Celine
Bicquart
Advanced
Laryngeal
Cancers
October 19, 2006
Overview of Talk
 Case
Presentation
 Anatomy and Lymph Node Drainage of the
Larynx
 Overview of Laryngeal Epidemiology
 Staging of Patient
 Review of Literature
 Patient Treatment Plan
DS
 ID:
49 y/o male
 HPI: Hoarse since January 2006 with
odynophagia and dysphagia. 10 lb wt loss
in August.
 Referred to ENT at OHSU.
 8/16/06- CT neck- 17 x 14mm enhancing
soft tissue lesion filling L piriform sinus.
Involves L. supraglottis, L glottis, L
subglottis with midline focal area of
destruction of thyroid cartilage. +Posterior L
level III adenopathy.
HPI cont’d

FNA of L neck node- Metastatic poorly- differentiated
SqCCa with high N:C ratio.

9/15/06- Total larynectomy, L neck dissection II-IV, L
hemithyroidectomy, Pec major flap.
Path: 4.3cm G3 Invasive Squamous Cell, negative
margins. Invades through thyroid cartilage, but thyroid
gland uninvolved. 4/14 Level II. +ECE. 2/6 Level III.
–ECE. 1/8 Level IV. –ECE. +perineural invasion.
Indeterminate angiolymphatic space invasion.

PMH: Seizures

Meds: Dilantin 300mg qd, Oxycodone q3-5h, Nicotine
patch 21mg qd

Allergies: NKDA

PSH: Laryngectomy

SH: Single. Lives in Portland. Receives disability,
previously did odd jobs. Smoked 1.5ppd x 30y. Cut back
in 05/06. Now uses nicotine patch. Drinks 1-2 drinks qd.

PE: Healing incisions of left neck dissection and pec
major flap. Stoma appears patent. No fistula noted. No
discharge from stoma noted.
Supraglottis- high incidence of LN metastasis: jugulodigastric,
jugulocarotid, juguloomohyoid.
GlottisSubglottis- 1 ant: mid and lower jugular to prelaryngeal node ????
2 post: paratracheal
12000 new cases yearly- 2% of all cancers
60-65% glottic
30-35% supraglottic
5% subglottic
M:F
p53-mutated in 47% smokers
Signs and Symptoms

Hoarseness- MC presenting sx of glottic ca
 Sore throat- MC presenting sx of supra ca
 Odynophagia- MC presenting sx of supra ca
 Foreign Body Sensation
 Dysphagia
 Stridor
 Pain
 Hemoptysis
 Otalgia- via vagus and nerve of Arnold.
 Weight loss
Risk Factors:
 Airway obstruction
-Tobacco
-Alcohol
Evaluation and Work-up

Complete H&P

Assess for adenopathy in neck.

Loss of Thyroid click: sign of post-cricoid
extension.

Mass over thyroid signifies thyroid cartilage
invasion.




Indirect mirror exam for visualization. “EEEeeeeee.”
Fiberoptic flexible laryngoscopy.
CXR for metastatic evaluation
CBC, LFTs. If abnormal, may get CT abd, bone scan.
CT, MRI





Performed before bx.
MRI is better to delineate soft-tissue extent of primary tumor.
CT is better for evaluating bone invasion.
CT also very useful for detecting subclinical LN metastasis.
Want to look for pre-epiglottic, periglottic space invasion,
subglottic and extralaryngeal extension, and cartilage invasion.

Direct laryngoscopy
with bx for tissue dx,
disease extent.

Usually performed as
part of panendoscopy
to r/u multiple tumors.
Squamous Cell Carcinoma of the Larynx
95% SqCCa.
TVC- well to mod-diff
Supra and subglottis- more poorly diff
 Following
surgery, DS has had a slow
recovery. FT still in place secondary to
residual swelling. Patient reports
dysphagia.
 Patient
also reports dyspnea on exertion.
Clinical Question
My patient’s cancer was a T4, for which the standard of
care had been a total laryngectomy followed by adjuvant
radiation.

TL results in disease control rates of 70-80%; and with
TE punctures for voice restoration, patients can
eventually regain their verbal communication skills.

In light of this good disease control rate, is there a way to
obtain equivalent survival while sacrificing less quality of
life?


