INDUCTION CHEMOTHERAPY WITH TPF IN HEAD & NECK CANCERS

INDUCTION CHEMOTHERAPY IN HEAD
& NECK CANCER
• Induction chemotherapy prior to RT may reduce tumor
volume and improve function prior to concurrent
chemoradiotherapy, thereby permitting more effective
and less toxic local therapy.
• Induction chemotherapy could treat subclinical distant
metastatic disease without delay
• Induction chemotherapy could improve local regional
control and organ preservation
• Induction chemotherapy can provide prognostic
information

FUNCTIONAL ORGAN PRESERVATION
APPROACH
The feasibility of functional organ preservation using induction
chemotherapy prior to definitive RT was established by the
Department of Veterans Affairs (VA) Laryngeal Cancer Study Group
larynx trial: After a median follow-up of 33 months, the estimated
2-year survival was 68 percent (95 percent confidence interval, 60
to 76 percent)

European cooperative group trial (EORTC 24891) The 10-year
progression-free survival probabilities for the chemotherapy plus
definitive RT and for the surgery arms were 11 and 9
percent, respectively
RTOG 91-11 : Laryngectomy free survival, Locoregional control &
Distant controls were significantly improved in both induction &
concurrent chemotherapy arm compared to control.
*all trials were used PF as induction chemotherapy regimen

MACH-NC trial
The Meta-Analysis of Chemotherapy on Head and Neck
Cancer (MACH-NC), which was updated in
2009, pooled individual patient data from 93 trials and
16,485 patients with resectable or unresectable
disease. In all trials, patients were randomly assigned
• to definitive locoregional therapy alone
(surgery and/or RT) or
• definitive locoregional therapy in combination with
chemotherapy (induction, concurrent, or adjuvant).
The trials included patients with oral
cavity, oropharyngeal, hypopharyngeal and laryngeal
cancers

MACH NC RESULTS
Concurrent chemotherapy – Concurrent chemotherapy was assessed in 50 trials,9605
patients. Mean follow-up was 5.6 years. Concurrent chemotherapy significantly
decreased the risk of death compared with definitive local therapy alone (HR
0.81, 95% CI 0.78-0.86);
Induction chemotherapy – In 31 trials with 5311 patients, there was no statistically
significant effect on overall survival from induction chemotherapy compared with
surgery and/or RT alone (HR 0.96, 95% CI 0.90-1.02). When results were analyzed
based upon the induction chemotherapy regimen, overall survival with cisplatin
plus 5-fluorouracil was significantly better than with surgery and/or RT alone (HR
0.90, 95% CI 0.82-0.99)
Concurrent chemoradiotherapy versus induction chemotherapy – Only six
trials, involving 861 patients, Analysis of these trials did not demonstrate a
statistically significant improvement in overall survival with concurrent therapy
compared with induction therapy (HR 0.90, p = 0.15). Secondary analyses
suggested that concurrent chemoradiotherapy was more effective at preventing
locoregional failure, while induction while induction chemotherapy provided a
relatively more pronounced effect on distant metastases
Adjuvant chemotherapy –there was no improvement in overall survival compared with
definitive local therapy alone (HR 1.06, 95% CI 0.95-1.16).

INTRODUCTION OF TAXANES TO
INDUCTION REGIME
Early clinical trials found that cisplatin and 5fluorouracil (PF, cisplatin, 100 mg/m2, and 5fluorouracil, 1000 mg/m2/day continuous 24hour infusion for five days) given every three
weeks as induction chemotherapy induced
higher rates of complete response.

TPF VS PF
Phase I and II studies of induction combination
chemotherapy with docetaxel plus cisplatin and
5-fluorouracil (TPF) in patients with locally
advanced SCCHN resulted in response rates
between 75% and 100%, excellent survival, and
high pathologic complete response rates at the
primary sites.
3 LARGE PHASE III STUDIES
• TAX324
• TAX323
• GORTEC

TAX324
Tax324
501 patients were randomly assigned to induction
with docetaxel , cisplatin, plus 5-fluorouracil (TPF) or
cisplatin plus 5-fluorouracil (PF).

