infradiaphragmatic lymph node involvement: IIA - diameter < 2 cm IIB - diameter 2 – 5 cm IIC - diameter > 5 cm Supra and Infra-diaphragmatic lymph node involvement A,B,C categories: as above Extralymphatic (nonpulmonary) visceral metastases 16 9. PRE-CHEMOTHERAPY WORK UP For all patients who are to have chemotherapy the specialist nurse will be available to explain the process and to provide them with written information. This will be reiterated when the patient attends Clatterbridge Centre for Oncology. The timing of chemotherapy cycles is important, as are arrangements and expectations for time off work, support from social services and arrangement for transport to and from the hospital. Cisplatin is nephrotoxic and adequate baseline renal function is required for administration, with the dose based on the patient’s weight and height. The drug is given intravenously with a crystalloid infusion to maintain good renal perfusion. It can induce significant nausea and vomiting. In addition cisplatin is neuro-toxic and can result both in peripheral neuropathy affecting the fingers and toes and ototoxicity causing loss of high frequency hearing. Although often reversible, the process can take up to 2 years to recover. Bleomycin has the rare but fatal complication of progressive pulmonary fibrosis causing irreversible damage to the lung resulting in progressive and ultimately fatal hypoxia. Etoposide can induce marrow suppression resulting in a fall in white cells and platelets. Cases of secondary leukaemia have been described. Any sign of infection or abnormal bruising requires prompt attendance at the hospital. Hair loss (alopecia) is universal as is tiredness. Other common side effects include taste change, a sore mouth, acne, skin pigmentation and runny eyes. Of particular importance is the effect of the chemotherapeutic agents on the germinal epithelium of the remaining testis. Spermatogenesis is eradicated by the chemotherapy but frequently returns to normal after about 12 months. For this reason all patients are offered sperm banking before starting chemotherapy. If for some reason spermatogenesis did not return, in vitro fertilisation would be an option for the couple. There is no evidence to suggest that a pregnancy may be abnormal if it occurs while spermatogenesis is undergoing recovery, and so contraception is not required (54). Long term late complications remain an area of investigation but secondary malignancies and cardiovascular disease have both been associated with GCT chemotherapy (55, 56). Patients should be counselled regarding long term toxicity at the time of consent and every effort made to provide smoking cessation advice and support where required. For those teratoma patients with abdominal or thoracic metastases, chemotherapy may eradicate them completely. However where residual masses remain it is usually appropriate to excise them surgically, and informing the patient at an early stage that treatment is a combination of chemotherapy and surgery allows the patient to understand the treatment plan. 17 10. FOLLOW-UP The follow up schedule takes into account the site and likely timing of relapse. 10.1 Stage 1 seminoma Surveillance In over 90% of patients with stage 1 seminoma the first site of relapse is the infradiaphragmatic (para-aortic) nodes (57). Adjuvant carboplatin Following chemotherapy relapse is rare but most likely to occur in the infradiaphragmatic nodes (usually para-aortic nodes) (57) Adjuvant radiotherapy Following para-aortic radiotherapy, relapse is most likely in the pelvic lymph nodes. With ‘dog-leg’ radiotherapy, the first detected site of relapse is more likely in the chest, or palpable neck or inguinal lymph nodes) (57) Table 4: Suggested surveillance for stage 1 seminoma post orchidectomy Intervention Examination & Markers* CXR and CT abdomen† Year 1 3 monthly Year 2 3 monthly Year 3 6 monthly Year 4 6 monthly 6 monthly 6 monthly End of year 3 End of year 4 Year 5 6 monthly Year 6+ Discharge at end of year 5 Table 5: Suggested follow up for stage 1 seminoma following adjuvant carboplatin Intervention Examination & Markers* CXR and CT