Approach towards reirradiation

1. © 2018 Journal of Current Oncology | Published by Wolters Kluwer ‑ Medknow 29
Introduction
The advancement of treatment modalities in surgery,
chemotherapy, and radiotherapy (RT) has improved survival
rate and locoregional control at many sites of cancer
occurrence. However, in‑field cancer recurrence after RT 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 radiation.[1,2]
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 cancers.[3]
Although
reirradiation was in common practice as early as in the early
20th
century, in the recent years, there is an increasing interest
among radiation oncologist toward delivering a second course
of radiation to patients who develop second primary tumors
within or close to previous RTportal or late in‑field recurrences.
This is mainly due to the availability of different modalities of
radiation and technology for more and more precise radiation
therapy.[4]
However, such rational treatment decisions demand
not only appreciation of the relevant clinical, pathological,
and technical aspects but also rather precise knowledge on
the long‑term recovery of occult radiation injury in various
organs.[1,5]
Finally, proper counseling of the patient about the
expected benefit and the potential hazards may help to make
an informed choice to proceed for reirradiation.
One of the major issue remains that whether reirradiation
toxicity outweighs the potential benefits, considering that the
median survival of reirradiated patients marginally exceeds the
benefits observed with chemotherapy or other systemic therapy
alone in many instances. However, full‑dose reirradiation
is often a viable treatment option for cancer sites, offering
long‑term survival for selected patients. The success of
full‑dose reirradiation depends on a variety of factors such as
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
Approach towards Re-irradiation of Common Cancers
Anis Bandyopadhyay, Kanhu Charan Patro1
, Poulami Basu, Kaushik Roy
Department of Radiotherapy, Medical College, Kolkata, West Bengal, 1
Department of Radiation Oncology, Mahatma Gandhi Cancer Hospital and Research Institute,
Vishakapatnam, Andhra Pradesh, India
Reirradiation, in combination with systemic therapy or biologicals, in recent years, has become a popular option for locally recurrent cancers
and for infield second malignancies in cases where surgical salvage is not feasible. However before embarking onto such a course of second
radiation a systematic approach is needed to avoid undesirable consequences and to gain meaningful advantage in terms of survival and local
control.An decision making approach for common cancers where re-irradiation is commonly used like the head and neck cancers, the gliomas
and in cases of gynecological cancers has been discussed. Proper selection of the cases and the choosing the intention for re-irradiation is
probably most important initial step. Care of the details of the initials course of radiation like the dose fractionation schedule, volume irradiated,
dose to the Organs at risk along with patient’s present general condition is of utmost importance. Issues like dose memory, threshold time
interval, maximum effective cumulative dose etc are still areas of research and their importance in each individual site needs to ascertain in
future. Finally, the aim is to have a perceived benefit over the potential of harm in a successful course re-irradiation.
Keywords: Gynaecological cancers, glioma, head and neck cancers, reiiradiation, recurrent
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How to cite this article: Bandyopadhyay A, Patro KC, Basu P, Roy K.
Approach towards re-irradiation of common cancers. J Curr Oncol
2018;1:29-34.
Abstract
Review Article
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2. Bandyopadhyay, et al.: Approach towards re-irradiation
Journal of Current Oncology ¦ Volume 1 ¦ Issue 1 ¦ January-June 201830
effects from initial RT, residual radiation tolerance of the
normal tissues, the duration of the relapse‑free interval, the
comorbidities, and dose fractionation of the reirradiation course
[Table 1].[6,7]
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 attempt is made in
this article for a systematic approach to the decision-making
for irradiation of patients with cancers of various sites that are
commonly considered for re-irradiation [Figure 1].
