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Testis cancer Part 2



Management of Testicular Cancer

Management of Testicular Cancer



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Testis cancer Part 2 Testis cancer Part 2 Presentation Transcript

  • Management of Testicular Cancers
    U. Prabagaran
    DMRT (PG)
  • Classification - Outline
    Intra tubular germ-cell neoplasia(IGCN)
    SeminomaClassic typeSpermatocytic type
    Non seminomatous germ-cell tumors
    Embryonal carcinoma
    Yolk sac (endodermal sinus) tumor
    Trophoblastic tumorsChoriocarcinomaTrophoblastic neoplasms other than choriocarcinoma Monophasic choriocarcinomaPlacental site trophoblastic tumors
    Dermoid cystMonodermalteratomaTeratoma with somatic type malignancies
    -- Mixed germ-cell tumors
  • Classification
    Classification of Sex-Cord Stromal Tumors of the TestisLeydig cell tumorSertoli cell tumorGranulosa cell tumorFibroma-thecoma stromal tumorSex cord-stromal tumor with annular tubulesGonadoblastomaSex cord-stromal tumor unclassified type
    Secondary Testicular Neoplasams
  • Staging – AJCC 7
    Tis - Intratubular germ cell neoplasia (carcinoma in situ)
    T1 - Tumorlimited to the testis and epididymis without vascular/lymphatic invasion;Tumormay invade into the tunica albuginea but not the tunica vaginalis
    T2 - Tumorlimited to the testis and epididymis with vascular/lymphatic invasion, or tumorextending through the tunica albuginea with involvement of the tunica vaginalis
    T3 - Tumorinvades the spermatic cord with or without vascular/lymphatic invasion
    T4 - Tumorinvades the scrotum with or without vascular/lymphatic invasion
  • N1 - Metastasis with a lymph node mass 2 cm or less in greatest dimension; or
    multiple lymph nodes, none more than 2 cm in greatest dimension
    pN1 - Metastasis with a lymph node mass 2 cm or less in greatest dimension and less than or equal to 5 nodes positive, none more than 2 cm in greatest dimension
    N2 - Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, any one mass greater than 2 cm but not more than 5 cm in greatest dimension
    pN2 - Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or more than 5 nodes positive, none more than 5 cm; or evidence of extranodal extension of tumor
    N3 - Metastasis with a lymph node mass more than 5 cm in greatest dimension
    pN3 - Metastasis with a lymph node mass more than 5 cm in greatest dimension
  • M1a - Non regional nodal or pulmonary metastasis
    M1b - Distant metastasis other than to non-regional lymph nodes and lung
    • III Any pT/Tx Any N M1 SX
    • IIIA Any pT/Tx Any N M1a S0
    Any pT/Tx Any N M1a S1
    • IIIB Any pT/Tx N1–3 M0 S2
    Any pT/Tx Any N M1a S2
    • IIIC Any pT/Tx N1–3 M0 S3
    Any pT/Tx Any N M1a S3
    Any pT/Tx Any N M1b Any S
    S0 - Marker study levels within normal limits
    S1 - LDH < 1.5 X N* AND hCG (mIu/ml) < 5000 AND AFP (ng/ml) < 1000
    S2- LDH 1.5 –10 x N OR hCG (mIu/ml) 5000–50,000 OR AFP (ng/ml) 1000–10,000
    S3 - LDH > 10 x N OR hCG (mIu/ml) > 50,000 OR AFP (ng/ml) > 10,000
    0 pTis N0 M0 S0
    I pT1–4 N0 M0 SX
    IA pT1 N0 M0 S0
    IB pT2 N0 M0 S0
    pT3 N0 M0 S0
    pT4 N0 M0 S0
    IS Any pT/Tx N0 M0 S1–3 (post orchiectomy)
    II Any pT/Tx N1–3 M0 SX
    IIA Any pT/Tx N1 M0 S0
    Any pT/Tx N1 M0 S1
    IIB Any pT/Tx N2 M0 S0
    Any pT/Tx N2 M0 S1
    IIC Any pT/Tx N3 M0 S0
    Any pT/Tx N3 M0 S1
  • Prognostic factors
    Non Seminoma:
    T stage is of prognostic value in early stage nonseminoma
    Serum Markers
    Site of metastasis
    Number (6) and Size of retroperitoneal lymph nodes found at RPLND . ?? Extracapsular extension??
