HYPOFRACTIONATION RETURNSRejil Rajan

Total dose

Dose per fraction

Number of fractions per day

Total duration

HISTORY AND EVOLUTION

Wintz was a leader of the Erlangen school, where it was believed that fractionated treatment was decisively inferior, to be judged a "primitive method" and "weak irradiation."

single

Popularised by Gosta Forsell

Stockholm

method

Fractionated treatments becoming more popular than hypofractionated ,And it was almost abandoned across world as curative treatment

HYPOFRACTIONATION RETURNS

In the early 1950s, the comeback of hypofractionation started quietly and came from Stockholm, the city where hypofractionation was first championed by Forsell 50 years previously.

Lars Leksell. Leksell had-“stereotaxy.” Working with a radiation physicist, Borge Larsson, they created the first

Gamma Knife (Elekta AB, Stockholm, Sweden).

RATIONALE High dose per fraction = High cell kill

High dose per fraction = Increase late effects

But always was preferred in palliative setting - because of logistic reasons

But as we understand radiobiology better, hypofractionation is back For the tumors with low α/β ratio like Prostate cancer where it is Seen that prostate cancer cell are sensitive to dose per fraction.

Interest also because of the newer conformal techniques like stereotactic treatments, IMRT have emerged where the chance of irradiating normal tissues with high dose per fraction is less.

Tumour control

Late adverse effects

CELL SURVIVAL CURVEalpha is the log of number of cells

sterilized non-repairable way per gray of ionizing radiation.

beta is the log of the number of cells sterilized in a

repairable way per gray squared.

ALPHA/BETA RATIO Mathematically, when αD = βD². i.e. when the two components are equally responsible

for cell kill, D = α/β.

i.e. the dose at which the linear and quadratic components of cell killing are equal. (Unit = Gy)

It is the ratio of “intrinsic radiosensitivity” to “repair capability” of a specified tissue.

HIGH (>8 Gy) for rapidly proliferating tissues and most tumors (eg HNSCC, mucosa).

SMALL (<6 Gy) for slowly proliferating tissues, including late normal-tissues and tumours like Ca prostate and Ca breast.

HYPOFRACTIONATION IN BREAST

RADIOBIOLOGY Assumption of better tumour control. Alpha/beta-3-5

LOGISTICS Logistic advantages. Economic favourability.

WHY INTEREST IN HYPOFRACTIONATION??

EVIDENCE OF HYPOFRACTIONATION IN CARCINOMA BREAST

1234 Patients, T1-2N0M0, C/M -ve ARMS: 50 Gy/25#/35 (622 patients) days Vs 42.5 Gy/16#/22 days

(612 patients). Primary endpoint: LR. Secondary endpoints: distant recurrence, OS, breast cosmesis

(EORTC rating), late RT toxicity.

JNCI, Vol. 94, No. 15, August 7, 2002

• To compare local recurrence• To compare disease free survival,

overall survival,cosmesis,late radiation toxicity of skin and subcutaneous tissue

aim• Post lumpectomy• Pathologically negative axillary lymph

nodes (pT1-T2N0M0)• Clear resection margins

Study patient

s

1234 Patients

50Gy/25#/35 days

42.5Gy/16#/22 days

RESULTS

JNCI, Vol. 94, No. 15, August 7, 2002

SURVIVAL

DFS, p=0.37DFS, p=0.37 OS, p=0.78

JNCI, Vol. 94, No. 15, August 7, 2002

LATE EFFECTS

Excellent to good cosmetic outcome at 3 yrs and 5yrs

76.8% (SA) Vs 77.0%(LA) 76.8% (SA) Vs 77.4%(LA)

JNCI, Vol. 94, No. 15, August 7, 2002

• To study effect of fraction size > 2 Gy on late normal tissue responses

• To compare change in breast appearance, palpable breast induration

aim• Post lumpectomy• T1-3 N0-1 M0• Clear resection margins• Under 75 years of age at presentation

Study patient

s

ELIGIBILITY:T1-3,N0-1,M0, <75 yrs.