Head‑and‑Neck Cancers
Locoregional failure is the most frequent pattern of failure in
locally advanced head‑and‑neck cancer patients, with nearly
half of the cases failing locoregionally within 24 months. For
nonnasopharyngeal head‑and‑neck cancers, this high rate of
locoregional failure was irrespective of the treatment received
as evident from the two large RT oncology group (RTOG)
trials (RTOG 90‑03 and RTOG 91‑11). Thus, the head and
neck region is one of the most common sites where re-
irradiation is increasingly being considered; owing to this
high local failure rates and the complexity of salvage surgery
[Table 2]. Although the basic guideline to approach toward
remains same [Figure 1], one should keep in mind the major
prognostic factors that affect the results of reirradiation. 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 advantage.[7]
An informed choice has to be made by the oncologist and
the patient after discussing the expected benefit and the
potential morbidity outcomes [Table 3]. Apart from the
various tumor‑related factors, the presence of comorbidities
and preexisting organ dysfunction (like nonfunctional organ,
nonhealingulcers,acuteandchronicdysphagia,trismus/fibrosis,
osteoradionecrosis, and carotid rupture) are probably the most
important factor before deciding on a course or reirradiation
in the head‑and‑neck region.[6-9]
The cumulative lifetime dose
to organs such as the spinal cord, brain stem, and parotids
needs to be respected. Wherever possible, intensity‑modulated
RT (IMRT) should be preferred for its obvious dosimetric
advantages over conventional or three‑dimensional 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 the skull, whereas for
small‑volume mucosal recurrence, interstitial brachytherapy
should always be tried.[10]
The reirradiation treatment plan and
the intended dose prescription should be decided after careful
evaluation of the treatment volume, prior dose distribution
and the modality of previous treatments. Care should be
taken to minimize the volume of overlap of the two treatment
schedules.[6,10]
For treatment near the carotid artery, Doppler
ultrasound before reirradiation is often recommended as
patients with significant stenosis can be considered for an
appropriate vascular intervention before reirradiation. Use
of concurrent chemotherapy wherever may possibly improve
the chance of survival in most cases.[11‑13]
Tumors that recur
or persist despite aggressive prior chemoradiation therapy
imply the presence of the chemo‑RT‑resistant clonogens; novel
targeted radiosensitizing agents with conformal high‑precision
radiation are required to overcome the resistance. Provision of
aggressive nutritional support during the course of irradiation
and after in cases of organ dysfunction is essential to minimize
treatment breaks.[14]
A curative dose of 50–60 Gy should be
attempted with IMRT to the new clinical target volume and
efforts should be made to minimize the cumulative spinal cord
dose to as low as reasonably achievable. Care should also
be taken to keep the reradiation dose to the salivary glands
to <25–30 Gy [Table 4].
Gliomas and Other Brain Tumors
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
resurgery, RT, systemic therapy, and the best supportive care.
However, the decision depends on the specific patient‑ and
Table 2: Basic rules of reirradiation
1 Multidisciplinary evaluation for the treatment of patients
with recurrent cancer
2 Reirradiation 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 locoregional draining lymph nodal
basin should be best avoided
5 For patients treated with curative intent, reirradiation 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,
for example, Conventional EBRT →brachytherapy/3DCRT
→SBRT. Highly conformal radiation techniques such as
IMRT are recommended over less conformal modalities
7 Bigger the volume of reirradiation ‑ worse is the outcome
8 To incorporate biological imaging for delineation of target
volume whenever feasible
SBRT: Stereotactic body radiotherapy, IMRT: Intensity‑modulated
radiotherapy, EBRT: External beam radiotherapy, 3D: Three‑dimensional
Table 1: Prerequisites for reirradiation
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 retreatment field
3 Precise knowledge of the radiation dose, portals, volumes of
the previous radiation
4 Clarity regarding the intent of retreatment
5 Absence of distant metastases (in case of curative reirradiation)
6 Salvage surgery is not feasible/too mutilating/risky
7 The expected harm‑benefit ratio of <1
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3. Bandyopadhyay, et al.: Approach towards re-irradiation
Journal of Current Oncology ¦ Volume 1 ¦ Issue 1 ¦ January-June 2018 31
tumor‑related factors. Re‑resection not only improves
symptoms and maintains the quality of life, but also delays
symptom progression, reduces corticosteroid doses, and
improves response to (and allow intra‑operative) chemotherapy
and/or RT.[15,16]
Young patients, with Karnofsky performance
