Traditionally, T4 larynx cancers are recommended to undergo surgery as the primary modality of treatment. However, a select group of patients may be treated with CTRT

1. T4 Larynx cancer CAN be
treated with larynx preservation
Dr Ajeet Kumar Gandhi
MD (AIIMS), DNB (Gold Medalist)
UICCF (MSKCC,USA)
Assistant professor, Radiation oncology
Dr RMLIMS, Lucknow

2. 1900-1980s
• Total Laryngectomies for all stages
• Partial Laryngectomies
1990-2019
• Laryngeal preservation with RT/CTRT
• Salvage Laryngectomies
• Total/Partial Laryngectomies with adjuvant RT
2019--
• Multimodality approach
• Individualized patient decision
Evolution of Larynx cancer treatment

3. Dysfunctional Larynx
best preserved by
Formalin
Laryngectomy is not the
solution to all larynx
cancers: Biology wins
over anatomy always!!
T4 Larynx cancer CAN be treated
with LARYNX PRESERVATION

4.  Phase III randomized controlled trials with defined
end points to that effect (Level I)
 Prospective controlled trials: Cohort studies (Level
II)
 Retrospective institutional/multi-institutional
analysis, case series (Level III-IV)
What is the gold standard
for evidence based oncology

5.  332 patients (stage III-IV) randomized to either Surgery + PORT
or PF+RT alone (chemo-selection)
 85 Patients were of T4 and 30 had cartilage invasion
 Complete response rate (confirmed histologically) : 64% and
combined CR+PR rates: 98%
 2-year survival 68% (60-75% CI) surgery vs. 68% (60-76% CI)
CRT group. Local recurrence higher (2 vs 12%), regional
recurrence similar, distant metastasis lower (17% vs 11%)
 Larynx preservation rate: 64%
 Higher rates (50%) of salvage laryngectomies for T4 tumors
(cartilage invasion)
 No difference in overall survival of T4 cancers as compared to
other stages
Veterans Affairs Laryngeal Cancer
Study Group

6.  Included T2,T3, T4 low volume disease (resectable disease)
 T4 disease (51/518) with penetration through cartilage or
extension more than 1 cm in to base of tongue excluded
 Laryngeal preservation rate: 84%; 5-year laryngectomy
free survival: 43%
 Speech dysfunction rate:5% and swallowing dysfunction
rate: 15%
 No outcome analysis for T stage
 Critique: Gold standard arm of laryngectomy is missing
RTOG 91-11

7. 10-Year
OS
10-year
LFS
LRC Larynx
preservation
rate
CTRT 28% 28.9% 65.3% 81.7%
ICRT 39% 23.5% 48.9% 67.5%

8.  Prospective evaluation of Larynx Preservation: Phase II
study
 97 Stage III-IV patients (33% T4 tumors)
 One cycle cisplatin plus 5-Fu followed by LP (CRT) or LT
 Patients also received 2 cycles of adjuvant chemotherapy
 Laryngeal preservation rate (70%)
 3-year cause specific survival 87% and OS 85%
 23% had salvage laryngectomy

9.  Prospective phase II study
with 36 patients
 3-year OS=78%; DFS=80%
 Laryngeal preservation
rate=58%
 This regimen further
tested in phase II study.
Dietz A. Ann Oncol 2018

10.  Larynx cancer is a chemo-sensitive disease with
ORR (CR+PR) with CT exceeding 80-90%
 Prospective phase III date on T4 larynx cancer is
lacking
 Selected patients of T4 cancers (low volume
disease, base of tongue extension less than 1 cm)
can be treated with larynx preservation strategy
 CTRT may be better than Induction CT->RT
approach
 Larynx preservation rate: 60-80%; Local control
rate: 50-60%
 Salvage laryngectomy rate: 50%
Lessons from prospective/RCTs

11.  High level of skill and cooperation among
various disciplines
 Adequate compliance from patients
 Careful documentation and appropriate
surveillance
 Routine application in Community practice with
un-selected patients detrimental
Organ preservation: Team Approach

12.  Rampant use of CTRT and the uses went up
 Improper selection of patients
 Non-operative (preferred) versus operative
Enthusiasm in application of technology

13.  Increase in CTRT from 3%
(1990) to 12%(2000)
 Increase in local tumor
excision 12% (1991) to >20%
(2001)
 Decline in survival for early
SGL cancer patients
 T4N0 patient had improved
survival

14.  All 810 patients:
southwestern region of
Germany
 Observational study
 30 pts CTRT compared
with 238 treated with
Surgery
 Combination of 2 population-based study
 Data regarding comorbidity, treatment intentions,
locoregional control, functional outcome, toxicity, patient
and physician preferences, tumor characteristics, such as
tumor volume and operability of the tumor, and quality
of life are not recorded.