    T stage is not useful in predicting risk of relapse in stage 1 seminomas
    Tumorsize and rete testis invasion are of independent prognostic value in seminoma
  • International Germ Cell Cancer Collaborative Group Consensus Classification – Metastatic Disease
    Good Prognosis Group: with all of
  • Intermediate Prognosis: with all of
  • Poor prognosis group : with any of
  • Marker levels should be determined before and after orchiectomy.
    Only marker levels that remain elevated after orchiectomy (taking into account AFP/HCG half-life) should be used to determine IGCCCG risk status before chemotherapy.
  • Distribution & Survival
  • Principles of Treatment
    Treatment should be aimed at one stage above the clinical stage
    Seminomas - Radio-Sensitive. Treat with Radiotherapy.
    Non-Seminomas are Radio-Resistant and best treated by Surgery and Chemotherapy
    Advanced Disease or Metastasis - Responds well to Chemotherapy
  • The initial management of a suspected malignant germ-cell tumor of the testis consists of obtaining serum AFP and Beta-HCG
    Radical INGUINAL ORCHIDECTOMY is Standard first line of therapy.
  • Scrotal violation is associated with a slight increase in local recurrence rate compared with inguinal orchiectomy (2.9% vs. 0.4%, respectively)
    Further management depends on the pathology.
  • Seminoma
    Stage IA, IB, IS :
    Active Surveillance
    Adjuvant Radiation
    Adjuvant Chemotherapy
  • Adjuvant Radiation
    Retroperitoneal and Ipsilateral Pelvic nodes. (Dog – Leg Field)
    Relapse-free survival rate - 97%
    Disease-specific survival almost 100%.
    But benefits only the 15% to 20% of patients harboring subclinical nodal disease.
  • Reduced Field Adjuvant Radiotherapy
    In “dog-leg” radiotherapy :
    • 60% - mild to moderate acute GI toxicity,
    • Under 5% -moderate chronic toxicity
    • Increased risk of second malignancies.
    As the predominant nodal drainage is to the para-aortic and renal hilar nodes the use of para-aortic fields alonehas been explored.
  • A UK MRC Trial randomized 478 men with stage I seminoma testis to either dog-leg or para-aortic radiotherapy.
    The 3-year RFS was 96.6% and 96%, and OS 99.3% and 100%, following dog-leg and para-aortic fields, respectively.
    The 3-year Pelvic RFS was 100% in the dog-leg arm and 98.3% in the para-aortic arm.
  • The omission of pelvic radiotherapy leads to a reduction in acute treatment toxicity (nausea, vomiting, myelosuppression) and a more rapid recovery of sperm count.
    Given a pelvic relapse rate of around 2%, it is considered reasonable by many not to treat the pelvic nodes and to treat the para-aortics alone.
  • Adjuvant Chemotherapy
    Carboplatin as Single Agent – 1 or 2 cycles.
    Several series reported on the use of one or two cycles of carboplatin following orchiectomy.
    Recurrences were all in the retroperitoneum and were readily salvaged with cisplatin-based chemotherapy.
    Disease-specific survival of 100% in all the reported series.
  • A UK MRC Trial randomized comparison of single agent carboplatin and nodal irradiation in stage I seminoma.
    With a median follow-up time of 4 years, radiotherapy and carboplatin arms, respectively.
    RFS at 3 Yrs 95.5% Vs 94.8%
    5Yrs 96% Vs 95%
  • In the adjuvant radiotherapy arm, the most common site of recurrence was either distant (57%) or in the pelvic nodes (31%).
    In the carboplatin arm, most of the relapses (74%) were in para-aortic nodes.
  • Active Surveillance
    With the availability of highly effective RT/ CT for salvage after relapse and with a low risk of occult retroperitoneal disease in well-staged patients, several investigators have examined a policy of postorchiectomysurveillance.
    Managed by surveillance - about 20% of patients will relapse at a median time of around 14 months.
  • A pooled analysis from four series on 638 stage I seminoma patients managed by surveillance was obtained.
    With a median follow-up time of 7 years
    5year RFS - 82.3% and 10-year RFS -78.7%,.
