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

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 5-fluorouracil (PF, cisplatin, 100 mg/m2, and 5-fluorouracil, 1000 mg/m2/day continuous 24-hour 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

Tax324501 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)

TAX324 RESULTS

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 survivalhypopharynx (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 improvedResponse rate over PF, 59% versus 72% (P = .006)

GORTEC 2000-01ORGAN 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 (Tax-PF) 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 studythe 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: OSSECONDARY 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 theTax-PF versus PF comparison and patient characteristics ,stage , site & other variables were uniformly distributed.

Median follow-up was 4.9 years

RESULTS

LOCOREGIONAL & DISTANT FAILURE

Tax-PF Versus PF Meta-AnalysisTax-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)

os

PFS

LRF

DISTANT FAILURES

• The TTCC2002• After the exclusion of this trial as a sensitivity

analysis, heterogeneity was not significant anymore (I2 0%for OS and for PFS)

With/without TTCC2002

DISCUSSION

• This individual patient data meta-analysis of Tax-PF 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 forOverall survival, organ preservation, andtoxicity of TPF over PF,we can safely conclude that TPF is now thestandard 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 TRIALIn 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, 5-fluorouracil, 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 TRIALIn 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).

thank you… Dr. Paul George