Role of NACT in Head and Neck Oncology

1. NEOADJUVANT CT IN HEAD
AND NECK CANCER
Dr AJAY MANICKAM MS, DNB
Fellow Head and Neck Oncology
Tata Medical center

2. NEO ADJUVANT CHEMOTHERAPY
Neo (adjuvant – in addition to)
chemotherapy the drugs may
shrink the tumor and give more
surgical options.

3. BACKGROUND
WHEN TO GIVE NACT (HEAD AND NECK )
WHAT REGIMEN
NACT + CRT / CRT - LEVEL OF EVIDENCE
NACT + SURGERY / SURGERY + STD RT/CRT (ORAL CAVITY)
NACT IN ORGAN PRESERVATION

4. When ?
• RESECTABLE ORAL CAVITY
TUMOURS
NACT
• NON RESECTABLE ORAL
TUMOURS
NACT

5. NACT IN RESECTABLE TUMOURS
 ITALY

6. LICITRA

7. LICITRA

8. LICITRA

9. LICITRA

10. CONCLUSION
 This study could not prove a favorable
effect on long-term local control of disease
and survival by the addition of primary
chemotherapy to a multidisciplinary
strategy comprising primary surgery and
postoperative radiotherapy.

11. UNRESECTABLE TUMOURS

12. WHAT ?
 TAX 323
 TAX 324

13. TAX 323
A total of 358 patients underwent randomization, with 177
assigned to the TPF group and 181 to the PF group.
At a median follow-up of 32.5 months, the median
progression-free survival was 11.0 months in the TPF group
and 8.2 months in the PF group (hazard ratio for disease
progression or death in the TPF group, 0.72; P=0.007).
Treatment with TPF resulted in a reduction in the risk of death
of 27% (P=0.02), with a median overall survival of 18.8
months, as compared with 14.5 months in the PF group.

14. TAX 323
There were more grade 3 or 4 events of leukopenia and
neutropenia in the TPF group and more grade 3 or 4 events
of thrombocytopenia, nausea, vomiting, stomatitis, and
hearing loss in the PF group. The rates of death from toxic
effects were 2.3% in the TPF group and 5.5% in the PF group.
Addition of docetaxel significantly improved progression- free
and overall survival in patients with un-resectable squamous-
cell carcinoma of the head and neck.

15. TAX 324 METHODS
TAX 324 was a randomised, open-label phase 3 trial comparing - three cycles of TPF
induction chemotherapy 1
 1) Docetaxel 75 mg/m2, followed by
 2) Intravenous cisplatin 100 mg/m2 and
 3) Fluorouracil 1000 mg/m2 per day, (administered as a continuous 24-h infusion for
4 days)
with three cycles of PF
 1) Intravenous cisplatin 100 mg/m2, followed by
 2) Fluorouracil 1000 mg/m2 per day as a continuous 24-h infusion for 5 days) in
patients with stage III or IV squamous- cell carcinoma of the head or neck.

16. TAX 324
Median follow-up was 72·2 months (95% CI 68·8–75·5).
Overall survival was significantly better after treatment with TPF
versus PF (hazard ratio [HR] 0·74, 95% CI 0·58–0·94), with an
estimated 5-year survival of 52% in patients treated with TPF and
42% in those receiving PF.
Median survival was 70·6 months (95% CI 49·0–89·0) in the TPF
group versus 34·8 months (22·6–48·0) in the PF group (p=0·014).

17. TAX 324
Progression-free survival was also significantly better in patients
treated with TPF (median 38·1 months, 95% CI 19·3–66·1, vs 13·2
months, 10·6–20·7; HR 0·75, 95% CI 0·60–0·94).
No significant difference in dependence on gastric feeding tubes
and tracheostomies between treatment groups. In the TPF group,
three (3%) of 91 patients remained feeding- tube dependent,
compared with eight (11%) of 71 patients in the PF group. Six (7%)
of 92 patients had tracheostomies in the TPF group, versus eight
(11%) of 71 in the PF group.