1410 Patients

50Gy/25#/5 weeks

42.9 Gy/13#/5 weeks

39 Gy/13#/5 weeks.

RESULTS

After a minimum 5-year follow up, the risk of scoring any change in breast appearance after 50 Gy/25 F, 39 Gy/13 F and 42.9 Gy/13 F was 39.6, 30.3 and 45.7%, from which an alpha/beta value of 3.6 Gy (95% CI 1.8-5.4) is estimated.

P=0.01

P=0.05P=0.01

P=0.18

LC RESULTS

After a median follow-up of 9.7 years for the 838 (95%) patients who survived, the risk of ipsilateral tumour relapse after 10 years was 12.1% (95% CI 8.8-15.5) in the 50 Gy group, 14.8% (11.2-18.3) in the 39 Gy group, and 9.6% (6.7-12.6) in the 42.9 Gy group(difference between 39 Gy and 42.9 Gy groups, chi2 test, p=0.027)

Lancet Oncol 2008; 9: 331–41

• To measure the sensitivity of normal and malignant tissues to fraction size

• To compare loco-regional relapse, distant relapse,disease free survival, overall survival, late normal tissue effects, quality of lifeaim

• Post lumpectomy/post mastectomy• pT1-3 N0-1 M0• Clear resection margins• > 18 years• No immediate surgical reconstruction

Study patient

s

2236 Patients

50Gy/25#/5 weeks

41.6Gy/13#/5 weeks

39 Gy/13#/5 weeks.

RESULTS

The estimated absolute differences in local-regional relapse rates compared with 50 Gy at 5 years were 0·2% (95% CI −1·3% to 2·6%) after 41·6 Gy and 0·9% (95% CI −0·8% to 3·7%) after 39 Gy. 

P=0.01

P=0.62

LRR: estimated maximum 2.1% and 3.2% excess risk with 41.6 Gy and 39 Gy compared with 50 Gy.

DFS, OS not significantly different.

Cosmesis: 39 Gy/13# more favourable.

a/b for LR relapse: 4.8 Gy (CI 0-16.3).

a/b for change in breast appearance: 3.1 Gy (CI 1.6-4.6).

CONCLUSIONS

START B TRIAL Patient criteria: pT1-3aN0-1M0,

post BCS/ Mastectomy, negative CM, age>18 years, no immediate reconstruction.

2215 patients from 23 UK centres.

Stratified by: centre, type of Sx (BCS Vs MRM), boost or not.

Randomised to: 50 Gy/25#, 40 Gy/15#

Lancet 2008; 371: 1098–107

• To compare loco-regional relapse, distant relapse,disease free survival, overall survival, late normal tissue effects, quality of lifeaim

• Post lumpectomy/post mastectomy• pT1-3 N0-1 M0• Clear resection margins• > 18 years• No immediate surgical reconstruction

Study patient

s

2215 Patients

50Gy/25#/5 weeks

40Gy/15#/3 weeks.

RESULTS

Lancet 2008; 371: 1098–107

P=0.01

P=0.35

CONCLUSION: 40 GY IN 15 FRACTIONS OFFER RATES OF LR RELAPSE AND LATE ADVERSE EFFECTS AT LEAST AS FAVOURABLE AS THE STANDARD SCHEDULE OF 50 GY IN 25 FRACTIONS.

Lancet 2008; 371: 1098–107

COMPARISON OF THE TRIALS

COMPARISON OF RESULTS

Eligibility: age>50 yrs, pT<3 cm, post BCS, CM –ve, N0M0, no NACT/Adj CT.

915 patients accrued.

RANDOMISED TO- 50 Gy/25#/5 weeks Vs 30 Gy/5#/5 weeks Vs 28.5 Gy/5#/5 weeks.

No boost in any arm.