Looked at induction chemo + definitive RT vs. conventional TL + PORT
Stratified according to KPS, Stage III vs. IV, Nodes, tumor site
322 T3 or T4 SqCC
2 cycles cisplatin + 5-FU
+ Response (CR of PR)
Larynectomy + RT: 50, 60, 65-73.8cGy
No response
1 more cycle + RT 66- 76 cGy
Salvage laryngectomy
Patients with no response or locally recurrent disease
underwent salvage laryngectomy.
VA Trial
 After
two cycles of chemotherapy: CR
31% and PR 54%. (Overall response
85%)
 At
median f/u of 33 months, the estimated
2-year survival was 68 percent (95% CI,
60 to 76%) for both tx groups (P = 0.9846)
VA Trial
VA Trial
 Toxicity
due to RT was similar in both
arms.
 Grade 2 mucositis slightly higher in chemo
group 38% vs. 24% in TL group.
 Higher incidence of surgical complications
in salvage cases after RT vs. just after
chemo.
VA Trial

Patterns of recurrence differed significantly between
the two groups, with more local recurrences (P =
0.0005) and fewer distant metastases (P = 0.016) in
the chemotherapy group than in the surgery group.

A total of 59 patients in the chemotherapy group
(36 percent) required total laryngectomy.

So….64% preserved their larynx without
compromising OS.

Induction chemo does enhance the
effectiveness of RT, but since no direct
comparison was made between chemoRT vs.
RT alone, the role of chemo remains uncertain.


Determine if chemo followed by XRT was comparable with standard surgery
+PORT in pts with T2-4, N0-2b SCCA of the pyriform sinus or AE fold
Multi-centered, prospective, randomized trial
T2-4 SqCCa of pyriform sinus of AE fold
100 induction chemo x 3 cycles
94 TL, PP + PORT
CR: XRT
PR or CR assessed after each cycle. If after any cycle, no response, went
directly to surgery. Only CR went on to XRT
EORTC Trial






97/100 pts. started chemo as randomized.
60/97 proceeded to complete chemo + RT.
(70Gy, 65Gy)
8/97 required surgical salvage. (55Gy, 60Gy)
92/94 pts. had surgery as randomized.
89/92 had post-op RT. (60Gy)
Chemotherapy complete responders were more
frequent among those with T2 disease (82%)
than those with T3 (48%) or T4 (0%) disease.
3y
Disease Free
Survival
CI: 0.52-1.43
Chemo 43%
+ RT
S+
31%
PORT
3y

Overall survival chemo
(57%)>surgery (43%) at 3
years but equal at 5 years.
NB- small number of pts. at
5y.
CI: 0.50- 1.48
Chemo 57%
+ RT
S+
43%
PORT
5y
25%
27%
5y
30%
35%





No difference in locoregional failure.
Increase in distant mets in surgery group (36%) compared to
(25%) in chemo arm. p<.041
Survival with functional larynx with no LR, tracheostomy, FT,
gastrostomy at 3 and 5 years = 28% and 17% respectively.
Rate of functional larynx in those who died of causes other
than local disease progression and died with a functional larynx
at 3 and 5 years= 42% and 35% respectively.
EORTC study: conclusions



Induction chemo is safe for hypopharyngeal cancer.
Fewer distant mets and increased time until mets appear
CR: T2 (82%) > T3 (48%) > T4 (0%)
Conclusions so far…





Organ preservation is possible
Role of induction chemo is still not exactly
known.
Distant metastases decreased, and time to
DM increased.
EORTC trial had small number of patients.
Lower larynx preservation rates in the EORTC
was a result of more stringent selection
criteria.



Determine role of induction chemo vs concurrent
chemo vs radiation alone in laryngeal preservation
for pts with stage 3 and 4 SqCCa of the larynx
T1 and high-volume T4 tumors where excluded
(>1cm into tongue base or penetrating cartilage
invasion)
Multi-center, prospective, randomized
-cisplatin 100mg/m2; 5-FU 1000mg/m2
-For concurrent: cisplatin given on day 1,22,43 of RT
-RT to primary: 70Gy in 35 @2Gy
-RT to neck, supraclav, post. neck: 50Gy
-Salvage RT for those who failed induction chemo was 5070Gy
-Questionnaires were filled out at baseline and at each f/u.
Induction Chemo Arm
 168/174
patients received induction
chemo.
 144 had either a CR (21%) or PR (64%),
allowing them to receive PORT.
 24/168 patients who could not go onto RT.
Only 7 went directly to RL.
 11/24 received chemo/RT, and all had CR,
and of these, only 1 needed TL.
 At end of RT: 150/174 (86%) had CR.
Concurrent ChemoRT arm
 120/172
(70%) received all 3 doses
cisplatin.
 40/172 (23%)received 2 doses.
 At end of RT: 154/172 (90%) had CR.
RT alone arm
 At
end of RT: 148/172 (86%) had CR.
2 and 5 year overall survival did not differ
• 76% vs 74% vs 75% at 2 years
• 55% vs 54% vs 56% at 5 years
Disease Free
Survival
Concurrent
2y
52% p<.02
61% p<.006
5y
38%
36%
RT alone
44%
27%
Induction
# LF
LCR
Induction
61
64%
Concurrent
35
80%
RT alone
72
58%
Concurrent resulted in
significantly fewer LRs
compared to both induction
chemo and RT alone.
Concurrent vs Induction
p<.02.
Concurrent vs. RT alone
p<.001
No statistical difference
between induction and RT
alone arms.
Effect on Distant Metastases
2y
5y
Induction
9%
15%
Concurrent
8%
12%
16%
22%
p<.03
RT alone
Chemo reduced the rate of DMs.
The only statistically significant difference was between the
concurrent vs. RT alone arm. p<.03
number
Laryngeal
Preservation
at 3.8y
%
Induction
125/173 72%
Concurrent
145/172 84%
RT alone
116/173 67%
IMPORTANT!! Induction
chemotherapy followed by
RT when compared to RT
alone, did not significantly
improve the rate of
laryngeal preservation.
Conclusion from RTOG 91-11

