Primary Chemoradiation Therapy for Loco-Regionally Advanced HNSCC: Analysis of 105 consecutive patients treated at

the Greater Baltimore Medical Center

Head and Neck Grand Rounds

Greater Baltimore Medical Center

David Zaboli

December 3, 2010

Disclosures

None

Overview

• Epidemiology• Risk Factors• Review of evidence for chemoradiation therapy

for primary treatment of HNSCC• Results of 105 patients treated with Brizel

Regimen at GBMC• Future Projects

Epidemiology

• 620,000 cases of Head and Neck Cancer worldwide in 2009

• 6th most common cancer

• 6% of all malignancies worldwide

• 1,529,560 cases of cancer in the USA

• 48,000 cases of HNC in USA in 2009

• 11,300 deaths from HNC

Incidence of HNC varies greatly by region

• Highest incidence/death rates Rural Georgia 12.5/2.9

• Lowest incidence Utah 8.06/1.7

• Top 5 states overall deaths DC, MS, LA, SC, TN

• Bottom 5 states MT, NE, CT, NM, UT

5-year Survival

Oral Cavity and Oropharynx• 1975-1977 53.1• 1978-1980 54.0• 1981-1983 52.6• 1984-1986 54.6• 1987-1989 54.2• 1990-1992 56.2• 1993-1995 58.4• 1996-1998 58.8• 1999-2005 62.5

Source: SEER Cancer Statistics Review 1975-2006

Larynx• 1975-1977 66.6• 1978-1980 66.0• 1981-1983 68.8• 1984-1986 65.7• 1987-1989 66.4• 1990-1992 66.6• 1993-1995 63.9• 1996-1998 65.1• 1999-2005 63.2

Racial Discrepancy in Survival

Overall White Black

Oral Cavity/Oropharynx

62.561.5 M64.7 F

64.464.1 M65.0 F

46.141.0 M57.0 F

Larynx 63.263.9 M60.6 F

65.566.1 M62.9 F

50.151.3 M46.5 F

Source: SEER Cancer Statistics Review 1975-2006

• Epidemiology• Risk Factors• Review of evidence for chemoradiation therapy

for primary treatment of HNSCC• Results of 105 patients treated with Brizel

Regimen at GBMC• Future Projects

Risk Factors

• Tobacco• Alcohol• Viral Infection (HPV, EBV)

• Occupational exposures

• Betel nut chewing

• Nutritional deficiency

• Immunodeficiency

• Previous radiation

• Poor oral hygiene

• Mechanical irritation

• Mouthwash that contains alcohol???

• Previous HNC

• Genetics

• Epidemiology• Risk Factors • Review of evidence for chemoradiotherapy for

primary treatment of advanced HNSCC• Results of 105 consecutive patients treated at

GBMC with the “Brizel” Regimen• Future Projects

RATIONALE Combination Chemotherapy and Radiotherapy (CRT) as primary treatment for

HNSCC• Improved efficacy

• Less morbidity

• Organ preservation AND often function

• Only option for patients with unresectable disease

Toxicity Associated with CRT

Acute-Mucositis-Pain-Swallow-Chemotherapy specific Long-Term-Swallowing dysfunction -Speech

-Soft-tissue complications-Vascular complications -Xerostomia, change in sputum-Cosmetic deformities-Change/Loss taste-Hypothyroid-Esophageal fibrosis-Psychological

Cisplatin

Mechanism-DNA intercalation> DNA damage> apoptosis-alkylating agent

Side Effects-peripheral neuropathy-ototoxicity-nephrotoxicity-electrolytes-myelosuppression

5-Fluorouracil

Mechanism

-noncompetitive inhibition of thymidylate synthase-antimetabolite

Side Effects-mucositis-myelosuppression-dermatitis-diarrhea-cardiac toxicity

Thymine5-FU

Mechanism

• Radioresistance of cancer cells a major problem

• Chemotherapy combined with RT to enhance radiosensitivity by – Decreasing tumor vol– Inhibit DNA repair– Inhibit tumor

repopulation– Selective kill hypoxic

cells

“Also provides some adjuvant treatment for potential distant metastatic disease” Brizel J. Clin Oncology 2006

• Insert picture of article

MACH-NC Findings

• CRT improved survival versus surgery alone, surgery + RT

• Addition of chemotherapy produced absolute survival benefit of 4.5% at 5 years

• If concomitant CRT, absolute survival 6.5% at 5 years• In mono-chemotherapy, platin better than non-platins• Concomitant more effective for LRC• Induction more effective for distant metastasis• Benefit of CRT decreases with age

