This document discusses normal tissue tolerance doses from radiation therapy. It describes the formation of a task force to establish tolerance protocols, with an emphasis on partial volume effects. The earliest publication of tolerance doses is cited from 1972. 28 critical organ sites were included and considered in terms of dose, time factors, and partial volumes irradiated. The significance of these parameters and a quantitative model for normal tissue complication probability are provided. Limitations of the available data and ongoing areas of research are also outlined.

2.  Deals with the normal tissue complications with differing
doses of radiation
 The aim of a radiation oncologist is uncomplicated
locoregional control of cancer by radiation therapy.
 For this it is a must to have the precise knowledge of –
› Tumoricidal doses
› Normal tissue tolerances

4.  As part of the NCI contract a task force chaired by the
primary author was formed.
 Extensive collection and study of literature was carried
out to establish the protocols presented in the paper
with special emphasis to partial volume effects.
 However it was stated that it was stated that it is not a
comprehensive work

5.  The earliest step was the pulication of Rubin and
Cassarett of the tolerance doses in 1972.
 It summated the tolerance in terms of –
› TD 5/5 (the probability of 5% complication with in 5 years from
treatment)
› TD 50/5 (the probability of 50% complication with in 5 years
from treatment)

6.  28 critical sites were included
 Only conventional (1.8-2Gy/day, 5#/wk) was considered
 most severe end point was chosen
 normal organs were considered in terms of – 1/3, 2/3,
3/3 or whole volume (organs in which such division
could not be carried out – optic nerve, optic chiasma,
lens – whole organ was considered
 only adult tissue tolerance was considered

7.  The significant parameters considered were –
› Dose – time factors
› Partial volumes of normal tissues irradiated
 Only the linear component of the linear quadrantic
model was used.
 The expression of the NTCP model equation may be
written as :
NTCP (D,v) = exp [-N0 v-k exp {-aDG}]

8.  G = [1+d/(a/b)]
 a is the coefficient of lethal damage
 b/a is the reciprocal of a/b
 N0 (depicts proportion of stem cells) and k (depicts volume
dependence) are the tissue/organ specific, non-negative
adjustable parameters
 V is the uniformly irradiated partial volume of the tissue/organ
(=V/Vref where V is the uniformly irradiated volume of the
normal organ, Vref is the reference volume of the normal
organ.

9.  It was observed that the tolerance doses either showed
or did not show volume dependence.
 No volume dependence could be shown for – femoral
head and neck, rib cage, skin (telangeictasia), optic
nerve, optic chiasma, cauda equina, eye lens, retina,
ear (middle/external), parotid, larynx (edema), rectum,
thyroid.

13. ORGAN TOLERANCE DOSE
Muscle TD 1/5 - 5000cGy
Thyroid TD 8/5 – 45Gy
TD 13/5 - 60Gy
TD 35/3 – 70Gy

15.  All the planning and reporting was in terms of 2D
planning.
 With the advent and use of CT scan based 3D
conformal RT, a better understanding was needed and
was possible for the non-uniform irradiation of normal
organs.

16.  The steering committee of QUANTEC was formed and it
defined three aims :
› To provide a critical overview of the current state of knowledge
of dose-volume, dose-response relationships.
› To produce practical guidelines allowing the clinician to
reasonably categorize toxicity risk based on dose-volume
parameters.
› To identify future research avenues that would help improve
estimation or mitigation of side effects.

17. Reporting of the following is not proper :
 Side effects (grades)
 Different follow up duration
 Risk factors of patients
 Effect of concurrent chemotherapy
 Effect of altered fractionation schedules
 Altered beams (multiple beams, rotational delivery).

