Disclosures None 1 Objectives Identify options after 1 st line - - PDF document

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Disclosures None 1 Objectives Identify options after 1 st line - - PDF document

Sep 04, 2023 193 likes •324 views

Winship Cancer Institute of Emory University Standard Dose Chemotherapy for Patients Failing First Line Chemotherapy in Metastatic Germ Cell Tumors Bradley Carthon, MD, PhD Assistant Professor, Genitourinary Medical Oncology Winship Cancer

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1 Winship Cancer Institute of Emory University

Standard Dose Chemotherapy for Patients Failing First‐ Line Chemotherapy in Metastatic Germ Cell Tumors Bradley Carthon, MD, PhD Assistant Professor, Genitourinary Medical Oncology Winship Cancer Institute, Emory University Atlanta, GA 30322

Disclosures

  • None
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Objectives

  • Identify options after 1st line chemotherapy in

advanced germ cell cancer

  • Review data regarding high dose

chemotherapy and conventional dosed chemotherapy as salvage therapy in advanced germ cell tumors

Germ Cell Tumors (GCT) Epidemiology

 8820 new cases/year (US, 2014)  380 deaths/year (US)  15‐34 year age group Most common tumor 10% of all cancer deaths  Caucasians 5 : 1 African American  Rising incidence over past 4 decades  Cure rates are increasing over last 2 decades

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Management of Advanced NSGCT

  • Includes patients requiring full doses of systemic chemotherapy: >Stage II or S1
  • Stratified by IGCCCG risk categories at presentation
  • Good Risk: EP x 4 or BEP x 3
  • Intermediate Poor Risk: BEP x 4 (VIP)
  • Strong role for surgical resection of any residual mass after chemotherapy

Half Lives HCG = 1-3 days AFP = 5-7 days LDH = 1 day

Curr Oncol Rep (2013) 15:232‐238; IGCCC 1997, JCO

NSGCT International Germ Cell Consensus Classification

16

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Salvage Options for Relapsed Testicular Cell Carcinoma

  • 20 to 30% of advanced GCT patients require salvage therapy
  • 40 to 50% of poor risk IGCCCG patients
  • Potential Cure Exists
  • Options, per NCCN Guidelines Include:
  • 1. Conventional Dose Chemotherapy +/‐ Surgery: Testicular

primary, Prior Complete Response, Low tumor markers, Low Disease burden

  • 2. High Dose Chemotherapy + Autologous Stem Cell Transplant

+/‐ Surgery: Incomplete response, High Tumor Markers, Extratesticular Primary

  • 3. Clinical Trials

Should ALL patients receive HDCT and ASCT?

Variance in Practices Around the World

Presented By Darren Feldman at 2014 ASCO Annual Meeting

CDCT = conventional dose chemotherapy

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Prognostic Models for High Dose Chemotherapy in NSGCT

Beyer, J. et al. J Clin Oncol. 1996; 14:2638‐45. Vaena et al. J Clin Oncol. 2004;21:4100‐4. Nieto, Y. Curr Oncol Rep (2013) 15:232‐238.

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Presented By Darren Feldman at 2014 ASCO Annual Meeting

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Slide 23

Presented By Darren Feldman at 2014 ASCO Annual Meeting

Prognostic Factors From High Dose Chemotherapy Regimen Trials

TI‐ CE Regimen Indiana University Regimen

  • 184 patents that progressed on cisplatin
  • Carboplatin 700mg/m2 + 750mg/m2 Etoposide

x 3 days + ASCT

  • 38.6% pts were initial Low risk, 21%

intermediate, 41% high risk

  • 8.2% of patients had Beyer Score 3‐4
  • No Mediastinal primaries in this study
  • 107 patients that had progressed on 1st line

therapy.

  • Extragonadal, incomplete response or relapse
  • n ifosfamide based salvage. Paclitaxel

200mg/m2 + Ifosfamide 2000mg/m2 for mobilization + Carboplatin AUC 8 + 400mg/m2 Etoposide x 3 days + ASCT x 3

  • 33% were extragonadal and 25% were on 3rd

line of therapy or higher

  • 2 or more prior lines of therapy, site of primary, Tumor burden, ICCCCG high risk, Platinum refractory

Feldman D R et al. JCO 2010;28:1706-1713. Einhorn LH et al. N Engl J Med 2007;357:340-348.

