Organ Preservation for Laryngeal Cancer

1
Organ Preservation for Laryngeal Cancer

• Adam Ray, MD
• Division of Otolaryngology-Head and Neck Surgery
• SIU School of Medicine

2
Objectives

• Discuss laryngeal preservation strategies
  designed and researched in landmark studies
• Compare and contrast these studies and their
  outcomes
• Discuss organ preservation vs function
• Future trial with novel agents
• What this means for training programs

3
Introduction

• 12,000 new cases per year
• Single modality treatment for early staged
  glottic cancers
• 60-65 glottic
• 30-35 supraglottic
• 5 subglottic
• Advanced staged glottic tumors can require
  multi-modality therapy
• Several trials have demonstrated organ
  preservation without compromise in survival

4
Introduction

• Organ preservation strategies
• Definitive radiation therapy (XRT)
• Induction chemotherapy followed by XRT
• Concurrent chemoradiotherapy

5
T classification

• Glottic
• T3 tumor limited to the larynx with vocal cord
  fixation and/or invades paraglottic space, and/or
  minor thyroid cartilage erosion (eg. Inner cortex)

• Supraglottic
• T3 tumor limited to the larynx with vocal cord
  fixation and/or invades any of the following
  post cricoid area, pre-epiglottic tissues,
  paraglottic space, and/or minor thyroid cartilage
  erosion (eg. Inner cortex)

6
T classification

• Glottic
• T4a tumor invades through the thyroid cartilage
  and/or beyond the larynx
• T4b invades prevertebral space, incases carotid
  artery, invades mediastinal structures

• Supraglottic
• T4a tumor invades through the thyroid cartilage
  and/or beyond the larynx
• T4b invades prevertebral space, incases carotid
  artery, invades mediastinal structures

7
XRT

• Mendenhall et al
• N75
• T3 T3N0 (79), T3N1 (15), T3N2b (6)
• XRT alone or with planned neck dissection
• 5-yr local control rate 63
• 5-yr absolute and cause specific survival rates
  54 and 78 respectively
• Favorable and Unfavorable characteristics
• T4 5-yr local control surgery at 62 and 48
  for selected glottic and suproglottic cancers
  respectively

8
XRT

• Altered fractionation schedules
• Hyperfractionation
• Increase the total dose given but decrease the
  dose per fraction
• Multiple fractions per day, duration unchanged
• Accelerated fractionation
• Shortens therapy
• Increase number of fractions per day, dose
  unchanged

9
XRT

• European Organization for Research and Treatment
  of Cancer (EORTC)
• Not site specific

• Radiation Therapy Oncology Group (RTOG)

10
XRT

• European Organization for Research and Treatment
  of Cancer (EORTC)
• Compared hyperfractionation vs conventional for
  T2-3, N0-1 oropharyngeal SCCA
• T3N0-1 treated with hyperfractionation had
  significant improved local regional control at 5
  years (p.02), no change in survival (p.07)

11
XRT

• Radiation Therapy Oncology Group (RTOG)
  (protocol R9003)
• Hyperfractionation and two variants of
  accelerated fractionation vs conventional
• Altered fractionation had better local control
  rates (p.045 and p .050 respectively)
• No difference in overall survival
• Significant increase in acute toxicity but no
  difference in late toxicity

12
XRT

• Non-site specific trials show increase in
  local-regional control of 10-15
• Overall time reduction 1.5 wks led to
  intolerable acute toxicity
• Delivery of more than 2 fractions per day led to
  higher incidence of late toxicity

13
Induction Chemotherapy

• The Department of Veterans Affairs Laryngeal
  Cancer Study Group
• Determine if induction chemo followed by XRT with
  TL for salvage was comparable to TL PORT for pts
  with stage 3 or 4 laryngeal cancer
• Multi-centered, prospective study
• 332 pts enrolled

14
Induction Chemotherapy

• VA study two arms
• Experimental arm
• 2 cycles of chemo (cisplatin and 5 FU)
• PR or CR assessed
• PR or CR had 3rd cycle of chemo followed by XRT
• Non-responders went on to TLPORT
• Control arm
• TL PORT

