Neoadjuvant Chemotherapy in Neoadjuvant Chemotherapy in Locally Advanced Squamous Cell Locally Advanced Squamous Cell Cancer of Head and NeckCancer of Head and Neck

Mei Tang, MDMei Tang, MD

Head and Neck CancerHead and Neck Cancer

Worldwide Worldwide New cases : 644,000New cases : 644,000 Cancer deaths: 350,000Cancer deaths: 350,000 About 5% of all cancers About 5% of all cancers

Local Recurrence: 40% - 60%Local Recurrence: 40% - 60% Distant metastatic disease: 20 - 30%Distant metastatic disease: 20 - 30%

SCCHNSCCHN

The Role of Concomitant The Role of Concomitant Chemotherapy in Locally Chemotherapy in Locally Advanced SCCHNAdvanced SCCHN

The Lancet March 18, 2000

MACH-NC 2000MACH-NC 2000

63 trials (10,741 patients)63 trials (10,741 patients) 1965 – 19931965 – 1993 Cancers of oropharynx, oral Cancers of oropharynx, oral

cavity, larynx, and hypopharynx cavity, larynx, and hypopharynx Many countries contributed to this Many countries contributed to this

reportreport

Overall Survival Benefit of Overall Survival Benefit of Chemotherapy Chemotherapy

Timing of Timing of ChemotherapyChemotherapy Neoadjuvant/induction Neoadjuvant/induction

chemotherapychemotherapy

Concomitant chemotherapy Concomitant chemotherapy (chemoradiotherapy, CRT)(chemoradiotherapy, CRT)

Adjuvant chemotherapy Adjuvant chemotherapy

Timing of Timing of Chemotherapy Chemotherapy

Concomitant chemoradiotherapy is Concomitant chemoradiotherapy is the current the current standard therapystandard therapy for for stage III and IV who do not stage III and IV who do not undergo surgeryundergo surgery

Induction Chemotherapy: an Induction Chemotherapy: an attractive optionattractive option

To allow the assessment of tumor To allow the assessment of tumor responseresponse

To select appropriate patient for To select appropriate patient for organ preservationorgan preservation

To improves local controlTo improves local control To reduce distant metastasesTo reduce distant metastases

Chemotherapy in Newly Diagnosed Chemotherapy in Newly Diagnosed vsvs Recurrent Recurrent Disease patientsDisease patients

Response RateResponse Rate

ChemotheraChemotherapypy

New DiagnosisNew Diagnosis RecurrenceRecurrence

DDP/BleoDDP/Bleo 71%71% 33%33%

DDP/Bleo/VinblDDP/Bleo/Vinbl 74%74% 45%45%

DDP/MTX/BleoDDP/MTX/Bleo 88%88% 25%25%

Bleo/MTX/VCRBleo/MTX/VCR 71%71% 43%43%

Evidence supporting induction Evidence supporting induction chemotherapychemotherapy

The VA trial No. 268 CT-RT vs Surg.-The VA trial No. 268 CT-RT vs Surg.-RT (P)RT (P)

The EORTC trials in early 1990s (PF)The EORTC trials in early 1990s (PF) Intergroup trial 91-11(PF)Intergroup trial 91-11(PF)

1.1. A higher organ preservation or as A higher organ preservation or as good as concomitant CRTgood as concomitant CRT

2.2. A lower rate of distant failure A lower rate of distant failure 3.3. A trend toward improved survival, A trend toward improved survival,

particularly in unresectable patientsparticularly in unresectable patients

Adding Taxanes into induction Adding Taxanes into induction regimen (TPF – RT)regimen (TPF – RT)

High complete response rate: 80-100%Local failure rate: 31%Distant failure rate: 6%Toxicity: Less nausea, mucositis, G-3 hearing loss, trombocytopenia and treatment related death. Higher neutropenic fever,

Dosage in Chemo-Dosage in Chemo-regimensregimens

TPF (q3wk)TPF (q3wk) PF(q3wk)PF(q3wk)

Docetaxol Docetaxol (T)(T)

75 mg/m275 mg/m2 N/AN/A

Cisplatin (P)Cisplatin (P) 75 mg/m275 mg/m2 100 mg/m2100 mg/m2

5-FU (F)5-FU (F) 1000 mg 1000 mg /m2 day 1-4/m2 day 1-4

1000 mg/m2 1000 mg/m2 day 1-5day 1-5

Timing of Timing of Chemotherapy Chemotherapy

Limitations of the Data Limitations of the Data

Trials between 1965-1993Trials between 1965-1993 Different chemotherapy regimens Different chemotherapy regimens

(drug/schedules)(drug/schedules) Platinum and 5-FU regimens are Platinum and 5-FU regimens are

associate with 5% survival benefit associate with 5% survival benefit at 5 yearsat 5 years

Response to chemotherapy was Response to chemotherapy was not taken into accountnot taken into account

5-FU/Cisplatin in Previously 5-FU/Cisplatin in Previously Untreated PatientsUntreated Patients

No. No.