    Most relapses (69%) –
    < 2 years of surgery,
    7% relapsed beyond 6 years.
    The 5-year cause-specific survival was 99.3%.
  • The predominant site of relapse:
    Retroperitoneum- 76% to 94%
    Mediastinum or Lungs - 5% to 15%
    Following relapse, 74% to 82% initially managed by radiation therapy, with a second relapse occurring in about 10% (6% to 16%).
    Second relapse almost always occurred at distant sites with a 90% to 95% rate of successfully salvage with chemotherapy.
  • Indicators of Relapse were:
    Tumor size
    Rete testis invasion
    Lymphovascular invasion
  • Surveillance policy:
    4monthly assessments – 1- 2 years,
    6 monthly assessments – 3-4 years,
    Annual assessments - 5 to 10years.
    Physical examination
    CT scan of abdomen and pelvis
    Chest x-ray.
  • The survival rate of 99.5% from the large surveillance series indicates that this therapeutic option produces a result equivalent to that achieved with standard adjuvant retroperitoneal nodal irradiation and is a safe and effective alternative management, provided guidelines are followed.
  • A Risk-Adapted Strategy: Prospective study including 314 patients with stage I seminoma.
    Tumorsize <4 cm and without rete testis invasion (100 patients) - managed by surveillance
    “High-Risk” patients with larger tumorsand/or rete testis involvement (214 patients) received two courses of carboplatin.
  • Median follow-up of 34 months, relapse was observed in six patients on surveillance (6%) and in seven patients given carboplatin (3.3%).
    All relapsing patients were successfully managed by further chemotherapy, resulting in a 5-year survival rate of 100%.
  • It is clear that the survival of patients with stage I seminoma approaches 100% whatever treatment strategy is employed.
    The goal of management is to limit treatment morbidity without compromising chance of cure.
    For the compliant patient, surveillance is probably the option of choice.
  • Stage II :
    The recommended treatment depends on the bulk of retroperitoneal nodal disease.
    IIA / IIB - Adjuvant Radiation Therapy (Retroperitoneal involvement is <5cm)
    Stage IIC - Adjuvant Chemotherapy
    Recurrence after RT related to initial bulk of the disease.
    Radiotherapy for Residual disease after chemo not established
  • Stage IIA or IIB
    Radiotherapy of 25 to 35 Gy is the treatment of choice.
    Irradiation of the para-aortic and ipsilateral pelvic nodes: recurrence rate of <10% and a disease-specific survival rate of 97% to 100%.
  • The most common site of relapse following infradiaphragmaticRT is in the SCF or mediastinum.
    Single agent carboplatin appear inferior to that with radiotherapy.
  • Stage IIC
    Systemic chemotherapy – Choice of treatment
    Cisplatin-containing combination:
    Etoposide/Cisplatin [EP]
    Bleomycin/Etoposide/Cisplatin [BEP].
  • Radiotherapy has relapse rate of 30%.
    If the mass is centrally located and does not overlie most of one kidney or significantly overlap the liver, primary radiation therapy remains an option.
    Nodal disease >10 cm - the relapse rate is over 40% with RT, and these patients should be managed with systemic chemotherapy.
  • Stage III
    Stage III disease or those with relapse following radiotherapy:
    3 courses of BEP or 4 courses of EP
    Stage III classified into either an intermediate prognosis or good prognosis group by the EGCCCG Consensus Classification.
    The 5-year OS :
    91% for good prognosis
    79% for intermediate prognosis.
  • Despite initial favorable reports, single-agent carboplatin is not as effective as cisplatin-based combination treatment.
    The efficacy of carboplatin combinations (e.g., with ifosfamide or cyclophosphamide) has not been adequately tested.
  • Post Chemo in Stage II / III
    For patients with stage II or III disease treated with primary chemotherapy, residual masses are present at 1 month in up to 80% of patients.
    Management strategies:
    Consolidative radiotherapy,
    Surgical resection,
  • Post Chemo RT
    MRC Testicular Tumour Working Party conducted a retrospective review of patients with advanced seminoma managed by chemotherapy.
    58% had residual masses on completion of CT
    Approximately half of these patients underwent postCT radiotherapy
    Radiotherapy did not significantly influence the risk of progression, contributing an absolute increase in progression-free survival of only 2.3%.