15
Induction Chemotherapy

• VA study results
• Overall tumor response to chemo85
• 2-yr and 10-yr follow up show significant
  difference in survival
• 36 in the organ preservation group required TL
• More local recurrences (p.001) but less mets
  (p.001) in experimental arm
• Overall laryngeal preservation rate 64

16
Induction Chemotherapy

• European Organization for Research and Treatment
  of Cancer (EORTC)
• 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
• 202 pts enrolled 100 (induction chemo) 94
  (immediate surgery)

17
Induction Chemotherapy

• EORTC study
• Experimental arm
• 3 cycles of chemo (cisplatin and 5-FU)
• PR or CR assessed after each cycle
• Only CR went on to XRT
• Control arm
• Partial laryngopharyngectomy PORT

18
Induction Chemotherapy

• EORTC study results
• Dz free survival chemoimmediate surgery arm at 3
  and 5 years
• 43 and 25 for chemo arm
• 32 and 27 for immediate surgery arm
• Overall survival chemo (57)surgery (43) at 3
  years but equal at 5 years
• No difference in localregional failure
• Increase in distant mets in surgery group (36)
  compared to (25) in chemo arm

19
Induction Chemotherapy

• EORTC study results
• Rate of functional larynx in those who completed
  the experimental arm 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)

20
Induction Chemotherapy

• VA and EORTC
• Organ preservation is possible
• Exact role of chemo not certain
• Distant metastases decreased
• EORTC trial had small number of patients
• Lower larynx preservation rates in the EORTC was
  a result of more stringent selection criteria

21
Concurrent Chemoradiotherapy

• RTOG 91-11
• Determine role of induction chemo vs concurrent
  chemo vs radiation alone in laryngeal
  preservation for pts with stage 3 and 4 SCCA of
  the larynx
• T1 and T4 tumors where excluded (tongue base or
  cartilage invasion)
• Multi-center, prospective, randomized
• 547 pts enrolled (173 arm 1) 172 (arm 2 and 3
  each)

22
Concurrent Chemoradiotherapy

• RTOG study

23
Concurrent Chemoradiotherapy

• RTOG study results
• 3 and 5 year survival did not differ
• 76 at 2 years overall
• Local-regional control significantly better in in
  the concurrent chemo/RT than the induction chemo
  or XRT alone
• 3 and 5 year dz free survival
• Arm 1 52 and 38
• Arm 2 61 and 36
• Arm 3 44 and 27

24
Concurrent Chemoradiotherapy

• RTOG study results
• Both chemotherapy arms showed significant
  decreases in mets
• Laryngeal preservation at 3.8 yrs median f/u
• 84 concurrent chemo/RT
• 72 induction chemoRT
• 67 XRT alone

25
Concurrent Chemoradiotherapy

• RTOG conclusions
• Induction chemo XRT and XRT alone was inferior
  to concurrent Chemo/RT in terms of local regional
  control, mets, and laryngeal preservation

26
Function and Quality of Life

• How does the larynx function after chemo/RT?
• How do patients feel about there ability to
  communicate and swallow, and how does this effect
  them socially?
• How toxic is to toxic?
• Can we accurately predict who will do better than
  others?

27
Quality of Life

• VA study
• At 6-,12-,and 24-
• Pts with preserved larynx had significantly
  better speech intelligibility, communication, and
  reading rates.
• No significant differences in swallowing function
• 1998 follow up 65 pts, 71 response rate
• 25 surgeryPORT, 21 experimental arm
• HNQOL, SF-36 General Health Measure Short Form,
  and the Beck Depression Inventory

28
Function/Quality of Life

• VA study
• Organ preservation had better QOL scores on all
  domains of the SF-36 than TL
• HNQOL showed better pain scores in pts with
  intact larynges.
• 10 of 45 pts had BDI scores consistent with
  moderate or severe depression (9 with TL)
• Communication scores not significantly different
  between groups