18.  Non-uniform dose distributions
 Uncertain alpha/beta ratio
 Need to confirm NTCP model by data in phase III trials
 Need to improve data analytic model
 Balancing the risks to different organs relating ‘‘whole
treatment’’ DVHs with acute toxicities
 Unknown applicability in children

20. DVH are not ideal representations of 3-D doses :
 As they assume all regions are of equal importance
 Do not consider fraction size variations
 Based on a single planning CT scan which does not
account for anatomic variations during treatment
 Variations in image segmentation, beam arrangement,
dose calculations, patient population limit its usefulness

22.  All the data available is for conventional 2Gy/#, 5#/week
schedule
 The data is for conventional parallel opposed fields with
shrinking field
 Now altered fractionation is widely used esp in trials
 The LQ model may not be of questionable benefit in
very novel fractions

23.  Chemotherapy exacerbates the severity of normal
tissue reactions
 Data regarding sequential/concurrent chemotherapy/RT
is lacking
 And the effects of different chemotherapy agent, doses,
schedules also differ

24.  Host factors – chronic liver disease, genetic, lifestyle –
may affect dose response relationships and are partly
responsible for inter-patient variations.
 Incorporating these data may produce better correlation
or analysis of toxicity.

25.  Earlier treatment was done keeping the normal organ
tolerance as the deciding factor
 Now the aim is to achieve a ‘tradeoff’ between the
benefit and risk from the planned treatment
 Aim is to have a good “quality of life adjusted tumour
control probability”

26.  Many times patients are lost to follow up
 Early death may result in a false low adverse event
reporting

27.  Relating acute toxicitiy during treatment with the DVH of
the whole treatment might be illogical
 Relating a late toxicity that occurs as a result of severe
acute toxicity with the DVH may give suboptimal results
of analysis

28.  In children the tissues develop at different rates and
temporal sequences
 In adults the same tissues are in a steady state with
relatively slow cell renewal kinetics.
 Same dose effect relationship does not exist with
children under radiation as with adults

30.  Generally, NTCP models attempt to reduce complicated
dosimetric and antomic information to a single risk
measure
 Most models fall into either of these three categories :
› DVH reduction models
› Tissue architecture models
› Multiple metric models

38.  Mechanism – damage to vasculature & myelin forming
oligodendriocytes diffuse cerebral edema & demyelination
 acute – nausea, vomiting, headache, seizures. Chronic –
radionecrosis, cognitive decline
 Endpoint – radionecrosis. Approx 1-2 yrs after RT
 Dose and volume dependent
 Toxicity increased by – age, chemotherapy, diabetes, spatial
factors, dose, dose/#, volume
 No evidence has shown that children are at increased risk of
radionecrosis

39.  For RT at <= 2.5Gy/#, incidence is 5% for 120 Gy (140-170
Gy) and 10% for 150 Gy (140-170Gy)
 Dmax < 60Gy – risk <3%
 For >2.5Gy/#, effect is unpredictable. Surprising toxicity with
>2Gy/# and 2#/day
 Risk increases if no of fractions/week >5
 For SRS, dose depends on volume. Maximum tolerated dose
for tumour volume –
› 31-40mm – 15Gy
› 21-30mm – 18Gy
› <20mm - >24Gy

41.  Neurocognitive decline is seen in children receiving >= 18Gy
within 4 yrs of RT.
 Enhanced by surgery, steroids, antiepileptics, opoids,
chemotherapy, female, NF-1 mutation, hydrocephalus
 13 point decreased IQ 5 yrs after RT. Poorer academic
achievement and self image and greater psychological
distress at 15 yrs
 In adults – many studies showed improved neurocognitive
effects due to antitumour effect of RT

42.  Mechanism – vascular damage radiation induced
optic neuropathy (RON).
 Other mechanisms – vascular insufficiency to optic
nerve/tracts, retina, occipital cortex
 Presents with rapid visual loss
 Endpoint – visual acuity 20/100
 Defined by the size and extent of the “visual field”
 Optic nerve – U/L, chiasm – B/L, optic tract spread out
near occipital cortes – small visual field defect

43.  Dmax is often the only data reported
 TD 5/5 – 50Gy, TD 50/5 – 65Gy (Emami et al)
 Researchers found incidence of RION is low for Dmax
<54Gy (<3%) with a steep increase in complications
>60Gy
 Complications for a given dose increase for dose >=
1.9Gy/#

