BOOK ON REIRRADIATION

3
EDITORS
Dr Voonna Murali Krishna
Dr Kanhu Charan Patro
Dr Partha Sarathi Bhattacharyya
Dr Chitta Ranjan Kundu,
Dr Venkata Krishna Reddy,
Dr Palla Madhuri,
Mr E B Rajmohan,
Mr A C Prabu,
Miss Subhra Das,
Mr A Anil Kumar

4
CONTENT
CHAPTER TITLE AUTHOR PAGE
1. Reirradiation-An Enigma! Dr Suryakanta Acharya 5
2. Approach Towards Re-Irradiation Dr Anis Bandyopadhyay 7
3. Radiobiology Of Reirradiation Dr Nanditha Sesikeran 21
4. Recovery And Tolerance Of The Organs At
Risk During Re-Irradiation
Dr Suman Das 35
5. The Physics Of Re-Irradiation Dr Raghavendra Holla 50
6. Re-Irradiation In CNS Tumors Dr Sayan Paul 56
7. Reirradiation In Head And Neck Cancers- A
Delicate Balance.
Dr Trinanjan Basu 62
8. Re-Radiation In Gynecological Cancers,
Present Experiences And Future Hopes.
Dr Susovan Banerjee 86
9. Nuclear Imaging In Re-Irradiation Dr Raghava Kashyap 104
10. Re-Irradiation By Brachytherapy: A
Technical Challenge
Dr Partha Sarathi
Bhattacharyya
117
11. Re-Irradiation In Breast MALIGNANCIES Dr V K Reddy 145
12. Interstitial Brachy Therapy In Head And
Neck Cancer
Dr C R Kundu 159

5
CHAPTER-1
Reirradiation-An enigma!
DR SURYAKANTAACHARYA
EMAIL-suryaoncology@gmail.com
Is always an enigma among radiation oncologists & underutilized to say
the least, due to lack of good understanding & lack of quality data in
support. The 'Tumor control probability-Normal tissue complication
probability curve' is even more important in reirradiation.
Understanding the advantages, selecting patients carefully & respecting
normal tissue toxicity limits are the cornerstones of reirradiation.
Broadly there are two types of indications for reirradiation, local relapse
& second primary in the radiated area. It could be palliative in most
cases but can be curative in some cases. Some good examples of re-
irradiation are eg; two fractions of 2 Gy for relapsed follicular
lymphoma (1), repeat radiosurgery for intracranial targets (2), and
brachytherapy for previously irradiated prostate cancer (3), in
combination with hyperthermia in chest wall recurrence in breast cancer.
Increasing the distance between organs at risk and the high-dose region,
e.g. by injectable or implanted spacers, is an interesting approach (4) but
only feasible in certain anatomical sites and in selected patients, but is
still important in giving a bit extra margin. Experimental and clinical
data have shown that most normal tissues recover from initial radiation
injury. However, decision-making on whether to reirradiate a patient is
really a complex process.
Factors to be taken into account include the type of tissue at risk for

6
injury (parallel or serial organ) total radiation dose & technique,
fractionation and interval from previous irradiation, observable normal
tissue changes resulting from previous irradiation (Organ function or
reserve), any co-morbidity limiting organ function (eg; COPD in lung),
the patient’s prognosis, disease extent etc etc.
Theoretically hyperfractionatedreirradiation seems good to have
relatively less late toxicity than conventionally fractionated reirradiation,
it needs more literature support. Also it would be interesting to see how
we benefit from hyperfractionated IMRT/IMPT in reirradiation.
Radiosurgery & brachytherapy are other examples of techniques which
work well in reirradiation apart from hyperthermia in selected cases. We
are yet to discover the ideal reirradiation, but in right path. Future is
promishing.
References-
1-Heinzelmann F, Ottinger H, Engelhard M et al (2010) Advanced-stage
III/IV follicular lymphoma: treatment strategies for individual patients.
StrahlentherOnkol 186:247–254
2-Raza SM, Jabbour S, Thai QA et al (2007) Repeat stereotactic
radiosurgery for high-grade and large intracranial arteriovenous
malformations. SurgNeurol 68:24–34
3-Moman MR, Van der Poel HG, Battermann JJ et al (2009) Treatment
outcome and toxicity after salvage 125-I implantation for prostate cancer
recurrences after primary 125-I implantation and external beam
radiotherapy. Brachytherapy 9:119–125
4-Kishi K, Sonomura T, Shirai S et al (2009) Critical organ preservation
in reirradiation brachytherapy by injectable spacer. Int J
RadiatOncolBiol Phys 75:587–594

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CHAPTER-2
Approach towards Re-irradiation
Anis Bandyopadhyay, Surya Kant Achraya, Kanhu Charan Patro
Email -anish_b123@yahoo.com
The advancement of treatment modalities in surgery, chemotherapy and
radiotherapy (RT) has improved survival rate and loco-regional control
at many sites of cancer occurrence. However, in-field cancer recurrence
after RT remains and second primary tumors occurring in previously
irradiated area are common clinical challenge. Moreover prognosis is
poor when a recurrent or new primary cancer develops in an area
previously treated with radiation1, 2
. In the absence of distant metastatic
disease, salvage surgery provides a durable disease control in
approximately a small percentage of such patients. In most others where
salvage surgery is not feasible or challenging, irradiation, alone or
combined with chemotherapy or biological therapy, as an organ-
preserving modality plays an important role in the treatment of such
cancers3
. Though re irradiation was in common practice as early as in
the early twentieth century, in the recent years availability of different
modalities of radiation and technology for more and more precise
radiation therapy, there is an increasing interest among radiation
oncologist towards delivering a second course of radiation to patients
who develop second primary tumors within or close to previous
radiotherapy portal or late in-field recurrences4
. However, such rational
treatment decisions demand not only appreciation of the relevant
clinical, pathological and technical aspects but also rather precise
knowledge on long-term recovery of occult radiation injury in various
organs1, 5
. Finally proper counseling of the patient about the expected
benefit and the potential hazards may help to make an informed choice
to proceed for re irradiation.

8
One of the major issue remains that whether re-irradiation toxicity
outweighs the potential benefits, considering that the median survival of
re-irradiated patients marginally exceeds the benefits observed with
chemotherapy or other systemic therapy alone in many instances.
However, full-dose re-irradiation is often a viable treatment option for
cancer sites, offering long-term survival for selected patients. The
success of full dose re-irradiation depends in a variety factors like the
initial cancer stage, type of initial treatment (radiation dose, technique,
dose per fraction, use of concurrent chemotherapy), response to initial
treatments, clinically apparent late effects from initial RT, residual
radiation tolerance of the normal tissues, the duration of the relapse-free
interval, the co-morbidities and dose fractionation of the re-irradiation
course6,7
. Hence careful selection of cases and judiciously use of the
appropriate technology, optimal dose fractionation for the second course
of radiation is warranted for meaningful gain in survival keeping the risk
for severe radiation induced morbidity to the minimum possible. An
approach to decision making for irradiation for patients of cancers
affecting various common sites follows.
Head and neck cancers
One of the most common sites where re-irradiation is increasingly being
considered is the head and cancers owing to high rates local failure and
the complexity of salvage surgery. Though the basic guideline to
approach towards remains same one should keep in mind the major
prognostic factors that affect results of re-irradiation. Since there are a
lot of vital organs in close proximity retreatment with radiation without
judicious selection may increase risk of serious toxicity and impaired
quality of life with an uncertain survival advantage9
.
An informed choice has to be made by the oncologist and the patient
after discussing the expected benefit and the potential morbidity
outcomes. Apart from the various tumor related factors, presence of co-
morbidities and preexisting organ dysfunction (like non functional
organ, non healing ulcers, osteo-radionecrosis, severe fibrosis) are
probably the most important factor before deciding on a course or re-

9
irradiation in the head and region6,9,10
. The cumulative life time dose to
organs like the spinal cord, brain stem and parotids needs to be
respected. Wherever possible, IMRT should be preferred for its obvious
dosimetric advantages over conventional or 3D conformal radiation
techniques which transfer into clinically measurable benefits in terms of
acute and late toxicity. Advanced radiation techniques, such as
tomotherapy or proton-beam therapy, may facilitate treatment near the
base of skull, whereas for small volume mucosal recurrence, interstitial
brachytherapy should always be tried11
. Re irradiation treatment itself
and the intended dose prescription should be evaluated carefully in
accordance with the treatment volume, prior dose distribution and the
modality of previous treatments so as to minimize the volume of
overlap6, 11
. For treatment near carotid artery Doppler ultrasound before
re-irradiation is often recommended as patients with significant stenosis
can be considered for an appropriate vascular intervention before re-
irradiation. Use of concurrent chemotherapy wherever may possibly
improve the chance of survival in most cases12, 13, 14
. Provision of
aggressive nutritional support during the course of irradiation and after
in cases of organ dysfunction is essential to minimize treatment breaks15
.
Gliomas and other brain tumours
Local recurrence of malignant glioma is a common problem in clinical
practice. A standard management regimen for recurrence does not exist.
The various options available are re-surgery, radiotherapy, systemic
therapy, and the best supportive care. However, the decision depends on
the specific patient and tumor-related factors. Re-resection not only
improves symptoms and maintains quality of life, it can delay symptom
progression, reduce corticosteroid doses, and also improve response to
(and allow intra-operative) chemotherapy and/or
radiotherapy16,17
. Young patients, with KPS more than 80 %, small
volume residual lesion involving noneloquent areas are the ideal
candidates for surgery17
. Re-irradiation is an option for a small
subgroup of selected patients. The first and foremost step before re-
irradiation is establishing recurrence and differentiating from
pseudoprogression. Patients with a KPS greater than 60%, a tumor size
of up to 40 mm, and progression more than 6 months from time of

