primary chemoradiation therapy with cisplatin/5-fu for
TRANSCRIPT
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/
Oropharynx62.5
61.5 M
64.7 F
64.4
64.1 M
65.0 F
46.1
41.0 M
57.0 F
Larynx 63.2
63.9 M
60.6 F
65.5
66.1 M
62.9 F
50.1
51.3 M
46.5 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 Toxicity
Mucositis, nephrotoxicity,
Neutropenia,
– Long-term Toxicity
Peg 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-Up
Years 1-2
– Every 2 months
Years 3-5
– Every 3-6 months
Years 5+
– Every 6-12 months
Assessment of Treatment Response
Clinical 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 American 15
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
– Unavailable8
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 0.03
Mod-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 0.01
Mod-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 distantrecurrence 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 anyrecurrence, mean time to event was 49 weeks
Mean 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 0.09
Larynx 2.11 0.95-4.67 0.07
Hypopharynx 2.96 1.36-6.45 0.01
T3/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 smoker
Increased survival
– No significant
Factors associated with Disease-Free Survival
Uni and Multivariate Analysis
Decreased survival
– Hypopharynx
HR 4.06 (1.89-8.72) p=0.0003
– T3/T4
HR 2.66 (1.3-5.45)
p=0.01
Variable HR 95% CI p-value
Male 0.56 0.28-1.10 0.09
Larynx 2.11 0.95-4.67 0.07
Hypopharynx 2.96 1.36-6.45 0.01
T3/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 18Head 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!
Bibliography
1. UpToDate.com Overview of head and neck cancer, Concurrent chemoradiation for locoregionally advanced head and neck cancer, Complications of radiotherapy for head and neck cancer, Quality of life in head and neck cancer
2. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology Head and Neck Cancers V.I.2010 www.nccn.org
3. Ferlay J et al. Estimates of worldwide burden of cancer in 2008:GLOBOCAN 2008
4. Surveilance Epidemiology and End Results (SEER) Cancer Statistics Review 1975-2006
http://seer.cancer.gov/csr/1975_2006/
Pocket Guide to TNM Staging of Head and Neck Cancer and Neck Dissection Classification, by American Academy of Otolaryngology- Head and Neck Surgery Foundation, Inc http://www.entnet.org/EducationAndResearch/upload/NeckDissectionPart1.pdf
5. Warren, S, Gates, O. Multiple primary malignant tumors. A survey of the literature and a statistical study. Am J Cancer 1932; 16:1358.
6. Du X, Liu C. Racial/Ethnic Disparities in Socioeconomic Status, Diagnosis, Treatment and Survival among Medicare-insured Men and Women with Head and Neck Cancer J. Health Care for the Poor and Underserved. 21 (3). 2010. 913-30.
Source: SDFSJ