Management of Non Seminomatous Germ cell tumors

of testis

ByDr Parneet Singh

Moderator- Dr Ritesh Sharma

Stage Wise Treatment

Treatment Modalities

• Surveillance

• Chemotherapy

• Surgery

• Radiotherapy for Brain mets

Surveillance Indications• Stage 1A

• Stage 1A after RPLND pN0

• Stage 1B for T2 only

• Stage 1B after RPLND pN0

• 1S post chemo complete response markers neg

• IIA post chemo mass <1cm with markers negSturgeon JF Eur Urol 2011

Zuniga BJU Int 2009

Surveillance• 25% to 30% of patients with normal serum tumor markers relapse

during surveillance

• 15% of T1 and 50% of patients with T2 to T4 tumors will relapse.

• <10% of relapses on surveillance for NSGCT occur more than 2 years after orchiectomy

• Presence of Vascular invasion or embroynal carcinoma or absence of yolk sac elements is associated with risk of occult nodal disease

• With presence of vascular inavasion relapse rates 50% and without it 15-20%

• Retroperitoneum is the site of relapse in 2/3rd of patients, the lungs or markers alone in approximately 1/3rd and then in other visceral sites. de Wit R J Clin Oncol 2006

Daugaard G APMIS 2003Read et al JCO 1992

• A study by Daugaard et al in APMIS 2003

• 1768 patients with range of f/u 19.5 -76 months

• Overall relapse rates 21.4% with 14 deaths

• Upto 95% who progressed did in 12 months

• 60% was in retroperitoneal LN

Prospective trials of Surveillance in Stage 1

Author No of Patients

Progression rate(%)

Death from disease

RP Progression rate(%)

Freedman et al

259 32 3 55

Jacobsen et al

83 28 nil 65

Peckhman et al

132 27 1 60

Read et al 396 25 5 61Sogani et al 102 25 3 72

Sharir et al 170 75 1 65

Gunderson Tepper 3rd edition

SURVEILLANCEBenefits Drawbacks

Excellent cancer cure rate Requires frequent follow-up CT scans, with associated long-term risks

No treatment-related toxicity Some patients may experience anxiety related to risk of recurrence

Excellent salvage rate Avoids overtreatment for the majority of patients

Chemo vs Surveillance• 2 cycles of BEP vs surveillance in stage I

• The 2-year recurrence-free survival was 98% in both arms

• Long-term toxicity was assessed by pre and post-treatment analysis of renal function, lung function, semen analysis, and audiometry.

• No major, clinically significant changes were observed.

• This demonstrates that the major toxic effects associated with BEP chemotherapy (renal,lung, hearing, fertility) were mild or absent following two cycles.

M cullen Annals of Oncology 2012

• CT is the recommended treatment in the Scottish Intercollegiate Guidelines Network guidelines 1998 (Scotland)

• The Clinical Oncology Information Network (UK) guidelines 2000 (England)

• The ESMO guidelines 2008 and the European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer 2008 (Europe)

• • The National Comprehensive Cancer Network

guidelines 2008 (USA)

• However, RPLND is still practised in some countries, and surveillance is favoured in others

Surgery• Orchiedectomy

• Retro Peritoneal Lymph node Dissection (RPLND)

• For Residual Retroperitoneal Mass

Radical Orchiectomy

• Radical orchiectomy is done for testicular tumor

• Done by inguinal incision to prevent alteration of the lymphatic drainage pattern of the testicle ( drainage to the retroperitoneal lymph nodes) by violating the scrotal wall (drainage to the superficial inguinal lymph nodes).

• Ligation of the vas deferens and testicular vessels at the internal inguinal ring, so no further need of inguinal canal exploration if RPLND to be done(therapy or staging).

Indications for RPLND• Stage 1A

• Stage 1B

• IIA,IIB upfront, marker negative

• IIA,IIB post chemo marker negative

• Post Chemo metastatic NSGCT with residual retroperitoneal mass with marker neg

Stephenson AJ JCO 2005

RPLND• RPLND done for diagnostic and therapeutic intent

• RPLND can be done either by thoracoabdominal or a transabdominal approach.

• Bilateral infrahilar RPLND has replaced the suprahilar dissection and is the standard

• Suprahilar dissection is done for residual hilar or suprahilar masses following chemotherapy for advanced-stage NSGCT

• A bilateral infrahilar RPLND includes the precaval, retrocaval, paracaval, interaortocaval, retroaortic, preaortic, para-aortic, and common iliac lymph nodes bilaterally.

Chang SS J Urol 2002

• Ipsilateral gonadal vein and surrounding fibro adipose tissue till the internal ring must be completely excised to minimize the possibility of a late paracolic recurrence

• Modified RPLND templates maximize rates of ejaculation by limiting dissection areas of reduced risk of metastatic spread.