45.  Increased risk in pituitary tumours
 Same tolerance for protons therapy (rather lower risk of
complications)
 For SRS, a dose of 12Gy for optic tolerance
 Risk increases with increasing age
 Inconsistent data on effect of diabetes, hypertension,
chemotherapy, previous irradiation

46.  Mechanism – vascular endothelial damage, glial cell
injury  pain, paresthesias, sensory deficits, paralysis,
bowel-bladder incontinence, Brown-Sequard syndrome
 Not included – Babinski’s sign, Lhermitte’s sign
 Endpoint – myelitis, MRI evidence of myelitis
 Presents after 6months to 2 years post RT
 Different tolerance for full thickness, partial thickness,
peripheral/central fibres may be defined in later years

47.  For 1.8-2Gy/#, estimated risk of myelopathy is 0.2%,
6% and 50% for doses of 50Gy, 60Gy and ~69Gy
 For Dmax SRS<=13Gy, hypofractionation <=20Gy
 For reirradiation, essentially no myelopathy if cumulative
dose <=60Gy
 Risk increased in immature spine, concurrent use of
intrathecal chemotherapy

48.  Cancer therapy evaluation programme (CTEP) grades
brain stem injury as –
› Grade 1 – mild/asymptomatic
› Grade 2 – moderate, not interfering with activities of daily living
(ADL)
› Grade 3 – severe, interfering with ADL
› Grade 4 – life threatening or disabling, intervention indicated
› Grade 5 - death

49.  End point – brain stem necrosis/MRI e/o injury
 Same mechanism as brain – brain stem has more white
matter
 Whole brainstem Dmax <54Gy, 1-10cc Dmax = 59Gy(2Gy/#) –
not different in pediatric age
 Risk increases > 64Gy
 Factors increasing risk – 2or more skull base surgeries,
diabetes, hypertension, V60> 0.9ml, hydrocephalus, tumour
close to brain stem
 SRS – cranial neuropathy >= 12.5Gy

50.  Does not refer to acute, chronic otitis media referred to
in Emami et al’s paper. It deals with damage to cochlea
and acoustic nerve
 Grading of hearing loss is done using Gardner-
Robertson hearing grade (GRGH scale)
 Sensorineural hearing loss (SNHL) is defined as an
increase in the bone conduction threshhold(BCT) at key
human speech frequencies (0.5-4kHz)
 Post RT hearing loss is more at higher frequencies

53.  For 2Gy/# are- mean dose to cochlea <=45Gy (<30%
risk of 4kHz frequency SNHL)
 For SRS dose <=12-14Gy
 Risk increased by – total dose, dose/#, FSRT better
hearing than SRS, adjuvant/concurrent cisplatin (not
with neoadjuvant cisplatin), older age, males>females,
better pre RT hearing, post RT otitis media, NF-2,
cerebral spinal fluid shunt

54.  Hearing assessment should be started 6 months post
RT and be done biannually
 Control is – pre RT hearing of same ear/C/L ear
hearing/age adjusted hearing data
 CAUTION –
› dose should be kept minimum with concurrent cisplatin
› Data presented may not be applicable for altered fractionation
› Data applies only to adult patients
› Data may not be representative in cases of vestibular
schwannoma with NF-2

55.  Stimulated saliva production is mainly (60-70%) from parotid
gland (balance from other glands). Unstimulated/resting from
submandibular sublingual and minor oral salivary glands
 Xerostomia leads to poor dental hygiene, oral pain, difficulty
in chewing and swallowing
 Endpoints –
› patient observation (loss of taste, dryness)
› objective – unstimulated and stimulated saliva production
› imaging (scintigraphy, dynamic MRI sialography

