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Induction Chemotherapy for Head and Neck Squamous Cell Carcinomas
William N. William Jr.
Assistant ProfessorChief, Head and Neck Section
Department of Thoracic / Head and Neck Medical OncologyM. D. Anderson Cancer Center
Outline
• Introduction
• Incorporating taxanes into induction PF
• Intensified chemoXRT +/- induction chemo
Outline
• Introduction
• Incorporating taxanes into induction PF
• Intensified chemoXRT +/- induction chemo
Chemotherapy Meta-Analysis (MACH-NC) Randomized trials 1965-2000
Timing No. trials No. pts. HR (95% CI) P-value 5 yr benefit
Induction 31 5311 0.96 (0.90 - 1.02) NS 2.4%
Adjuvant 12 2567 1.06 (0.95 - 1.18) NS -1.0%
Concurrent 50 9615 0.81 (0.78 - 0.86) <0.0001 6.5%
Pignon et al. Lancet 355:949-955, 2000Pignon et al. Radiotherapy and Oncology 92:4-14, 2009
Survival:
Chemotherapy Meta-Analysis (MACH-NC) Randomized trials 1965-2000
Pignon et al. Lancet 355:949-955, 2000Pignon et al. Radiotherapy and Oncology 92:4-14, 2009
Survival:Survival:
P=0.43
P=0.001
P<0.0001
P=0.04
Induction Chemotherapy: Phase III Randomized Trials (1990 – 2000)
PatientsChemotherapy Surv. Benefit
Martin 1990 75 FP NoJortay 1990 187 VBM NoMazeron 1992 131 FPBM NoJaulerry 1992 100 PBVdMi NoJaulerry 1992 108 FPVd NoTejedor 1992 42 CpFt NoDepondt 1993 324 FCp NoDiBlasio 1994 69 FP Advantage standard RxHasegawa 1994 50 FP NoPaccagnella 1994 237 FP No*Dalley 1995 280 FP NoVolling 1996 97 FCp NoDomenge 2000 318 FP Yes
*Survival benefit in unresectable patients only
Chemotherapy Meta-Analysis (MACH-NC) Randomized trials 1965-2000
Timing No. trials No. pts. HR (95% CI) P-value 5 yr benefit
Induction 31 5311 0.96 (0.90 - 1.02) NS 2.4%
PF subset 15 2487 0.90 (0.82 – 0.99)
Adjuvant 12 2567 1.06 (0.95 - 1.18) NS -1.0%
Concurrent 50 9615 0.81 (0.78 - 0.86) <0.0001 6.5%
Pignon et al. Lancet 355:949-955, 2000Pignon et al. Radiotherapy and Oncology 92:4-14, 2009
Survival:
Outline
• Introduction
• Incorporating taxanes into induction PF
• Intensified chemoXRT +/- induction chemo
• Stage of III or IV HNSCC without metastases
• Tumors had to be considered unresectable by
a multidisciplinary team
• PS 0-1
Induction PF versus PF + Docetaxel (TPF)TAX 323: Eligibility Criteria
Vermorken JB, et al. N Engl J Med. 2007;357(17)1695-1704.
*Conventional fractionation or accelerated/hyperfractionated.
Vermorken JB, et al. N Engl J Med. 2007;357(17)1695-1704.
RANDOMIZE
Radiation*
Follow-up12 weeks
after RT andthereafter
TPF Induction (n=177)
4 cycles, q 3 wk
Docetaxel75 mg/m² day 1
cisplatin75 mg/m²
day 1
fluorouracil750 mg/m²/day
days 1–5++
PF Induction (n=181)
4 cycles, q 3 wk
cisplatin100 mg/m²
day 1
fluorouracil1000 mg/m²/day
days 1–5+
12 weeks 7 weeks
Induction PF versus PF + Docetaxel (TPF)TAX 323: Trial Design
Primary endpoint: progression-free survival
Vermorken JB, et al. N Engl J Med. 2007;357(17)1695-1704.
Induction PF versus PF + Docetaxel (TPF)TAX 323: PFS
PF TPF
Median PFS 8.2 months 11 months
3-year PFS 14% 17%
HR 0.72 (95% CI 0.57-0.91), p=0.007
Vermorken JB, et al. N Engl J Med. 2007;357(17)1695-1704.
Induction PF versus PF + Docetaxel (TPF)TAX 323: OS
PF TPF
Median OS 14.5 months 18.8 months
3-year OS 26% 37%
HR 0.73 (95% CI 0.56-0.94), p=0.02
• Stage III, IVA, IVB HNSCC unresectable or potentially resectable
–Low surgical curability (advanced T or N)
–Goal of organ preservation
• PS 0-1
Induction PF versus PF + Docetaxel (TPF)TAX 324: Eligibility Criteria
Posner MR, et al. N Engl J Med. 2007;357(17):1705-1715.
Posner MR, et al. N Engl J Med. 2007;357(17):1705-1715.
RANDOMIZE
TPF Induction (n=255)
3 cycles, q 3 wk
Docetaxel75 mg/m² day 1
cisplatin100 mg/m²
day 1
fluorouracil1000 mg/m²/day
days 1–4++
PF Induction (n=246)
3 cycles, q 3 wk
cisplatin100 mg/m²
day 1
fluorouracil1000 mg/m²/day
days 1–5+
9 weeks
ConcurrentCRT
carboplatin(AUC 1.5) weekly;7 doses maximum
+Radiation
7 weeks
Induction PF versus PF + Docetaxel (TPF)TAX 324: Trial Design
Primary endpoint: overall survival
Induction PF versus PF + Docetaxel (TPF)TAX 324: PFS
PF TPF
Median PFS 13 months 36 months
HR 0.71 (95% CI 0.56-0.90), p=0.004
Posner MR, et al. N Engl J Med. 2007;357(17):1705-1715.