Both induction regimens were given every three weeks
for three cycles. This was followed by concurrent
chemoradiotherapy using weekly carboplatin ( [AUC] of
1.5)

TAX 324 RESULTS
3YR SURVIVAL 62 VS 48% (p .01)
LOCOREGIONAL FAILURE 32 VS 38% (p .04)
DISTANT METS 5 VS 9%(p.14)
Oral cavity cancer (HR, .70, P = .07)
the best site for survival
hypopharynx (HR, .67, P = .18) and
larynx (HR, .58, P = .07).

TAX 323
N Engl J Med 2007; 357:1695-1704October 25, 2007DOI:
10.1056/NEJMoa071028

The EORTC 24971/TAX 323 trial randomly assigned 358
patients of unresectable stage III/IV to four cycles of a
slightly different TPF induction regimen or the same PF
regimen used in the TAX 324 trial.
With median follow up of 32 months,

PFS: 11 vs 8.2 months(HR, .72; P = .007)
Overall survival:18.8 vs 14.5 months(HR.73;P.02)
TPF therapy also resulted in an improved
Response rate over PF, 59% versus 72% (P = .006)

GORTEC 2000-01
ORGAN PRESERVATION

With a median follow-up of 35 months 220
patients, the 3-year actuarial
Larynx preservation rate was better in the TPF
arm compared to the PF arm, 73% versus
63%, (P = .036).
The complete and partial response rate was
significantly higher among patients who
received TPF compared to PF, 82.8% vs
60.8%, respectively (P = .0013)

• Recently, randomized trials have studied whether induction
regimens comprising taxane, cisplatin,and fluorouracil (TaxPF) could be superior to PF. Most of them have shown a
significant increase in OS and progression-free survival (PFS)
in the Tax-PF arms, but the power associated with each of
them prevented studying more specific end points.
• Therefore, in 2008, the MACH-NC Collaborative Group
launched an update of the MACH-NC database to include all
taxane trials so that they could summarize their results on
survival end points, pattern of failure, toxicity, and interaction
between treatment effect and patient subgroups.

• The aim of this meta-analysis was to study
the efficacy and toxicity of Tax-PF and PF and
to identify differences in outcomes in subsets of
patients.

STUDY DESIGN
• Trials must have been properly randomized and have
completed accrual before January 2007
• nonmetastatic patients with locoregionally advanced
HNSCC treated with a curative intent
• to compare Tax-PF with PF followed by radiotherapy (RT; or
CRT) or
• to compare Tax-PF followedby RT (or CRT) with upfront CRT.
PRIMARY END POINT: OS
SECONDARY ENDPOINT: PFS, LRF, DISTANT FAILURE
&COMPLIANCE

Six trials fulfilled the inclusion criteria. Among them,
• 4 compared Tax-PF with PF induction chemotherapy,
• 1 compared Tax-PF induction with no induction
chemotherapy, &
• 1 was a three-arm trial comparing Tax-PF, PF, and no
Induction
Overall, five trials (1,772 patients) were available for the
Tax-PF versus PF comparison and patient characteristics ,
stage , site & other variables were uniformly distributed.
Median follow-up was 4.9 years

LOCOREGIONAL & DISTANT FAILURE

Tax-PF Versus PF Meta-Analysis
Tax-PF induction chemotherapy improved OS as compared with PF
• HR of death of 0.79(95%CI, 0.70 to0.89; P.001) and an absolute
benefit at 5 years of 7.4%, (35.0% to 42.4%)
• PFS: HR of 0.78 (95% CI, 0.69 to 0.87; P .001) and an
absolute benefit at 5 years of 7.1%, from 28.4% to 35.5%
• locoregional failures HR of 0.79 (95%CI,0.66 to0.94; P.007) and an
absolute decrease of 7.4% at 5 years, 51.6% to 44.2%
• distant failures HRof 0.63 (95% CI, 0.45 to 0.89; P.009) and an
absolute decrease of 6.4% at 5 years, from 20.1% to 13.7%
• head and neck cancer mortality in favor of the Tax-PF arms (HR
0.74; 95% CI, 0.65 to 0.84; P .001), with an absolute difference of
9.3%, from 60.1% to 50.8%
• No difference in head and neck noncancer mortality was observed
(HR1.12; 95% CI, 0.82 to 1.51; P.47)

• Treatment compliance and toxicity. The hazard
ratio of mortality120 days after randomization
was 0.91 (95% CI, 0.62 to 1.33;P .62), showing
a nonsignificant reduction in the risk of early
death in favor of Tax-PF
• Compliance with RT was significantly better in
the Tax-PF arms, with 73% starting the
planned RT versus 67% in the PF arms (P
.004)