56.  Reduction upto 25% of pre RT saliva production
 “recovery overshoot” can occur with >100% saliva production
as compared to pre RT production
 Effect of doses –
› Minimum effect -10-15Gy (in 1 week of starting RT)
› Increases at 20-40Gy
› strong reduction (>75%) at >40Gy
 Severe xerostomia avoided if one parotid spared <20Gy or
both parotid <25Gy for 1.5-1.8Gy/#
 When oncologically safe, submandibular gland preservation
<35Gy reduces xerostomia

57.  Recording grade 4 xerostomia
 Recovery by 24 months
 Xerostomia risk is reduced by sparing atleast one
parotid or even one submandibular gland
 Under evaluation – hyperfractionation decreases effect,
sparing submandibular gland to achieve >25% pre RT
saliva production
 Amifostine increases tolerance of submandibular and
parotid by 9Gy

59.  80% present within 10 months of RT
 Approx 5-50% lung, 5-10% mediastinal LN, 1-5% lung
cases treated with RT develop RP
 Problems –
› Relevant grade of symptoms is controversial
› Dyspnea is non specific
› Different physicians have different assesment
› Lung tumour shrinkage makes symptoms better sometimes

60.  The gradual increase in dose response suggests that there is
no absolute MLD below which there is no pneumonitis
 Tolerance vary for different fraction sizes

61.  Tolerance depends on technique used
 Radiation associated dyspnea is seen more in lower
lung tumous than upper lobe
 Factors affecting risk of RP –
› Lesser in young age <60-70yrs
› Increased for mesothelioma treated with IMRT
› Effect of surgery not yet established
› INTERESTINGLY, CURRENT SMOKERS HAVE A LESSER
RISK
› Chemo may increase risk (docetaxel, gemcitabine) (not
cisplatin, carboplatin, paclitaxel, etoposide)

62.  No definite threshholds described
 Prudent to keep V20<= 30% and MLD <=20-23Gy
(conventional fractionation)
 Mesothelioma – V20<= 4-10% and MLD <= 8Gy
 Limit central airway dose to <= 80Gy to reduce risk of
bronchial stricture

63.  Acute esophagitis peaks 4-8 weeks after starting RT,
grade 2 or higher is considered
 Stricture develops ~3-8 months after RT. Later
esophagitis grade 1 or higher is considered
 Differentiate symptoms with that of candidiasis, herpes
simplex esophagitis, preexisting GERD, incidental
irradiation of stomach  gastritis, intero-observer
variation

64.  To assess dose, whole length of esophagus should be
included in the scan
 Parameters studied – absolute volume (a V dose),
absolute area (aAdose), percentage of a reference
volume (V dose), reference area (Adose)
 Intermediate toxicity develops at 30-50Gy
 DVH showing cumulative dose >50Gy has high
statistical significance of esophagitis
 Rates of acute grade 2 or greater esophagitis increasing
to >30% as V70 > 20%, V50>40%, V35>50%

65.  Risk increased by hyperfractionation, concurrent boost,
CCT, preexisting dysphagia, increasing nodal stage
 Ongoing Phase III Intergroup Trial (RTOG0617) has
recommended but not mandated – mean dose to
esophagus <34Gy and V60 be calculated for all patients

66.  Nausea & vomiting within hours after radiation
 Days to weeks later – dyspepsia, ulceration, bleeding (may
be life threatening)
 Long term effects – long-term dyspepsia, ulceration
 Emami et al referred to the TD5/5 (50Gy) and TD 50/5
(65Gy) for late effects and not for the acute effects
 Whole stomachD100 <45Gy  <5-7% risk of ulceration
 SBRT dose, limit Dmax <22.5Gy to <4% or 5cc with max
point dose of <30Gy for 3 fraction SBRT

67.  1-2 weeks after RT – cramping and diarrhea d/t
interference with nutrient absorption  weight loss
 Weeks to months post RT – late obstruction as a result
of adhesions that restrict intestinal mobility
 Long term effects – (usually within 3 yrs post RT)
ulceration, fistula, perforation, bleeding
 Grade 2-4 toxicity is usually considred life threatening