PatientsPatientsResponseResponse

(%)(%)Complete Complete ResponseResponse

(%)(%)

RTOGRTOG 84’84’ 2323 9191 3939

RooneyRooney 85’85’ 6161 9393 5454

VALCSGVALCSG 91’91’ 166166 8585 3131

PaccagnellaPaccagnella 94’94’ 118118 8080 3131

AthanasiadisAthanasiadis 97’97’ 7171 8383 3232

Rationales of Induction Rationales of Induction ChemotherapyChemotherapy

1. There is increased 1. There is increased responsiveness in previously responsiveness in previously untreated patientsuntreated patients

2. Possible improvement in survival2. Possible improvement in survivalImprove locoregional controlImprove locoregional control

Decrease distant metastasesDecrease distant metastases

3. Surgical modification/organ 3. Surgical modification/organ preservationpreservation

Patient Selection 1Patient Selection 1

Patient Selection 2Patient Selection 2

TPF Improves PFS and OS When It Was Compared to PF in Induction

TFP has better local control but no significant benefit in control of distant disease comparing to PF .

OS PFS

Patient Selection Outside Patient Selection Outside Clinical TrialsClinical Trials

Young (55 yo)Young (55 yo) PS 0-1PS 0-1 No majoy comorbilities (RI, uncontrolled No majoy comorbilities (RI, uncontrolled

DM, recent heart attached..)DM, recent heart attached..) Large primary: T3 or T4Large primary: T3 or T4 Extensive LN involvement (N2b or Extensive LN involvement (N2b or

above)above) Good nutrition standard Good nutrition standard

Targeted Therapy in Targeted Therapy in SCCH-NCSCCH-NC Cetuximab-RT Cetuximab-RT vs.vs. RT: RT: PF PF vs.vs. PF + Cetuximab PF + Cetuximab

It seems safe and effective:It seems safe and effective: Carboplatin (AUC 2)/Taxol (135 Carboplatin (AUC 2)/Taxol (135

mg/m2)/Cetuximabmg/m2)/Cetuximab TPF/CetuximabTPF/Cetuximab TPF-RT+cetuximabTPF-RT+cetuximab

Targeted Therapy in Targeted Therapy in SCCH-NCSCCH-NC Everolimus: mTOR inhibitorEverolimus: mTOR inhibitor

Panitumumab + chemoPanitumumab + chemo

Nimotumumab (EGFR ab)Nimotumumab (EGFR ab)

Is it time to change treatment Is it time to change treatment paradigm?paradigm?

No direct comparisonNo direct comparison of induction of induction chemotherapy to concomitant chemotherapy to concomitant treatment using the newer treatment using the newer regimenregimen

Induction chemotherapy has no defined role in

definitive treatment strategies

SummarySummary

Chemotherapy has established role in Chemotherapy has established role in locally adv. SCCHN locally adv. SCCHN

TPF – CRT is an alternative treatment TPF – CRT is an alternative treatment options besides the standard options besides the standard concomitant chemoradiotherapy.concomitant chemoradiotherapy.

CRT, not RT after TPF. CarboplatinCRT, not RT after TPF. Carboplatin TPF is better than PF in induction. It is TPF is better than PF in induction. It is

possible but not proven that TPF-CRT possible but not proven that TPF-CRT is better than CRT with cisplatin. is better than CRT with cisplatin.

Dosage of Cisplatin in Dosage of Cisplatin in CRT CRT 80% of pts tolerated > or = 6 doses of 80% of pts tolerated > or = 6 doses of

30 mg/m2 weekly. Total: 180-210 mg 30 mg/m2 weekly. Total: 180-210 mg 50% of pts tolerated 100 mg/m2 X 2. 50% of pts tolerated 100 mg/m2 X 2.

Total: 200 mgTotal: 200 mg Weekly is flexibl. The goal is to Weekly is flexibl. The goal is to

continue XRT with delay or dose continue XRT with delay or dose reduction.reduction.

No G-3 or 4 renal toxicity in weekly No G-3 or 4 renal toxicity in weekly dose.dose.

SCCH-N in GBMC 2009SCCH-N in GBMC 2009

Total 238 cases of head neck cancer

Eighty cases of cancers in oral cavity, oropharynx, larynx and hypopharynx

Stage I: 22Stage II: 9Stage III: 14Stage IV: 28Unknown or Stage 0: 7