abdomen† Year 1 3 monthly Year 2 3 monthly End of year 1 End of year 2 Year 3 6 monthly Year 4 6 monthly Year 5 6 monthly Year 6+ Discharge at end of year 5 Table 6: Suggested follow up for stage 1 seminoma following adjuvant radiotherapy Intervention Examination & Markers* CXR +CT pelvis (paraaortic radiotherapy) * AFP and bHCG Year 1 3 monthly Year 2 3 monthly Year 3 6 monthly End of year 1 End of year 2 End of year 3 Year 4 6 monthly Year 5 6 monthly Year 6+ Discharge at end of year 5 † CT to include pelvis if prior inguino-scrotal surgery 18 10.2 Metastatic seminoma Table 9: Suggested follow up for metastatic seminoma (radiotherapy or chemotherapy) Intervention Examination & Markers* CXR + CT abdomen† 10.3 Year 1 Year 2 Year 3 Year 4 Year 5 Year 6+ Consider 3 monthly 3 monthly 6 monthly 6 monthly 6 monthly discharge at end of year 5 If post treatment CT abdomen/pelvis is normal, no further routine CT scans. If post treatment scan abnormal, repeat at 4-6month intervals, but stop as soon as normal / stable Stage 1 NSCGT Surveillance Following orchidectomy for NSGCT, patients may be assigned Stage 1, if there is no distant spread on CT and can enter a surveillance programme which involves serum tumour marker estimations and regular CT follow-up. Of those patients with Stage I tumours who will relapse (15-20%), 80% will do so within 1 year, and >95% within 2 years. Table 7: Suggested follow up for low risk Stage 1 NSCGT post orchidectomy Intervention Year 1 Year 2 Year 3 Year 4 Year 5 Examination & Markers* monthly 2 monthly 3 monthly 4 monthly 6 monthly CXR + CT abdomen† 3 and 12 months Year 6+ Consider discharge at end of year 5 No further routine scans For high risk stage 1 NSCGT who do not elect to receive adjuvant chemotherapy and enter surveillance, it is suggested that CT thorax and abdomen is performed at 3, 6, 12 and 24 months 19 Adjuvant chemotherapy Table 8: Suggested follow up following chemotherapy for high risk stage 1 NSCGT post orchidectomy Intervention Year 1 Year 2 Year 3 Year 4 Year 5 Examination & Markers* 2 monthly 3 monthly 6 monthly 6 monthly 6 monthly CXR + CT abdomen† 10.4 Year 6+ Consider discharge at end of year 5 No routine scans required Metastatic NSCGT Table10: Suggested follow up for patients following treatment for metastatic NSGCT Intervention Examination & Markers* CXR + CT abdomen† Year 1 Year 2 Year 3 Year 4 Year 5 Year 6+ Consider 2 monthly 3 monthly 6 monthly 6 monthly 6 monthly discharge at end of year 5** If post treatment CT thorax/abdomen is normal, no further routine CT scans. If post treatment scan abnormal, repeat at 4-6 month intervals, but stop as soon as normal / stable ** Long term follow up required annually if TD in resection specimen. Further notes Brain metastases are haemorrhagic and are frequently clearly identified on precontrast scans using CT or MRI. Nodal metastases in NSGCT may become cystic on treatment. PET CT is indicated for residual masses in seminoma >3cm and >1cm in NSCGT, also detection of relapse in NSCGT and seminoma where standard CT scans are normal / indeterminate 20 10.5 Management of Post-Chemotherapy Residual Masses Following successful treatment with chemotherapy a further CT scan is required about 4 weeks later to assess the metastatic disease. The post-treatment CT scan is reviewed in the MDT. In patients with teratoma where residual masses remain (usually >1 cm) surgical excision is required. For patients with seminoma, residual masses have been shown to be nearly always necrotic and due to the intense fibrosis that occurs adjacent to them surgical excision is not regarded as necessary or wise. In the case of residual tumour >3cm a PET scan at least 6 weeks after chemotherapy may be indicated. If the mass is PET positive then this is strong evidence for active tumour and resection should be considered (58). In the absence of a PET scan lesions >3cm should be followed only until regression or progression. Surgery for retro-peritoneal para-aortic masses requires the patient to be prepared with considerable care. The surgery is usually performed through a long midline abdominal incision or via a thoraco-abdominal