15.  NCDB Analysis 2003-2006
 969 patients. 64% received CRT
 Not all patients received 70 Gray
(35%)
 No data on chemotherapy cycles
and completion
 N2/N3 patients received more
CRT (40% versus 24%)
 High volume centers received TL
 Medically inoperable patients
treated with CRT
 Patient characteristics not coded

16.  Generalization: Distinction between T4a and T4b has not been
done in studies and databases
 Stage III-IV patients (T2N1-T4N3)
 Selection Bias (Lin CC, et al. Cancer 2016;122:2845-2856)
 Better insurance and supportive families: Surgery
 Isolated, poorer patients and those with medical co-
morbidities: Radiation therapy
 Non-operative management often includes RT alone
(Timmermans AJ, et al. Head Neck 2016;38(Suppl. 1):E1247-
E1255)
 Institutional Bias (Grover S, et al. Int J Radiat Oncol Biol Phys
2015;92:594-601)
 Surgery: Centre of excellence
 Radiation: Closer to home, convenience
Flaws in the studies

17.  221 sequential patients of
T4 laryngeal cancers
treated with MDACC
(1983-2011)
 161 TL patients and 60 LP
patients
 Median overall survival for
patients LP vs TL: 64
months (NS)
 Poor loco-regional control
in LP arm but OS same

18.  SEER database analysis
of >3000 patients
 Patients with advanced
laryngeal cancer who
underwent complete
CRT were found to have
overall and cause-
specific survival rates
similar to those of
patients undergoing
surgery.

19.  Multivariate analysis and
propensity score matching
were used to explore the
association between the
intervention and OS.
 A total of 1559 patients who
underwent SRT, 1597 patients
who underwent CCRT, and
386 patients who underwent
ICRT were included.

21. T4 Larynx cancer CAN be treated
with larynx preservation
Optimizing the outcomes!!

22.  Patient subgroups:
 T4a disease who can safely swallow and have a serviceable voice
 Low volume disease (12cm3)-Bryant C, et al. Hong Kong J
Radiol 2013;16:198-202
 Medically inoperable patients
 Skin infiltration, Base of tongue invasion
 Nodal bulk of disease
 Patient`s Wishes
 TALK score (T stage, albumin, Liquor use, KPS) [Laryngoscope
2012;122:1043-50]
 High p53, low Bccl-Xl, high p16 better LP [JCO 2008;26:3128-37]
Optimizing outcomes: Patient selection

23.  TPF vs PF as induction chemotherapy: better LP rates (70%
vs 60%) [GORTEC Trial, JNCI 2009;101:498-506]
 TPF vs PF as induction chemotherapy: better LP rates and
improved survival [TAX 324. NEJM 2009;20:921-7]
 Concurrent CTRT: Cisplatin 3 weekly
 TPF vs PF followed by Cisplatin-RT vs. Cetuximab-RT:
Better LP rates but more toxicities [TREMPLIN Study. JCO
2013;31:853-9]
Optimizing outcomes: Chemotherapy
regimens

24.  Induction chemotherapy a valid strategy
 Allows chemo-selection
 IPD analysis showed no detriment in OS compared with
surgery [MACH-NC, Lancet 2000;355 (9208):949-55]
 Lesser toxicity rates compared to CTRT
 Concurrent chemoradiotherapy
 Fit patients deemed to tolerate the entire course of therapy
 Higher LP rates and LCR
 Higher toxicities compared to Induction trials
 Limited Induction (1 cycle) f/b CTRT
Optimizing outcome: Sequencing

25.  Response to chemotherapy: 50%,80%,90%
 Larynx preservation: Anatomic vs Functional
 Baseline speech and swallowing function
evaluation
 Endpoints
 Laryngo-esophageal dysfunction free survival
 Overall Survival
 Correlative biomarker study: EGFR, ERCC-1,E-
Cadherin, TP-53 mutation
Optimizing outcome: Defining end
points

26.  RCTs used older RT techniques: More
toxicities and dose modulation was not
possible
 Dose escalated IMRT with CTRT ( 67.2
Gray/28# and 56 Gray/28#) [Nutting C.
IJROBP 2012;82:539-547]
 13/60 had T4a tumors
 2-year LP rate in dose escalated arm: 96.4%
 CTRT with IMRT: Laryngectomy free
survival at 2 years (89%)
30% had T4a tumour [MSKCC experience.
IJROBP 2007]
Optimizing outcome: Radiation
technology

27. At present, this cannot
be answered because the
goal can vary (superior
OS, better Quality of
Life, less morbidity),
depending on patient
and physician
preference
Which treatment protocol is
best

28. Learnings from Larynx treatment
outcomes

29.  Tumor Factors:
 Margin negative surgery
 Reconstructive issues
 Functional morbidity
 Patient factors:
 Co-morbidities
 Age >65-70 Years
 Pre-operative aspiration
 Surgeon and hospital factors
 Training issues (Holsinger FC et al. J Am Coll Surg 2005)
 Maintenance of skill issues
 Volume outcome relationships (Eskander A et al. Head Neck
2014)
Laryngectomy: Key Issues

30.  Selected patients of T4 larynx cancer can be and should be
treated with larynx preservation
 Goals and outcomes of treatment discussed with patients:
shared decision making
 LP is not for all T4 patients as also not TL
 Multimodality approach yields comparable outcomes to TL
 Rather than shying away from LP. We should focus on
optimizing outcomes towards a Individualized approach