RTOG 9512 - Glottic Ca T2 RT

Randomised Trial of Hyperfractionation Versus

Conventional fractionation in T2 Squamous cell carcinoma of

The Vocal CordRTOG 9512

(EORTC 22992)

Pages : 958-963

REFERENCE :

ADDITIONAL REFERENCES :

Objectives

Primary : To test whether Hyperfractionation improves the local

control rate for early stage (T2N0) squamous cell carcinoma of the true vocal cord (compared to conventional fractionation)

Secondary : To determine the acute and late radiotherapy toxicity

associated with each of the fractionation schedules To examine overall and disease-free survival patterns

associated with each of the fractionation schemes

Sample Size

The protocol specified a target sample size of 240 patients

Based on detecting a 55% reduction in local failure

Corresponding to an improvement in 5-year local control from 70% to 85% or a hazard rate (HR) of 0.456

The sample size was increased by 10% to guard against patients retrospectively being reclassified as ineligible

Patient Selection

Inclusion criteria : Patients with histologically proven invasive squamous cell carcinoma

arising from the true vocal cord

Disease limited to stage T2N0

The bulk of the tumor must be present on the vocal cord with extension to adjacent areas

For lesions causing impaired mobility (T2b) at least two physicians must be in agreement that the vocal cord is impaired

The minimum age for entry is 18 years

Karnofsky performance status > 60

The patient must sign a study-specific informed consent form

Patient Selection

Exclusion Criteria : Patients with verrucus carcinoma or adenocarcinoma were excluded

Patients with tumors extending to pre-epiglottic space, pyriform sinus, a fixed cord or cartilage invasion were not eligible (T3-T4)

Clinical or radiographic evidence of lymphadenopathy in the neck

Evidence or suspicion of distant metastases

Patients with a prior or concurrent malignancy (other than non-melanoma skin cancer) were ineligible, unless previous cancer was treated 5 years or more prior to the current tumor and the patient had remained continually disease free

Patient Selection

Exclusion criteria (continued) : Karnofsky status < 60

Patients with complete stripping or laser excision of all gross disease

Prior radiotherapy to the mid-neck or larynx

Patients with recurrence or persistent tumor following any treatment

Patients for whom follow-up by the registering physician was not feasible

PROTOCOL SCHEMA

AJCC ‘T’ STAGING FOR GLOTTIC CANCER : 7th EditionT2 - Tumour extends to supraglottis and/or subglottis, and/or with impaired vocal cord mobility

MODIFIED AJCC ‘T’ STAGING FOR GLOTTIC CANCER T2a - Tumour extends to supraglottis and/or subglottis, without impaired vocal cord mobility

T2b – Tumour causes impaired vocal cord mobility with or without extension into supraglottic or subglottic structures

Radiation Therapy Technique

Beam : Cobalt 60

Linear Accelerators with 4-6 MV Photon beams With 6 MV Photons : Bolus (2-5mm) over the anterior half of the larynx

in patients with lesions involving the anterior larynx or patients with minimal soft tissue anterior to the thyroid cartilage


Radiation Dose-Fractionation

Standard Fractionation Arm : Treatment to the primary site :

70 Gy in 35 fractions (2 Gy per fraction, once a day, five days a week in seven weeks )

Boost fields :

Will begin at 50 Gy so that the target volume (primary site plus at least 1.0 cm dosimetric margin) should receive at least 90% of maximum dose

Hyperfractionation Arm : Treatment to the primary site :

79.2 Gy in 66 Fractions (1.2 Gy per fraction, twice a day with a minimum of a 6 hour interval, five days a week in 6-1/2 weeks)

Boost fields :

Will begin at 60 Gy so that the target volume (primary site plus at least 1.0 cm dosimetric margin) should receive at least 90% of maximum protocol dose


Radiation Therapy Irradiation Portals

Lateral opposing fields At least a 2.0 cm margin in all directions around the tumor volume will be used

for the first 50 Gy (Standard fractionation arm) and 60 Gy (Hyperfractionation arm)

6x6 cm field - Centred over the mid thyroid cartilage Upper border : 0.5-1.0 cm above the thyroid notch

Posterior border : 1 cm behind the thyroid cartilage

Inferior border : At the bottom of the cricoid cartilage

At least 1 cm fall off anteriorly

Tissue compensators (wedges) : Encouraged to enhance homogeneity

Typical field arrangement for Lateral opposing Fields


Boost Fields :

Weighted lateral fields, oblique fields or an AP field may be used to boost the primary tumor

