This document discusses reirradiation in recurrent head and neck cancer. It notes that radiation therapy plays a central role in head and neck cancer treatment but recurrence still occurs in 20-35% of patients. Reirradiation presents challenges due to prior radiation exposure and damage to normal tissues. The document discusses treatment options, appropriate patient selection, techniques like IMRT to minimize dose to organs at risk, optimal timing and dosing of reirradiation, and management of toxicities.

1. ABC OF REIRRADIATION IN RECURRENT
HEAD AND NECK CANCER
Dr Kanhu Charan Patro
RADIATIATION ONCOLOGIST
2/25/2018 1

2. Background
• Radiation therapy plays a central role in the
treatment of head and neck cancer (HNC) patients.
• Both organ-preserving definitive chemo-
radiotherapy (CRT) and selective postoperative CRT
improve loco-regional recurrence (LRR) and prolong
overall survival .
• Nevertheless, despite improvements, LRR after CRT
continues to be a vexing problem for 20–35% of
patients.
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3. Background-contd.
• As radiation is delivered more precisely with smaller
margins, the potential for recurrences related to
'marginal misses' has increased.
• Over protective for OARs also give marginal misses.
• Longer survival leads to second primary and ongoing
exposure to carcinogens, such as cigarette smoke,
leads to a 3–5% yearly risk of a second malignancy.
• Improved cancer treatment..
• Longer survival due to less chance of distant
metastasis in head and neck cancer.
• Commercialization of radiotherapy treatment.
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6. Definition
Irradiation in a previously irradiated field due
to Recurrent lesion or second primary after a
definitive cure .
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7. Treatment options
• Salvage surgery f/b Re-irradiation +chemotherapy
• Re-irradiation + chemotherapy
• Chemotherapy alone
– NACT
– Definitive
– Metronomic
• Best supportive care
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8. Approach
• The care of these patients should be coordinated by an
interdisciplinary team, consisting of representatives from
– Radiology,
– Pathology,
– Otolaryngology,
– Medical Oncology,
– Radiation Oncology,
– Dentistry,
– Speech Pathology
– Nutrition.
• Chances of cure/at least towards cure
• Expected survival-how long?
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9. Postoperative Re-RT
• The therapeutic ratio is lower than in re-RT of non-resectable
disease
– While risk of recurrence may be high, the tumor may not recur
even if we do not re-irradiate
– In high risk patients, tumor may recur in sites which are not the
highest-risk sites
– Not having a GTV, radiation volumes may be larger compared to
treating gross recurrent disease
– The risk of complications is nearly as high as treating recurrent
non-resectable tumor.
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10. Postoperative Re-RT
• Randomized study of post-op chemo-re-RT
– 130 pts, previously irradiated, with recurrent
tumors who underwent surgery with complete
macroscopic tumor resection.
– Randomized to:
• Post-op RT: 60 Gy concurrent with 5-FU and HU; RT to
tumor bed +first echelon nodes
• Observation only
–Janot F et al, JCO 2008
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11. Postoperative Re-RT
• Randomized study of post-op chemo-re-RT
• Late toxicities: RT arm: 39%. Observation: 10%
• Late toxicities (RTOG>3) in the RT arm:
– Subcutaneous-22%
– Osteonecrosis-17%
– Trismus-28%
– Laryngeal damage-6%
– Feeding tube dependency- 25% (compared with 10% in the
observation arm)
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12. Randomized study of post-op re-RT
– Disease-free survival (DFS) was significantly improved
in the RT arm, with a hazard ratio of 1.68
– overall survival (OS) was not statistically different.
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13. Post-op RE-RT: Recommendations
• Discuss with patients: high complication risk,
better LR control, no survival benefit.
Alternative: wait for LR recurrence and re-RT at the time of
recurrence.
• Offer re-RT only to the highest risk patients
(ECE, +margins, diffuse tumor infiltration)
• Target only the high risk volumes
– the neck level with ECE
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14. Radiotherapy Indication
• Radical-Reirradiation is the only potentially curative
treatment when surgery is not an option.
• Post operative-after salvage surgery
• Palliative condition
– Comp/Haemmorage/Obstruction/Pain
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21. What to look?
• Co-morbidities.
• Performance status.
• Speech and swallowing function.
• Sequel of previous treatment
– Fibrosis,
– Carotid stenosis,
– Osteoradionecrosis
– other severe toxicity
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23. Hiccoughs
• Optimal Gap
• Optimal Dose
• Optimal Imaging
• Target Volume Delineation
• What Technique
• Addressing OARs.
– Spinal Cord Dose
– Mandible-ORN
– Skin- Fistula, Fibrosis etc.
– CAR
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Re-RT is more challenging than initial
treatment because of the side effects of prior
therapy and concerns about the risks of high
cumulative radiation doses to normal
structures.