10
surgery appear to be the best candidates16
. The most common approach
involves the use of fractionated stereotactic radiotherapy with or without
intensity modulation and a median total dose of 30–36 Gy. Stereotactic
radio surgery and interstitial brachytherapy are not favoured because of
their high concern for toxicity (20-30%) and its suitability for very
small tumours (<30 cc volumes)18,19
. Effort should be made to keep the
cumulative EQD2 around 100 Gy with conventional technique and
slightly higher with conformal and stereotactic radiotherapy20
.
Gynaecological cancers
Although with improvement of external beam radiotherapy and
brachytherapy techniques and increase in dose delivered to the pelvic
tumours has improved local control, local pelvic recurrence after
radiotherapy still occurs in about one third of cases. These recurrences
can be central or peripheral and surgery if possible is the mainstay of
treatment. The pelvic re-irradiation must not be the first choice for such
patients with recurrent pelvic tumours after a previously course of
irradiation. As minimal data is available on the toxicity of additional
radiation therapy, this approach would be considered only when there in
no other alternative for effective therapy and in the face of progressive
and severe symptom. Pre-existing late rectal or bladder toxicity is a
strong deterrent for consideration of reirradiation. Cumulative dose to
several organs at risk like femoral heads, bone marrow, small bowel,
urethra, vagina and sigmoid should also be considered. As per as
technique is concerned preference should be given to intraoperative
radiotherapy or brachy therapy. Combining surgery with postoperative
radiotherapy gives best results.
Bone and Brain Metastases
Re-irradiation for painful bone metastases is considered when there is no
pain relief after first-time radiation or there is partial response to first
time radiation and those in whom a better response is desired and in
cases of pain relapse after either partial or complete response to the first

11
time radiation. The ideal approach towards re irradiation will involve
proper evaluation of the pain, evaluation for associated fracture, soft
tissue component and weight bearing 30, 31
. Dose and fractionation of the
initial radiation is important as retreatment after a single fraction (4, 6 or
8Gy) treatment is quite feasible and tolerable29
. Also the response to the
initial radiation and pain relief provided needs to be considered, since
there is little evidence that the initial non responders will benefit from
reirradiation. For most patients a single treatment with 8 Gy is non-
inferior to treatment with 20Gy in 5 fractions or other protacted
courses28, 31
.
The role of WBRT, surgical excision, SRS and chemotherapy for
patients with newly diagnosed brain metastases is well known, but
limited salvage options exist for patients with multiple recurrent brain
metastases treated previously with whole brain radiation therapy
(WBRT) or SRS-SRT33
. For those individuals who survive long enough
to experience recurrence/progression of previously treated brain
metastases treatment of recurrent/progressive brain metastases be
individualized based on functional status, extent of disease,
volume/number of metastases, recurrence or progression at original
versus non-original site, previous treatment and type of primary
cancer34,35
. The most important consideration prior to re-irradiation is the
expected survival of the patient and performance status and the
pretreatment neurological status. For isolated recurrences in patients
initially treated with WBRT or SRT, with good performance status
surgical option should always be sought36
. Systemic therapy and
chemotherapy options for widespread recurrences should also be kept in
mind37-41
.
Table 1: Prerequisites for Re-irradiation
1. Confirmation of recurrence or second primary (preferably by
histology)
2. Precise knowledge of the late radiation response of the normal
tissue within the proposed re treatment field

12
3. Precise knowledge of the radiation dose, portals , volumes of the
previous radiation
4. Clarity regarding the intent of re-treatment
5. Absence of distant metastases (in case of curative re irradiation)
6. Salvage surgery is not feasible/too mutilating/risky
7. The expected harm benefit ratio of less than 1
Table 2: Basic rules of re irradiation
1. Multidisciplinary evaluation for treatment of patients with
recurrent cancer
2. Re-irradiation should be offered for patients who have
responded well to the first course of radiation
3. To minimize the overlap of the treated volumes of the two
courses as far as possible
4. Prophylactic irradiation to loco regional draining lymph
nodal basin should be best avoided
5. For patients treated with curative intent, re-irradiation to
doses of 60 Gy or greater to the recurrent disease are
recommended
6. To try to use different portals for the second course, to try
and use different technique of radiation wherever possible
e.g. EBRT –brachytherapy. /3D conformal-SBRT. Highly
conformal radiation techniques such as IMRT are
recommended over less conformal modalities
7. Bigger the volume of re-irradiation – worse is the outcome
8. To incorporate biological imaging for delineation of target

14
Tables 3: Steps for re-irradiation process
Steps Issues
1. Defining Intent Whether palliation or intent curative
2. Ethical and
Medicolegal
considerations
The patient should be explained about
the potential benefit with reirradiation,
options of alternative therapies,
possibilities of fatal complications and
serious morbities before obtaining
informed consent.
Proper Documentation of
communication with other specialities,
patient’s data, radiation rationale,
details and toxicity.
3. Pretreatment
evaluation /assessment
Biopsy
Exclusion of contraindication for
radiation
Performance status
Preexisting organ dysfunction
Organ reserve volumes and residual
normal tissue tolerances
Nutritional and rehabilitation needs
4. Radiotherapy planning Use of appropriate imaging, preferably
functional
Use of appropriate conformal technique
/brachytherapy/SRT
Target volumes definition as per ICRU
recommendations
Dose fractionation- consideration of the
previous biological dose. Calculation of
the cumulative EQD2. Normal tissue
tolerance doses to include repair effects
over time. TD5/2 preferred over TD5/5
5. Concurrent therapy Chemotherapy should be incorporated
for sites where it increases the chance

15
of success like head and neck, gliomas
etc and avoided in others like breast
6. Supportive care Nutritional support
Hydration
Control of anaemia, cytopenia, pain
relief
Edema and seizure prophylaxis.
7. Post treatment
evaluation and follow
up
Anticipation of complications and
mitigation
Response assessment
Quality of life indices
*adapted from Joseph K et al. Clinical Oncology 201022
.
Figure 1: general approach for re-irrradiation

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Is it a true recurrence
or a new primary - is it
biopsy proven
yes
is it amenable to surgery
No
Is there any significant co-morbidity
no
is there any significant
organ dysfunction
no
is the tumour of low volume (T1,T2/less than 2cm
Diameter)
Is brachytherapy an option
yes
consider reirradiation with
HDR/PDR interstitial
brachytherapy 6,7
no
consider reirradiation with IMRT, SBRT/SRT or
other experimental therapy (proton/carbon
ion)
yes
consider systemic therapy
consider palliative care
yes
consider palliative reirradiation
consider palliative care only
yes
consider resection -followed by
reirradiation withor without
systemic therapy for high risk
features 5
no
imaging available

17
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22
CHAPTER-3
RADIOBIOLOGY OF RE-IRRADIATION
DR NANDITHA SESIKERAN, DR MANOJ GUPTA
E MAIL-nanditha007@gmail.com
INTRODUCTION
The treatment options for recurrent tumors are limited. Re-irradiation
is being increasingly considered as an option, in view of the advances in
treatment techniques, particularly the ability to document doses,
overlay plans, intensity modulation and image guidance. However, data
regarding indications, outcomes, fractionation, concurrent treatment
and cumulative doses to normal tissues is in the nascent stage. Unlike
first line radiation regimens, which have been tried and tested in
several large prospective randomized trials, re-irradiation trials suffer
from lack of homogeneity and much smaller numbers to draw any
statistically sound conclusions. This review attempts to collate the
existing evidence about the radiobiological considerations in re-
irradiation.
The various factors that need to be taken into consideration are the
type of normal tissues at risk, the dose fractionation, interval from
previous radiation, the current extent of disease, overall patient
prognosis, observable normal tissue damage that has resulted from the
previous radiation.
Calculating total cumulative dose

23
Tissues are broadly divided into early responding and late responding.
The early responding tissues (high α/β ratio) have a rapidly proliferating
stem cell compartment, which migrate into the irradiated tissue and
restore normal architecture and function rapidly. The α/β ratio is
considered to be 10 for such tissues and thereby the physical dose gives
a fair idea of the biologically effective dose at various fractionation
schedules. However, for tissues with low repair capacity (low α/β ratio,
approximately 3) the BED (Biologically Effective Dose) rather than
physical dose, should be considered while evaluating irradiation
protocols (1). The BED values can be calculated according to the linear-
quadratic formula, which is the generally accepted standard model for
dose-fractionation analysis. This is then expressed as 2Gy equivalent
dose to allow uniform comparison of various studies. The aim of various
pre-clinical and clinical studies, has been to estimate the total
cumulative (EQD2) doses also termed as Normalized Total Dose (NTD)
(2), that can be delivered to various tissues. However, for fraction sizes
beyond 5Gy, particularly high dose single fraction radiosurgery, the
validity of linear quadratic model is questionable (3).
Spinal cord
Experiments in rhesus monkeys studied by Ang et al, looked at re-
irradiation tolerance at varying time intervals after the first course and
concluded that for a time interval of 1, 2 and 3 years between the
treatment courses, cumulative doses of 150, 156 and 167% of the first-
line setting’s tolerance dose appear possible (4). These findings have
also been reflected in clinical experience in humans. Neider et al,
compiled individual patient data from multiple reports and proposed a
risk assessment model for myelopathy. The factors which contribute to
the score include Cumulative BED (assuming α/β of 2 for cervical and
thoracic spinal cord and 4 for lumbar), time interval < 6 months
between the two courses, any single course with a BED ≥102Gy2

24
Risk score for development of Radiation myelopathy (5)
Factors 0 1 2 3 4
5 6 7 8 9
Cumulative
BED (Gy2)
≤120 120.1-130 130.1-140 140.1-150 150.1-160
160.1-170 170.1-180 180.1-190 190.1-200 >200
Interval <
6 months
x 4.5
One BED
course ≥
102
x 4.5
Risk group for development of Radiation myelopathy (5)
Risk group Score Myelopathy %
Low risk ≤ 3 0
Intermediate 4-6 33%
High >6 90%
The above model provides a practical guide to spinal cord re-irradiation
tolerance. However needs to be validated in prospective studies.
Brain