Boost field borders must encompass the initial tumor volume with at least a 1.0 cm margin

Target volume for Initial large field Minimal target volume for Boost fields

Evaluation and Follow up

Acute Toxicity :

During Radiation Therapy

4 weeks after the completion of Radiation Therapy

Tumour control and Late Toxicity

Clinically by mirror examination or clinic endoscopy

Every 3 months in 1st year

Every 4 months in 2nd year

Twice an year in 3rd year

Annually thereafter

Statistical Analysis

Enrolment : Prospective Randomised controlled trial

April 1996 – July 2003

87 Institutions

250 patients diagnosed to have biopsy proven Squamous cell carcinoma, T2N0 Glottic cancer were enrolled and randomised

11 patients were excluded from the final analysis and data analysis was done for a total of 239 patients

250 patients of Biopsy proven Squamous Cell Carcinoma,

T2N0 Glottic cancer enrolled and Randomised in 1:1 ratio

Data of 239 patients used for final evaluation purposes

11 Patents excluded from the final data analysis

4 – Standard Fractionation arm:

2 – Nodal disease2 – Restaged as T3-T4

7 – Hyperfractionated arm :3 – Nodal disease

3 – Restages as T3-T41 – Withdrawn consent

COMPARABLE


Local control rates

Cumulative incidence method to account for the competing risk of death without local failure.

Patients were censored for loco regional control after 5 years.

Disease-free and overall survival rates

Kaplan-Meier method.

Cox proportional hazards model with T-subcategory as a covariate :

Used to estimate and test the Hazard Ratio (HR) between the Hyperfractionated (HFX)and the Standard Fractionation (SFX) arms.

HR<1 indicated a reduction in failure rate after HFX.


Patients without clinical complete response (CR) in the primary site :

Classified as having a local failure (LF)

The time of failure was backdated to study day 1

Patients with CR who subsequently experienced local recurrence :

Considered as failures on the date of reported relapse

Otherwise patients were censored at their last follow-up visit

Patients were considered to be at risk for failure until they died


Disease-free survival (DFS) included :

Local recurrence or persistent local disease

Nodal failure

Distant metastasis

Second primary tumor of all sites, or

Death from any cause

The date of DFS failure was the first occurrence of any of these events, otherwise patients were censored at their last follow up visit

Patient-reported voice quality was not measured

Results

Acute Toxicity : Similar Grade 1 and 2 toxicities in both arms

Higher incidence of Acute grade 3 toxicity was seen with Hyperfractionation than with Standard fractionation

33.3% vs 22.7%; p=0.084

Seen mainly in forms of :

Laryngeal oedema

Mucosal reactions

Skin reactions

Results

Late Toxicity : No difference in 5-year cumulative incidence of late grade 3 toxicity

8.5% after Standard fractionation

8.5% after Hyperfractionation

Occurrence of Grade 1 and 2 toxicities were also found to be similar in both arms

3 patients required tracheostomy after standard fractionation while 2 required following Hyperfractionation

COMPARABLE

Results

117 Deaths

25% attributed to the study cancer

20% to second primary cancers

40% unrelated to cancer or treatment (comorbid conditions)

15% unknown

Results Local Control :

67 patients experienced local failure by 5 years

35 in Standard fractionation versus 26 in Hyperfractionation

Local control rates :

70% versus 78% for Standard fractionation and Hyperfractionation

HR=0.70, p=0.14

Locoregional Control : 10 patients had isolated nodal relapse as site of first failure

4 in Standard fractionation versus 6 in Hyperfractionation

Loco regional control rates :