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25. Optimal gap
• There is no clear cut guideline.
• Most of the studies are gap of more than two
years of prior radiation.
• Relative contraindications:
– Less than one year since previous RT
• Lower chance of cure
• Higher risk of severe complications
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26. Imaging-staging
• Biopsy is mandatory.
• The sensitivity and specificity of PET-computed tomography (CT)
for detecting distant metastasis is reported to be 86–91 and 84–
93%, respectively.
• [Gourin CG et.al, Perlow A et.al]
• Re-staging is of paramount importance as up to 25% of patients
will have metastatic disease.
– [Gourin CG et.al, Perlow A et.al]
• MRI demonstrated a trend towards improved sensitivity (96.4 vs
82%) for detecting local recurrence of nasopharyngeal
carcinoma when compared with PET-CT
– [Comoretto M,et al]
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27. What should be the target?
• Treatment volumes for ReRT are in general
more limited than for initial courses of
radiotherapy
• To minimize toxicity to nearby critical OARs,
the smallest possible target volume is used
• Elective nodal irradiation is generally not
recommended, as the risk of failure in these
sites is low (0–6%).
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28. What should be the targets?
From Popovtzer A, et al, IJROBP 20092/25/2018 28

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30. Which technique?
• IMRT is a potentially useful tool for a second
course of radiation as a means of reducing the
volume of high radiotherapy doses as well as
minimizing doses to critical normal structures.
• SBRT
• Brachytherapy
• Electron
• IMPT
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33. IMPT
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34. Optimal dose?
• Prescribed as cumulative BED.
• The maximal cumulative prescribed dose is expected
to be 140-160 Gy.
• No clear cut guideline.
• Doses near 60 Gy was planned in studies.
• (Salama jk IJROBP 2006)
• Schaefer u et al, radiology 2000,
• Datta NR int j clin oncol 2003
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36. Fractionation schedule?
• Conventional fractionation@2Gy/# is standard of care
• Hyper fractionation
• Accelerated fractionation
• Hypo-fractionation-SBRT
• Recent data (GORTEC, RTOG) suggests no benefit of
altered fractionation with conc. chemo vs. standard
fractionation with conc. chemo, regarding tumor
control/survival.
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37. Hyperfractionation
• Potential for reduced late effects
• 70 Gy at 1.25 BID/6 weeks, conc with cisplatin-5FU
• 66 patients
• 23% 3-year DFS.
• 29% late complications grade III, notably dysphagia.
–Popovtzeretal,IJROBP2009
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38. Hypofractionation
• Unger et al, IJROBP 2009 (Georgetown U)
– 38 patients
– 21-35 Gy (median 30)/2-5 fractions
– Higher total doses and nasopharyngeal sites:
improved OS
– Severe toxicity: 11%
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39. Hypofractionation
• Heron et al, IJROBP 2009: Phase I study of
escalating hypofractionation doses
– 25, 32, 36, 40, 44 Gy, all in 5 fractions over two
weeks
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40. Hypofractionation-summary
• Tumor-related outcome seems to be similar
to series of standard fractionated RT, however,
SRS series have much shorter f/u and late
toxicity rates are not yet known.
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SBRT

