Branislav Jeremic, MD, PhD Professor and Head Division of ... · Division of Radiation Oncology...

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HYPOFRACTIONATION AND DRUGS:OPPORTUNITIES AND CHALLENGES

Branislav Jeremic, MD, PhD

Professor and Head

Division of Radiation Oncology

Stellenbosch University and TygerbergHospital

Cape Town

South Africa

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CONFLICT OF INTEREST

NONE TO DECLARE

Fakulteit Geneeskunde en Gesondheidswetenskappe

Faculty of Medicine and Health Sciences

RADIOTHERAPY AND DRUGSEXPLOITABLE MECHANISMS

1. SPATIAL CO-OPERATION

2. INDEPENDENT CELL KILL

3. PROTECTION OF NORMAL TISSUES

4. ENHANCEMENT OF TUMOUR RESPONSE

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Steel & Peckham, 1979

Tirapazamine

Temozolomide, Cisplatin

Amifostine

Cetuximab

Adjuv. Chemo.

Trastuzumab

Tirapazamine

Temozolomide, Cisplatin

Amifostine

Cetuximab

Adjuv. Chemo.

Trastuzumab

5 Mechanims for Drug - Radiation InteractionsUpdated from Steel-Peckham‘s terminology: Clinically-oriented point of view

Bentzen, Harari, Bernier, Nature Clin. Practic Onc., 2007

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DOSE/FRACTIONATION

• Majority of studies with conventional fractionation

• Hypofractionation (HypoFx) mostly used in palliation

• LQ warning about HypoFx (alone or with drugs)

• More HypoFx radical regimens in recent years

• HypoFx and drugs???

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HypoFx issues – indirect

• RT and drugs given in lower doses – most effective

• Greatest RT-enhancement with drugs given

immediately before the RT fraction

• Dose-escalation may not be effective in RT + drugs

because cytotoxicity and radiosenzitization may be

mutually exclusive

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HypoFx issues – direct

• Hypoxia expected to be significant with HypoFx RT

• Loss <3 logs of cell-kill when CF changed into HypoFx

• Hypoxia may have the largest negative effect on cell

survival after RT given with less than ca. 10 Fx

• Is LQ appropriate for high dose/Fx ?

(5 Gy, 10 Gy, 15-18 Gy)

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HypoFx issues – direct

High dose/Fx may enhance cell killing

• Rapid endothelial cell apoptosis in tumour vessels

• Non-targeted pharmacodynamics effects mediated by

TNF-α, TRAIL, PAR-4, ceramide

(intratumoural bystander and abscopal effects)

• Increased host immune recognition of RT-induced

enhanced antigen presentation – enhance RT effects

• Better response of heterogenous tumours with

different cell populations whose clonal radiosensitivity

considerably differs

Impact of high-dose ablative RT on

tumor micro-environment components

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Tumour cells

Cancer stem cells

T cells

B cell response

Endothelial cells

Hypoxic cells

Metastatic tumour killImmune activation

High-dose RT

Bystander/abscopal effects

Hypoxic cell damage Endothelial cell damage

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TYPES OF HypoFx

EXTREME

1-5 fractions

dose/fx >10 Gy

MODERATE

6-15 fractions

dose/fx 5-10 Gy

MILD

15-25 fractions

dose/fx 2.5-5 Gy

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HypoFx and DRUGSimportant issues

• SEQUEENCING

• DRUGS

• DOSAGES

• POTENTIAL ADVANTAGES

• POTENTIAL DISADVANTAGES

• POTENTIAL CLINICAL SITES

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EXTREME HypoFX

1-5 Fx RT

SEQUENCING

• Likely not concurrent

• Neoadjuvant and/or adjuvant

• Duration of each

• Drugs will affect mostly subclinical disease

• Efficacy will depend on micrometastatic potential

• DM rates as guidance?

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EXTREME HypoFX

1-5 Fx RT

DRUGS

• Chemo, hormonal, targeted

• Hypoxic cell sensitizers

• Opportunity for dublets and triplets

• Similarity with drug therapy alone

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EXTREME HypoFX

1-5 Fx RT

DOSAGES

• Similar to drug therapy alone

• Dependent of efficacy and toxicity

• Dependent on the number of cycles

• Dependent on maintenance (or not)

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EXTREME HypoFX

1-5 Fx RT

POTENTIAL ADVANTAGES

• Treat subclinical disease early

• Enable more cycles to be given

• Should not compromise RT delivery

• May enable non-cross resistance

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EXTREME HypoFX

1-5 Fx RT

POTENTIAL DISADVANTAGES

• Local Tx (RT) starts late

• Risks of impaired local control

• Drugs may not be effective, yet toxic

• No influence on local control

• Too toxic if drugs given close to RT?

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EXTREME HypoFX

1-5 Fx RT

POTENTIAL CLINICAL SITES

EARLY STAGE NSCLC

• Adjuvant and/or maintenance drugs

• Possibility of chemo and targeted

• Total of 4-6 cycles

• Hypoxic cell sensitizer given with RT?

