17 Sep 2005 Joint Hospital Surgical Grand Round Update on Management of Anaplastic Thyroid Carcinoma Dr Sunny YS Cheung Department of Surgery United Christian Hospital

 Introduction – epidemiology & Dx  Case Presentation  Current Therapy Available  Novel Experimental Therapy

Introduction  ATC - aggressive malignancy  1.6% of all Thyroid CA Gilliland 199  F:M = 1.5:1 McIver 2001  Peak Age :  Rapidly enlarging neck mass with local compressive symptoms Dysphagia, dysphonia, dyspnoea  40% had evidence of metastasis at diagnosis  All considered stage IV

Diagnosis & Staging Investigation  FNAC of thyroid mass or LN met  Accurate in 90% Us-Krasovec 1996  Immunohistochemical staining Distinguish ATC from lymphoma or medullary CA  CT neck / thorax / liver  Endoscopy – laryngeal / pharyngeal extension  Bone scan

Survival Data Mayo Clinic Experience McIver 2001  Retrospective case series of 134 ATC  Subsequent Therapy 79 XRT 12 CHEMO for distant met 13Multimodality

Survival Data Mayo Clinic Experience McIver 2001  Median Survival : 3 months  1-year survival : 10%  Disease-specific mortality rate 97%  Operation & XRT significantly improved survival over palliative treatment alone 3.5 months vs 2.3 months vs 3 weeks

 Extent of Operation & Resection Completeness No significant impact on survival (4 vs 2.3 months) Local recurrence rate : 37% (median 2.5 months)  Adjuvant XRT did not reduce local recurrence Slightly longer time to recurrence (5 vs 3 months) Survival Data Mayo Clinic Experience McIver 2001

Case Presentation  M/85  Dysphonia and dysphagia for 2 months  Rapidly growing left thyroid mass with neck LN  FNAC: papillary CA thyroid  MRI scan extensive extracapsular tumor infiltrating overlying strap muscles and paraglottic area

 Total thyroidectomy + Partial Pharyngectomy, Total laryngectomy + left RND + PM Flap  Pathology: Anaplastic CA arising from papillary CA thyroid  Patient complicated by anastomostic leak, require non-oral feeding  Patient develop neck swelling D30

 Recurrence of tumor  Died D50  Survival 3 months

Problems  Diagnosis: sampling error by FNAC  Complications associated with aggressive therapy  Short survival despite aggressive therapy

Can we do better ?

Local Control High Dose Accelerated Radiotherapy Mitchell 1999  ATC have short tumor doubling time  To deliver total dose of RT over as short period as possible  Increase its efficiency by decreasing tumor repopulation  17 ATC patients (8 with metastasis) recruited from 1991 to 1995  Accelerated RT given BD, 5 days per week, total dose of 60.8Gy in 32 fractions over days

Results 1. Local control and survival 59% achieved Partial / Complete Local Response 29% had stable disease Overall survival – median 10 weeks 76% died with metastatic disease 2. Toxicity Grade 3 or 4 toxicity for esophagitis, dysphagia and skin erythema

Author’s Conclusion  High dose accelerated RT showed high response rate & local symptom control in ATC  Significant toxicity Unacceptable morbidity in patients with poor prognosis  More effective systemic treatment is needed

Systemic Chemotherapy Pasieka 2003  Doxorubicin is the most frequently used chemotherapeutic agents  <20% response rate  No evidence of complete response  Combination with cisplatin or bleomycin showed very little improvement in clinical response  Limited by drug toxicity

Treatment of ATC with Paclitaxel: Phase II Trial Ain 2000  20 patients with persistent or metastatic disease despite surgery or local RT  96-hour continuous infusion every 3 weeks for 1 to 6 cycles  53% response rate (29-76%)  1 complete response and nine partial response  Median survival in responders: 8 months

Multimodal Therapy Crevoisier 2004  A prospective study Surgery, chemotherapy and hyperfractionated accelerated external RT  30 patients recruited from 1990 – 2000 Surgery performed before RT-CT 2 cycles of doxorubicin + cisplatin before RT and 4 cycles after RT RT given in BD fractions of 1.25Gy, 5 days per week to total 40Gy

Results 1. Survival Median survival = 10 months Overall survival rate  1 year = 46% (28-64)  3 year = 27% (10-44) 2. Toxicity pharyngoesophagitis (23 & 10%) neutropenia (3 & 70%) thrombocytopenia (3 & 10%) anaemia (27%)

Prognostic Factors for Survival Univariate Analysisp-value T3 vs T40.02 Tracheal extension Neg vs Pos Metastasis Neg vs Pos Mixed ATC with WDTC ≥20% vs <20% 0.05 Surgery without metastasis Complete vs Incomplete 0.02

Prognostic Factors for Survival Multivariate AnalysisHazard Ratiop-value Tracheal Extension2.8 ( %)0.03 Macroscopic complete tumor resection 2.7 ( )0.04

Are we doing something good?

Novel Therapy in Experiment  Rediffernetiation Therapy Retinoid Acid Schmutzler 2000 Histone Deacetylase Inhibitors Fumihiko 2004 Restore radioiodide uptake and retention in ATC To allow effective radioiodide therapy  Molecular Thearpy Epidermal growth factor receptor-targeted therapy Nobuhara 2005  Gene Therapy Combined suicide/cytokine Gene therapy Luisa 2005

Summary  ATC is an aggressive malignancy  Aggressive multimodal therapy is needed for prolong survival  Survival improved but Treatment toxicity limit the benefit to our patients  Far from achieving a cure  “ palliate ” vs “ prolong survival ”

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