Induction PF versus PF + Docetaxel (TPF)TAX 324: OS
PF TPF
Median OS 30 months 71 months
3-year OS 48% 62%
HR 0.70 (95% CI 0.54-0.90), p=0.006
Posner MR, et al. N Engl J Med. 2007;357(17):1705-1715.
Induction PF versus PF + Docetaxel (TPF)TAX 324: Long-term OS
PF TPF
Median OS 34.8 months 70.6 months
5-year OS 42% 52%
HR 0.74 (95% CI 0.58-0.94), p=0.014
Lorch JH, et al. Lancet Oncol. 2011 Feb;12(2):153-9
TPF PF P
TAX 323 81 to 85% of the first relapses were locoregional
TAX 324 30% 38% 0.04
TPF PF P
TAX 323 68% 54% 0.006
TAX 324 72% 64% 0.07
TPF PF P
TAX 323 13% 10% N/A
TAX 324 5% 9% 0.14
Locoregional Failure
Distant Metastases
Response Rates
Induction PF versus PF + Docetaxel (TPF)TAX 323 and 324: Patterns of Failure
• Response rates to induction chemotherapy are higher with TPF compared to PF
• Induction chemotherapy with TPF improves survival compared to PF, primarily due to increased locoregional control
• Rate of distant failure is low with both TPF and PF• It is unknown whether induction chemotherapy is
superior to upfront chemoXRT• It is unknown whether the improved survival with TPF
would be observed in the setting of definitive treatment with concurrent cisplatin / XRT
TAX 323 and TAX 324: Summary
Outline
• Introduction
• Incorporating taxanes into induction PF
• Intensified chemoXRT +/- induction chemo
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GSTCC Trial – 2x2 Factorial Design Induction vs. Concurrent / Cetuximab vs. cisplatin and 5-FU
Ghi et al. ASCO 2014
Patients’ Characteristics
*HPV analysis in progress
Ghi et al. ASCO 2014
Patients’ Characteristics
Ghi et al. ASCO 2014
Compliance with Concomitant Treatments
TPF + concomitant
n=185
Concomitant
n= 199p value
PF 2 cy/cetuximab 7 wks - no modifications
86% 56%
88%59% 0.772
RT completion - no modifications
93%61.5%
93%64.5%
0.820
Median RT dose, Gy (range)
70 (8-73) 70 (18-70) 0.199
Median RT duration, weeks (range)
7.3 (1-13) 7.4 (3-11) 0.674
Pts with RT interruption > 3 consecutive days (%)
51 (27.5%) 59 (30%) 0.607
Death from any cause within 30 days after treatments
6 (3%) 7 (3.5.%) 0.772
Ghi et al. ASCO 2014
Overall Survival
median OS mo: 53.7 vs 30.3
HR: 0.72; 95% CI 0.55- 0.96; p=0.025
57.6
45.7
Presented by: MG Ghi, MD
no ICIC
Ghi et al. ASCO 2014
OS subgroup analysis (unplanned)Cox model
- 415 patients- 4 arms- 6 possible comparison- unplanned- hypothesis generating- random effect?
Presented by: MG Ghi, MDGhi et al. ASCO 2014
Overall Survival According to Primary Site
Non-oropharynx Oropharynx*
*HPV analysis in progress
HR: 0.82; 95%CI 0.55-1.21
median OS mo: 53.7 vs 44.6
63.5
52.8
Presented by: MG Ghi, MD
no ICIC
HR: 0.65; 95%CI 0.43-0.97
median OS mo: 33.6 vs 18.7
48.7
37
no ICIC
Ghi et al. ASCO 2014
• DECIDE and PARADIGM were underpowered studies that did not demonstrate an improvement in survival of adding induction chemo prior to chemoXRT
• Induction chemo reduced the rate of distant mets in DECIDE
• GSTCC was the first TPF induction vs. chemo / XRT trial to show a benefit in survival
• Largest (and more adequately powered) study• Differences in patient population, prognosis, and possibly HPV
frequency compared to DECIDE• Inclusion of oral cavity cancers, frequent XRT interruptions, and 2x2
factorial design limit broad applicability of the findings
Induction Chemo Followed by ChemoXRT
• Induction TPF associated with high response rates
• Induction TPF reduces the risk of locoregional recurrence and distant metastases when given prior to XRT or carbo/XRT compred to induction PF
• Induction TPF improves survival compared to induction PF, in the setting of less intense local therapy
• ChemoXRT with cisplain after induction TPF is feasible, but patient selection is key
• DECIDE and PARADIGM investigated the role of induction TPF in the context of “intensified” chemoXRT
• Both studies were underpowered and did not take into account superior prognosis of HPV-positive tumors
• Suggestion of a reduction in distant metastases, at least in DECIDE
• GSTCC demonstrated an OS improvement for induction TPF followed by concurrent systemic therapy compared to systemic therapy upfront in a higher risk patient population
• Better patient selection will be extremely important for successful development of induction chemotherapy
Take Home Messages