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T4 Larynx cancer can be treated with Chemoradiotherapy

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

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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
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
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
 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
 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
 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

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T4 Larynx cancer can be treated with Chemoradiotherapy

  • 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

Editor's Notes

  1. Salvage laryngectomies: Glottic> SGL Fixed cord>Mobile cords Gross invasion of cartilage>No involvement of cartilage Stage IV vs III (49% vs 22%)
  2. Increase in CTRT from 3% (1990) to 12%(2000) Increase in local tumor excision 12% (1991) to >20% (2001) Majorly non-operative treatment consisted of RT alone
  3. Distinction between T4a and T4b came in 2003 Patients who received nonsurgical therapy were largely those with unresectable or medically inoperable disease
  4. However, it might be incorrect to equate poor larynx function with extensive T3 or T4a disease.