25
The biology of radiation damage in the brain is similar to that of the
spinal cord and is characterized by a long period of latency. The earliest
evidence of damage is in the form of segmental demyelination and
nodal widening which can be observed by 2 weeks. Remyelination can
be observed by 2 months. After a latent period of 4-6 months, areas of
white matter necrosis can be observed, as a result of critical
depopulation of oligodendrocytes and vascular damage. The probability
of occurrence of necrosis and the latent period is a function of dose (6)
Re-irradiation is being considered as a valid option for recurrent
gliomas in select cases. There have been several large case series
reporting re-irradiation doses and incidence of radiation necrosis. The
normalized total dose (NTDcumulative) which can be delivered depends
on the re-irradiation volume and the technique of radiotherapy. A
comprehensive account of clinical data available for re-irradiation of
brain was presented by Mayer et al in 2008. An NTDcumulative of >
100Gy for conventional fractionation was associated with radiation
induced white matter necrosis. . Smaller volumes and more conformal
techniques like Fractionated stereotactic radiotherapy and LINAC based
single fraction SRS allow safe delivery of higher NTD cumulative doses
(90–133.9 Gy for FSRT, 111.6–137.2 Gy for SRS). However, they found
no correlation between time interval of the radiotherapy courses and
incidence of complications (7)
Lung
Re-irradiation of lung has historically been used in a palliative setting.
With a wide variety of systemic treatments available for treatment of
lung cancers, survival is increasing and thereby the scope for re-
irradiation in the setting of a localized relapse or for symptom control.
Lung is considered a late reacting tissue with an estimated α/β ratio of

26
4 (8) . The primary endpoint of radiation damage is Radiation
pneumonitis and more uncommonly, bronchial stricture, necrosis and
fistulas. The tolerance dose for lung is fairly established in the denovo
setting, with conventional fractionation. It is a function of dose and
volume (V20, Mean lung dose – MLD etc). In the relapsed setting,
multiple factors affect the tolerance of lung – prior RT dose, systemic
treatments, prior surgery, cardiac function, tumor size and location.
Stereotactic radiotherapy allows delivery of meaningful doses without
excessive spillage into normal lung.
Clinical data on use of re-irradiation with conventional fractionation in
non-small cell lung cancer shows that it is feasible. In a series of 34
patients, who received a median dose of 60Gy in the initial course,
received a second course of median dose 50Gy after a median interval
of 23 months, 75% showed symptomatic improvement, but 19 patients
had symptomatic pneumonitis, none of which were fatal (9).
Subsequently, a prospective trial with similar cumulative doses
reported much lesser incidence of radiation pneumonitis (22% grade 1-
2, No grade 3 or > pneumonitis) (10). With the use of stereotactic RT,
delivery of much higher doses was found to be feasible. While a BED OF
>100Gy is recommended for primary SABR, in the salvage setting, more
conservative dose fractionation (40-50Gy in 4 fractions) equivalent to a
BED of 80Gy have been recommended and found to be safe (11)(12).
Bladder
Bladder is considered a late reacting tissue due to the low proliferating
potential of urothelial cells. However, acute radiation cystitis occurs
within 2-4 weeks of starting radiotherapy and presents as reduced
bladder capacity due to functional biochemical changes (release of
prostaglandins by urothelium). The late effect on bladder may present
after a long latent period of several years and is characterized by
ulceration, telangiectasia, fibrosis presenting as reduced bladder

27
capacity, dysuria and hematuria. The α/β for late effects is considered
to be 6, in contrast to other late responding tissues with α/β of 3, which
implies less dependency on fraction size. The dose-volume tolerance
parameters prescribed for bladder are difficult to interpret as volume
changes with bladder filling and not all areas of the bladder have equal
functional importance (13).
Re-irradiation experiments on mouse bladder suggest that long term
recovery of bladder injury after a course of radiotherapy is poor.
Thereby, a longer time interval between courses does not provide
additional tolerance unlike other organs like brain and lung. The re-
irradiation dose delivered hence entirely depends on the initial dose
received and cumulative doses can only be as high as bladder tolerance
to a single course of RT (14). Clinical studies with SBRT for pelvic
relapses, suggest that maximum cumulative dose (EQD2) can be as high
as 120Gy3 to a volume of 10cc (15).
Rectum
Late rectal toxicity is a major concern in pelvic radiotherapy. Attempts
are made to reduce rectal dose while treating prostate and cervical
malignancies by using IMRT and brachytherapy. Clinical studies in
cervical cancer have demonstrated clear correlation between rectal
dose volume parametres and toxicity. Using a cut-off of D2cc dose of
<75Gy, results in <5% rate of late rectal toxicity. However, it is difficult
to define such precise cumulative dose constraints for rectum in re-
irradiation (16) . Studies have reported acceptable toxicity to the
rectum after re-irradiation with stereotactic techniques. A study by
Abusaris et al, utilized cyberknife to deliver SBRT to 27 patients who
had prior pelvic radiotherapy. A cumulative dose of upto 110Gy3 was
allowed to 10cc of rectum. With this limit, none of the patients
experienced grade 3 or more toxicity (15). Re-irradiation has also been
used in selected cases of primary rectal cancers with local relapse,

28
having previously received pre-op or post-op radiotherapy. Patients
were treated with three or four coplanar fields with either
hyperfractionated (1.2Gy per fraction, 2 fractions per day) or with
conventional 1.8-2Gy per fraction upto a cumulative dose of 85.8Gy
(70.6-108Gy). Late toxicities reported were chronic grade 3 diarrhoea
(22%), small bowel obstruction (15%), fistula (4%) and skin ulceration
(2%). Patients who received hyperfractionated RT and had an interval
of >24 months since the first course of RT had significantly less
toxicities (17).
Skin and mucosal tissues
Skin after radiation therapy is characterized by a faint, dried epidermis
and changes in the structure of keratinization. The superficial epithelial
cells are acutely responding and are assumed to have an α/β of 10,
while subcutaneous tissues that lie at a depth of > 5mm are responsible
for late effects and are assumed to have an α/β of 3. Based on animal
experiments of mouse tail re-irradiation, it was found that upto 90% of
tolerance dose could be given after an interval of 6 weeks to 10 months
from prior radiation with tolerance dose. The tolerance dose after third
irradiation reduced to 65% (18). The Radiation Therapy Oncology Group
(RTOG) reported the skin tolerance of 5% ulceration in an irradiated
area of 5 x 5 cm2 to be 70 Gy (19). Reirradiation studies in recurrent
skin cancers sing superficial X rays, has shown that a cumulative BED of
110Gy to skin surface and not more than 55Gy at 5mm depth was
tolerable (20). In subsequent studies of recurrent breast cancers using
megavoltage photons, cumulative doses EQD2 upto 100Gy have been
reported, with 10% acute grade 3 toxicity, 8.5% of grade 3 fibrosis and
2% skin necrosis (21).
Re-irradiation studies in head and neck upto total cumulative doses of
120Gy, reported grade 2 and 3 late toxicities in the form of cervical
fibrosis (41%) and mucosal necrosis (21%) (22).

29
Tolerance of skin and mucosal acute effects seems to be tolerable in
the dose range of 110-120Gy EQD2, with slightly higher incidence of
late grade 2-3 toxicities.
Mesenchymal tissues
The mesenchymal tissues including cartilage, bone and muscle, are
often not given any constraints in planning. Radiotherapy to cartilage
upto even 10Gy results in growth retardation in children. High dose to
bones results in osteoradionecrosis and fractures. The dose volume
parameters for mandible for the end point of necrosis have been
quoted in various studies. Studies in oral and oropharyngeal cancers,
showed D2%>65Gy (24), V43 ≥ 42%, V24 ≥ 94% (23) to be associated
with increased risk of necrosis. Risk of necrosis of the mandible is
around 5 with megavoltage radiotherapy with modern techniques.
Studies on re-irradiation suggest that the incidence of ORN with a
cumulative dose of 120Gy is reported to be 8-11%, the incidence being
higher in patients treated at a time interval of <3yrs, concurrent
chemotherapy and higher total dose (24)(25). Though it has been
proposed that cumulative dose to mandible should not exceed 70Gy, it
is unclear what volume can tolerate this dose (26).
Carotid blowout is one of the life-threatening complications of re-
irradiation in head and neck. Its incidence has been reported to be
between 5-8% (26). Factors associated with increased risk of blowout
include >180degree encasement of carotid, skin ulceration and
irradiation of lymph nodes (27).
Altered fractionation
The role of hyperfractionation has been explored in various sites like
head and neck and non-small cell lung cancer. The concept of

30
hyperfractionation seems particularly attractive in the re-irradiation
setting. The delivery of multiple small fractions (<1.8-2Gy) per day, with
sufficient time between fractions to allow for sub-lethal damage repair
(>6hrs), offers a therapeutic gain in terms of reducing late effects of
normal tissues which have a low α/β (1.5-5Gy). In contrast, the high
α/β values (6–14 Gy) observed for acutely responding normal tissues
indicate that the response is relatively linear over the dose range of
clinical interest. Another strategy to increase therapeutic gain is to limit
the treatment volume by using techniques which are highly conformal
such as stereotactic radiotherapy, brachytherapy and intra-operative
radiotherapy (28).
Low dose ultrafractionation: In vitro studies have shown that some
human tumor cell lines are sensitive to low radiation doses of ≤1Gy, a
phenomenon that has been termed low-dose hypersensitivity (HRS).
This radiosensitivity seems to be more apparent in radioresistant cells
such as glioma cell lines. The mechanism underlying HRS in specific cell
types appears to be related to defective DNA repair systems and cell
cycle regulation. HRS is more likely to affect early responding
proliferative tissue and hence a novel concept for re-irradiation. A
prospective randomized trial was initiated by EORTC-NCIC in newly
diagnosed inoperable glioblastoma patients, with a regime of 0.75Gy
per fraction, 3 fractions per day with a minimum of 4 hours interval
(five days a week; six consecutive weeks), prior to the establishment of
stupp regimen (29). This trial showed a marked number of long term
survivors with a 2yr survival rate of 15.48% (30). Subsequently a phase
II trial was conducted with this regimen in combination with
temozolamide which showed median OS of 16 months, 2yr OS of 32.4%
which was superior to the stupp trial results (31). A case series of 11
patients, utilized low dose ultrafractionation for re-irradiation in various
sites and reported effective palliation with minimal toxicity. This
concept appears promising and warrants larger prospective trials in re-
irradiation setting (32).