  • Instead, the most important prognostic factors for progression were
    Presence of prechemotherapy visceral metastases
    Raised LDH,
    Persistent visceral metastases postchemotherapy.
  • Surgical Excision
    Memorial Sloan-Kettering Cancer Centre:
    A total of 55 patients with advanced seminoma underwent resection or biopsy of residual mass within 4 weeks of chemotherapy.
  • Of 27 with a mass >3 cm, eight (30%) had residual tumor.
    No viable tumor was found in any of the 28 patients with a residual mass <3 cm in maximal diameter.
    It is clear that observation alone is adequate for a residual mass <3 cm in size.
  • Two patterns of response to chemotherapy are evident on CT:
    Well defined mass with discrete, well-defined borders,
    Mass with indistinct borders merging into surrounding structures and resembling a fibrous plaque.
    The former are more amenable to surgical resection.
  • Positive histology can be found in 50%
    If the tumor is well defined on CT
    > 3 cm in greatest dimension,
    It is reasonable to resect these masses.
    If the mass is poorly defined, even if larger than 3 cm, the chance of finding positive histology is <10%.
    These should be observed.
  • PET scan has been shown to have a high predictive value in the evaluation of postchemotherapy residual disease and can be further used to guide management.
  • Intratubular Germ-Cell Neoplasia
    5% have ITGCN in the contralateral testis.
    50% will progress to invasive disease within 5 years.
    Surveillance is an option, but eventually almost all cases will progress to invasive disease.
    Cisplatin-based combination chemotherapy results only in temporary disappearance.
  • Radiotherapy is the treatment of choice for contralateral IGCN.
    16 to 20 Gy is capable of eradicating IGCN while preserving most of the Leydig cell function.
    Ablation of germ cells in the remaining testis will result.
  • Nonseminomatous Germ-Cell Tumors
    Stage I:
    50% at presentation.
    Options for management include:
    Retroperitoneal node dissection (RPLND)
    Adjuvant chemotherapy
    All lead to a survival rate of close to 100%.
    Adjuvant radiotherapy has no role.
  • Surveillance
    The relapse rate - 28% (range 13% to 37%)
    Disease specific survival rate is 98%.
    The median time to relapse is 6 months, with almost all relapses occurring within 2 years.
    50% of relapses occur in the retroperitoneum and 25% in the lungs.
  • Risk Factors for Relapse
    Elevated tumor markers in – 2/3 of relapse
    20% relapse rate with elevated markers only.
    Venous invasion,
    Presence of undifferentiated elements
    Absence of yolk sac elements
    T2 – T4 – 50% relapse
  • Surveillance Schedule
    A bilateral infrahilar RPLND includes:
    Common iliac lymph nodes bilaterally.
    Since the gonadal vessel itself or the adjacent tissue may harbor disease, the ipsilateral gonadal vein and surrounding fibroadipose tissue from its insertion to the internal ring must be completely excised to minimize the possibility of a late paracolic recurrence
  • Suprahilardissection is reserved today for residual hilar or suprahilar masses following chemotherapy for advanced-stage NSGCT
    The most consistent long-term morbidity bilateral RPLND has been retrograde ejaculation and subsequent infertility secondary to sympathetic nerve fiber damage.
    Two general approaches have been used to protect these structures: a modified template RPLND and “nerve-sparing” dissections
    Overall Survival of 99%.
    20% to 30% of patients will be found to have pathologic stage II disease.
    Pathologic stage I disease has a relapse rate of about 11%, almost exclusively at distant sites,
    Pathologic stage II disease has a subsequent relapse rate of 20% to 30%.
  • This relapse rate can virtually be eliminated with the use of adjuvant chemotherapy, typically two cycles of BEP or EP.
    Modified Nerve-Sparing RPLND, has greatly reduced operative morbidity and has reduced the frequency of retrograde ejaculation to 5%.
  • Adjuvant Chemotherapy
    Two cycles of BEP is an effective treatment strategy for patients with high-risk stage I disease.
    Reduced the relapse risk from an expected 50% to 2% in a MRC phase II trial.
    Stage IS isoften not limited to the retroperitoneum, - should receive initial systemic chemotherapy.