incision. Residual masses usually lie adjacent to the aorta and often close to the renal artery. To perform complete excision of these masses it is sometimes necessary to include a nephrectomy to remove the masses en bloc. For this reason, the patient requires a pre-operative intravenous urogram to confirm both kidneys function normally and to help define the location of the para-aortic masses. During the dissection within the standard template along the aorta the sympathetic nerves may be divided which can lead to retrograde ejaculation. The patient needs to be informed of this risk. Although pulmonary function tests, including the transfer factor, can be normal in patients following bleomycin chemotherapy, there is evidence that these patients are at a higher risk of developing reduced gas transfer intra-operatively either due to oxygen sensitivity or relative pulmonary oedema if over-transfused with crystalloid (59). All tissue following such surgery is examined histologically. About 40% of cases show necrotic tissue resulting from tumour death following the chemotherapy. About 40% 50% show mature or differentiated teratoma. This tissue has responded to the chemotherapy by differentiating, but has the potential to de-differentiate at a later time. Such tissue may develop back into teratoma or squamous or sarcomatoid differentiation can be seen. It is for this reason that complete excision of residual masses is important. In 10%, there is residual malignant teratoma present within the excised mass (60). Depending on the extent of the disease and the patient’s tumour marker status further chemotherapy or surveillance may be recommended (61). Follow up after resection of residual masses A post-operative follow up appointment at 4 to 6 weeks is made for assessment of wound healing and any complications. The histology of the resected masses is reviewed in the testis MDT. The intensity of post treatment follow up is determined by the prognostic group the patient was in at presentation and how well they have responded to treatment. 21 Teratoma patients who have required post chemotherapy node dissection will require long term follow up and CT scanning if the histology showed differentiated teratoma or active tumour was found. For patients who develop post treatment relapse the outcome is less good. Second line chemotherapy ha a 40% complete remission rate, probably because of the development of multiple drug resistant tumour differentiation. Response to chemotherapy however is not always durable and the surgical resection of any residual masses remains an integral part of the patient’s management. Management of Post-treatment Relapse Patients (i) Tumour marker relapse. Rising tumour marker levels will usually precipitate further imaging to identify metastatic disease or a new primary tumour; this usually requires CT of chest, abdomen and pelvis together with ultrasound of the remaining testicle. If no new disease is seen, an MRI of the brain is also indicated as this may be a site of occult metastatic disease. 18FDG PET-CT should also be considered. (ii) recurrence of distant metastases. Salvage chemotherapy is available for patients with relapsed disease with bone marrow transplant support available if required (Professor Richard Clarke, Royal Liverpool Hospital). 11. MANAGEMENT TUMOUR OF METACHRONOUS CONTRALATERAL TESTIS Should this occur, the patient will be managed in exactly the same way as a patient with a new diagnosis of a testicular tumour, although matters of fertility and subsequently hormone replacement therapy will be discussed if orchidectomy and therefore complete castration is anticipated. Professor Vora, Consultant Endocrinologist at the Royal Liverpool Hospital kindly supplies a clinical service for hormone replacement therapy. 