46. Addressing OARs.
• Vital
– Cord
– Optic apparatus
– Brain[temporal lobe, Brain stem]
• Less vital
– Cochlea
– Carotid
– Parotid
– mandible
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keep in mind ,The α/β of
prior irradiated tissue is not
the same as
Non-irradiated tissue

47. Complication-acute toxicity
• MUCOSITIS
– The rate of grade 3–4 mucositis was lower for previously
irradiated patients. More contemporary trials have
demonstrated similar results.
– Primary CRT is associated with higher rates of grade 3–4
mucositis (71–77%) when compared with CRRT (14–26%). This is
probably due to the smaller RT target volumes that are
commonly used for a course of salvage Re-RT
• [Brizel DM et al, Calais G et al]
• HEMATOLOGIC TOXICITY
– Hematologic toxicity appears to correlate with the intensity of
the systemic therapy regimen and is also not influenced by prior
therapy
• DEATH DURING TREATMENT
– This may be related to the fact that functional reserve is
compromised in heavily pretreated patients[Glisson BS et al]
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48. Complication-Late toxicity-ORN
• It is possible that the rates of ORN are less in patients
treated with more modern radiotherapy techniques for
CRRT. Increasing photon energies, 3DCRT and IMRT
ameliorate this phenomenon.
• One series, cases of ORN only occurred in patients
receiving a cumulative RT dose of greater than 120 Gy
– [De Crevoisier R et al, Sulman EP et al]
• In a cohort of 105 patients treated between 1996 and
2005, 70% of whom received IMRT, only one case of grade
2 osteitis was reported.
– [Lee N et al]
• In another cohort of 74 patients all treated with IMRT
between 1999 and 2004, only 5% developed ORN
– [Sulman EP et al]
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49. ORN
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50. SPINAL CORD RECOVERY
• On the basis of literature data (and with due
caution), the risk of myelopathy appears small
after ≤135.5 Gy2
– Carsten Nieder, M.D. IJROBP 2004
• From the sparse clinical and primate data, it
appears that at least 50% recovery of 45 Gy
would be obtained 2 years after treatment.
– Supe et al. Radiobiological considerations .Rep. Pract.
Oncol. Radiother. 7 (2) 2002
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58. CENTRAL AND PERIPHERAL AND CNS TOXICITY
• Radiation Myelopathy
• Brachial Plexopathy
• Temporal lobe necrosis
• Brain necrosis
We would recommend limiting the dose to
this level, whenever technically feasible
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60. Carotid artery rupture (CAR)
• Devastating condition due to
– Tumor recurrence,
– Chronic infection,
– Surgery (pharyngocutaneous fistula and neck dissection),
– Poor nutrition
– Chronic inflammation
– (long-term tracheostomy and nasogastric tubes)
A meta-analysis of CRRT trials reporting CAR showed a
crude incidence rate of 2.6% at a median of 7.5 months
following CRRT
[McDonald MW et al]
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64. Complication-Late toxicity-contd.
• In the GETTEC–GORTEC randomized trial, the
actuarial rate of grade 3–4 toxicity at 2 years
was 39%.
• The crude rates of grade 4 or higher toxicity in
RTOG 96-10 and RTOG 99-11 were 3 and
31.8%, respectively
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65. Role of radio protector
• Amifostine
– Concentrates actively in salivary glands, but not in
most other tissues
– Randomized studies assessing acute
mucositis/late swallowing with or without
amifostine are inconclusive
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66. IJROBP 20092/25/2018 66

