QUANTEC IN BRIEF

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.