• Epidemiology• Risk Factors • Case Presentation• Review of evidence for chemoradiotherapy for

primary treatment of advanced HNSCC• Results of 105 consecutive patients treated at

GBMC with the “Brizel” Regimen• Future Projects

Study Objectives

Primary Endpoints

Overall Survival (OS)Date of Death- Date Completion of CRT

Loco-Regional Control (LRC)Date of Local OR Regional Recurrence – Date

Completion of CRT

Disease-Free Survival (DFS)Date of Local OR Regional OR Distant

Recurrence – Date Completion of CRT

Study Objectives

Primary Endpoints

Overall Survival (OS)

Date of Death- Date Completion of CRT

Loco-Regional Control (LRC)

Date of Local OR Regional Recurrence – Date Completion of CRT

Disease-Free Survival (DFS)

Date of Local OR Regional OR Distant Recurrence – Date Completion of CRT

Secondary Endpoints

– Short-term ToxicityMucositis, nephrotoxicity, Neutropenia,

– Long-term ToxicityPeg Usage, ORN, Peripheral Neuropathy, Ototoxicity

– Unplanned Hospitalizations– Causes of death

Cancer of Head and Neck

Second Primary

Co-Morbidity

Treatment-Related

Unknown

– Second Primary Malignancies

Methods

• Retrospective Review

• Locally Advanced Head and Neck Squamous Cell Carcinoma (Stage III-IVb)

• All patients treated at GBMC between 2000-2007

• N=105

• Medical records reviewed in Milton Dance Center, Radiation Oncology, and Medical Oncology

• Exclusion from review

– Cancer of sinus, salivary glands

– Unknown primary

– Recurrent cancer

– Previous therapeutic radiation to Head or Neck

– Previous systemic chemotherapy

Treatment Regimen

Chemotherapy– Cisplatin (12 mg/m2/h)– 5-Fluorouracil (600

mg/m2/20h)– Given as inpatient for five

days concomitant with first and last weeks of radiation

– CBC, BMP pre-treatment, post week 1, post week 5, post 4 weeks

Radiation Therapy– Hyperfractionated 1.25 Gy

BID x 28-30 days– Primary total dose 70-75

Gy– Involved Cervical LN 60 Gy– Uninvolved Cervical and

Supraclavicular LN 50 Gy– Interruptions minimized– Treatment break one week

after 40Gy

Prophylactic PEG

Regimen- Continued

6-12 weeks later…– Visit with provider and exam

of primary tumor site and neck

– PET/CT

Neck Dissection– Offered to all patients with

Nodal disease of N2 or greater

– All but one eligible patient received

– Type of neck dissection made on individual basis

Follow-UpYears 1-2

– Every 2 months

Years 3-5– Every 3-6 months

Years 5+– Every 6-12 months

Assessment of Treatment ResponseClinical Response: Physical Exam and Imaging

Complete

Primary Total disappearance

Neck PE < 1 cm or PET FDG consistent with inflammatory change

Partial

Primary Partial shrinkage 30-50% longest dimension

Neck Palpable LAN or FDG activity suggestive of viable metastatic LN

Pathologic Response Biopsy of Primary Tumor or Pathology of LN

Complete

Incomplete

Primary Biopsy reveals viable cancer

Neck LN reveal viable cancer

Patient CharacteristicsN=105

Mean age (y) 58.7

Range 43-79

<55 40

≥55 65

Sex

-Female 21

-Male 84

Race

-Caucasian 90

-African American15

Site *

-Oropharynx 78

-Hypopharynx 15

-Larynx 13

AJCC Stage

-III 30

-IV 75

Tumor (T)

-T1 6

-T2 36

-T3 45

-T4 18

Nodal (N)

-N0 14

-N1 24

-N2 56

-N3 11

Patient Characteristics continuedSmoking

– No 23– Yes 82– <20 PY 21– 20-40 PY 21– 40-60 PY 18– >60 PY 18– Unknown 4

Alcohol– No 8– Unknown 7– Yes 90– Social 21– Moderate 21– Heavy 18

HPV Status (Oropharynx only)– Positive 25– Negative 20– Unknown 32

Pre-treatment Hemoglobin– <12 26– >12 71– Unavailable 8

KPS– <70 9– 80 29– 90 31– 100 27– Unknown 9

Self-reported Weight Loss (lbs)– None/less than 10 28– >10 67– Unknown 10

Response

• Complete clinical response 88%

• Partial clinical response 12%

Overall Survival

Median F/U surviving

patients = 56 months (3-119)