31
Response modifiers
Strategies to enhance radiation sensitivity including various
chemotherapy drugs, targeted therapy and hyperthermia have been
used concurrently in the re-irradiation setting. The mechanism being
similar to their use in the first line. Common radiosensitizers are
cisplatin and cetuximab in head and neck, 5FU in rectum. With the
emerging role of immunotherapy and its potential interaction with
radiotherapy, it remains to be seen whether this strategy adds to the
armamentarium of radiation response modifiers.
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36
CHAPTER-4
Recovery and tolerance of the Organs at Risk during Re-irradiation
Dr. Suman Das, Dr. AshutoshMukherji
EMAIL-drsumandas@gmail.com
Abstract:
In the last few decades, there have been major improvements both in
diagnosis, staging and management of cancer which has translated into
better disease outcomes and longer survival rates and with better quality
of life. This improvement in the quality of life is by better normal tissue
sparing caused by the increasing use of newer techniques and
technologies especially in surgery and radiotherapy. Along with higher
survival, there is now greater acknowledgement of the need to treat local
recurrences and hence the increased use of re-irradiation. Better
technology such as IMRT translates into better sparing of normal tissue
but at the same time late toxicity is still of concern. Factors such as
residual late damage, total dose, fraction size, technique, type of tissue,
and time interval to re-irradiation still guide prescription of the re-
irradiation dose. Knowledge of long term recovery of organ at risk is
hence of importance in re-irradiation. This review article has
emphasized on the recovery and tolerance of organs at risk like Spinal
cord, Brainstem, Brain etc. This is important in prescribing doses for the
target volume for re-irradiation and in setting constraints for surrounding
critical organs during the planning process.
Key words:
Local recurrence, Reirradiation, Radiotherapy,Organ at risk in
reirradiation, normal tissue tolerance for re-irradiation.
Introduction:

37
In the last few decades, there have been major improvements both in
diagnosis, staging and management of cancer which has translated into
better disease outcomes and survival rates. Patients who receive optimal
therapy are now expected to survive longer and with better quality of life
compared to a perhaps three or four decades back. This improvement in
the quality of life is by better normal tissue sparing caused by the
increasing use of newer techniques and technologies especially in
surgery and radiotherapy. Present treatment strategies put a higher onus
of organ and function preservation and depend more on multi-modality
therapy to optimize response and survival. The improved cure rate and
survival has brought into focus the situation of a localized disease
recurrence in an otherwise preserved patient requiring additional modes
of treatment measures for local control and palliation.
The availability of newer technologies like Stereotactic Radiosurgery /
Radiotherapy (SRS / SRT), IMRT/IGRT and Brachytherapy has
prompted many clinicians to consider re-irradiationbecause of the ability
of these techniques to spare critical and late reacting tissues. The single
most important factor in planning re-irradiation is the ability using these
techniques to determine the doses to various tissues in the irradiated
volume. There are also other various factors to be considered while
considering for the re-irradiation. It is important to remember that tissues
which have once been irradiated may or may not have the same
tolerance to a repeat course of radiotherapy. There can be many factors
which will determine such tolerance and these may include residual
tissue injury present (presence of residual stem or corrective cell
depletion still present in the tissue); the interval between the two courses
of radiation which will determine the extent of tissue regeneration; the
volume of tissue required to undergo re-irradiation; fractionation
schedule used in prior course as higher the dose per fraction, more will
be the late effects and consequent less tolerance for repeat course of
radiotherapy as well as expected survival of the patient after such repeat
irradiation.In this review we will discuss the importance of respecting
tissue tolerances and their recovery after re-irradiation.

38
Discussion
As we explained in the introduction, the tolerance of normal surrounding
tissues as well as their recovery after re-irradiation depends on several
factors such as previous dose given, time interval between the two
courses of radiation, type of tissue being irradiated (made up of
predominantly acute or late reacting tissue type), volume of tissue being
irradiated, dose fractionation, disease extentand hence expected survival,
use of chemotherapy and / or surgeryas well as the technique of
radiation therapy being used. Newer modalities of irradiation whether
used upfront or during re-irradiation are expected to cause much less
normal tissue damage and hence permit dose escalation to the target
volume. Thus it is important to first calculate the expected dose received
from the previous course of radiation to all normal structures in the
volume expected to be irradiated (calculation should be for late effects
i.e. BED3Gy) before prescribing a fresh course of radiation therapy.
The fractionation and total dose will be guided again by the total of the
biologically equivalent dose for 3 Gy fraction size (BED3Gy) for both the
courses. In the re-irradiated volume also the normal tissues can be
divided into early reacting (skin, mucosa, lung, intestine) and late
reacting (muscle, connective tissue, vasculature, brain, spinal cord,
brainstem, lungs, heart, bladder and kidney). Most of the acutely
reacting tissues are thought to recover from the radiation induced
sequelae within a few months at the most and therefore theoretically
these tissues can tolerate a repeat course of irradiation (depending on the
total dose, fractionation, and technique) even 6 months down the line.
Some late reacting tissues however such as the heart, bladderand kidney
either do not show long term recovery or limited recovery and therefore
even at the first instance are amenable to only partial volume irradiation.
For cases in which these tissues need to be re-irradiated, doses have to
be carefully calibrated to avoid crossing the BED3Gy tolerance limits at
all.The subsequent paragraphs will discuss the tolerances of some of
these normal tissues wherein data from re-irradiation studies are
available.

39
Acute reacting tissues – Skin and mucosa:
As mentioned these tissues are expected to recover faster after the initial
course of radiation therapy and the tolerance of these tissues to a
subsequent course of irradiation depends on the time interval between
the two courses as well as the dose per fraction both times. In general,
for re-irradiation, prophylactic lymphatic or connective tissue volumes
(for microscopic disease) is not included as target volume which
includes only the gross tumour volume (GTV) with a minimal margin of
0.5 – 1.0 cm. Most of data for acute reactions are available from animal
studies. A study by Terry et al (1) in mice reported that acute reactions
after re-irradiation with single doses of 15-30 Gy were similar to those
of the first course of irradiation when the interval was more than 2
months while in cases wherein re-irradiation with single doses of 34.5 –
37. 5 Gy were given within a month of previous radiotherapy, complete
breakdown of the skin and ulcerations were noted. A similar study by
Symmonds et al (2) on pig skin reported similar findings with tolerance
improving as the interval was lengthened to beyond 52 weeks (1 year).
Similar findings have been reported for both lung mucosa and head and
neck mucosa. (3,4) From these studies, we can say that there is a
recovery of the viability and function of both skin and mucosa by
accelerated repopulation leadingto restoration of the original cell number
when the interval between two courses of irradiation is higher especially
when more than 6 months.(5)
Spinal Cord:
Spinal cord is the major dose limiting organ in radiotherapy. The present
era of more aggressive multi-modality management of head and neck
cancers has improved survival and many more patients report with either
a relapse or a second primary close to the site of the primary tumour. In
many of these cases the target volume is close to or overlies the spinal
cord. Radiation induced myelopathy is the most common catastrophic
side effect of radiotherapy involving spinal cord.The risk benefit ratio is
the most important point to be considered during re-irradiation.

40
Clinical data is very sparse in terms of toxicity and tolerance of spinal
cord re-irradiation. There has been significant research in animal models
to define the factors responsible for recovery of irradiated spinal cord.
Ruifruck et al (6) noticed that ED50 value was higher for mouse retreated
after 6 months. The long term recovery from primary radiation was 40-
45% after 6 months. Wong et al (7,8) also studied sensitivity of the
cervical spinal cord in mice to fraction sizesduring repeat irradiation as
well as long term recovery and re-irradiation tolerance. He found that
the latent time to paralysis (loss of cord function) was inversely
proportional to level of initial injury. Similarly there have been studies
in rhesus monkeys by Ang et al (9), in which the researchers noticed that
there was significant recovery from the initial average dose of 44 Gy
after 2 years’ time and single vascular injury showed less recovery than
white matter damage. Cumulative doses below 100 Gy2 did not produce
any myelopathy while electrophysiological changes of myelopathy were
seen above 130 Gy2.(9) These experiments in animal models showed
that the spinal cord recovery following re-irradiation depends on volume
of spinal cord irradiated, total dose received, dose fractionation and time
interval for the retreatment.
Studies bySchiff et al (10) and Grosu et al (11) have suggested that the
human spinal cord after an initial exposure of 46 Gy in 2 Gy/Frmay
tolerate an additional 23-24 Gy in conventional fraction sizes if there is a
gap of 1-2 years between the 2 courses. Also it is important to keep the
cumulative dose as low as possibleas was shown byNeider et al (12) in
his analysis of 8 reports involving 39 patients with long term follow up
in which he concluded that besides the cumulative doses of more than
100-110 Gy2 (especially if larger fraction sizes are used) and an interval
less than 6 months increases the risk of myelopathy. From the
QUANTEC data on spinal cord re-irradiation of the full cord cross-
section at 2 Gy per day after prior conventionally fractionated treatment,
cord tolerance appears to increase at least 25% at 6 months after the
initial course of RT.(13)