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68. Role of radio-sensitizer
• Radiobiological tenant that tumor hypoxia
confers radioresistance has been confirmed
clinically in HNC
• Prior radiotherapy, surgery and/or systemic
therapy may worsen tumor hypoxia in recurrent
HNC.
– Cisplatin
– TPZ
– Carboplatin
2/25/2018 68

69. TPZ STUDY
• 25 patients received cisplatin (50 mg/m2) and TPZ (260
mg/m2) on weeks 1, 3 and 5 during daily RRT to a total
dose of 72 Gy.
• Additional TPZ (160 mg/m2) was given on days 1, 3 and
5 of week 2, and possibly week 4, based on
randomization.
• Locoregional control was 56% overall and the 1- and 2-
year rates of OS were 56 and 27%, respectively.
• Treatment-related toxicity was comparable with other
CRRT trials
– Dische S. Chemical sensitizers for hypoxic cells: a decade
of experience in clinical radiotherapy. Radiother.
Oncol.3(2), 97–115 (1985)]
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70. Role of chemotherapy
• Still to be established.
• NACT
– for high volume disease
– Prolonging the period for Re-RT
• CONC.
• Mostly as radio-sensitizer
• Common drugs
– HFX REGIMEN-[HU+5FU+RT]
– Cisplatin
– Carboplatin
– Taxanes
– Gemcitabine
– Cetuximab/Biomab
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71. RTOG study of chemo-re-RT
• 79 patients
• Treatment: 1.5 Gy BIDx5 weekly x4 weeks,
alternating weeks, total 60 Gy over 8 weeks
• Concurrent 5-FU and HU
• 76%- recurrent tu, 23%- new primary tumors
• Most common sites: oral & oropharyngeal
– Spencer S et al, Head Neck 2008
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72. RTOG study of chemo-re-RT
• Toxicities
– Acute:
• 2 fatal hemorrhages due to tumor lysis
– Late:
• Feeding tube at last follow-up: 70%
• Other: subcutaneous fibrosis (5%), laryngeal damage
(2%), neurologic toxicity (2%), pain (2%), “other” (2%)
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73. RTOG study of chemo-re-RT
• Tumor control and survival
– At 2 years: 15% survival.
• 75% of deaths due to persistent/recurrent cancer,
8% due to treatment complications
• Slightly better (but statistically sig) survival if
interval between treatments >1 year
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78. Summary
• Currently no single optimal treatment schema for Re-RT of patients
with HNSCC due to widely ranging differences in the location and
extent of recurrent tumor,
• Initial radiation parameters, amount of time since prior treatment,
degree of existing normal tissue toxicity, and limitations of available
data on normal tissue recovery from prior treatment and tolerance
to Re-RT.
• Most Re-RT experiences have targeted the recurrent gross disease
with limited margin, without elective nodal Re-RT.
• The chance of local control is higher in patients receiving an
additional dose of at least 60 Gy.
• Advanced radiation techniques (eg, intensity modulated radiation,
stereotactic body radiosurgery, or proton therapy) should be used
to protect nearby critical normal structures. :
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79. Summary contd.
• The prognosis for recurrent HNSCC treated with chemotherapy
is poor.
• With the average survival time being about 1 year.
• The overall 2-year survival rate is just 26%.
• These data demonstrate superiority to those seen in separate
trials of patients treated with palliative chemotherapy alone.
• Retrospective data in patients undergoing Re-RT suggests that
overall survival can improve if local control is obtained.
• While toxicities may be reduced with newer targeted radiation
modalities, 28% to 40% of patients Re-RT with conventional
radiation techniques experienced significant
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80. Summary contd.
• Heterogeneous patient population, very limited level I
evidence is available to inform decision making of
physicians and patients.
• When planning for radiation for first time don’t be so
over-protective for less vital OARs ,otherwise it may give
geographical miss, which may need Re-RT.
• When planning for re-irradiation try for conformal
avoidance of even less vital OARs.
• Re-RT should be offered to patients with detailed
discussion of the expected results
• A multidisciplinary approach.
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