    RPLND is recommended if re-evaluation after chemotherapy demonstrates new disease.
  • Stage IIA/IIB
    RPLND or Primary Chemotherapy - Prefered
    Surveillance is also appropriate with nodes <2 cm in diameter and < 6 nodes, where the relapse risk is around 25%.
    Relapse can be managed with salvage chemotherapy.
  • RPLND has been the standard approach to Clinical stage IIA tumors, some IIB tumors, and normal serum levels of AFP and HCG
    For bulkier nodal disease, the risk of relapse is over 50% - chemotherapy is often administered
    Surveillance is still an option.
    Either approach results in a survival of 98%.
  • Chemotherapy
    Likelihood of Unresectabledisease or distant metastatic disease:
    Retroperitoneal suprahilar or retrocrural LN
    B/L retroperitoneal LN
    Back pain
    Contralateral LN
    Nodal disease greater than 3 cm & >6 nodes.
    Elevated AFP and/or HCG that persist after orchiectomy and are not declining at half-life
    Such cases - Initial chemotherapy is preferred.
  • Chemotherapy
    Typically three cycles of chemotherapy are used, resulting in a CR in 2/3, with a further third requiring a RPLND to remove a residual mass.
  • Survival is similar whichever strategy is chosen.
    Following a primary RPLND:
    1/3 relapse and require chemotherapy
    Following primary chemotherapy:
    1/3 have a residual mass and require surgery
  • Stage IIC or III
    Primary Chemotherapy –
    Good Prognosis - 3 cycles of BEP or 4 cycles of EP
    Intermediate or Poor – 4 cycles BEP / VIP or Trial.
    1/3 have a radiographically apparent residual mass or masses after chemotherapy – RPLND
    These should be excised:
    30% to 50% will be found to have necrosis,
    25% - Teratoma
    10% to 20% of undifferentiated carcinoma.
  • Necrosis or Teratoma - Low risk of recurrence after surgical excision
    Unnresectedteratoma may give rise to later relapse or progression.
    Patients with persistent carcinoma require additional 2 cycles of EP chemotherapy
  • RT
    Palliation or management of brain metastases.
    Newly diagnosed brain metastases, although rare, are still potentially curable. All require systemic chemotherapy.
    Resection should be considered of solitary metastases.
    Control of central nervous system disease is usually achieved
  • Relapse after CT and Refractory Disease
    Twenty percent to 30% of patients with advanced GCT relapse or fail to achieve a complete response to conventional cisplatin-based chemotherapy.
    Salvage Chemotherapy
    Conventional dose
    High dose
  • Prognostic Factors: Salvage Chemotherapy
    Testis or Retroperitoneal primary site
    Complete response to initial chemotherapy
    Dose-intensive / New Agent:
    Incomplete response to initial therapy
    Relapsing mediastinalNSGCT
  • High-dose, stem-cell supported, carboplatin-containing chemotherapy.
    Primary mediastinal GCT refractory to initial and salvage chemotherapy
    “absolute refractory” disease (rising markers or radiographic evidence of progressive disease within 4 weeks of cisplatintherapy)
    High HCG levels
  • Conventional-Dose Salvage Therapy
    Ifosfamideplus cisplatin, etoposide, and vinblastine (VeIP)
    25% of patients achieve a durable complete response.
    An improved CR reported when paclitaxel (250 mg/m2) was substituted for vinblastine.
  • High-Dose Therapy
    Carboplatin and Etoposidewith or without cyclophosphaor ifosfamide – 30 – 50% CR
    Paclitaxel has been incorporated into a four-drug regimen with three cycles of high-dose therapy - 56% CR.
  • High-dose chemotherapy has been studied as a treatment component for all patients who relapse following a complete response or fail to achieve complete remission to (B)EP.
    Current data suggest that two cycles of high-dose therapy are necessary to cure refractory GCT.
  • Surgery after Salvage Chemotherapy
    Viable tumor- 50%
    Teratoma - 30%
    Necrosis - 20%
    Additional standard-dose chemotherapy confers no survival benefit in patients with viable NSGCT in the resected specimen after salvage chemotherapy
  • Surgery should be avoided in patients in whom serum tumor marker concentrations remain elevated.