67% versus 73% for Standard fractionation and Hyperfractionation

HR=0.77, p=0.26

Trend towards improved Local Control in Hyperfractionated arm

Results – Sub stage analysis

Sub stage analysis

T2a T2b

5 year Local Control

76.8% 70.0% HR=1.51 95% CI = 0.93-

2.44 p=0.10

5 year Locoregional

control

74.1% 63.3% HR=1.65 95% CI = 1.05-

2.59 p=0.03

5 year Disease Free Survival

52.4% 31.4% HR=1.62 95% CI = 1.19-2.22 p=0.002

5 year Overall Survival

77.5% 50.0% HR=2.06 95% CI = 1.43- .97 p=0.0001

Results – Sub stage analysis based on Fractionation

T2a T2b

P value for interaction

5 year Local Control

HR=0.58 95% CI 0.30-1.12

p=0.11

HR=0.87 95% CI 0.42-1.78

p=0.70

0.42

5 year Locoregional control

HR=0.61 95% CI 0.33-1.14

p=0.12

HR=1.00 95% CI 0.52-1.93

p=0.99

0.28

5 year Disease Free Survival

HR=0.74 95% CI 0.49-1.11

p=0.15

HR=0.86 95% CI 0.54- 1.38

p=0.54

0.63

5 year Overall Survival

HR=0.6595% CI 0.39-1.08

p=0.10

HR=1.06 95% CI 0.62-1.79

p=0.84

0.19

NOT

SIGNIFICANT

Discussion

The only prospective trial of Hyperfractionation conducted specifically in T2N0 glottic cancer

Results showed an 8-point difference in local control (78% vs 70%) at 5 years favouring hyperfractionation (p=0.14)

This corresponded to a 30% reduction in the hazard rate (HR=0.70) as well as a trend for improved disease-free survival

There were no significant differences in outcomes between Standard fractionation and Hyperfractionation by sub stage (T2a vs T2b)

Discussion

The rationale for hyperfractionation in this trial was drawn from 2 large fractionation studies enrolling mostly non larynx cases

EORTC 22791 – Oropharyngeal tumors Better local control and overall survival with Hyperfractionation

RTOG 9003 – Locally advanced head and neck cancers Better local control, disease free survival and overall survival i]with

Hyperfractionation and concomitant boost

Discussion

Accelerated fractionation 225 cGy per fraction per day (Slight Hypofractionation)

Found to be effective at increasing local control with acceptable toxicity

Yamazaki et al 1 :

Significant benefit from accelerated fractionation in a randomized trial of T1 glottic carcinomas using 2.25 Gy per fraction up to 63 to 66 Gy (LC, 92%vs 77%; p=0.004)

Moon et al 2 :

Compared 225 cGy fractions to 63 to 67.5 Gy for T1-T2 glottic cancers in a randomized trial

Local progression free survival was 11 points higher (89% vs 78%) in the hypofractionated arm

Underpowered to show significance (p=0.213)1. Hideya Yamazaki, Kinji Nishiyama, Eiichi Tanaka, Masahiko Koizumi, Masashi Chatani, Radiotherapy for early glottic carcinoma (T1N0M0): Results of prospective randomized study of radiation fraction size and overall treatment time, International Journal of Radiation Oncology*Biology*Physics, Volume 64, Issue 1, 1 January 2006, Pages 77-81

2. Sung Ho Moon, Kwan Ho Cho, Eun Ji Chung, Chang Geol Lee, Kyu Chan Lee, Gyu-Young Chai, Ki Mun Kang, Jong Young Lee, Woong-Ki Chung, Woo Yoon Park, Jin Hee Kim, A prospective randomized trial comparing hypofractionation with conventional fractionation radiotherapy for T1–2 glottic squamous cell carcinomas: Results of a Korean Radiation Oncology Group (KROG-0201) study, Radiotherapy and Oncology, Volume 110, Issue 1, January 2014, Pages 98-103

Discussion

Hliniak et al 3 :

Randomized with T1- T3, N0 glottic and supraglottic cancers

66 Gy in 33 fractions over 45 days or accelerated treatment of 66 Gy in 38 days by delivery twice a day on Thursdays.

There was no benefit in overall locoregional control (p=0.37)

In the subset of glottic cancers, Loco regional control was higher (p=0.04)

3. A. Hliniak, B. Gwiazdowska, Z. Szutkowski, E. Kraszewska, P. Kukolowicz, A. Jarzabski, B. Sochacka, M. Mazurkiewicz, K. Paprota, W. Oliskiewicz, O. Zadrożna, P. Milecki, M. Kubiak, L. Czopkiewicz, M. Jagas, S. Góźdź, A. Wieczorek, A. Woytowicz, B. Cisowska, H. Magdziarz, S. Nowakowski, W. Kośniewski, I. Laskosz, A. Serafin, E. Gradoń, A multicentre randomized/controlled trial of a conventional versus modestly accelerated radiotherapy in the laryngeal cancer: influence of a 1 week shortening overall time, Radiotherapy and Oncology, Volume 62, Issue 1, January 2002, Pages 1-10

Discussion

Retrospective analysis at several centers have found that 225 cGy fractions over 25-28 treatments produce excellent outcomes

Chera et al 1 :

T1-T2 Glottic Cancer patients

Found overall treatment time to be a significant factor

Better outcomes with 225-cGy fractions

Le et al 2 :