CONCLUSION:

 At 3years median follow-up, 28.5Gy in 5 fractions is comparable to 50Gy in 25 fractions, and significantly milder than 30Gy in 5 fractions, in terms of adverse effects in the breast.

Radiotherapy and oncology 2011

RECENT UPDATES OF START A AND START B

START A START B

DISEASE FREE SURVIVAL

START A START B

LATE ADVERSE EFFECTS

EVIDENCE OF HYPOFRACTIONATION IN CARCINOMA PROSTATE

• STAGE-T1b-T3aN0M0• PSA <30 ng/mL• PS-0 or 1• Estimated risk of seminal vesicle involvement less

than 30%

450 Patients

74Gy/37#/7.4weeks 60 Gy/20#/4 weeks 57 Gy/19#/3.8

weeks.

  50·5 months med ian fo l low-up :

6 (4 ·3%) o f 138 men in the 74 Gy group had bowel tox ic i ty of g rade 2 o r worse on the RTOG sca le a t 2 years , 5 (3 ·6%) o f 137 men in the 60 Gy group, and 2 (1·4%) o f 143 men in the 57 Gy group.

For b ladder tox ic i t ies , 3 (2 ·2%) o f 138 men, 3 (2 ·2%) o f 137 , and none (0 ·0%; 97·5% CI 0 ·0–2·6) o f 143 had scores o f g rade 2 o r worse on the RTOG sca le a t 2 years .

Hypofractionated high-dose radiotherapy seems equally well tolerated as conventionally fractionated treatment at 2 years.

Same patient characteristics as previous CHHiP TRIAL

2100 Patients

74Gy/37#/7.4weeks 60 Gy/20#/4 weeks 57 Gy/19#/3.8 weeks.

Median follow-up was 50·0 months Comparison of 74 Gy in 37 fractions, 60 Gy in 20 fractions, and 57 Gy in 19

fractions groups at 2 years showed (respectively (74 Gy vs 60 Gy, ptrend=0.64, 74 Gy vs 57 Gy, ptrend=0·59).

no overall bowel bother in 269 (66%), 266 (65%), and 282 (65%) men; very small bother in 92 (22%), 91 (22%), and 93 (21%) men; small bother in 26 (6%), 28 (7%), and 38 (9%) men moderate bother in 19 (5%), 23 (6%), and 21 (5%) men, and severe bother in four (<1%), three (<1%) and three (<1%) men

No differences between treatment groups in change of bowel bother score from baseline or pre-radiotherapy to 24 months.

The incidence of patient-reported bowel symptoms was low and similar between patients in the 74 Gy control group and the hypofractionated groups up to 24 months after radiotherapy.

Intermediate-risk or high-risk patients aged between 44 and 85 years Stage T1b–T4 NX-0MX-0 PSA concentration of 60 ng/mL or lower WHO performance status of 0–2

820 Patients

78Gy/39#/8weeks 64.6 Gy/19#/6.5 weeks

median follow-up was 60 months The incidence of grade 2 or worse genitourinary toxicity at 3 years was 39·0%

(95% CI 34·2-44·1) in the standard fractionation group and 41·3% (36·6-46·4) in the hypofractionation group

The incidence of grade 2 or worse gastrointestinal toxicity at 3 years was 17·7% (14·1-21·9) in standard fractionation and 21·9% (18·1-26·4) hypofractionation.

Cumulative grade 3 or worse late genitourinary toxicity was significantly higher in the hypofractionation group than in the standard fractionation group (19·0% [95% CI 15·2-23·2] vs 12·9% [9·7-16·7], p=0·021

no significant difference between cumulative grade 3 or worse late gastrointestinal toxicity (2·6% [95% CI 1·2-4·7]) in the standard fractionation group and 3·3% [1·7-5·6] in the hypofractionation group; p=0·55).

EVIDENCE OF HYPOFRACTIONATION IN CARCINOMA GLOTTIS