Concurrent chemoRT is superior to both induction
chemo and RT alone in regards to locoregional control,
laryngeal preservation, and distant metastases.

Induction chemo showed benefits in only improving DFS,
and decreasing rate of DMs. No effect on LR or OS.

Overall survival does not differ significantly between
treatment arms. (76% at 2y)

Concurrent chemo does cause twice as severe mucosal
effects, potentially contributing to delayed recovery of
swallowing in this group.
Is laryngeal preservation (LP) with induction chemotherapy (ICT)
safe in the treatment of hypopharyngeal SCC? Final results of the
phase III EORTC 24891 trial.
Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 22, No 14S (July 15 Supplement), 2004: 5531
Chemo +
RT
5y PFS
10yPFS
32%
11%
8.5%
S + PORT 26%




5y OS
10y OS
Chemo +
RT
38%
13%
S+
PORT
33%
14%
Ultimate disease control, including successful salvage after XRT, was not significantly
different between both arms.
As of 12/2003, 14 % of pts in arm 1 and 17 % of pts in arm 2 were still alive. The
hypopharynx SCC evolution was the cause of death in 43 pts in arm 1 and in 41 pts
in arm 2.
In arm 2 survival with a functional larynx in place was 22 % at 5y and 9 % at 10y.
Conclusions: this final analysis has confirmed the preliminary results with similar
survival curves as compared with conventional treatment and allowed 2/3 of the
survivors to retain their larynx.
Additional therapies

Molecular targets have been identified which may hold
promise in the treatment of H&N SqCCa.

Overexpression of EGFR is recognized in more than
95% of SqCCas. The EGFR and its ligands, EGF and
TFG alpha are important in cell proliferation, adhesion,
invasion and angiogenesis.

Administration of the EGFR monoclonal antibody
(cetuximab) has been shown to increase
radiosensitization, decrease tumor cell line growth and
increase apoptosis.

Other novel chemotherapeutics include agents to inhibit
tyrosine kinase, angiogenesis inhibitors, and agents that
have selective toxicity to hypoxic cells.
Function and Quality of Life
 Preserving
the larynx is great, but not as
great if the larynx is not effective.
 How
well does it function after concurrent
chemoRT?
 How
do patients feel about their ability to
communicate and swallow?
Long-term Quality of Life After Treatment of
Laryngeal Cancer
Jeffrey E. Terrell, MD; Susan G. Fisher, PhD; Gregory T. Wolf, MD; for the
Veterans Affairs Laryngeal Cancer Study Group
.
Arch Otolaryngol Head Neck Surg. 1998;124:964-971

1998 follow up: 46/65 surviving pts, 71% RR
• 25 surgery+PORT, 21 experimental arm
• HNQOL, SF-36 General Health Measure Short
Form, Beck Depression Inventory, alcohol and
smoking surveys.
Quality of Life f/u of VA Study

Those with larynx fared significantly better from the
standpoint of speech communication.

At 2 years post-treatment, patients with successful organ
preservation had regained their pretx level of functioning
for 2/3 measures tested (intelligibility and reading rate)
and exceeded pretx performance on the 3rd (a
communication profile used to assess general
communication status).

TL + PORT pts had a decrease in all 3 speech
communication-related measures despite availability of
all modes of speech rehabilitation and therapy.