41
The introduction of Stereotactic Radiosurgery/Radiotherapy (SRS/SRT)
has revolutionized radiation treatment by its ability to deliver very high
dose to a very precisely defined target volume and therefore avoiding the
whole circumference of the cord. Sahgal et al (14) has recommended
that thethecal sac point maximum P(max) EQD2 of 20-25 Gy appears
safe provided the total P (max) dose did not exceed 70 Gy and the SBRT
thecal sac P(max) EQD2 does not exceed 50% of the total
normalisedBED.
Brain:
Brain tumors and especially high grade gliomas frequently relapse close
to or at the margins of the previously irradiated volume and may require
re-irradiation. These cases also run the risk of developing radiation
necrosis or gliosis with resultant functional deficit if tissue tolerances are
not respected. While there is no randomiseddata evaluating the role of
re-irradiation in brain, clinical practice recommendations by Maranzano
et al (15) have suggested that each course of radiation to the brain limit
the dose to 60 Gy with a cumulative dose not crossing 140-150
Gy2.They have also suggested practice recommendations for re-
irradiation to the brain and spinal cord (Table 1) as well as indications
and contra-indications. Ramona et al (16) in their analysis of brain re-
irradiation in glioma patients have reported that the Normalised Total
Dose (NTD Cumulative) ranges from81.6Gy-101.9Gy in conventional re-
irradiation to 90Gy-133.9Gy inFractionated Stereotactic Radiotherapy
(FSRT) and even up to111.6-137.2Gy inStereotactic Radiotherapy
(SRS).
It has been noted that patients treated with conventional fractionation
usually do not show radio-necrosis but patients receiving FSRT can
developradiation necrosis after a NTD Cumulative more than 105Gy and
SRS more than 135Gy. This total cumulative dose is the most important
factor for the development of radiation necrosis in normal brain tissue
and while there is not enough literature on the minimum time interval
required between two courses of radiotherapy; as with other CNS sites, a
minimum of 3 months is recommended by Ramona et al. (16)

42
Brainstem:
Brainstem is a critical structure and at risk of being radiated during re-
irradiation of tumour involving Nasopharynx and Brain tumors. Wong et
al (17) analysed retrospectively 448 patients and reported that patients
can tolerate repeat course of irradiation of up to 39 Gy if there is
minimum interval of at least 12 months between the two radiotherapy
courses. It is important to note that the EQD2 Dmaxis 79Gy while the
BED3Gy is a maximum of 140 Gy3. Point doses were also assessed in this
study and it was found that the tolerated D0.1ccreceived 71Gy and D
0.5cc received 65Gy and D 1.0 cc of 60 Gy. The tolerance to cumulative
dose increases further with increase in interval between the primary
radiation and re-irradiation.
Aorta and Great vessels:
Dose limitations to the great vessels, the heart, the lung as well as the
coronary arteries have been traditionally the limitations in planning
thoracic radiation both as initial and during re-irradiation. New
techniques such as IMRT or SRT have helped achieve these dose targets
while sparing the organs at risk in the thorax. A study by Evans et al
(18) retrospectively analysed 360 patients with non-small cell lung
cancers of whom 35 patients received re-irradiation. All of these patients
had the aorta inside the target volume. The authors reported that aortic
toxicities (stenosis or rupture) was seen in 1-2% of treated patients only
and have estimated the tissue tolerance to a cumulative Dmax (to 1 cc of
tissue) at 100 Gy2; with normalized dose calculations pointing at a cut-
off of 120 Gy2 for raw dose and 90 Gy2 after correction for tissue
recovery.
The Carotid Blowout Syndrome (CBOS) is a much discussed side effect
of radiation especially in head and neck cancer radiotherapy. Yamazaki
et al (19) analysed 7 JapaneseCyberknife®
studies and they suggested
CBOS index a predictive model which includes >180O
of carotid
invasion, presence of ulceration and lymph node irradiation (0-3points).

43
Lungs:
Radiation pneumonitis is a common side effect of irradiation to the lung.
Due to limited survival after relapse and re-irradiation of lung tumors
there is sparse data on re-irradiation. Terry et al (20) analysed in murine
model and reported that a low priming dose is the most important factor
for re-irradiation. Clinical data is limited but the available literature
supports the results of animal model. Jackson et al (21) observed no
symptomatic radiation pneumonitis in 22 patients with non-small cell
lung cancer re-irradiated to 20-30 Gy in 2Gy per fraction after a primary
dose of 55 (50-60) Gy @2-2.2Gy per fraction after a period of 15 (6-
48)months. A similar effect was reported by Montebello et al (22) who
assessed re-irradiation to a dose of 30 Gy after an initial 60 Gy.
However late effects have not been described in this study as the median
survival was only 5.5 months.
Heart:
The cardiac tolerance dose was defined as the dose causing at least 50%
function loss (ED50). Wondergem et al (23) assessed re-irradiation
tolerance in mouse model and suggested the priming dose and interval
between the primary radiation and re-irradiation being the most
influential factor for heart. However definite clinical data is still lacking.
According to an analysis by Sumita et al, the cumulative dose to the
heart (BED3Gy) should not exceed 70 Gy3 and the point dose (0.1 cc)
Dmax not more than 49 Gy3. (24) In this study it was also seen that the
late toxicities to re-irradiation were lesser if the interval between the two
courses of radiation was more than 24 months.
Head and Neck Cancers:
The incidence of second primary neoplasms is between 16-30% with
response rates between 10-40% and median survivals of 6-8 months.
The target volume and field size is the most significant factor in
determining tissue tolerance; elective volume irradiation is not
recommended. According to a review by Jagtap and Sunku (25)
recommended re-irradiation doses with conventional fractionation are

44
58-60 Gy at an interval of at least 6 months; while according to Roh et
al, for Stereotactic Radiation recommended doses range from 18-40 Gy
over 3-5 fractions. (26)
Soft tissue Sarcomas:
Large scale prospective studies are not available in this set of patients
and analogies can only be drawn from limited case series’ present.
However in most of these the cumulative dose has been limited to below
150 Gy2 with little or no late effects. It was also seen that local control at
relapse was better achieved with re-irradiation to doses over 50 Gy
(27,28).
Pelvic Tumours (Anorectal):
Rectal cancers which relapse locally have been re-irradiated by many
different techniques and hence it is difficult to produce matching sets of
data to draw conclusions for dose tolerance recommendations. Various
studies by Mohiuddin et al (29), Alektiar et al (30) amongst others have
put a cumulative tolerance dose of 70-100 Gy2 for the rectum.
Table 1: Recommended / accepted re-irradiation normal tissue
tolerances:
Organ /
Tissue
Accepted Re-
irradiation
dose –
Fractionated
(Gy)
Accepted
Re-
irradiation
dose –
Stereotactic
(Gy)
Accepted
Time
interval
between RT
courses
Extent of
OAR
recovery
Skin /
mucosa
50-60 Gy in
conventional
fractions
- > 6 months full
Soft tissue /
Muscle
Doses over 50 Gy
conventional EBRT produce
better control(27,28)
> 12 months
Large scale
data not
available; only
case series’
present

45
Brain /
Brainstem
Cumulative BED not exceed
130-159 Gy withan α/βratio
equal 2 Gy2(15)
>12 months partial
30 - 40 Gyin
fractionated RT
(17)
24 Gy for
tumour
volume < 20
mm, 18Gy
for volume
21-30 mm
and 15 Gy
for volume
31-40
mm.(31)
Spinal Cord
cumulative BED should not
exceed 130 Gy2 (15)
>12 months partial20-24 Gy in10-
12
fractions(10,11)
-
Heart
cumulative dose to the heart
(BED3Gy) should not exceed 70
Gy3 and the point dose (0.1 cc)
Dmax not more than 49 Gy3
(24)
> 24 months partial
Great
Vessels
cumulative BED should not
exceed 90-100 Gy2 (18)
>36 months
interval can
produce
estimated65%
OAR
recovery. (18)
1-2% aortic
toxicities
noted; carotid
blowout
Lungs
30 to 60 Gy by
EBRT (21,22)
20-30 Gy in
6-10 Gy
fraction sizes
2-3 times per
week for
total of 3-6
> 12 months
Central
mediastinal /
thoracic
tumours not
treated by
SRT; recovery

46
fractions may not be
complete here;
peripheral
tumours more
amenable to
SRT
Head and
neck
Optimal
schedule not
yet defined.
The dose
ranges from 58-
60 Gy. (25)
18–40 Gy in
3-5 fractions
to the 65%–
85% isodose
line over
consecutive
days (26)
> 6 months –
1 year
Depends on
target volume,
lesser volume
and more
mucosa means
more OAR
recovery
Anorectum
Total
cumulative
doses ranges
from 70 to 100
Gy with a
median total
dose of 85 Gy.
(29,30)
IORT dose
of 10-20 Gy
(29,30)
Peripheral
neuropathy
most
commonly
seen with
IORT.
Breast
• 40 to 50 Gy
given within
4 days with
PDR Brachy
• minimum re-
radiation
dose in
fractionated
schedule is
40 Gy
Minimum 6
months
Moderate skin
and
subcutaneous
tissue side
effects seen;
most
commonly
erythemas and
skin
telangiectasias.
Expected full
OAR
recovery.