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CDCT for Initial Salvage: VIP/VeIP

Adapted from: Feldman, D., 2014 ASCO Annual Meeting

Standard Dose Chemotherapy for Initial Salvage: VIP or VeIP

Pizarro ‐Poor /Int Risk Included 28/36. VIP not effective in those with primary refractory, progressors or mediastinal primary. Farhat – Poor risk included. 17% non‐testicular primary. 39% of patients with advanced dx. McCaffrey –Poor risk included, extragonadal primaries. Loehrer‐Poor risk included. 32/135 extragonadal NSGCT. Excluded primary progressors. Kondagunta G V et al. JCO 2005; 23: 6549-6555

TIP Chemotherapy Salvage at MSKCC

Patients: Gonadal Primary AND achieved a CR or PR lasting > 6 months with 1st line therapy N = 46. Median F/U = 69 Months Outcomes Overall Survival Outcome N %

CR 32 70 Chemotherapy 29 63 Chemo + Surgery 3 7 IR (PR‐marker neg) 14(2) 30(4) Relapsed 3 7 Sustained NED 29 63 2 yr OS 36 78

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8 CDCT vs. HDCT Overall Survival Rates In IPFSG Database Retrospective Review

Lorch A et al. JCO 2011;29:2178-2184

Very Low Low ntermediate High Very High

All Pts

(N=1594)

N 5 YR OS CDCT 773 41% HR = 0.65 p< 0.001 HDCT 821 53%

CDCT vs. HDCT Overall Survival Rates by Retrospective Review of UK and German Databases

  • Pts between 1981 and 95.
  • N =193.
  • UK MRC and German Center

patients

  • Matched base on: primary

tumor location, response, duration, and tumor markers. Multivariate analysis.

  • 5/5 matches for 38 pairs. 4/5

matches for 17 pairs.

  • Suggest OS improvement of 9‐

11% with HDCT Beyer et. Al. Ann Oncol (2002) 13 (4): 599‐605. 4 or 5 factor matched pairs 4 factor matched pairs

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9 CDCT vs. HDCT OS Retrospective Review of German GTCSCG Database

Berger et al. J Cancer Res Clin Oncol (2014) 140: 1211‐1220

  • N= 143 Patients
  • 73% Gonadal Primary
  • 31% with LBB mets
  • 59% had CR response to

initial therapy

  • 34% 48/143 had CDCT

Salvage (>3)

  • 66% 95/143 had HDCX

Salvage (3)

No OS Benefit: IT‐94 Randomized Control Trial of CDCT vs. HDCT for Salvage Treament in Advanced GCT

Pico J et al. Ann Oncol 2005;16:1152-1159

  • The sole RCT completed
  • No Difference in OS
  • Between 2/94 and 09/01
  • 280 patients from 43

institutions and 11 countries

  • Randomized to VeIP x 4
  • r VeIP x 3 + High Dose

Chemo

  • Median F/U 45 Months
  • 7% treatment related

mortality in HDCX arm

  • Only includes 1 dose

HDCX P=0.16 No Difference in OS

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10 Points to Consider from These HDCT Trials in 1st Line Setting

  • Only retrospective reviews and case matches with OS benefit due

to HDCT + ASCT

  • Subject to bias, small numbers, and patient heterogeneity
  • Newer retrospective analysis shows no OS benefit with high dose
  • chemotherapy. Improved care?
  • Newer studies with TIP conventionally dosed chemotherapy show

2 year OS up to 78%

  • Randomized Controlled trial on of CDCT vs. HDCT and Transplant

showed no overall survival benefit

  • NO RANDOMIZED CONTROLLED DATA to suggest benefits for all

patients across the board.

  • Heterogeneity exists & randomized controlled trial Needed

Considerations with High Dose Chemotherapy with ASCT for Advanced Germ Cell Tumors

  • Potential for Cure, especially in poor risk patients
  • Notable Toxicities and Adverse Events
  • Highly Specialized and expensive
  • 1‐7% Mortality in Past Studies
  • Not Universally Available to All Patients
  • Notable retrospective data, but limited prospective data
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Alliance 031102 / EORTC 1407 (TIGER)

Presented By Darren Feldman at 2014 ASCO Annual Meeting

Conclusions

  • Various patterns of practice exist for patients failing 1st line

chemotherapy in advanced germ cell

  • Options include conventional dose chemotherapy and high dose

chemotherapy with ASCT with varying practice patterns

  • Prognostic models have been validated and help risk stratify
  • Data in small heterogenous populations, vary, but does suggest

benefit, particularly in some POOR risk patients

  • Increased effectiveness with conventional dosed chemotherapy
  • Randomized Clinical trial of HDCT + ASCT vs. CDCT planned
  • Currently, high dose chemotherapy for ALL patients remains

controversial and may be an overtreatment for some