Measures of swallowing dysfunction were similar
between both arms.
Quality of Life f/u to VA study
Pts with successful organ preservation:



had better scores on all domains of the SF-36
compared to those who underwent TL.
scored significantly better on the bodily pain and
mental health domain of the SF-36.
scored significantly better on the emotion domain and
their impression of their response to treatment on the
HNQOL survey.
At long-term f/u, 10 of 45 patients had BDI scores
consistent with moderate or severe depression.

9 of those 10 had undergone TL.
Conclusions from VA Study

Better QOL in the CT+RT appears to be
related to more freedom from pain, better
emotional well being, and lower levels of
depression than to preservation of speech
function
RTOG91-11 Speech
Percentages of speech impairment at 1 and 2y.
Induction

1y
2y
6%
3%
Concurrent 11%
6%
RT alone
8%
13%
No difference among 3 groups in regard to speech at 12
or 24m.
Moderate speech impairment: difficulty in pronouncing some words and being
understood on the telephone.
RTOG 91-11-Laryngeal Function @1y
Soft foods
Induction


No swallow
9%
0%
Concurrent
23%
3%
RT alone
15%
3%
No difference in groups’ QOL
2-yr all three groups similar with 16%, 15%, 14% reporting difficulty
swallowing
Grade and frequency of toxic acute effects was similar in the induction and RT
alone arms: mostly grade 3 in-field effects on skin and mucous membranes.
Concurrent chemoRT had chemo-related toxic acute effects (neutropenia, severe
N/V, increased rates of severe radiation-related mucosal, pharyngeal and
esophageal effects.
Rates of late toxic effects were similar among groups.
 Patients
who are treated with larynxpreserving modalities are still at risk of
having to undergo salvage laryngectomy
in the future.
 In
these patients, is there any added
morbidity associated with salvage
laryngectomy?
Danish Society for Head and Neck
Oncology (2003)




Wanted to look at surgical outcome of 472 pts with
salvage laryngectomy after XRT from 1987-1997
Specific outcome looked at was development of
pharyngocutaneous fistula.
89 fistulas lasting > 2 weeks; Overall fistula rate = 19%
Number of TLs per year decreased linearly (from 58 to
37), whereas the annual number of fistulae increased
slightly (from 7 to 11).
• RR in 1987 =12%
• RR in 1997 =30%
•Grau C, Johansen LV, Hansen HS, Andersen E, Godballe C, Andersen LJ, Hald J, Moller H, Overgaard M,
Bastholt L, Greisen O, Harbo G, Hansen O, Overgaard J. Salvage Laryngectomy and Pharyngocutaneous
Fistulae after Primary Radiotherapy for Head and Neck Cancer: a National Survey From DAHANCA. Head and
Neck. Sep 2003. 25:711-716.
Danish Study

Increased rate attributed to:
• Higher stages offered XRT as definitive therapy
• Decrease in individual surgical experience with TL

Other significant RFs for fistulae included:
-younger patient age
- primary advanced T and N stage.
RR 2x’s higher in initial T3-4 than T1-2
- nonglottic primary site. Fistula OR 2.08




Surgical complication rates were low.
No differences in systemic complications between
treatment arms
Complications independent of the time from the end
of treatment to TL
Fistulas occurred in:
• Arm 1 = 25%
• Arm 2 = 30%
• Arm 3 = 15%
Conclusions from RTOG Salvage



Salvage post laryngeal
preservation has
acceptable morbidity.
1/3 will develop fistula
Locoregional control is
excellent:
74%, 74%, 90%
Overall Survival for TL
patients at 2y:
69% 71% 76%
Conclusions from RTOG Salvage
Survival following salvage laryngectomy not influenced by initial organ
preservation treatment.
Treatment of DS

Although had TL, needs post-op RT:
-cartilage invasion
-perineural invasion
-multiple positive nodes
-nodes with ECE
He will be treated on RTOG 0234:
Surgery + RT + Cetuximab followed by either
docetaxel or cisplatin.
Setup of Radiotherapy of the Larynx

Patient supine.
 Face mask on.
 Borders: superior- 2cm above mastoid tip
inferior- bottom of cricoid cartilage
posterior- behind spinous process
Off cord at 40Gy.
Cord block on laterals.
Wedge used.
Boost stoma.
Dose Plan
BEV Supraclav
BEV- Lateral
Side Effects of RT to larynx
 Soreness
 Dysphagia
 Odynophagia
 Erythema,
Desquamation of Neck
 Weight Loss
Acknowledgments

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Dr. John Holland
Dr. Carol Marquez
Dr. Charles Thomas
Dr. Arthur Hung
Dr. Marsha Crittenden
Dr. Parag Sanghvi
Dr. Tarka McDonald
Dr. Patrick Gagnon
Dr. Sam Wang
Lori Ismach
Tony He