47
Conclusion:
In the present day the possibility of re-irradiation has increased due to
the availability of image guidance, IMRT etc. but at the same time the
risk benefit ratio should be considered before deciding on the treatment.
The performance status and availability and feasibility of other less toxic
treatment alternatives should also be taken into consideration.The
knowledge of previous radiation field, portals, dose per fraction,
technique, dose distribution and exact dose of critical organs are
important determinants in prescribing dose and volume for re-
irradiation. Though there have been substantial research in animal
models regarding the recovery of OAR for re-irradiation but they cannot
be exactly applied into clinical practice. While there is an increasing
body of data in favour of re-irradiation in select sites and situations
using newer modalities to respect tissue tolerances; in many other sites
limited survival data hampers long term tolerance studies. Many acutely
reacting tissues like skin and mucosa usually recover early after first
dose of radiation and tolerate re-irradiation; and there is data in select
situations for late reacting tissues such as brain, spinal cord, rectum,
breast, and even head and neck cancers and soft tissue sarcomas. Other
tissues such as heart, vessels and lungs lack robust prospective data.
References:
1. Terry NHA, Tucker SL, Travis EL: Time course of loss of residual
radiation damage in murine skin assessed by retreatment. IntJ Radiat
Bio, 1989; 155: 271-83.
2. Simmonds RH, HopewellJW, Robbins MEC: Residual radiation-
induced injury in dermal tissue: Implications for retreatment. BrJ
Radio, 1989; 162: 915-20.
3. Trott KR: The mechanisms of acceleration of repopulation in
squamous epithelia during daily irradiation. ActaOnco, 1999;
138:153-7.
4. Montebello JF, Aron BS, Manatunga AK, et al: The reirradiation of
recurrent bronchogenic carcinoma with external beam irradiation. Am
J ClinOncol, 1993; 16: 482-8.
5. De Crevoisier R, Bourhis J, Domenge C, et al: Full-dose reirradiation
for unresectable head and neck carcinoma: Experience at the Gustave-

48
Roussy Institute in a series of 169 patients.J ClinOncol, 1998; 16:
3556-62.
6. Ruifrok ACC, Kleibuer BJ and Kogel AJVD. Fractionation sensitivity
of the rat cervical spinal cord during radiation retreatment.
RadiotherOncol 1992;25:295-300.
7. Wong CS, Minkin S, Hill RP.Reirradiation tolerance of the rat spinal
cord to fractionated X-ray doses. RadiotherOncol 1993; 28:197-202.
8. Wong CS, Poon JK and Hill RP.Reirradiation tolerance in the rat
spinal cord: influence of level of initial damage. RadiotherOncol
1993;26:132-8.
9. Ang KK, Price RE, Stephens LC, Jiang GL, Feng Y, Schulthesis TE
and Peters LJ: The tolerance of primate spinal cord to reirradiation.
Int J RadiatOncolBiolPhys 1993;25:459-64.
10. Schiff D, Shaw E, Cascino TL (1995) Outcome after spinal
reirradiation for malignant epidural spinal cord compression. Ann
Neurol 37:583–9.
11. Grosu AL, Andratschke N, Nieder C, Molls M. Retreatment of the
spinal cord with palliative radiotherapy. Int J
RadiatOncolBiolPhys(2002),52:1288–92.
12. Nieder C, Grosu AL, Andratschke NH, Molls M. Update of human
spinal cord reirradiation tolerance based on additional data from 38
patients. Int J RadiatOncolBiolPhys(2006a) 66:1446–9.
13. John P. Kirkpatrick, Albert J. Van Der Kogel,Timothy E.
Schultheiss. Radiation Dose–Volume Effects in the Spinal Cord. Int J
RadiatOncolBiolPhysVol. 76, No. 3, Supplement, pp. S42–S49, 2010.
14. Sahgal A, Ma L, Weinberg V et al (2012).Reirradiation human
spinal cord tolerance for stereotactic body radiotherapy. Int J
RadiatOncolBiolPhys82:107–116
15. Maranzano E, Trippa F, Pacchiarini D, Chirico L, et al. Re-
Irradiation of Brain Metastases and Metastatic Spinal Cord
Compression: Clinical Practice Suggestions. Tumori, 2005, 91: 325-
30.
16. Ramona M ,Peter S. Reirradiation Tolerance of the Human Brain.
Int J RadiatOncolBiolPhys2008, Vol. 70, No. 5, pp. 1350–60.

49
17. Wang, H.Z. et al. The Tolerance of Brainstem in Reirradiation
With Intensity Modulated Radiation Therapy in Recurrent
Nasopharyngeal Carcinoma. Int J RadiatOncolBiolPhys, Vol. 96,
Issue 2, E340.
18. Evans JD, Gomez DR, AminiA et al. Aortic dose constraints when
reirradiating thoracic tumors. RadiotherOncol (2013),106:327–332.
19. Yamazaki H, Ogita M, Kodani N et al (2013) Frequency, outcome
and prognostic factors of carotid blowout syndrome after
hypofractionated re-irradiation of head and neck cancer using
CyberKnife: a multi- institutional study. RadiotherOncol 107:305–
309.
20. Terry NHA, Tucker SL, Travis EL: Residual radiation damage in
murine lung assessed by pneumonitis. Int J
RadiatOncolBiolPhys14:929-93.
21. Jackson MA, Ball DL: Palliative retreatment of locally recurrent
lung cancer after radical radiotherapy. Med J Aust 147:391-394,
1987.
22. Montebello JF, Aron BS, Manatunga AK, et al. The reirradiation
of recurrent bronchogenic carcinoma with external beam irradiation.
AmJ ClinOncol, 1993; 16:482-8.
23. WondergemJ, van Ravels FJ, Reijnart IW, et al.Reirradiation
tolerance of the rat heart. Int J RadiatOncolBiolPhys36:811.
24. Sumita et al. Re-irradiation for locoregionally recurrent tumors of
the thorax: a single-institution, retrospective study. RadiatOncol
(2016) 11:104.
25. Sunku R, Jagtap VK. Re-Irradiation in Head And Neck Cancers: A
Wise Selection From Available Data. NJMR,Volume 6,Issue 4,Oct –
Dec 2016: 1-5.
26. Roh KW, Jang J, Kim M, Sun D, Kim BS, Jung S et al.
Fractionated Stereotactic Radiotherapy as Reirradiation for Locally
Recurrent Head and Neck Cancer. Int J Rad OncolBiolPhys 2009;74:
1348-55.
27. Emami B, BignardiM, Devineni VR, Spector GJ &Hederman MA.
Re-irradiation of recurrent headand neck cancers. Laryngoscope,
1987, 97, 85-8.

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28. Pomp J, Levendag PC & Van Putten WLJ. Re-irradiation of
recurrent tumours in the head and neck. Am J ClinOncol, 1988; 11,
543-9.
29. Mohiuddin M, Marks G, Marks J. Long-term results or
reirradiation for patients with recurrent rectal carcinoma. Cancer.
2000; 95: 1144-50.
30. Alektiar KM, Zelefsky MJ, Paty PB, et al. High dose rate
intraoperative brachytherapy for recurrent colorectal cancer. Int J
RadiatOncolBiolPhy. 2000; 48: 219-26.
31. Buatti JM, Friedman WA, Meeks SL, Bova FJ. RTOG 90-05: the
real conclusion. Int J RadiatOncolBiolPhys, 2000, 47: 269-71.

51
CHAPTER-5
The physics of Re-irradiation
Raghavendra Holla
E MAIL-raghavendra.holla@gmail.com
Introduction: The most difficult problems in Radiation Oncology is the
patient who has been clinically treated by radiation therapy and presents
with no evidence of systemic disease but with persistent local disease in
the original volume irradiated. With the development of new
technologies including Intensity Modulated Radiation Therapy, Image
Guided Radiation Therapy, Tomotherapy, Stereotactic Body
Radiosurgical Techniques and Proton Beams we can try to address these
problems. Along with these technical developments has been a better
understanding of altered fractionation technologies and how they might
be used in developing a treatment program to previously irradiated
volumes.
There can be two significant situations present in this matter. One is the
patient who has local recurrence in the volume previously irradiated
with no evidence of systemic disease and the other being those patients
with recurrence within the original irradiated volume, but with evidences
of metastatic disease either controlled or active. In some respects, the
local treatment program is similar in the two circumstances and is based
upon the previously irradiated volume, the total dose delivered,
fractionation/protraction techniques used in management, all of which
have a significant impact on what might be done subsequently. In the
patient who presents with local recurrent disease with no active systemic
disease with appropriate proper consent from the patient, it is possible to
pursue a curative approach to the problem with or without systemically
administered chemotherapy. With the patient who has local recurrent
disease in a previously irradiated volume with systemic disease under
control, a similar approach to the problem is valid. In the situation with

52
local persistent disease and uncontrolled systemic disease, a more
conservative palliative approach to the problem is possible.
Radiobiological considerations:
Animal studies on the retreatment tolerance of previously irradiated
tissues have generally been performed in the 1980’s and 90’s. Generally,
the retreatment tolerance of different tissues and organs differ for early
and late responding tissues. Early responding tissues are characterized
by rapid proliferation and a clearly defined stem cell compartment
(epidermis, mucosal lining of GI-tract) with the timing of response
related to the turnover times of stem cells. Late tissue reactions in slowly
or non-proliferating tissues show a much more limited long term
recovery which is also dependent on the dose of the initial treatment. An
example of such a tissue is the lung, contrasting with the kidney that
does not show any recovery at all. A paradoxical exception is the
central nervous system, which based on its proliferation characteristics is
not expected to show any significant recovery. However, extensive
studies in several institutions have shown that the spinal cord shows
almost complete recovery when the initial dose is approximately 50-75%
of full tolerance.
For Skin, Using hind-limb deformation as an endpoint for late
subcutaneous fibrosis (Brown and Probert,1975), there is a clear
reduction in tolerance for re-irradiation after 6 months. The effect of re-
irradiation was much more pronounced after more aggressive initial
radiation protocols
In a mouse study for Lung using death from pneumonitis to evaluate
lung re-irradiation tolerance (Terry et al., 1988), there was complete
recovery from an initial dose of 6–8Gy (approximately 30–50 per cent of
a full tolerance dose). The time to restitution was, depending on the
initial dose, in the range of 1–2 months. After higher initial doses (70 per
cent of the initial tolerance), re-irradiation tolerance increased from 1
day to 3 months, at which time tolerance was approximately 75 per cent
of tolerance in previously untreated mice. Yet, at 6 months a decline in
retreatment tolerance was then observed. The remarkably good re-