12. SPECIALIST PALLIATIVE CARE There are some patients who are particularly likely to require specialist palliative care. Referral is made as early in the patient’s disease course as is possible. These include: • Patients with pre-existing psychological problems. • Patients with young children. • Patients with complex or multiple symptom control problems. • Patients with disfiguring illness. • Patients with personality change Issues of hydration and nutrition are often problematic for patients, carers and health care professionals. Where no improvement can be achieved by further treatment of the tumour, time must be given to gentle and through explanation of the situation, and what 22 can realistically be achieved. Specialist palliative care input may be required to assist with these discussions. It is inappropriate to try to stimulate appetite (e.g. with steroids) when ingestion is painful, limited or difficult. Patients are usually able to take sufficient, often in the form of nutritional liquid supplements, to satisfy thirst and appetite. Meticulous attention must be paid to: Mouthcare – seek specialist nurse advice. Pain control – use of regular non-oral medication. Anti-emesis – delivered via subcutaneous infusion where necessary. Relief of constipation – regular non-bulk forming laxative plus rectal measures as necessary. Haematuria Continence problems Catheter problems Intravenous or subcutaneous hydration and PEG /jejunostomy for enteral feeding are rarely indicated or required and should only be used with specialist advice. How to Obtain Urgent Symptom Control Advice District General Hospital Input - Primary Care Contact Specialist Community Team - Contact Specialist Hospital Team Each team will have individual arrangements or out of hours access to advice and review. The Liverpool Care Pathway for the Dying Patient (LCP) has been developed in the U.K to transfer the hospice model of care into other care settings. It is a multi-professional document that provides an evidence- based framework for end of life care. The LCP provides guidance on the different aspects of care required, including comfort measures, anticipatory prescribing of medicines and discontinuation of inappropriate interventions. Additional, psychological and spiritual care and family support are included. 13. CLINICAL TRIALS All patients that are suitable for any current National Clinical Trials are considered at the time of the Specialist MDT and would be seen by the Research Practitioner Nurses, who co-ordinate clinical trials. 23 14. PATIENT INFORMATION All patients will be offered clear and comprehensive information in a format which is suitable to their needs and their stage of treatment in the cancer journey. This should include Nature of the disease Diagnostic procedures being undertaken Treatment options available Likely outcomes of treatment in terms of benefits, risks and side effects Management of side effects of treatment, and who would be most appropriate to contact for advice Details of future appointments/contacts Contact details of clinical nurse specialist/key worker for urological cancers Contact details of clinical nurse specialist for other individual issues (stoma care/continence advice/sexual issues/body image issues) as appropriate Cancer information services such as Cancer BACKUP Where appropriate patients should receive a copy of any medical/clinical communications. Details of MDT Hard copies of the information, available within the Merseyside and Cheshire Cancer Network for patients with urological cancer and their carers, can be obtained from the clinical nurse. This information will meet agreed MCCN / National Patient Information Guidelines, as per mapping Access will be made available for all patients/carers to a named nurse whose specialist knowledge is in urological cancers. Patients in the 16 – 24 year age group will be notified to the Teenage and Young Adult MDT to ensure that appropriate psycho-social support is available from the dedicated TYA specialists within the team eg CLIC Sargent social worker. 