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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
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!