Management of recurrent and refractory germ cell tumors

• Good risk GCTs achieve a very good long term cure approaching 95%

• Poor-risk GCTs require four cycles of BEP that attains an approximately 45% long-term disease-free survival

• A significant proportion are either refractory to the platinum first line chemo regimens,,or the relapse early

Standard guidelines for advanced disease

Management for residual disease

What does the NCCN say?

Therapy for early relapse and refractory disease

Salvage regimens…

VeIP/VIP

Results..

• N : 135• 49.6 % pts achieved dis. free status after

chemotherapy ( with or without surgery for residual)

• 32% are alive• 23.7% are continually free of disease• All pts had a minimal f/u of 6 yrs from entry

into study

Variable No of pts Percentage %Assessable 56 n/aResponse

CR 20 36IR 36 64

Status..Alive disease free 19 34Alive with disease 4 7

Dead 33 59Alive, continuously

disease free13 23

• N : 189 ( 1985 to 2012)• CR: 18.5%• Marker normalization: 35.4%• 2yr PFS: 34.3%• 5yr OS: 42.1%

Contribution of gemcitabine…

Prognostic factors with salvage chemo

Outcomes with second-line salvage therapy for recurrent germ cell tumors.

Sonpavde G et al. The Oncologist 2007;12:51-61

©2007 by AlphaMed Press

Role of HDCT and auto BMT?

Indiana university experience..

• Pts included:– Those , who received high dose chemotherpay as

salvage and has not progressed within 4 weeks after the last dose

• Stem cells were harvested with GCSF stimulation• High dose chemo was given with

– Carboplatin 700mg/m2– Etoposide 750mg/m2– On days -5, -4 and -3 of stem cell infusion

German data..

• N : 74pts• ORR : 63% with CR in 31%• EFS of sensitive disease at 2 yrs: 50%• Only one pt of 23 who had refractory disease

had 7mo event free survival• OS at 2 yrs: 44%

Other European data..

• N: 150• Median follow up : 55months• EFS: 29%• OS: 29%

• N: 80• 3 # TIP followed by HDCT• 70% responded to TIP• 66% responded to HDCT• 3 yr OS: 30%• 3 yr EFS: 25%

Italian experience.

• N : 84• Median follow up 46months• DFS rates:

– Good risk: 69%– Int. risk: 13%– Poor risk: 0%

High dose chemo: blessing or a curse??

Design..

• 280 pts

• Pts refractory to platinum based chemo were excluded

four cycles of cisplatin, ifosfamide

and etoposide (or vinblastine)

three such cycles followed by transplant

Roles of surgery??

• N: 125 pts who underwent postchemotherapeutic resention

• Mean f/u: 120monthns• 57% long term survivors who had raised TM• Conslusion: salvage surgery results in long

term survival of more than 50%

• N : 16pts• Six patients (37%) are alive and free of disease

at a mean of seventy-four months following surgery (range 20 to 145 months).

• Five had RP disease only. • Ten patients died of disease at a mean of eight

months postoperatively (range 5 to 21 months).

• N: 114• 5 yr OS: 53.9%• Sixty-one patients (53.5%) are alive with a medium

follow-up of 72 months• Retroperitoneal pathology revealed

– germ cell cancer in 53.5% of patients, – teratoma in 34.2% of patients, and – fibrosis in 12.2% of patients, with – 5-year survival rates of 31.4%, 77.5%, and 85.7%,

respectively (P < .0001).

Surgery after HDCT and auto BMT

• Complete resection in 93% pts• Pts with viable tumor had poor survival

comapred to teratomas or fibrosis

Therapy of late relapses

• Defn: relapses occurring after 2 yrs and in the absence of a second primary tumor

• Typically chemo refractory• Different disease biology

• N: 83• Indiana university• Available specimens were

investigated for expression of the transcription regulator FoxD3 and apurinic/apyrimidinic endonuclease and the presence of chromosome 12 abnormalities.

Results…

• Forty-three of 49 patients who underwent surgery were rendered disease free (NED), and 20 (46.5%) remain continuously NED

• Thirty-two patients received chemotherapy, but only six (18.8%) obtained a complete remission.

• Eighteen of these 32 patients were successfully rendered NED by postchemotherapy surgery, and 12 remain continuously NED.

Overall..

• 69 of the 81 treated patients (85.2%) ultimately achieved an NED state, and – 38 (46.9%) remain continuously NED with median

follow-up from LR therapy of 24.5 months (range, 1 to 83 months),

– whereas nine other patients are currently NED after therapy for subsequent relapses

– Conclusion on moleular markers could not be made i/v/o low no. of samples tested

• Follow up of 530pts

• 25 cases of late relapse identified

• Risk was lower with good risk pts

Characteristics of relapse..

• Median survival 23.9mo• Median follow up 50.3months• Only 9 survivors• CRs were observed with only TIP regimen

To summarize..

• Refractory disease and early relapse to be managed in same lines with salvage chemo +/- surgery

• HDCT with auto BMT also has shown promising results

• Later relapse:– Poor prognosis– Surgical resection whenever feasible– Chemo has poor outcomes