53
irradiation tolerance of the lung demonstrated in experimental studies
only applies for the pneumonitis phase. It is likely that retreatment
tolerance for late lung fibrosis may be poorer, although no conclusive
evidence is available.
Approximately half of all patients with lung cancer (LC) experience loco
regional failure after initial treatment (3)
. Historically, thoracic re-
irradiation (ReRT) has been limited by toxicity concerns and lack of
robust evidence. Re-irradiation with SBRT technique for in-field
recurrent lung tumors appears to be an effective and well-tolerated
option for cautiously selected patients. The lower BED doses could still
provide excellent Local Control for recurrent lung tumors in the
previous RT field with an acceptable complication rate. Despite
heterogeneity of patient cohorts, RT techniques and duration of follow-
up, ReRT appears to be a feasible option for recurrent thoracic disease.
The kidneys are among the most radiosensitive of organs, although the
latent period before expression of clinically manifest radiation effects
may be very long, particularly after low doses. Progressive, dose-
dependent development of functional damage, without apparent
recovery, has been clearly demonstrated in rodents (Stewart et al., 1989,
1994). This is consistent with clinical observations of slowly progressive
renal damage, which develops any years after irradiation. Based on the
known dose-dependence of renal radiation injury, large initial doses
(14Gy) result in complete loss of function and hence re-irradiation
cannot cause any further damage. After an initial dose of only 6Gy (25
per cent of the EQD2tol) the tolerance for retreatment actually decreases
with time between 2 weeks and 26 weeks.
Spinal cord has been studied most extensively with regard to
retreatment, in various rodent species and in non-human primates. There
is evidence for substantial long-term recovery, indicating that
retreatment is feasible.
In the treatment of head and neck cancer, 15 to 50 percent of patients
will develop recurrent disease. Re-irradiation with or without the
addition of chemotherapy may hold promise for long-term survival for

54
appropriately selected patients. Patient selection is critical since re-
irradiation, with or without chemotherapy, is associated with
considerable acute and late toxicity(1)
. Patients who recur within the high
dose radiation area less than six months after the first course of radiation
generally have radiation-resistant disease and are not usually considered
candidates for a second course of radiation. Tissues of the head and neck
such as skin, nerves, blood vessels, and spinal cord normally receive
maximally tolerated radiation doses during the initial course of radiation
therapy (RT). Re-irradiation exposes these tissues to further radiation
and thereby incurs a risk of severe complications such as carotid artery
stenosis or rupture, osteoradionecrosis, pharyngocutaneous fistulas, non-
healing skin ulcers, and spinal cord damage. The development of a
tumor recurrence in a previously irradiated field suggests the existence
of a radioresistant clone that would limit the therapeutic effect of re-
irradiation. Patients with tumor recurrence within six months after the
first course of radiation are generally thought to have radiation-resistant
disease and therefore to be unlikely to benefit from a second course of
radiation.
Retreatment with a second full course of radiation to the whole breast is
used with caution as increased toxicity of skin and subcutaneous tissue is
feared (2)
. Nevertheless, in recent years several investigators reported on
re-irradiation either alone or combined with concurrent hyperthermia or
chemotherapy. Irradiation was applied as external beam therapy,
brachytherapy or intra-operative radiotherapy. Re-irradiation is feasible
and saves at least within the first five years after retreatment with low to
modest side effects offering a second curative chance with breast
conserving therapy. In palliative intended treatment, results are good to
excellent lasting for most of the patients' lifetime. The duration and
percentage of local control is dose dependent. The minimum second
radiation dose in fractionated irradiation should be 40 Gy though higher
doses might be possible depending on the treatment volume. With regard
to possible late side effects, a dose per fraction of 1.8 to 2 Gy in curative
intent is recommended.

55
Re-irradiation up to 30 Gy, even with chemotherapy, has been shown to
be safe for palliation and possible cure for resectable locally recurrent
rectal cancer, and doses up to 40 Gy can be used for limited volumes.
Hyper fractionation is used to reduce late effects of re-irradiation, and
although this is most important for patients with curative intent, hyper
fractionated RT may still have a role in palliative treatment using dose
escalated regimens. However, for some patients treated with palliative
intent, once-daily RT may be optimal depending on their performance
status and extent of metastatic disease,
Secondary radiation therapy for brain metastasis remains a controversial
intervention with potential challenges. Repeat irradiation concerns
include toxicity and limited symptom palliation efficacy. There are
different re-irradiation options depending on the initial brain irradiation
technique (5). Several publications have evaluated the outcomes of
repeat irradiation, and most studies have concluded that repeat
irradiation is an effective intervention with tolerable side effects. Brain
re-irradiation can offer symptom palliation efficacy with tolerable
toxicity. Although re-irradiation is a feasible option for patients with
high grade gliomas(6), results are similar to those observed with
chemotherapy alone; better results are obtained with chemo radiation.
Conclusion: If (curative) re-irradiation is to be administered, optimum
treatment planning (dose conformation), a proper choice of fractionation
protocol (hyperfractionation) and new available technology are required.
REFRENCE
Enrique Jurado Martin , Vladimir Suarezb, Ismael Herruzo et al;
Reirradiation in head and neck cancer a curative intent in recurrence or
second tumors;
Journal of nuclear medicine & Radiation Therapy 2016 7:2

56
Florian Würschmidt Jörg Dahle et al ;Reirradiation of recurrent breast
cancer with and without concurrent chemotherapy ; Radiation
Oncology;2008 3:28
C. Suzanne Drodge, Sunita Ghosh, Alysa Fairchild et al ; Thoracic
reirradiation for lung cancer: a literature review and practical guide;
Journals of Annals of Pallative medicine; 2014 Apr;3(2):75-91
Koom WS, Choi Y, Shim SJ, Cha J, Seong J, Kim NK, Nam KC, Keum
KC ; Reirradiation to the pelvis for recurrent rectal cancer. J Surg
Oncol. 2012 Jun 1;105(7):637-42
Son CH, Jimenez R, Niemierko A, Loeffler JS, Oh KS, Shih H;
Outcomes after whole brain reirradiation in patients with brain
metastases; Int J Radiat Oncol Biol Phys. 2012 Feb 1;82(2): 167-72.
Maurizio Amichetti and Dante Amelio ;A Review of the Role of Re-
Irradiation in Recurrent High-Grade Glioma (HGG); Cancers 2011, 3,
4061-4089

57
CHAPTER-6
Re-irradiation in CNS Tumors
DR SAYAN PAUL, DR NANDITHA SESIKERAN.DR KAUSIK
BHATTACHARYA
EMAIL-drsayanpaul@gmail.com
Radiotherapy in relapsed brain tumors has been used sparingly because
of the risk of toxicity, particularly white matter necrosis. However,
evidence from pre-clinical animal models and increasing data from
clinical series, show that brain and spinal cord have marked repair
potential and re-irradiation should be considered a valid option in
selected patients.
Radiobiology of CNS Toxicity:
The mechanism of CNS damage involves different functional and
structural components. The neurons, glial cells (oligodendrocytes and
astrocytes) and vascular tissue are the key players in radiation induced
damage. The phases of CNS toxicity are classified as Early (days-
weeks), Early delayed (1-6 months) and Late (>6 months). Early and
early delayed phases occur due to transient demyelination due to
apoptosis of oligodendrocytes. However, this damage is repaired by the
stem cell compartment consisting of oligodendrocyte type 2 astrocyte
cell (O-2A) (1). Late damage is a complex interplay of demyelination
due to O2A cell damage and vascular changes due to endothelial
damage. A critical depopulation of cells and permeability changes in the
vasculature leading to haemorrhage and infarcts, precipitates white
matter necrosis (2).
Studies regarding recovery of CNS structures comes from pre-clinical
evidence of radiation induced myelopathy after re-irradiation at different
intervals in animal models. Brain and spinal cord are known to have a
low α/β. Though sensitive to large fraction sizes, the CNS has
remarkable recovery potential and can withstand upto 50% of tolerance
dose after 1yr and 65-70% of tolerance dose after 3yr interval from the

58
first course of radiation (3). This study comes close to clinical scenarios
of head and neck radiotherapy where the cord has initially received a
dose of around 45Gy at conventional fractionation and there is
requirement of a second course after ≥ 1yr. A risk model proposed by
Neider et al, suggested that an interval of < 6months and a cumulative
BED of any one course of > 102Gy were significant contributors to
myelopathy risk (4).
Re-irradiation tolerance :
Re-irradiation tolerance of brain has been extrapolated to a large extent
from the pre-clinical studies of spinal cord. In a metanalysis of 21 re-
irradiation studies of gliomas, Mayer et al attempted to compile
information regarding cumulative dose , interval, fractionation and effect
of concurrent therapies on brain tolerance. An NTDcumulative
(Normalized total dose = sum of 2Gy equivalent doses of both courses)
of > 100Gy for conventionally fractionated 3DCRT was associated with
radiation induced white matter necrosis. Smaller volumes and more
conformal techniques like Fractionated stereotactic radiotherapy and
LINAC based single fraction SRS allow safe delivery of higher NTD
cumulative doses (90–133.9 Gy for FSRT, 111.6–137.2 Gy for SRS).
However, they found no correlation between time interval of the
radiotherapy courses and incidence of complications. There was an
unusually high rate of necrosis of 6% when hyperfractionated RT was
used with a conservative cumulative dose of 87.5Gy, indicating that
complete recovery probably does not occur within 6 hours (5).
Concurrent treatment:
Higher incidence of necrosis was also reported with use of hyperbaric
oxygen in a study by Koshi et al, where patients received hyperbaric
oxygen immediately followed by gamma knife radiosurgery. A
relatively low median cumulative dose of 86Gy was associated with an
incidence of brain necrosis of 28%. This was suggested to be due to the
radiosensitivity of the well perfused surrounding normal tissue (6).
Concurrent weekly paclitaxel with fractionated stereotactic radiosurgery
delivered once a week, also showed high rates of necrosis of 10% (7).