18. NACT + CRT VS CRT
NEOADJUVANT CT FOLLOWED BY CRT VS CRT
PARADIGM
DECIDE
TTCC

19. PARADIGM
 Patients were eligible if their tumour was either unresectable or of low surgical curability on the
basis of advanced tumour stage (3 or 4) or regional-node stage (2 or 3, except T1N2), or if they
were a candidate for organ preservation.

20. PARADIGM
Between Aug 24, 2004, and Dec 29, 2008, we enrolled
145 patients across 16 sites.
After a median follow-up of 49 months (IQR 39–63),
41 patients had died—20 in the induction
chemotherapy followed by chemoradiotherapy group
and 21 in the chemoradiotherapy alone group.

21. PARADIGM
3-year overall survival was 73% (95% CI 60–82) in the induction
therapy followed by chemoradiotherapy group and 78% (66–86)
in the chemoradiotherapy alone group (hazard ratio 1·09, 95% CI
0·59–2·03; p=0·77).
More patients had febrile neutropenia in the induction
chemotherapy followed by chemoradiotherapy group (16 patients)
than in the chemoradiotherapy alone group (one patient).

22. PARADIGM CONCLUSION
Although survival results were good in both groups
there was no difference noted between those patients
treated with induction chemotherapy followed by
chemoradiotherapy and those who received
chemoradiotherapy alone.

23. DECIDE
 Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were randomly assigned to CRT alone
(CRT arm; docetaxel, fluorouracil, and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other
week) versus two 21-day cycles of IC (docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1, and
fluorouracil 750 mg/m2 on days 1 to 5) followed by the same CRT regimen (IC CRT arm).

24. DECIDE
Serious adverse events were more common in the IC arm
(47% v 28%; P .002). With a minimum follow-up of 30 months,
there were no statistically significant differences in OS (hazard
ratio, 0.91; 95% CI, 0.59 to 1.41), RFS, or DF-free survival.
Conclusion
IC did not translate into improved OS compared with CRT
alone

25. TTCC
Overall, this trial failed to show any advantage of ICT-CCRT
over CCRT alone in patients with unresectable LASCCHN

26. METAANALYSIS
Five randomized trials representing 1,772 patients were identified. Updated
individual patient data (IPD) were retrieved for all trials. The log-rank test,
stratified by trial, was used for comparison. Interaction or trend tests were
used to study the interaction between covariates and treatment.

27. FOREST PLOT OS AND LRF

28. CONCLUSION
Although induction Tax-PF is superior to PF in terms of
OS, PFS, and loco-regional and distant control, its
precise role compared with upfront CRT in the
management of loco-regionally advanced HNSCC
remains to be defined.

29. BUDACH

30. BUDACH

31. BUDACH
Additional induction CHX with TPF before RT-CHX did
neither result in a significant improvement of OS (Hazard
Ratio: 1.010, 95% confidence limits (CL) 0.84–1.21, p =
0.92), nor in a statistically significant benefit of PFS
(Hazard Ratio: 0.91, 95% CL 0.75–1.1, p = 0.32).
Conclusion: Additional induction CHX with TPF before RT-
CHX does not improve OS and PFS in locally advanced
HNSCC compared to definite RT-CHX.

32. NACT + SURGERY VS SURGERY

33. ZHONG
 A prospective open-label phase III trial was conducted. Eligibility criteria
included untreated stage III or IVA locally advanced resectable OSCC.
 Patients received two cycles of TPF induction chemotherapy (docetaxel
75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1, and fluorouracil 750
mg/m2 on days 1 to 5) followed by radical surgery and postoperative
radiotherapy (54 to 66 Gy) versus up-front radical surgery and
postoperative radiotherapy.