• RT- and drug-related toxicity not to overlap

RTOG 0236:

SBRT in medical inoperable stage I NSCLC

Phase II, 2004-2006

55 inoperable patients,

peripheral T1-T2 NSCLC, <5 cm

54 Gy in 3 fxs over 1.5-2 weeks.

3 Year endpoints (Median f/u 2.9 years)

Tumor control – 98% (95%CI 84.3-99.7%)

LRC – 87% (95%CI 71-94.7%)

OS – 55.8 % (95%CI 41.6-67.9%)

Toxicity: Grade 3 (13%), Grade 4 (4%)

RTOG 0236:

SBRT in medical inoperable stage I NSCLC

(Timmerman et al: JAMA 303:1070, 2010)

Phase II, 2004-2006

55 inoperable patients,

peripheral T1-T2 NSCLC, <5 cm

54 Gy in 3 fxs over 1.5-2 weeks.

3 Year endpoints (Median f/u 2.9 years)

Tumor control – 98% (95%CI 84.3-99.7%)

LRC – 87% (95%CI 71-94.7%)

OS – 55.8 % (95%CI 41.6-67.9%)

Toxicity: Grade 3 (13%), Grade 4 (4%)

SBRT in stage I NSCLC1-yr, 2-yr OS rates: 93.0% and 78.2%

(Chang et al: ASTRO 2011)

MST = 60 mos

LC : 98.5% at 2yrs

LN: 8.5%

DM: 23.1%

No G 4/5 toxicity

G2 RP: 10.7%

G3 RP : 3.1%

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MODERATE HypoFX

6-15 Fx RT

SEQUENCING

• Likely “limited” concurrent

• Neoadjuvant and/or adjuvant still predominate

• Duration of each

• Drugs will affect both T and N and M component

• LRC vs DM rates as guidance?

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MODERATE HypoFX

6-15 Fx RT

DRUGS

• Chemo, hormonal, targeted

• Less hypoxic cell sensitizers

• Opportunity for dublets and triplets

• Similarity with drug therapy alone

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MODERATE HypoFX

6-15 Fx RT

DOSAGES

• Similar to drug therapy alone

• Dependent of efficacy and toxicity

• Concurrent part may be more toxic

• Dependent on the number of cycles

• Dependent on maintenance (or not)

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MODERATE HypoFX

6-15 Fx RT

POTENTIAL ADVANTAGES

• Treat subclinical disease early

• As early as possible start concurrent part

• Should not compromise RT-drug delivery

• May enable non-cross resistance

• May require different drugs post-RT/drugs

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MODERATE HypoFX

6-15 Fx RT

POTENTIAL DISADVANTAGES

• Local Tx (RT) starts late

• Risks of impaired local control

• Drugs may not be effective, yet toxic

• Too toxic if drugs given pre-, during and post-RT

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MODERATE HypoFX

6-15 Fx RT

POTENTIAL CLINICAL SITES

PANCREAS, BREAST

• Adjuvant and/or concurrent and/or maintenance?

• Possibility of chemo and targeted

• Total of # cycles dependent on concurrent part

• RT- and drug-related toxicity not to overlap

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MILD HypoFX

16 - 25 Fx RT

SEQUENCING

• Concurrent part predominates

• Neoadjuvant and/or adjuvant still possible

• Duration of each important

• Drugs will affect both T and N and M component

• LRC vs DM rates as guidance?

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MILD HypoFX

16 - 25 Fx RT

DRUGS

• Chemo, hormonal, targeted

• Likely no hypoxic cell sensitizers

• Opportunity for dublets and triplets

• Similarity with drug therapy alone

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MILD HypoFX

16 - 25 Fx RT

DOSAGES

• Similar to drug therapy alone

• Dependent of efficacy and toxicity

• Concurrent part may be more toxic

• Dependent on the number of cycles

• Dependent on maintenance (or not)

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MILD HypoFX

16 - 25 Fx RT

POTENTIAL ADVANTAGES

• As early as possible start concurrent part

• Should not compromise RT-drug delivery

• May enable non-cross resistance

• May require different drugs post-RT/drugs

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MILD HypoFX

16 - 25 Fx RT

POTENTIAL DISADVANTAGES

• Induction chemo may lead to impaired local control

• Induction hormones may do good

• Drugs may not be effective, yet toxic

• Too toxic if drugs given pre-, during and post-RT

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MILD HypoFX

16 - 25 Fx RT

POTENTIAL CLINICAL SITES

BREAST, H&N, PROSTATE, LUNG

• Concurrent +/- adjuvant +/- maintenance?

• Possibility of chemo/hormonal and targeted

• Total of # cycles dependent on concurrent part

• RT- and drug-related toxicity not to overlap

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HypoFX and DRUGSCONCLUSIONS

• RADIOBIOLOGICAL ASPECTS REMAIN UNCLEAR

• EXTREME HypoFx/DRUGS VIRTUALLY NOT PRACTICED

• PRACTICE IT AND DOCUMENT LATE TOXICITY

• MODERATE HypoFx/DRUGS WITH DIFFERENT OPPORTUNITY

• HIGH-DOSE PALLIATION AS POTENTIAL MODEL?

• MILD HypoFx/DRUGS ALREADY IN USE

• TOXICITY ACCEPTABLE, LONGER F/U MANDATORY!

Table Mountain - a view from Western Seaboard

Gracias!