status (KPS) more than 80%, small volume residual lesion
involving noneloquent areas are the ideal candidates for
surgery.[17]
Reirradiation is an option for a small subgroup
of selected patients. The first and foremost step before
reirradiation is establishing recurrence and differentiating
from pseudoprogression [Table 3]. Patients with a KPS greater
than 60%, a tumor size of up to 40 mm, and progression
more than 6 months from time of surgery appear to be the
best candidates.[15]
The most common approach involves the
use of fractionated stereotactic RT with or without intensity
modulation and a median total dose of 30–36 Gy. Stereotactic
radiosurgery and interstitial brachytherapy are not favored
because of their high concern for toxicity (20%–30%) and
its suitability for very small tumors (<30 cc volumes).[17,18]
Effort should be made to keep the cumulative EQD2 around
100 Gy with conventional technique and slightly higher with
conformal and stereotactic RT.[19]
The increasing conformity
of the reirradiation plan helps in reducing the interval period
before reirradiation may be attempted. Using conventional
RT after a median interval of 30 months approximately, a
cumulative EQD2 of 90–97 Gy can be safely attempted as
compared with the use of fractionated stereotactic RT, which
allows to attempt further higher doses to a cumulative EQD2
of 110 Gy [Table 4].[20]
Gynecological Cancers
Although the improvement of external beam RT and
brachytherapy techniques and increase in dose delivered to
the pelvic tumors have improved local control, local pelvic
recurrence after RT 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 reirradiation
must not be the first choice for such patients with recurrent
pelvic tumors after a previous course of irradiation.As minimal
data are available on the toxicity of additional radiation
therapy, this approach would be considered only when there
is no other alternative for effective therapy and in the face of
progressive and severe symptom.[21,22]
Preexisting late rectal
or bladder toxicity is a strong deterrent for consideration of
reirradiation. Cumulative dose to several organs at risk such
as femoral heads, bone marrow, small bowel, urethra, vagina,
and sigmoid should also be considered. As far as technique
is concerned, preference should be given to intraoperative RT
or brachytherapy. Combining surgery with postoperative RT
gives best results. For central pelvic recurrences, interstitial
brachytherapy is the preferred modality with the aim of
achieving the reirradiation EQD2 of 35–45 Gy in 5–7#. For
nodal recurrences, stereotactic body RT obviously holds edge
and an reirradiation EQD2 of 24–30 Gy in 3/5 fractions should
be attempted [Table 4].[24]
Bone and Brain Metastases
Reirradiation 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 time radiation.The ideal
approach toward reirradiation will involve proper evaluation
of the pain, evaluation for associated fracture, soft‑tissue
component, and weight bearing.[25,26]
Dose and fractionation
of the initial radiation is important as retreatment after a single
fraction (4,6,or8 Gy)treatmentisquitefeasibleandtolerable.[27]
Furthermore, the response to the initial radiation and pain relief
provided needs to be considered since there is little evidence that
theinitialnonresponderswillbenefitfromreirradiation.Formost
patients, a single treatment with 8 Gy is noninferior to treatment
with 20 Gy in 5 fractions or other protracted courses.[27,28]
Table 3: Steps for reirradiation process
Steps Issues
1 Defining intent Whether intent is palliative or 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 morbidities before
obtaining informed consent
Proper documentation of communication
with other specialties, 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 the 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 of success such
as head and neck, gliomas, etc., and avoided in
others like breast
6 Supportive
care
Nutritional support
Hydration
Control of anemia, cytopenia, pain relief
Edema and seizure prophylaxis
7 Posttreatment
evaluation and
follow‑up
Anticipation of complications and mitigation of
the same
Response assessment
Quality of life indices
*Adapted from Joseph et al. Clinical Oncology, 2010.[23]
SRT: Stereotactic
radiotherapy, ICRU: International Committee Radiation Units
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4. Bandyopadhyay, et al.: Approach towards re-irradiation
Journal of Current Oncology ¦ Volume 1 ¦ Issue 1 ¦ January-June 201832
The role of whole‑brain radiation therapy (WBRT), surgical
excision, stereotactic radiosurgery (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 WBRT or SRS‑stereotactic RT (SRT).[29,30]
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 nonoriginal site, previous treatment, and type
of primary cancer.[31,32]
The most important consideration
before reirradiation is the expected survival of the patient and
performance status and the pretreatment neurological status.