34. ZHONG

35. ZHONG

36. ZHONG

37. ZHONG
After a median follow-up of 30 months, there was no
significant difference in OS (hazard ratio [HR], 0.977;
95% CI, 0.634 to 1.507; P .918) or disease-free survival
(HR, 0.974; 95% CI, 0.654 to 1.45; P .897) between
patients treated with and without TPF induction.

38. LARYNX - GORTEC AND RTOG

39. GORTEC 2000 01

40. GORTEC
 Operable patients with untreated stage III or IV larynx
or hypopharynx invasive squamous cell carcinoma
who required total laryngectomy were randomly
assigned to three cycles of induction chemotherapy
with either TPF or PF, followed by radiation therapy for
responders

41. GORTEC
213 Pts were treated with median follow-up of 105 months.
The 5 and 10-year larynx preservation rates were 74.0% (95% CI =
0.64 to 0.82) vs 58.1% (95% CI = 0.47 to 0.68) and 70.3% (95% CI
= 0.58 to 0.8) vs 46.5% (95% CI = 0.31 to 0.63, P = .01) in the TPF
vs PF arm, respectively.
 The 5 and 10-year LDFFS rates were 67.2% (95% CI = 0.57 to
0.76) vs 46.5% (95% CI = 0.36 to 0.57) and 63.7% (95% CI = 0.52
to 0.74) vs 37.2% (95% CI = 0.24 to 0.52, P = .001), respectively.

42. GORTEC
Long-term follow-up confirms that induction
chemotherapy with TPF increased larynx
preservation and larynx dysfunction–free
survival.

43. RTOG 91 11
Patients with stage III or IV glottic or supraglottic squamous cell cancer
were randomly assigned to induction cisplatin/fluorouracil (PF)
followed by RT (control arm), concomitant cisplatin/RT, or RT alone.

44. RTOG 91 11

45. RTOG 91 11

46. RTOG

47. RTOG
Both chemotherapy regimens significantly improved LFS
compared with RT alone (induction chemotherapy v RT alone:
hazard ratio [HR], 0.75; 95% CI, 0.59 to 0.95; P .02;
concomitant chemotherapy v RT alone: HR, 0.78; 95% CI, 0.78
to 0.98; P .03).
Overall survival did not differ significantly, although there was
a possibility of worse outcome with concomitant relative to
induction chemotherapy (HR, 1.25; 95% CI, 0.98 to 1.61; P .08).

48. RTOG
Concomitant cisplatin/RT significantly improved the larynx
preservation rate over induction PF followed by RT (HR, 0.58;
95% CI, 0.37 to 0.89; P .0050) and over RT alone (P .001),
whereas induction PF followed by RT was not better than
treatment with RT alone (HR, 1.26; 95% CI, 0.88 to 1.82; P .35).

49. RTOG CONCLUSION
These 10-year results show that induction PF followed
by RT and concomitant cisplatin/RT show similar
efficacy for the composite end point of LFS.
Loco-regional control and larynx preservation were
significantly improved with concomitant cisplatin/RT
compared with the induction arm or RT alone

50. MACH NC

51. MACH - NC
Both the indirect and the direct comparisons were consistent
on survival, event-free survival and loco-regional failure,
showing a clear advantage in favour of concomitant
chemotherapy.
The 5 year survival rates in the control arm were, respectively,
27% and 30% in concomitant and induction trials.

52. MACH NC
 concomitant chemotherapy had a pronounced effect on loco-regional
failure, which was not observed for induction chemotherapy.
 Induction chemotherapy provided a relatively more pronounced effect
on distant metastases, compared to concomitant chemotherapy,
suggesting the need to use a relatively high dose of chemotherapy to
influence the occurrence of distant metastases.

53. WHEN TO GIVE NACT (HEAD AND NECK )
WHAT REGIMEN
NACT + CRT / CRT - LEVEL OF EVIDENCE
NACT + SURGERY / SURGERY + STD RT/CRT (ORAL CAVITY)
NACT IN ORGAN PRESERVATION
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