68.  Emami et al , whole organ TD5/5 – 40Gy, TD 50/5 –
55Gy. Partial organ TD5/5 - 50Gy, TD 50/5 – 60 Gy
 In modern series doses are concordant with the Emami
series
 Restrict V15 < 120cc – when delineating individual bowel
loops and V45 <195cc - when delineating entire
peritoneal cavity.
 For SBRT , volume receiving >12.5 Gy be kept < 30cc
and max point dose <30Gy

70.  Acute – pericarditis
 Several months to years - CHF, CAD, MI (leading
cause of death in HL survivors). Significant endpoint
 Relative risk of these are within a range of 1.2-3.5 yrs
 Subclinical damage not well documented
 Risk increased by – age, gender, DM, smoking,
hypertension, total cholestrol, LDL, HDl, high CRP,
parentla history of MI <60yrs

71.  Anthracyclines routinely used for breast and HL cause risk of
dilated cardiomyopathy (after doxorubicin >550mg/m2 and
epirubicin >900mg/m2).
 They have potential synergistic cardiotoxic effects with RT
with increased incidence of MI, CHF, valvular d/s

72.  Pericarditis data better obtained from DVH of
pericardium rather than whole heart and that of MI,CHF
from heart volume (whole heart – pericardium)
› For pericarditis, risk increases if mean pericardium dose >26Gy,
V30 > 46%
› For other effects, keep dose to heart to minimum without
compromising tumour coverage. A NTCP of >= 5 could
jeopardize beneficial effect on survival of RT
› For partial irradiation, V25 < 10% (in 2 Gy/#) will be associated
with <1% cardiac mortality ~15yrs

73.  Acute effects (within 3 months) – subclinical
 Subacute (3-18 months) – decreased GFR, increased
serum beta-2 microglobulin
 Chronic (>18 months) – benign/malignant hypertension,
elevated creatinine levels, anemia, renal failure
 If no changes in renal perfusion/GFR occur in 2 yrs post
RT, subsequent chronic injury is unlikely
 Damage associated with parenchyma, not tubules

75.  Whole kidney tolerance (as in TBI) is in accordance with
Emami et al – TD5/5 – 18-23Gy and TD 50/5 – 28Gy in
0.5-1.25 Gy/#. Creatinine clearence affected after 10-20
Gy. Mean dose <15-18Gy
 Other parameters for <5% clinically relevant renal
dysfunction –
› V12 <55%
› V20 <32%
› V23 < 30%
› V28 <20%

76.  These findings improved with time due to the reserve
capacity of the spared renal tissue though reparative
capacity blunted with RT
 Pediatric kidneys are very sensitive with 12-14 Gy at
1.25-1.5Gy/# causing decreased GFR etc. no kidney
failure after 10-12 Gy in 1.5-2Gy/#
 Age <5 yrs associated with increased risk of acute renal
dysfunction post TBI

77.  Risk increased with –
› Chemotherapy
› Diabetes
› Hypertension
› underlying renal
insufficiency
› liver disease
› heart disease
› smoking

78.  Acute – during/soon after RT. softer./diarrhea-like stools,
pain, sensation of rectal distention and cramping,
frequency, occasionally ulceration and bleeding
 Late – 3-4 years after RT. Stricture, diminished rectal
compliance, decreasing storage capacity  frequent
bowel movements, anal musculature damage  fecal
incontinence/stricture

79.  Endpoint – rectal bleeding/grade>=2 rectal toxicity
 Significant late rectal toxicity with >=60Gy. Vdose has not
been found to be significant for rectal doses <=45Gy
 Risk increased by DM, hemorrhoids, inflammatory
bowel disease, advanced disease, IBD, androgen
deprivation therapy, rectum size, prior abdominal
surgery, severe acute rectal toxicity
 Severe acute toxicity can result in high late rectal
proctopathy

80.  Dose limits described to limit grade 2 toxicity to <15%
and grade 3 <10% for upto 79.2Gy in 1.8-2Gy/# –
› V50 <50%
› V60 <35%
› V65 < 25%
› V70 < 20%
› V75 < 15%