For isolated recurrences in patients initially treated with WBRT
Is it a true recurrence or
a new primary - is it
biopsy proven
imaging available
yes
yes
yes
yes
yes
no
proper imaging -CECT/MRI
is it amenable to surgery
No
No
No
No
Is there any significant comorbidity
consider resection - followed by
reirradiation with or without
systemic therapy for high-risk
features 6
is there any significant
organ dysfunction
consider palliative reirradiation
consider palliative care only
consider systemic therapy
consider palliative care
is the tumor of low volume (T1,T2/less than
2cm Diameter)
Is brachytherapy an option
consider reirradiation with
HDR/PDR interstitial
brachytherapy 6,7
consider reirradiation with IMRT, SBRT/SRT,
or other experimental therapy
(proton/carbon ion)
High-risk features:
Gross residual lesion,
positive margin, and
extracapsular extension.
Figure 1: General approach for reirrradiation
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5. Bandyopadhyay, et al.: Approach towards re-irradiation
Journal of Current Oncology ¦ Volume 1 ¦ Issue 1 ¦ January-June 2018 33
or SRT, with good performance status, surgical option should
always be sought.[33]
Systemic therapy and chemotherapy
options for widespread recurrences should also be kept in
mind.[34‑38]
Conclusion
Reirradiation for selected locoregional recurrences and
second primary cancers is feasible option when surgery is
difficult and mutilating. Proper selection of cases is the main
factors deciding favorable outcome. Apart from the interval
and the initial radiation dose–volume issues that should be
kept in mind before contemplating a course of reirradiation
are the performance status of the patient, expected survival,
and the organ at least damage caused by the initial radiation
treatment. Dose memory and threshold time gap is not
established conclusively and are areas of research for most
sites. Finally, a balance has to be maintained between the
perceived gain and the potential harm caused by such a
course.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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Table 4: Common dose fractionation and concurrent regimens used for reirradiation for different sites
Site/primary Dose to the
PTV
Preferred
fractionation
Outcome Concurrent/
systemic therapy
Trial/
reference
Adverse
Reactions
Head‑and‑neck
cancer
40‑60 Gy 1.5 Gy/# bid/5# per
week × 4 weeks
MST 12.1 months
2‑year OS ‑ 25.9%
Paclitaxel and
cisplatin (daily)
RTOG 9911
Median OS=8.5 months
2‑year OS ‑ 15%
5 FU and HU RTOG 9066
60 Gy Conventional RT 2‑year OS 24%
5‑year OS 14%
5 FU+HU De Crevoisier
et al.
Severe 29%
68 Gy 1.25 Gy bid ×
6 weeks
2‑year OS 40%
2‑year LCR 27%
Cisplatin Papovtzer
et al.
Acute 26/66
G4 11
Late G3 29%
60 Gy 2‑year OS 58%
2‑year LRC 64%
Platinum based Sulman et al. Severe 20%
66‑70 Gy Conventional RT 2‑year OS 24.8% No chemotherapy Salama et al. Acute 18%
Gynecological EQD2 42 Gy
(37‑46 Gy)
Only ISRT
MUPIT (24 patients)
Vienna (6 patients)
2‑year LCR 44%
2‑year DFS 42%
Mahanshetty
et al.
GU and
GI grade 3
toxicity 10%
EQD2
48.8 Gy
EBRT + VBT
3 patients
Only VBT
17 patients
3‑year LCR 45% Zolciak
siwinska
et al.
GU 10%
GI 5%
Gliomas 37.5 Gy/2.5
+ TMZ
14‑month interval of
initial treatment
KPS 70‑9.7 months
KPS 60 ‑ OS ‑ 6 84%
PFS ‑ 6 months 42%
OS ‑ 12 months 33%
PFS ‑ 12 months 8%
TMZ Minniti et al. 11% severe
toxicity
RT: Radiotherapy, PTV: Planning target volume, EBRT: External beam radiotherapy, VBT: Vaginal brachytherapy, TMZ: Temozolomide, RTOG: Radiation
therapy oncology group, LRC: Locoregional control, KPS: Karnofsky performance status, MST: Median survival time, MUPIT: Martinez universal
perineal template, ISRT: Interstitial brachytherapy, LCR: Local control rate, OS: Overall survival, PFS: Progression free survival, GI: Gastrointestinal, GU:
Genitourinary
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