1. INDUCTION CHEMOTHERAPY
LAHNC
INDUCTION CHEMOTHERAPY
THE NEW STANDARD
TREATMENT
Ricardo Hitt
Hospital 12 de Octubre
SEOM 2009

2. BASIS OF ICT CELLULAR BASIS BIOLOGICAL CONCEPT PARAMETER OF SURVIVAL
PATIENTS SELECTION

3. OROPHARYNX TUMOR

5. PHARYNX TUMOR

6. PHARYNX TUMOR

9. LOCAL-CONTROL AND TUMORAL VOLUME

12. Prognostic impact of tumor volumetry in patients with locally advanced head and neck cancer treated by radiotherapy alone or radiochemotherapy (Plataniotis et al Int J Radiation Oncol 2004)
Tumor volume is one of the main reported factors determining the outcome of treatment HNC
CT digitized: tumor volume cubic centimeters
Total gross tumor volume < 22.8cc were more likely to achieve a complete response and had a median survival of 45 months
Total gross volume > 22.8 cc median survival of 12 months.(p=0.01)

13. UNRESECTABLE SCCHN
Phase III Trial Unresectable SCCHN (JCO 2003, Adelstein)
A: Radiotherapy (OS= 23%)
295 patients
B: CRT, Cisplatin 100 mg/m2( OS= 37%)
3 years
C: Split course CF (OS= 27%)

14. R91-11 Schema RANDOMIZE STRATIFY CDDP/5-FU Location: Glottis
Supraglottic
RANDOMIZE
CR,PR x 1 Cycle RT
STRATIFY
Arm 1:
CDDP/5-FU x 2 cycles
T Stage: T2
T3, Fixed cord
T3, No cord fixation
T4, with base of tongue 1 cm
NR Surgery RT
Arm 2:
Radiation Therapy + CDDP
N Stage
N0, N1
N2, N3
Arm 3:
Radiation Therapy

15. Overall Survival FORASTIERE NEJM Dead / Total RT + Induction 89 / 173
RT + Concomitant 106 / 171
RT Alone / 171
FORASTIERE NEJM

16. CHEMORADIOTHERAPY CRT IS BETTER THAN RT
IS THERE SOME CHANGE IN THE NATURAL HISTORY OF LAHNC?
YES:
CRT IS BETTER THAN RT

17. Results : Overall survival
105 comparisons and pts
Chemotherapy
timing
Risk
reduction
Absolute benefit
at 5 years *
p-value
Adjuvant
Neoadjuvant
Concomitant
-6 %
4 %
19 % NS
<
- 2 %
2 %
8 %
The results of this update confirmed those of the first MA, with a somewhat deleterious effect of the adjuvant setting, the almost nil effect in terms of OS for the NACT but it was before the taxane era, and a small but significant impact of concomitant, platinum-based chemoradiation.
Total
12 %
<
5 %
* 5-year survival rate in control group : 30%

18. ASCO 1982: The Platinum Revolution
35 previously untreated pts: 3 cycles cisplatin-5FU (CF)
Response > 50%
Complete response
94%
63%
Decker D et al. ASCO Annual Meeting. Saint Louis 1982, Abstract C-757
Decker DA et al. Cancer 1983;51:1353-5
60 tumors treated with platinum-based chemotherapy
42 responses > 50%
18 responses < 50%
25 years ago medical oncologists treated the first head and neck cancer patients with cisplatin therapy. In those years the different researchers reported a high response rate to this therapy without rigurous evaluation about the response.
after RT
after RT
Ensley J et al. ASCO Annual Meeting. Saint Louis 1982, Abstract C-767
Ensley JF et al. Cancer 1984;54:811-4
97% 6%

19. Rationale for induction CT
Induction CT: high RR ( 70%-80%); RC (5% - 30%)
1- 4 cycles prior to RT
Subsequent RT or surgery not compromised
Not clear if local control increased
Response to induction CT predicts response to RT
Part of a larynx preservation strategy
What was the rationale for the use of induction chemotherapy? High response rate as front line, in patients with response the following treatment was not altered, response to induction chemotherapy predicted response to radiotherapy and was a part of laryx preservation strategy.

20. Improved Complete Response Rate and Survival in Advanced Head and Neck Cancer After Three-Course Induction Therapy With 120-Hour 5-FU Infusion and Cisplatin
MICHAEL ROONEY, MD,.t JULIE KISH, MD,JOHN JACOBS, MD.( JEANNIE KINZIE, MD,ARTHUR WEAVER, MD., JOHN CRISSMAN. MD. AND MUHYl AL-SARRAF. MD
This is a classical report from Al-Sarraf. In this paper it was demonstrated
Cancer 55: I

21. That patients with complete response to induction chemotherapy had benefits in survival. For this reason complete response to induction therapy may predict benefits in overall survival.