3-year OS 75%

– Stage III 77%

– Stage IV 72%

5-year OS 60%

– Stage III 63%

– Stage IV 58%

Causes of death (N=38)

Number

Head and neck cancer 21

Co-morbidity 3

Second primary malignancy 7

Treatment-related 2

Unknown 5

Factors associated with Overall Survival Univariate Analysis

Variable HR 95% CIp-value

Age > 55 2.31 1.12-4.75 0.02

Male 0.39 0.19-0.78 0.01

Hgb < 12 0.96 0.43-2.15 0.92

Weight Loss 1.45 0.74-2.83 0.28

KPS ≤70 0.81 0.19-3.39 0.77

Larynx 1.95 0.83-4.55 0.12

Hypopharynx 2.96 1.36-6.45 0.01

T3/T4 2.34 1.11-4.95 0.03Mod-Heavy drinker 1.92 0.98-3.75 0.06

Ever Smoker 3.63 1.12-11.80 0.03

>40 PY 2.82 1.05-7.54 0.04

HPV 0.65 0.24-1.73 0.39

Decreased survival– Age

– Hypopharynx

– T3/T4

– Ever Smoker

– > 40 PY

Increased survival– Male

Factors associated with Survival Uni and Multivariate Analysis

Univariate Multivariate

Variable HR 95% CIp-value HR 95% CI

p-value

Age > 55 2.31 1.12-4.75 0.02 2.47 1.19-5.13 0.02Male 0.39 0.19-0.78 0.01Hgb < 12 0.96 0.43-2.15 0.92Weight Loss 1.45 0.74-2.83 0.28KPS ≤70 0.81 0.19-3.39 0.77

Larynx 1.95 0.83-4.55 0.12 1.62 0.69-3.82 0.27

Hypopharynx 2.96 1.36-6.45 0.01 3.97 1.77-8.93 0.001

T3/T4 2.34 1.11-4.95 0.03 2.91 1.33-6.35 0.01Mod-Heavy drinker 1.92 0.98-3.75 0.06Ever Smoker 3.63 1.12-11.80 0.03>40 pack-years 2.82 1.05-7.54 0.04

Loco-regional Control

Local or regional recurrence occurred in N=13 patients *

3-year LRC 76%

5-year LRC 68%

Of those that had LRC, Mean time to event was 59 weeks

Mean survival after LRC was 2.5 years

Factors associated with LRC Univariate Analysis

Variable HR 95% CI p-value

Age > 55 1.13 0.52-2.45 0.76Male 0.70 0.28-1.76 0.45Hgb < 12 1.00 0.39-2.54 1.00Weight Loss 1.83 0.86-3.92 0.12

Larynx 1.70 0.63-4.56 0.29

Hypopharynx 1.24 0.36-4.24 0.73

T3/T4 2.22 0.94-5.23 0.07Mod-Heavy drinker 1.29 0.57-2.93 0.55Ever Smoker 3.92 0.93-16.54 0.03

Disease-Free Survival

Local or regional or distant recurrence occurred in N=25 patients, and 16 of these presented with distant recurrence

3-year DFS 64%5-year DFS 56%

Of those that had any recurrence, mean time to event was 49 weeksMean survival after LRC was 1.3 years

Factors associated with Disease-Free Survival Univariate Analysis

Variable HR 95% CIp-value

Male 0.56 0.28-1.10 0.09Larynx 2.11 0.95-4.67 0.07Hypopharynx 2.96 1.36-6.45 0.01T3/T4 2.34 1.11-4.95 0.03

Ever Smoker 3.631.12-11.80 0.03

>40 PY 2.82 1.05-7.54 0.04

HPV 0.70 0.28-1.76 0.44

Decreased survival– Hypopharynx

– T3/T4

– Ever Smoker

– Mod-Heavy smokerIncreased survival – No significant

Factors associated with Disease-Free Survival Uni and Multivariate Analysis

Decreased survival

– HypopharynxHR 4.06 (1.89-8.72) p=0.0003

– T3/T4HR 2.66 (1.3-5.45) p=0.01

Variable HR 95% CI p-value

Male 0.56 0.28-1.10 0.09Larynx 2.11 0.95-4.67 0.07Hypopharynx 2.96 1.36-6.45 0.01T3/T4 2.34 1.11-4.95 0.03