• This approach minimizes contralateral dissection, thereby reducing trauma to the hypogastric plexus and contralateral postganglionic sympathetic fibers.

• Preservation of antegrade ejaculation with this approach ranges from 50% to 80%.

Chang J Ural 2002

• Nerve-sparing techniques to preserve ejaculation.

• For right-sided tumors, the interaortocaval nodes and paracaval nodes are removed, with preservation of the left sympathetic chain

• For left-sided tumors, the para-aortic and interaortocaval nodes are removed and the right autonomic chain is preserved.

• If significant lymphadenopathy is revealed at surgery, a more extensive surgical resection is performed.

• JCO 2007

• Chemotherapy is preferred for

Elevated post-orchiectomy serum tumor markers Retroperitoneal LN greater than 2 cm Involving multiple nodes

• RPLND is preferred modality for

Normal postorchiectomy serum tumor markers Solitary retroperitoneal mass less than 2cmin size

Residual Retroperitoneal Mass• Post chemo residual masses with normal serum

markers

• Should be done 4 to 6 weeks after chemo

• On histology 50% show necrosis

• 35% are mature teratoma

• 15 % have malignant disease

Krege et al 2008 Eur Ural

Complications of surgery• Minor complications include Lymphocele(30-40%) Atlectasis(25-30%) Wound infection(10%) Prolonged ileus.

• Long-term morbidity with a standard bilateral RPLND has been retrograde ejaculation(50-60%) and subsequent infertility secondary to sympathetic nerve fiber damage.

• Mortality rate of less than 1%

• Major complications such as hemorrhage, ureteral injury, bowel obstruction, pulmonary embolus, and wound dehiscence are rare.

Shienfeld urology 2007

Chemotherapy Indications• IA ,IB

• IIA,IIB

• III

• Stage I,II post RPLND with pN1-pN3

• All stages marker positive

• Relapse

• Metastatic disease NCCN 2015

2nd Line Therapy for Metastatic Disease• Patients not having complete response or recurrence• Second line chemo can be conventional dose and high

dose Ct followed by ASCT• After 2nd line CT if no complete response then disease is

usually incurable• Except if there is solitary site of metastasis which can

be surgically removed Favorable factors Unfavorable FactorsTesticular primary site Incomplete responsePrior complete response High level of tumor

markersLow serum tumor markers

Extra testicular tumor

Low volume diseaseLorch JCO 2010

Palliative Therapy

• All patients with persistent or recurrent disease should be given Pallitative CT

• Chemo can be

Gem+Carbo Pacli+Carbo, Gem+ Pacli +/- Carbo Oral Etoposide daily

Mulherin JCO 2011Pectasides ANN oncol 2004

Chemotherapy Complications• Nausea ,vomiting

• Alopecia

• Myelosupression

• Pulmonary fibrosis (Bleomycin Toxicity)- fatal in 1 to 2% cases.

• Secondary leukemia (Etopside) :relative risk of leukaemia induced by standard doses of etoposide is 2%

• Infertility is seen in around 60-70% with bleomycin

Kollmannsberger C et al.J Cancer Res Clin Oncol1998

Cisplatin : • Nausea, vomiting

• Hearing impairment(22%)

• Raynaud phenomenon (39%)

• Ischemic heart disease

• Renal insufficiency(15%)

• Sensory Neuropathy (10–30% )

• BEP causes immediate azoospermia, but, with time, more than half of patients may recover normal or near-normal spermatogenesis.

• Paternity rate following 2 to 4 cycles of BEP is 70% to 85%.

.Nuver JCO 2005

Brain Metastasis

• Prognosis of brain mets poor

• Primary CT with CDDP in patients with brain mets with radiotherapy

• If feasible surgical resection of mets should be done

5 year Survival• Stage I nonseminoma has a 5-year OS of approximately 99%.

Surveillance has 30% relapse rate RPLND has a10% relapse rate

• Stage II nonseminoma, the 5-year OS is around 98%.• For stage IIA disease Chemotherapy (<5% relapse rate) RPLND plus chemotherapy (<5% relapse rate) is used. • Stage IIB or IIC disease, chemotherapy is given, with a 5%

relapse rate.

• Stage III disease is managed with chemotherapy(20-25%)

Stephenson AJ BJU 2009

• The good-prognosis group (60% of cases) has an approximately 86% 5 year OS.

• The intermediate prognosis group (26% of cases) has an approximately 80% 5 year OS.

• In the poor-prognosis group (14% of cases), the 5 year OS is around 50

Huyghe Cancer 2004