• The TTCC2002
• After the exclusion of this trial as a sensitivity
analysis, heterogeneity was not significant
anymore (I2 0%for OS and for PFS)

DISCUSSION
• This individual patient data meta-analysis of TaxPF induction chemotherapy shows that
• Tax-PF significantly improves OS, PFS, head and
neck cancer mortality, and locoregional and
distant failure compared with PF for locally
advanced HNSCC.
• Tax-PF is also associated with a better compliance
with induction chemotherapy.
• More patients in the Tax-PF group proceeded to
concomitant chemoradiotherapy, likely reflecting
the higher response rates

The limitations of the analysis are mostly related to the
heterogeneity of trials and missing data.
• First, the meta-analysis includes two types of Tax-PF
regimens using different taxanes: docetaxel or
paclitaxel(SPAIN 1998)
• one trial was a larynx preservation trial,10 which is a
different setting compared with locally advanced
HNSCC (GORTEC)
• 1 trial had a short follow-up and no data on the type of
relapse(SPAIN 1998)
• one trial had heterogeneous survival results compared
with the others (TTCC2002)

CONCLUSION
Given that MACH NC trials demonstrated superiority for
Overall survival,
organ preservation, and
toxicity of TPF over PF,
we can safely conclude that TPF is now the
standard of care for induction treatment.
However, these studies did not answer the fundamental
question about the relative efficacy of adding induction
chemotherapy to chemoradiotherapy compared with
chemoradiotherapy alone, the current standard of
care……………………….????????

TPF vs CRT
• there is no evidence from randomized trials
suggesting that Tax-PF followed by RT
(concomitant chemotherapy) is superior to
concomitant CRT.
• the decrease in locoregional failure associated
with Tax-PF is lower than the one associated
with platinum-based concomitant CRT in
MACH-NC(13.5% at 5 years)

DECIDE TRIAL
In the DeCIDE trial, 280 patients were randomly assigned to induction
with two cycles of docetaxel, cisplatin, and 5-fluorouracil followed
by chemoradiotherapy or chemoradiotherapy alone .
Chemoradiotherapy consisted of docetaxel, 5fluorouracil, and hydroxyurea (given as five “cycles” in combination
with RT at 150cGy bid, repeated every other week).
An analysis of the trial was presented at the 2012 American Society of
Clinical Oncology (ASCO) meeting. There was no statistically
significant difference in overall survival, the primary endpoint of the
study (hazard ratio 0.91, 95% CI 0.59-1.41).
Differences in relapse-free survival and distant metastasis free survival
with induction chemoradiotherapy were not statistically significant.

PARADIGM TRIAL
In the PARADIGM trial, 145 patients were randomly assigned to
concurrent chemoradiotherapy (with cisplatin on weeks 1 and
4) or to sequential chemotherapy using three cycles of a
standard TPF regimen for induction, followed by concurrent
chemoradiotherapy.
At a median follow-up of 49 months, there was no statistically
significant difference in three-year overall survival, the
primary endpoint of the trial 73% vs 78 %, HR for death
1.09, 95% CI 0.59-2.03 and no clear benefit in any subset.
Notably, dilution of the already small patient numbers by
biologically and prognostically distinct HPV positive patients
further hinders the ability to make any statistical conclusions
from this study.

The role of sequential therapy based upon the DECIDE
and PARADIGM trials remains inconclusive due to
early termination, low patient numbers, and the
probable inclusion of a large number of biologically
distinct HPV positive patients.

Further studies addressing this issue have been
completed and await reporting and might contribute to
conclusions about sequential therapy.

The question of whether the addition of induction
chemotherapy to concurrent chemoradiotherapy
improved survival over concurrent chemoradiotherapy
alone remains unfortunately unanswered and it might
not be answered soon.

Despite the lack of strong evidence,
generally sequential therapy should be reserved for
healthy patients with high risk of distant and
locoregional failure (especially the combination of
N2C, N3 nodal stage plus T2 or greater primary stage).

INDUCTION CHEMOTHERAPY WITH TPF IN HEAD & NECK CANCERS

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INDUCTION CHEMOTHERAPY WITH TPF IN HEAD & NECK CANCERS