59
Temozolamide used concurrently has not demonstrated additional late
toxicity (8). Bevacizumab in recurrent high grade glioma used
concurrent with RT (median dose 36Gy) was found to be superior in
terms of progression free survival and overall survival in a retrospective
series. Bevacizumab was also associated with lower incidence of
radiation related adverse events (9).
Role of brachytherapy:
Brachytherapy in various forms has been explored as an option for
recurrent gliomas. Low dose rate interstitial brachytherapy with I125
permanent seeds (15cGy/hr, lifetime dose of 100-400Gy), temporary
implants (30-60cGy/hr, 4-6 days, 50-65Gy) gliasite and high dose rate
Ir192 (15-60Gy, 7-12 days) have been used in recurrent GBMs with
varying success. Patients with good KPS, volume < 30cc were found to
benefit more from these techniques. Median survival of 10.5-12 months
have been reported. However, high rates of complications including
radionecrosis, meningitis, CSF leak have been reported (10).
Target volume delineation:
Consensus guidelines have been compiled by ASTRO, with regard to
volume delineation and dose prescription for re-irradiation of
glioblastomas. Tumors < 2cm can be treated with single fraction 24Gy,
2-3cm tumors with single fraction 18Gy, larger tumors may be treated
with FSRT at 5-6Gy per fraction/day in 5 days. Target volume is defined
as contrast enhancing tumor on MRI + 5mm. When conventional
fractionation of 1.8-2Gy/day is used, larger volumes may be treated
safely (11).
Imaging challenges:
Post- radiotherapy relapses can be challenging to accurately delineate on
an MRI. Areas of necrosis, gliosis, non-specific blood-brain barrier
disturbances represent challenges I identifying the tumor accurately.
Biological imaging with C11 Methionine PET aids in these diagnostic
dilemmas and can be used for target delineation (12).

60
Newer radiotherapeutic modalities:
High LET radiation like proton therapy, Boron neutron capture therapy
and intra-operative radiotherapy have been tried with varying results in
the setting of recurrent glioblastomas (13).
Conclusion:
The choice of technique and dose fractionation for re-irradiation depends
on tumor characteristics (Volume, location), previous RT dose and
volume, patient characteristics (Age, performance status). For small
volume tumors in non-eloquent areas, single fraction SRS and
brachytherapy may be good options. For small and intermediate volume
tumors in eloquent areas, FSRT or hypofractionated RT may be used.
For large volume recurrences, requiring partial brain irradiation,
conventional fractionation is safer and offers palliation with minimal
risk of radiation induced toxicities (14).
References:
1. Belka C, Budach W, Kortmann RD, Bamberg M. Radiation
induced CNS toxicity--molecular and cellular mechanisms. Br J
Cancer [Internet]. 2001;85(9):1233–9. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/11720454%5Cnhttp://www.p
ubmedcentral.nih.gov/articlerender.fcgi?artid=PMC2375250
2. van der Kogel AJ. Radiation-induced damage in the central nervous
system: an interpretation of target cell responses. Br J Cancer Suppl
[Internet]. 1986;7:207–17. Available from:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=214979
2&tool=pmcentrez&rendertype=abstract
3. Ang KK, Jiang GL, Feng Y, Stephens LC, Tucker SL, Price RE.
Extent and kinetics of recovery of occult spinal cord injury. Int J
Radiat Oncol Biol Phys. 2001;50(4):1013–20.
4. Nieder C, Grosu AL, Andratschke NH, Molls M. Proposal of
human spinal cord reirradiation dose based on collection of data
from 40 patients. Int J Radiat Oncol Biol Phys. 2005;61(3):851–5.
5. Mayer R, Sminia P. Reirradiation Tolerance of the Human Brain.

61
Int J Radiat Oncol Biol Phys. 2008;70(5):1350–60.
6. Brady LW. Medical Radiology Radiation Oncology Series Editors
[Internet]. Radiation Oncology. 2011. Available from:
http://www.springerlink.com/index/10.1007/978-3-642-12468-6
7. Lederman G, Wronski M, Arbit E, Odaimi M, Wertheim S,
Lombardi E, et al. Treatment of recurrent glioblastoma multiforme
using fractionated stereotactic radiosurgery and concurrent
paclitaxel. Am J Clin Oncol. 2000 Apr;23(2):155–9.
8. Minniti G, Scaringi C, De Sanctis V, Lanzetta G, Falco T, Di
Stefano D, et al. Hypofractionated stereotactic radiotherapy and
continuous low-dose temozolomide in patients with recurrent or
progressive malignant gliomas. J Neurooncol. 2013
Jan;111(2):187–94.
9. Flieger M, Ganswindt U, Schwarz SB, Kreth F-W, Tonn J-C, la
Fougere C, et al. Re-irradiation and bevacizumab in recurrent high-
grade glioma: an effective treatment option. J Neurooncol. 2014
Apr;117(2):337–45.
10. Combs SE, Debus J, Schulz-Ertner D. Radiotherapeutic alternatives
for previously irradiated recurrent gliomas. BMC Cancer [Internet].
2007;7(1):167. Available from:
http://www.biomedcentral.com/1471-
2407/7/167%5Cnhttp://www.embase.com/search/results?subaction
=viewrecord&from=export&id=L351165862%5Cnhttp://dx.doi.org
/10.1186/1471-2407-7-
167%5Cnhttp://sfx.library.uu.nl/utrecht?sid=EMBASE&issn=1471
2407&id=doi:10.1186%2F1471-2
11. Cabrera AR, Kirkpatrick JP, Fiveash JB, Shih HA, Koay EJ, Lutz
S, et al. Radiation therapy for glioblastoma: Executive summary of
an American Society for Radiation Oncology Evidence-Based
Clinical Practice Guideline. Pract Radiat Oncol [Internet].
2016;6(4):217–25. Available from:
http://dx.doi.org/10.1016/j.prro.2016.03.007
12. Miwa K, Matsuo M, Ogawa S, Shinoda J, Yokoyama K, Yamada J,
et al. Re-irradiation of recurrent glioblastoma multiforme using
11C-methionine PET/CT/MRI image fusion for hypofractionated

62
stereotactic radiotherapy by intensity modulated radiation therapy.
Radiat Oncol [Internet]. 2014;9:181. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/25123357%5Cnhttp://www.n
cbi.nlm.nih.gov/pubmed/25123357
13. Miyatake S-I, Kawabata S, Hiramatsu R, Kuroiwa T, Suzuki M,
Kondo N, et al. Boron Neutron Capture Therapy for Malignant
Brain Tumors. Neurol Med Chir (Tokyo) [Internet]. 2016;361–71.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/27250576
14. Amichetti M, Amelio D. A review of the role of re-irradiation in
recurrent high-grade Glioma (HGG). Cancers (Basel).
2011;3(4):4061–89.

63
CHAPTER-7
Reirradiation in Head and neck cancers- a delicate balance.
Dr Trinanjan Basu MD , Dr Shikha Goyal MD, DNB ,
Dr Kanhu Charan Patro MD .Dr Sarbani Laskar
EMAIL-trinanjan.doctor@gmail.com
Introduction:
Multimodality management of head and neck squamous cell carcinomas
(HNC) have yielded excellent results. However there are still instances
of treatment failure and disease progression and sizeable proportion of
them being loco-regional. Surgical salvage, palliative chemotherapy and
conventional radiotherapy all being tried but outcome and toxicities
never matched a balance.
Radiotherapy techniques have also taken a giant leap in terms of
technology, delivery methods, better documentation and available
guidelines for toxicity outcome. The scenario with recurrent HNC and
reirradiation(rRT) are not as dismal as it used to be. Several literatures
have been published in last 10 years with modern techniques for rRT.
We tried to summarize them with special emphasis on available Indian
data.
Magnitude of the problem:
In India HNC are frequently presented as locally advanced stage [1,2].
The curative intent treatment though have given high success rate,
recurrence especially loco-regional is a concern. The treatment
advancement, better early stage detection techniques and optimal
therapy all will also increase second malignancy in previously treated
HNC [3].
The Indian council of medical research (ICMR) data re-emphasises the
need of guidelines for recurrent HNC. In the Hospital Based Cancer

64
Registry report, cancer of the mouth is also ranked as the leading site in
Mumbai in males and was within the first five leading sites in all
registries in males. The high incidence of carcinoma of the Buccal
Mucosa in our country is attributable to the extensive use of tobacco in
various forms and the locally advanced cancers account for about 70%
of the cases at the time of presentation.The reported 5 year survival rates
for Buccal Mucosa cancers in India ranges from 80% for stage I disease
to 5-15% for locally advanced disease [4-6].
The global data suggests previously irradiated patient has1% per year
risk of second malignancy [7]. We are not even sure of the Indian data in
this regard. The widespread use of tobacco in several forms, varied
geographical and socio-economic status, non-standard management due
to lack of available technologies and delayed stage at presentation all
clubbed together possess a therapeutic challenge in re-irradiation setting
for recurrent and 2nd
primary HNC [8].
The western data which we have always relied upon have come a long
way. The pioneering work from Radiation Therapy Oncology Group
(RTOG) studies 9610 and 9911 although achieved some hope in terms
of survival the toxicity rates were high [9,10]. Modern rRT techniques
utilizing Intensity-ModulatedRadiation Therapy (IMRT) and
Stereotactic Body Radiation Therapy (SBRT)have proved to be
beneficial in terms of improved tumor control, decreased toxicity, and
improved quality-of-life in recurrent HNC [11-16].
In India we are still in the process of implementing and documenting
modern RT techniques (IMRT and SBRT) in the rRT setting. Yes, there
are isolated mostly single centre reports of rRT data and few review
articles, but nationwide data is still lacking [3,17-21].
Background essential knowledge:
A. Indications:

65
1. Loco-regional recurrences after successful completion of initial
curative treatment for HNC (Surgery followed by adjuvant RT,
radical RT, conc chemoradiation-CTRT). Since at recurrence
only 30-40% will be surgically salvageable, rRT is a valid
option [22].
2. Metachronous HNC in an rRT setting. The estimated risk of
development at 3.5.8 years post primary treatment would be
9%, 14% and 23% respectively [7].
B. Techniques:
The rRT techniques (the salvage surgery and chemotherapy alone
options are beyond the scope of discussion here) can broadly be
divided into the following types. However we will be
concentrating upon IMRT and SBRT techniques.
1. Conventional RT techniques with or without salvage surgery.
2. IMRT.
3. SBRT.
4. Proton therapy.
5. Brachytherapy.
The conventional RT techniques with or without salvage surgery
have been tabulated together (table 1and 2). These are mainly for
historical background.
Table 1: salvage surgery followed by rRT with conventional
techniques: [23-29]
Study Yea
r
Numb
er of
patien
ts
Stud
y
type
Outco
me @
2 yrs
Late
toxiciti
es
(grade
¾,
RT dose Interv
al to
rRT

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