Celine Bicquart Advanced Laryngeal Cancers

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Celine BicquartAdvanced Laryngeal Cancers

• October 19, 2006

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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

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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.

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HPI contd

• FNA of L neck node- Metastatic poorly-
  differentiated SqCCa with high NC 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.

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• 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.

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Supraglottis- high incidence of LN metastasis
jugulodigastric, jugulocarotid,
juguloomohyoid. Glottis- Subglottis- 1 ant mid
and lower jugular to prelaryngeal node ????
2 post paratracheal
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12000 new cases yearly- 2 of all cancers60-65
glottic30-35 supraglottic5 subglotticMFp53
-mutated in 47 smokers
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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
• Airway obstruction

Risk Factors -Tobacco -Alcohol
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Evaluation and Work-up

• Complete HP
• Assess for adenopathy in neck.
• Loss of Thyroid click sign of post-cricoid
  extension.
• Mass over thyroid signifies thyroid cartilage
  invasion.

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• Indirect mirror exam for visualization.
  EEEeeeeee.
• Fiberoptic flexible laryngoscopy.
• CXR for metastatic evaluation
• CBC, LFTs. If abnormal, may get CT abd, bone
  scan.

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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.

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• Direct laryngoscopy with bx for tissue dx,
  disease extent.
• Usually performed as part of panendoscopy to r/u
  multiple tumors.

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Squamous Cell Carcinoma of the Larynx
95 SqCCa. TVC- well to mod-diff Supra and
subglottis- more poorly diff
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• 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.

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Clinical Question

• My patients 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?

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• Looked at induction chemo definitive RT vs.
  conventional TL PORT
• Stratified according to KPS, Stage III vs. IV,
  Nodes, tumor site

Patients with no response or locally recurrent
disease underwent salvage laryngectomy.
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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)

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VA Trial
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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.

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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.

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• 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.

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• 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

PR or CR assessed after each cycle. If after any
cycle, no response, went directly to surgery.
Only CR went on to XRT
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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.

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Disease Free SurvivalCI 0.52-1.43
3y 5y
Chemo RT 43 25
S PORT 31 27
3y 5y
Chemo RT 57 30
S PORT 43 35

• Overall survival chemo (57)gtsurgery (43) at 3
  years but equal at 5 years. NB- small number of
  pts. at 5y.
• CI 0.50- 1.48

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• No difference in locoregional failure.
• Increase in distant mets in surgery group (36)
  compared to (25) in chemo arm. plt.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) gt T3 (48) gt T4 (0)

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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.

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• 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 (gt1cm
  into tongue base or penetrating cartilage
  invasion)
• Multi-center, prospective, randomized

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-cisplatin 100mg/m2 5-FU 1000mg/m2-For
concurrent cisplatin given on day 1,22,43 of
RT-RT to primary 70Gy in 35 _at_2Gy-RT to neck,
supraclav, post. neck 50Gy-Salvage RT for those
who failed induction chemo was 50-70Gy-Questionna
ires were filled out at baseline and at each f/u.
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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.

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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.

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• 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

2y 5y
Induction 52 plt.02 38
Concurrent 61 plt.006 36
RT alone 44 27
Disease Free Survival
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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 plt.02. Concurrent
vs. RT alone plt.001 No statistical difference
between induction and RT alone arms.
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Effect on Distant Metastases
2y 5y
Induction 9 15
Concurrent plt.03 8 12
RT alone 16 22
Chemo reduced the rate of DMs. The only
statistically significant difference was between
the concurrent vs. RT alone arm. plt.03
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Laryngeal Preservation at 3.8y
number
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.
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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.

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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
5y OS 10y OS
Chemo RT 38 13
S PORT 33 14
5y PFS 10yPFS
Chemo RT 32 11
S PORT 26 8.5

• 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.

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Additional therapies

• Molecular targets have been identified which may
  hold promise in the treatment of HN 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.

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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?

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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. 1998124964-971
.

• 1998 follow up 46/65 surviving pts, 71 RR
• 25 surgeryPORT, 21 experimental arm
• HNQOL, SF-36 General Health Measure Short Form,
  Beck Depression Inventory, alcohol and smoking
  surveys.

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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.

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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.

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Conclusions from VA Study

• Better QOL in the CTRT appears to be related to
  more freedom from pain, better emotional well
  being, and lower levels of depression than to
  preservation of speech function

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RTOG91-11 Speech

• Percentages of speech impairment at 1 and 2y.
• 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.

1y 2y
Induction 6 3
Concurrent 11 6
RT alone 13 8
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RTOG 91-11-Laryngeal Function _at_1y
Soft foods No swallow
Induction 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

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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.
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• Patients who are treated with larynx-preserving
  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?

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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 gt 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.
  25711-716.

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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 2xs higher in initial T3-4 than T1-2
• - nonglottic primary site. Fistula OR 2.08

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• 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

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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

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Conclusions from RTOG Salvage
Survival following salvage laryngectomy not
influenced by initial organ preservation
treatment.
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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.

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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.

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Dose Plan
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BEV Supraclav
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BEV- Lateral
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Side Effects of RT to larynx

• Soreness
• Dysphagia
• Odynophagia
• Erythema, Desquamation of Neck
• Weight Loss

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Acknowledgments

• 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

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