29
Function/Quality of Life

• VA study
• 2-yr post-treatment, laryngeal preservation group
  scored better on intelligibility, reading rate,
  communication
• TL pts had decrease in all three measures
• Swallowing dysfunction similar between groups

30
Function/Quality of Life

• 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

31
Function/Quality of Life

• RTOG study
• No difference in groups QOL
• 1-yr
• 23 in concurrent chemo/RT could swallow only
  soft foods, 3 could not swallow
• 9 in inductionXRT and XRT alone could swallow
  only soft foods, none could not swallow
• 2-yr all three groups similar with 14-16
  reporting difficulty swallowing

32
Quality of Life

• Hanna et al (2004)
• 42 pts with stage III or IV larynx CA
• No significant difference in QOL
• TL group had trend for greater difficulties with
  social functioning (p.18)
• TL group reported significantly greater sensory
  disturbances, use of pain medicines, and coughing
  (p.001, p.049, p.004)
• Chemo/RT increase in dry mouth (p.02)

33
Function

• Lazarus et al (1996)
• 9 pts with XRT or CTRT assessed for swallowing
• All pts had tongue base or laryngeal movement
  abnormalities
• Gillespie et al (2004)
• 19 pts with larynx/hypopharynx stage III or IV
  SCCA treated with surgeryPORT or concurrent
  chemo/RT
• No difference on MD Anderson Dysphagia Inventory

34
Function

• Carrara-de Angelis et al (2003)
• 19 pts treated with concurrent chemo/RT
• Voice analysis shows 40 mod dysphonia and 27
  with severe dysphonia
• Most were mild to moderate with intelligible
  communication
• Swallowing efficient in most
• 3 normal
• 7 with mild dysphagia
• Moderate dysphagia in 2 and severe in 2

35
Function

• Staton, Robbins et al (2002)
• 45 pts assessed after RADPLAT for stage III and
  IV dz
• All dz free
• Persistent use of a g-tube or tracheostomy 6 mos
  after completion
• Fixed vocal cord had highest incidence of poor
  functional outcomes

36
Salvage Laryngectomy

• Danish Society for Head and Neck Oncology (2003)
• 472 pts with salvage laryngectomy after XRT from
  1987-1997
• 89 fistulas lasting greater than 2 weeks
• Overall fistula rate 19
• TL decreased per year from 58-37
• Fistula rate increased
• RR in 1987 12
• RR in 1997 30

37
Salvage Laryngectomy

• Danish Study
• Increased rate attributed to
• Higher stages offered XRT as definitive therapy
• Decrease in individual surgical experience with
  TL
• RR 2xs higher in initial T3-4 than T1-2
• Pts with nonglottic tumors had a fistula odds
  ratio of 2.08

38
Salvage Laryngectomy

• Lavertu et al (1998)
• Compared complications between pts treated with
  XRT and concurrent chemo/RT
• 30 salvage laryngectomies performed
• Major and Minor Complications
• Conclusion
• Major and minor complications did not differ
  between groups
• Morbidity rates for salvage laryngectomy was
  acceptable

39
Salvage Laryngectomy

• RTOG (2003)
• 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

40
Salvage Laryngectomy

• RTOG Conclusions
• Acceptable morbidity
• 1/3 will develop fistula
• Local regional control is excellent
• Survival following salvage TL not influenced by
  initial organ preservation treatment

41
Conclusions

• Laryngeal preservation is available to pts with
  advanced disease
• More research is needed to identify criteria
  leading to optimal patient outcomes
• QOL
• Functional outcomes

42
Conclusions

• Current studies suggest that pts are more
  concerned with the physical consequences of
  surgery and interference with social activities
  than with impairments in function
• As we move away from TL towards organ
  preservation, Head and Neck surgeons will face
  challenging salvage surgery

43
What is most important and ethical is to
objectively inform our patients of the various
options and provide them with reasonable
expectations of outcomes as it relates to each
treatment approach. K. Thomas Robbins, MD

• Arch Otolaryngol Head Neck Surg/Vol 131, p819,
  Sept 2005

44
References

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