22. SCCHNC HOW CAN WE IMPROVE THESE RESULTS? Change the schedule of ICT
Change the approach
of treatment
Now how can we improve these results? Probably by changing the schedule and changing the approach of the treatment

23. Phase III Study Comparing Cisplatin (P) & 5-Fluoruracil (F) Versus P, F and Paclitaxel (T) as induction therapy in Locally Advanced Head & Neck Cancer (LAHNC)
Hitt et al (JCO 2005)

24. Time to Treatment Failure
PF (n= 193): 133 (69%) events
PFT (n= 189): 108 (57%) events
Log-rank, p=
Tarone-Ware, p=
PF (median)= 11.6 ( )
PFT (median)= ( )

25. HNSCC: Taxotere in Locally-Advanced Disease
Overall Survival
TAX % reduction in risk of death
TAX % reduction in risk of death 50 10 20 30 40 60 70 80 90
100
TPF
Survival Probability (%) PF
TPF
Here we have both studies where we observe that PF schedule was improved with the addition of Taxotere, in terms of overall survival PF 6 12 18 24 30 36 42 48 54 60 66 72 6 12 18 24 30 36 42 48 54 60 66 72
Survival Time (months)
Survival Time (months)
Posner et al. ASCO 2006.
Remenaer et al., ASCO 2006

26. CHANGE APPROACH INDUCTION CHEMOTHERAPY CHEMORADIOTERAPY CR/PR
OBJECTIVE: FINAL CR
BENEFIT SURVIVAL?

27. On behalf of the Spanish Head and Neck Cancer Cooperative Group, Spain
Final results of a randomized Phase III trial comparing induction chemotherapy (ICT) with cisplatin/5-FU (PF) or docetaxel/cisplatin/5-FU (TPF) followed by chemoradiotherapy (CRT) versus CRT alone as first-line treatment of unresectable locally advanced head and neck cancer (LAHNC)
Ricardo Hitt, MD, PhD
JJ Grau, A Lopez Pousa, A Berrocal, C Garcia-Giron, A Irigoyen,
J Sastre, J Martinez-Trufero, H Cortés-Funes, J Cruz-Hernandez
On behalf of the Spanish Head and Neck Cancer Cooperative Group, Spain

28. Study design R CRT Neck dissection PF 3 cycles q3w CRT Surgery N=439
sample size refres to IIT population. Check demographics etc to see if all are PP
TPF 3 cycles q3w
CRT

29. Safety: Adverse events
Grade 3/4 AEs, % patients
CRT (N=119)
PF plus CRT (N=156)
TPF plus CRT (N=153)
Total ICT (TPF + PF) (N=309)
Neutropenia 20 38 34 36
Febrile neutropenia 1 3 18 10
Thrombocytopenia 4
Asthenia 9 14 11
Mucositis 31 46 42 44

30. Secondary endpoint: LCR (evaluable)
% patients
CRT (N=119)
Combined ICT + CRT (N=234)

31. Primary endpoint: TTF (evaluable)
CRT; median 5.0 months
HR = 0.57; 95% CI, 0.45–0.74; p<0.0001
ICT + CRT; median 12.5 months
ICT + CRT
CRT
E N
Number of patients at risk
120 78 48 26 10 36 17 11 4
(months)

32. Secondary endpoint: TTP (evaluable)
CRT; median 13.1 months
HR = 0.79; 95% CI, 0.60–1.03; p=0.056
ICT + CRT; median 18.5 months
ICT + CRT
CRT
E N
Number of patients at risk
149 95 57 29 10 65 42 26 17 5
(months)

33. CHEMORADIOTHERAPY HNC
STANDARD TREATMENT
OLD STANDARD
GOLD STANDARD
CRT
TPF/CRT

34. PROBLEMS WITH ICT/CRT PATIENTS SELECTION CENTER EXPERIENCE
INTENSIVE SUPPORTIVE CARE

35. Head and Neck Cancer Pretreatment considerations
Comorbid chronic diseases
Pulmonary
Cardiovascular
Digestive
Malnutrition
Resulting from poor dietary habits or symptoms
Severe in over 25% of patients
Oral health
Periodontal disease, infections, and caries common
Dental rehabilitation indicated prior to radiotherapy
AS YOU CAN SEE, HEAD AND NECK CANCER PATIENTS HAVE A LOT OF PROBLEMS APART FROM THEIR CANCER SITUATION .FOR EXAMPLE THEY MAY HAVE PULMONARY PROBLEMS ETC, BUT, THE BIGGEST PROBLEM IS USUALLY MALNUTRICION.WE SHOULD REMEMBER THAT THESE COMORBILITY SITUATIONS ARE STRONGLY RELATED TO THE TOXICITY THAT DIFFERENT TREATMENTS GENERATE.
Schantz SP, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;

37. SURVIVAL PARAMETER OVERALL SURVIVAL TIME TO PROGRESSION
TIME TO TREATMENT FAILURE: time from response, toxicity, death

38. LAHNC
STANDARD TREATMENT
OLD STANDARD
GOLD STANDARD
CRT
TPF/CRT