24 Appendix A - Pathway Patient presents with Testis Tumour Acutely ill – Peter Clark/Judith Carser IMMEDIATELY Otherwise – Pre-op markers Radical Orchidectomy Advice about body image & Testis Prosthesis Within 24 hours Refer directly to Peter Clark/Judith Carser postop markers Key: Histology and radiology reviewed for SMDT Local Urology Team Specialist Testis Team Patient staged: CT scan at RLBUHT if not already done Within 2 weeks Long term follow-up Surveillance & repeat CT scans Patient seen – results & treatment plan agreed Advice about Sperm banking Relapse Follow-up Clear CT Chemotherapy Repeat CT Decision about RPLND Surgery or resection of other residual masses Follow-up Within 2 months of decision re surgery Relapse Histology and Followup Surgery Post Surgery CT Consider salvage options: Surgery Chemo High dose chemotherapy transplant 25 APPENDIX B DEPARTMENT OF PATHOLOGY ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITAL TRUST STANDARD OPERATING PROCEDURE HT78000: 1(4) AUTHORISED BY: PAS REVISION: 8 CHECKED BY: VIA REVISION DATE: 23/09/09 PREPARED BY: VIA DATE: 23/09/08 AREA: HISTOLOGY: HANDLING AND CUT-UP OF SURGICAL SPECIMENS TESTIS PURPOSE Adequate examination, sampling, description and diagnosis of specimen. PERSONNEL Medical and Technical Staff. 1. Handling at cut-up: a) Weigh: y b) Ink margins: n Tumour: Open the tunica vaginalis, weigh and measure the testis. Cut the testis sagitally, while it is in a fresh state and fix in formalin. Cut serial slices, about 3mm thick, of each testicular half, perpendicular to the original section, stopping just at the level of the tunica albugenea and examine each surface. Cut the epididymis longitudinally throughout its length. 2. 3. Special features for description: Size of testis in 3 dimensions Length of spermatic cord Tumour – size in 3 dimensions, colour, consistency, homogeneity or lack of it, presence of cysts, necrosis, haemorrhage, bone or cartilage-, tumour extension to tunica albugenea, epididymis, cord and other structures. Features of non-neoplastic testis-, atrophy, fibrosis or nodules. Blocks - from where and how many: Tumour: at least three blocks or one section for each centimetre of tumour, whichever is greater; at least one of which should include some uninvolved testis. Uninvolved testis: two blocks. Epididymis. Spermatic cord and surrounding soft tissue at point 1cm from testicle -, one cross section block. 26 Spermatic cord and surrounding soft tissue at line of resection; one cross Copyright 9 Department of Pathology, RLBUH NHS Trust HT78000: 2(4) section block. 4. Routine special stains: None. Ziehl-Neelsen staining may be required if tuberculosis is suspected, but note that this is often spuriously positive in the testis anyway because the sperm heads contain a ZN-positive protein. 5. Processing - special instructions: None. 6. Report: Specific features to include: Neoplasms Reporting should be according to the British Classification and, in the case of teratoma, should mention the presence of venous or lymphatic invasion, undifferentiated elements, amount and type of differentiated tissue, and the presence or absence of trophoblastic and yolk sac differentiation. The report should include all the data required by the "Minimum dataset for testicular tumour histopathology reports" issued by the Royal College of Pathologists, April 2000 (see below). BRITISH CLASSIFICATION Classification of tumours of testis, epididymis and related structures. 1. TUMOURS OF THE TESTIS Seminoma (S): Teratoma: Classical Spermatocytic Anaplastic Teratoma Differentiated (TD) Malignant Teratoma Intermediate (MTI) with differentiated or organoid components, but also containing undifferentiated elements. Malignant Teratoma Undifferentiated (MTU) with no mature tissues or organoid structures. Malignant Teratoma Trophoblastic (MTT)-existing cyto and syncytotrophoblastic differentiation arranged in a papillary growth pattern. Yolk-sac Tumours (YST) Combined Tumour: Seminoma and teratoma in the same testis (CT) Sertoli-cell/ Mesenchyme Tumours (SMT) Interstitial-cell Tumours (ICT) Malignant Lymphomas Miscellaneous Tumours Metastases Tumours of Uncertain Diagnosis 27 Copyright Q Department of Pathology, RLBUH NHS Trust HT78000: 3(4) 2. TUMOURS OF EPIDIDYMIS AND CORD Adenomatoid Tumour Tumours of Connective Tissue and Muscle Subdivided into: Benign: Fibroma, leiomyoma, lipoma, etc. Malignant: Embryonic sarcoma, fibrosarcoma, leiomyosarcoma, etc. Miscellaneous Tumours Metastases Tumours of Uncertain Diagnosis TESTICULAR BIOPSIES - JOHNSEN COUNTS Tubular cross-sections in one histological section of each testicular biopsy a re evaluated systematically and each cross-section is given a score from 1 -10 according to the following criteria: Score 10 9 8 7 6 5 4 3 2 1 Complete spermatogenesis with many spermatozoa; germinal epithelium organised in a regular thickness leaving an open lumen. Many spermatozoa present but germinal epithelium shows marked sloughing or obliteration of the lumen. Only few spermatozoa (<5-10) present in section. No spermatozoa, but many spermatids present. No spermatozoa and only a few spermatids (>5-10> present. No spermatozoa, no spermatids but several or many spermatocytes present. Only few spermatocytes (<5) ad no spermatids or spermatozoa present. Spermatogonia are the only germ cells present. No germ cells but Sertoli cells are present. No cells in tubular section. A mean score for each testis is calculated as in the following example: (1) Score 10 9 8 7 6 5 4 3 2 1 Total (2) No. of tubules with score 63 14 8 14 0 1 1 0 0 0 101 (3) (1) x (2) 630 126 64 98 0 5 4 0 0 0 927 (4) Copyright Q Department of Pathology, RLBUH NHS Trust 28 HT78000: 4(4) Mean score = (4) / (3) = 927 / 101 = 9.2 Notes: 1. 2. 3. 4. Bouin's fluid should be used for fixation of the biopsy. This testicular biopsy score system devised by Johnsen provided an accurate method of registering the degree of spermatogenesis, and gives a mathematical index of the functional state of the testicular tissue. The mean score in normal testes is 9.38 0.48 (Mean 2 S.D.). Analysis of results suggests that pregnancy is unlikely with a score count of less than 6.0 which represents the point at which spermatids appear in the tubules in the biopsy material. Risk Assessment See SOP No. HT00100 for risk assessment guidelines. 29 Copyright Q Department of Pathology, RLBUH NHS Trust APPENDIX C - TNM PATHOLOGICAL STAGING (7th EDITION) (62) The classification applies only to germ cell tumours of the testis. The assessment of the serum tumour markers alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG) and lactate dehydrogenase (LDH) contributes to the staging. 30 Appendix D Treatment algorithm Pre-operation: Tumour marker estimation Operation: Radical orchidectomy Post-operation: Tumour marker estimation: Staging CT scan Histological assessment: Seminoma, NSGCT, other Seminoma Stage I adjuvant chemotherapy or surveillance, consider (para-aortic radiotherapy only if contraindication to the above) Stage II stage IIA abdominal radiotherapy is an option stage IIa-c – chemotherapy BEP x 3 Stage III and IV Good prognosis: BEP x 3 (3 day regimen) Intermediate prognosis: BEP x4 (5 day regimen) NSGCT Low risk surveillance Stage I High risk Stage II, III, IV 2 cycles BEP Good prognostic group: BEP x 3 (3 day regimen) Intermediate /poor prognostic group: BEP x 4 (5 day regimen). Secondary prophylaxis with pegfilgrastim is indicated following any episode which may compromise dose intensity (eg neutropenic sepsis, uncomplicated neutropenia resulting in treatment delays) 31 Appendix E Chemotherapy protocols Adjuvant Stage 1 pure seminoma Carboplatin AUC 7 for one cycle (based on EDTA creatinine clearance) Stage 1 NSCGT High risk tumours LVI + BEP3 Bleomycin Etoposide Cisplatin 30000iu iv days 1,8,15 165mg/m2 iv days 1-3 50mg/ m2 iv days 1,2 21 day intervals for 2 cycle Metastatic Good prognosis –all GCT BEP3 Bleomycin Etoposide Cisplatin 30000iu iv days 1,8,15 165mg/m2 iv days 1-3 50mg/ m2 iv days 1,2 21 day intervals for 3 cycles AFP, bHCG day 1 each cycle CXR day 1 each cycle review by radiologist CT CAP one month post treatment 32 Intermediate – poor prognosis all GCT BEP5 Bleomycin Etoposide Cisplatin 30000iu iv days 1,8,15 100mg/m2 iv days 1-3 20mg/m2 iv days 1,2 21 day intervals for 3 cycles, then EP5 for cycle 4 (ie omit bleomycin) AFP, bHCG day 1 each cycle CXR day 1 each cycle review by radiologist CT CAP one month post treatment Initial organ failure / poor performance status Etoposide Cisplatin 100mg/m2 iv days 1-3 20mg/m2 iv days 1-3 Repeat daily x 2-3 depending on clinical scenario. 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