81.  Acute – during or soon after RT. Dysuria, haematuria,
frequency, nocturia
 Late – underreported due to latency period of decades.
Dysuria, urgency, frequency, contacture, spasm, reduced
flow, incontinence, hematuria, fistula, obstruction, ulceration,
necrosis
 Symptoms may be urethral in origin and difficult to
differentiate
 Physician observation differences may be there

82.  Risk increased by – pre RT GU morbidity, increasing
age, hormonal therapy, surgery (TURP), prostatectomy,
hysterectomy, biopsy), chemotherapy
 Prescribed dose limits –
› Dmax <=65 (for <=6% grade 3 RTOG toxicity)
› V65 < 50%
› V70 <35%
› V75 < 25%
› V80 < 15%

83.  Grade 2,3,4,5 liver dysfunction ( jaundice, asterixis,
encephalopathy, coma, death respectively) rarely occur with
RT. Elevation of liver enzymes occur (grade 1 CTCAE) in 3-4
months
 Endpoint – Child Pugh score >=2, reactivation of hepatitis B
 Divided into classic (elevation of liver enzymes 2 fold,
pathologic evidence of injury) and non classic (elevation of
liver enzymes >5fold, child pugh score >=2) RILD (radiation
induced liver disease)

84.  Risk increased in – HCC> metastases, Child Pugh B/C
> A, cirrhosis, hepatitis B carrier, prior transcatheter
arterial chemoembolization, concurrent chemotherapy,
portal vein tumor thrombus, tumour stage, male,
increased dose/#

87.  Progressive edema & fibrosis after RT could defeat the
purpose of RT – organ & functional preservation
 Endpoints – laryngeal edema, vocal function
 Edema – RTOG grade 0 – no edema, 1- slight edema,
2- moderate, 3 – severe, 4 – necrosis
 Vocal function – assessed by patient focused
questionnaire, instruments (videostroboscopy,
aerodynamic measurement of phonation time, human
observation

88.  Risk increased by – initial advanced disease,
concurrent chemotherapy (doubles risk)
 Vocal dysfunction develops as a result of damage to
larynx, supralaryngeal structures, decreased saliva
production, damage to intrinsic musculature and soft
tissue

89.  Endpoints – instruments (modified barium swallow,
esophagography), subjective evaluation (CTCAE,
RTOG), patient reported QOL
 Risk of dysphagia  aspiration could be decreased by
keeping dose to supraglottic area, larynx, upper
esophageal sphincter to < 60Gy or using brachytherapy
to reduce pharyngeal dose
 Nasogastric tube decreases risk

90.  Prescribed dose limits
› Vocal dysfunction – Dmax <66Gy
› Aspiration – mean dose < 50Gy
› Edema – mean dose < 44Gy
- V50 < 27%

91.  Erectile dysfunction is a common complication following RT
for prostate cancer. Rates are
› 24% after brachytherapy alone
› 40% after brachy + EBRT
› 45% after EBRT alone
› 66% after nerve sparing –RP
› 75% after non-nerve sparing RP
› 87% for cryosurgery
 Time course – days to years, then evolves gradually
 Additive effect of age, diabetes, hypertension, smoking

93.  Assessment by self-administered questionnaires of IIEF
(international Index of Erectile Function).
 Tests - nocturnal penile tumescence, somatosensory
evoked potentials, bulbocavernous reflex latency, penile
electromyography, colour duplex doppler ultrasound,
dynamic infusion cavernosometry, pharmacotesting
 IIEF scoring below 21 is to be considered – none (25-
22), mild (21-17), mild to moderate (16-12), moderate
(11-8), severe (7-5)

94.  It is prudent to keep dose to
95% of penile bulb volume
<50Gy. D70 < 70Gy, D90 <
50Gy
 Its acknowledged that penile
bulb may not be the critical
component of the erectile
apparatus, but is used as a
surrogate.