  • Chemotherapy
    Single Agent Carboplatin – AUC 7 IV on Day 1.
    Etoposide-100mg/m2 IV on Days 1-5
    Cisplatin 20 mg/m2 IV on Days 1-5
    Rpt every 21 days
    Etoposide 100 mg/m2IV on Days 1-5
    Cisplatin 20mg/m2 IV on Days 1-5
    Bleomycin 30 units IV wkly on D1,8 & 15
    Rpt every 21 Days
    Other Schedules are VIP, VAB-6, VeIP, TIP, Pacli+Gemcita.
  • Radiation Therapy
    Active Inflammatary Bowel Disease
    Previous Abdomino-Pelvic RT or bilateral RPLND – i.e ( Second Metachronous GCT)
    Horse-Shoe Shaped Kidney
  • Stage I (CTV):
    Left renal hilar nodes - For left-sided tumors.
    Ipsilateralexternal iliac and common iliac - If there is concern about aberrant drainage.
  • Stage II
    GTV- From Diagnostic Imaging
    CTV –
    As for Stage I
    Also includes the ipsilateral pelvic nodes.
  • Technique
    Position: Supine
    Portals: AP / PA
    6 -18 MV photon beams
    Borders: - “Dog Leg”
    Upper – T10-T11 Interspace (T9-T10)
    Lower – Superior Border of Obturator Foramen
    Lateral – Tips of the transverse process (Left renal hilum included in left sided disease)
    There is no difference in OS between Para-aortic and Dogleg Field In MRC trial. But slight difference in 3yr RFS (98% vs 100%)
  • Dog-Leg Field (Left Renal Hilum Included)
  • Reduced Field - Paraaortic
    Superior: Superior plate of T12
    Inferior : Inferior border of L5
    Laterally: Tips of the transverse processes,
    Expanded at the left renal hilum for left-sided tumors.
  • Para Aortic Field
  • Stage IIA disease, standard dog-leg fields are used to treat the para-aortic and ipsilateral pelvic nodes.
    Contralateral common iliac nodes may be included if there is concern about the risk of retrograde spread.
    For stage IIB disease (2 to 5 cm diameter), the field width should be appropriately widened to encompass the mass as visualized on CT with a margin of 2 cm
  • Dosage
    Stage I: 25 Gy in 20 fractions
    Stage IIA: 25 Gy in 20 fractions
    26 to 30 Gy at 2 Gy per fraction.
    Stage IIB : 35 Gy.
    The first 25 Gy is typically delivered to an initial volume, and a boost of 10 Gy in five fractions is given to a reduced field that encompasses the nodal mass with an adequate margin
  • Stage IIC: Same principles as stage IIB.
    The abdominal fields are larger to encompass the known volume of disease.
    The field size should be reduced as the tumor shrinks.
    Abdominal CT scan repeated after the first 3 weeks of radiation therapy may allow significant reduction of the treatment volume
  • Sequelae of RT
    Early Effects:
    Mild & Minimal
    Nausea, Vomitting and Diahrroea & transient decrease in blood counts.
    Late Effects:
    Infertility - Hormonal function and spermatogenesis may be compromised at dose levels as low as 0.5 Gy, and that cumulative doses above 2 Gy probably lead to permanent injury.
    GI Toxicity
    Second Neoplasm
  • Sequelae of CT
    Nausea and vomiting.
    Bleomycin-induced pulmonary fibrosis
    Cisplatin nephrotoxicity.
    Cumulative dose of cisplatin was predictive of excess leukemia risk, being 3.2 with the commonly administered dose.
    Etoposide exposure increases the risk of leukemia. Morphologically, these leukemias are usually monocytic or myelomonocytic.
  • Scrotal Shielding
    Scrotal Shield - ‘Clamshell’ Shield
    Reduce 1-2% of the prescribed dose
  • Follow Up – Seminoma
    After Dog Leg RT
    Every 3-4 mths for first yr
    Every 6 mths for second yr
    Annually thereafter
    After Para Aortic Only RT
    Pelvic CT Annually for first 3yrs in addition to above
  • Thank You
    When a man in Ancient Rome was required to give an oath, he would cup his testicles with his hand as he spoke. It's from this that we get the words testify, testimonial and testament.