Ever Smoker 3.631.12-11.80 0.03

>40 PY 2.82 1.05-7.54 0.04

HPV 0.70 0.28-1.76 0.44

Neck Dissection

• 65 patients underwent either uni or bilateral ND

• Residual carcinoma identified in 18/65 (28%) patients

• Pathology status unknown for 2 patients

Neck Dissection- Continued

• Of the N=13 patients with Loco-regional recurrence, 8 underwent neck dissection

• 5/8 (63%) had positive LN (versus 28% overall)

Second Primary Malignancies

• Patients with HNC at high risk for SPM

• Estimated to occur at rate of 3%/yr

• Metachronous > 6 months

• Synchronous < 6 months

• Simultaneous

Warren-Gates criteria• Both the index and secondary

tumors are malignant• At least 2 cm of normal

mucosa between the two tumors

• However, if the tumors are in same location, should be separated in time by ≥5 years

• Not a metastatic tumor

Source: UpToDate: Second primary malignancies in patients with head and neck cancers

Second Primary Malignancies

Total SPM 18

Head and Neck 1

Non-Head and Neck 17

Lung 8

Prostate 2

Colon 2

Renal 1

Pancreatic 1

Thyroid 1

CLL 1

Leukemia 1

• Average time to diagnosis of SPM was 31 months (median 29, range 12-62)

• The median time to occurrence of SPM was 2.4 years (similar to other publications of 2.8 years, Argiris 2004)

• In a meta-analysis, of the SPM, frequency of most common sites HNC (35%), lung (25%), esophagus (9%)

Toxicity

Grade 3 or 4 mucositis: Data available for 66/105 (63%) patients.

The rates of grades 3 and grade 4 mucositis were 24 (36%) and 39 (59%)

Osteoradionecrosis: N=5

PEG Dependence: Data available for 96/105 patients.

The mean duration of PEG use = 255 days (range 31-1570 days), which included patients who died with a PEG in place.

46/96 (48%) patients required PEG use greater than 6 months.

15/96 (16%) of patients required PEG greater than 12 months.

Hypopharynx poorer outcomes

Hypopharynx Entire Cohort

N 14 105

Stage IV 13/14 (93%) 75/105 (71%)

Positive LN 6/11 (55%) 18/65 (28%)

Any Recurrence 8/14 (57%) 25/105 (24%)

Distant 7/8 (88%) 16/105 (15%)

Comparison to Other Cohorts

Study Regimen 3-year OS 5-year OS

GBMC RT +Cisp/5-FU 75% 60%

Bachaud Cisplatin/5FU 36%

Calais Carbolatin + 5FU

51%

Vokes RT + Cisp/5-FU + Hydrox

55%

Jeremic RT+ Cisp 46%

Brizel/Duke 1998

RT +Cisp/5-FU 55%

Adelstein et al RT +Cisp/5-FU 74 50

Study Critiques

Weaknesses– Retrospective Review– Heterogenous cohort, mainly

oropharynx– HPV unavailable for half of

oropharynx, mainly the earlier patients before HPV widely tested

– Toxicity not always available, may be underreported

Strengths– Large patient cohort– Uniform treatment protocol– Excellent follow-up– Enough time for interval events to

occur– Availability of excellent records via

electronic and paper charts– Exhaustive review of records from

three departments

Conclusions

• The CRT regimen described demonstrated excellent outcomes with high rates of great organ preservation

• However, loco-regional and distant recurrences continue to cause significant mortality and highlight the need for more effective therapies to prevent and manage these events.

Future Projects

• Compare Brizel and Gainseville cohorts (efficacy and toxicity and hospitalizations)

• Compare impact of salivary gland transfer (on xerostomia and dehydration, infection, need for hospitalization)

• Cetuximab and other biological agents• Identify high-risk patients and determine if more

intensive treatment plan is reasonable• Use of epigenetic salivary markers for diagnosis or

prediction of recurrence

Areas of Clinical Interest

• Management of Neck• Decision-making in patients with Complete versus Partial

response to CRT• Decision-making in patients with positive versus negative

neck pathology• Tailor treatment in high-risk patients??

Acknowledgements

• Dr. Patrick K. Ha• Dr. Marshall Levine• Dr. Mei Tang• Dr. Eva Zinreich• Hrishikesh Gogineni• Spencer Lake • Katherine Fan

• Dr. Joseph A. Califano• Dr. John R. Saunders • Dr. Ray G. Blanco• Dr. Sara Pai • Dr. Simon R. Best • Marianna L. Zahurak • Barbara Messing • Karen Ulmer• All staff at Milton Dance

Center, Radiation Oncology, Medical Oncology

THANK

YOU!

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