Fraction size, total dose, and overall time had impacts on the control of T2 glottic cancers

1. Bhishamjit S. Chera, Robert J. Amdur, Christopher G. Morris, Jessica M. Kirwan, William M. Mendenhall, T1N0 to T2N0 Squamous Cell Carcinoma of the Glottic Larynx Treated With Definitive Radiotherapy, International Journal of Radiation Oncology*Biology*Physics, Volume 78, Issue 2, 1 October 2010, Pages 461-466

2. Quynh-Thu X. Le, Karen K. Fu, Steward Kroll, Janice K. Ryu, Jeanne M. Quivey, Thomas S. Meyler, Richard M. Krieg, Theodore L. Phillips, Influence of fraction size, total dose, and overall time on local control of T1–T2 glottic carcinoma, International Journal of Radiation Oncology*Biology*Physics, Volume 39, Issue 1, 1 August 1997, Pages 115-126

Discussion

Garden et al :

Retrospective evaluation of 228 T2 Glottic Cancer patients

3 different fractionation schedules

Conventional : <=2 Gy/fraction; Once daily treatment

Accelerated : >2Gy/fraction; Once daily treatment

Hyperfractionation : 1.1-1.2 Gy/fraction; Twice daily treatment

80% local control with both Hypofractionation and Hyperfractionation

Discussion

Tumors with impaired cord mobility (T2b) are found to have poorer prognosis as compared to without impairment of vocal cord mobility (T2a)

In this study, there was a trend for better local control in T2a versus T2b disease

Significant differences in loco regional control, disease-free survival, and overall survival

No differential effect by fractionation was seen

These results were in concordance with the meta analysis conducted by McCoul and Har-El 1

Pooled data from 21 reports and found a statistically better outcome in T2a disease

Comparison of 5-year local control of disease for lesions with impaired vocal cord mobility (T2b) vs those with normal vocal cord mobility (T2a) showed a statistically significant difference

Odds Ratio = 1.83; 95% CI 1.52-2.20; P < .001

1. McCoul ED, Har-El G. Meta-analysis of Impaired Vocal Cord Mobility as a Prognostic Factor in T2 Glottic Carcinoma.Arch Otolaryngol Head Neck Surg.2009;135(5):479-486

Conclusions

This trial was the 1st prospective randomised control trial done to see the effectiveness of Hyper fractionated Radiation Therapy in T2N0 Glottic cancers

The trial did not achieve its aim of 55% reduction in local failure at 5 years with improvement in 5 year local control from 70% to 85%

However, this trial did show an improvement in local control with Hyperfractionation as compared to conventional fractionation (78% versus 70%), with acceptable toxicity

Conclusions

This trial did not compare accelerated fractionation (2.25Gy/fraction per day) with Hyperfractionation

The accelerated fractionation regimen still holds good for good local control and survival benefit in T2N0 glottic cancers

Conclusions

Tumors with impaired cord mobility (T2b) have a worse outcome as compared to T2a tumors

The sub staging should be included in the AJCC Classification

Also, as there was no effect of fractionation seen in T2b tumors, other modalities of treatment should be explored

? Addition of concurrent chemotherapy

THANK YOU !!!!!

EORTC 22791

325 patients with T2-3 oropharyngeal cancer

Randomized to :

Conventional fractionation : 70 Gy in 35 fractions (2Gy per fraction)

Hyperfractionation : 80.5 Gy in 70 fractions (1.15Gy per fraction; Twice daily treatment)

Hyperfractionation increased :

5 year Local Control (40→59%)

5 year Overall Survival (31→47%)

Benefit primarily for T3 tumors

RTOG 9003

268 patients with locally advanced Head and neck cancer

Randomized to

Conventional fractionation : 70 Gy in 35 fractions (2Gy per fraction)

Hyperfractionation : 81.6 Gy in 68 fractions (1.2Gy per fraction; Twice daily treatment)

Split-course : 67.2 Gy in 42 fractions (1.6Gy per fraction; Twice daily treatment with a 2 weeks break)

Concomitant boost : 72 Gy [with b.i.d. RT for last 12 fractions (1.8 and 1.5 Gy)]

Concomitant boost and hyperfractionated RT improved 2-year LRC (54%), DFS (39%), and OS (53%) compared to standard or split-course accelerated RT

RTOG 9512 - Glottic Ca T2 RT

Healthcare

Transcript of RTOG 9512 - Glottic Ca T2 RT