This document discusses various chemical modifiers of radiation response, including radiosensitizers and radioprotectors. It summarizes research on using oxygen mimetics, hypoxic cytotoxins and EGFR inhibitors to radiosensitize tumors, as well as the radioprotective effects of amifostine. Palifermin and benzydamine are mentioned as agents that can mitigate oral mucositis caused by radiation therapy.

1. CHEMICAL MODIFIERS
OF RADIATION
RESPONSE
Dr. SAADVIK R Y
JR-2

2. • CHEMICAL RADIOSENSITISATION
• CHEMICAL RADIOPROTECTORS

3. CHEMICAL
RADIOSENSITISATION
• THE OXYGEN EFFECT
• TUMOUR HYPOXIA

4. THE OXYGEN EFFECT

5. TUMOUR HYPOXIA
• Tumor hypoxia reduces radiosensitivity in vitro and
in vivo.
• Well-oxygenated cells (partial pressure of oxygen or
PO2 >10 mm Hg) are approximately 2.5 times
more sensitive to a given dose of ionizing radiation
than their hypoxic counterparts.

8. • Increased delivery of oxygen to tumor,
• Preferential sensitization of hypoxic cells with
oxygen mimetic agents,
• Cytotoxic agents that selectively target hypoxic
tumor cells.

9. INCREASED DELIVERY OF
OXYGEN TO TUMOUR
• HYPERBARIC OXYGEN
• CARBOGEN
• NICOTINAMIDE
• EFAPROXIRAL
• ANAEMIA

10. HYPERBARIC OXYGEN
• Clinical trials of hyperbaric oxygen (HBO) and RT were
conducted from the 1950s - 1970s.
• Trials conducted in patients with cancers of the central
nervous system,lung, bladder,and skin showed no benefit
from the addition of HBO.
• The cumbersome logistics associated with HBO delivery in
conjunction with RT necessitated the utilization of
nonconventional hypofractionated treatment regimens.
• This reality has prevented HBO from being incorporated
into routine clinical use.

11. CARBOGEN
• 95% O2 & 5% CO2
• With or without NICOTINAMIDE.

12. • Accelerated RT with carbogen and nicotinamide was tested in a
phase II trial of 215 head and neck cancer patients.
• Ninety-seven percent had stage III or IV disease, and the
primary tumor site was laryngeal in 46%, hypopharyngeal in
23%, and oropharyngeal in 23%.
• Nicotinamide was administered 1 to 1.5 hours prior to RT at 60
to 80 mg/kg.
• Five-year locoregional control rates were 48% for hypopharynx
primaries, 77% for larynx and 72% for oropharynx primaries.
• Nicotinamide-induced nausea and vomiting necessitated
discontinuation of the drug in 10% of patients receiving the lower
dose and 31% of patients receiving the higher dose.

13. EFAPROXIRAL
• A phase III open label trial of whole-brain RT and oxygen
breathing with or without daily infusion of efaproxiral was
conducted in 538 patients with brain metastases.
• Fifty-four percent of the patients had metastatic non–small
cell lung cancer and 20% had metastatic breast cancer.
• Overall, no improvement in survival was detected.
• The phase III ENRICH trial, which examined efaproxiral and
supplemental oxygen with whole-brain radiotherapy in breast
cancer patients with brain metastases.
• Showed no significant difference in overall survival.

14. ANAEMIA
• Polarographic electrode oxygen measurements in
head and neck cancer have demonstrated that
anemic patients are significantly more likely to have
poorly oxygenated tumors than nonanemic patients.
• Methods to correct anaemia
1. Blood transfusion
2. Erythropoiten.

15. BLOOD TRANSFUSION
• The use of blood transfusions in cervical cancer patients
gained traction after an initial publication from Princess
Margaret Hospital showing an improvement in pelvic
control and cure rates associated with correction of
anemia.
• However, subsequent publications from the same group
showed no survival benefit to transfusion.
• In head and neck cancer patients, studies suggest that
blood transfusions may have a negative effect on
survival.

16. ERYHTROPOITEN
• Correction of anemia via erythropoietin (EPO) administration was
evaluated in a double-blind, placebo-controlled randomized trial in
351 head and neck patients treated with RT.
• The primary end point was local-regional progression-free survival.
• Eighty-two percent of patients who received EPO maintained >14
g/dL (women) or 15 g/dL (men), while only 15% of the patients in
the placebo arm attained this benchmark.
• The relative risk of locoregional progression, however, was 1.62 in
the EPO arm, compared to placebo (P = .0008) , however
detriment was seen for survival in those patients who received
EPO.

17. • A systematic review pooling data from five
randomized studies with a total of 1,397 patients
showed significantly worse overall survival in head
and neck cancer patients with the addition of EPO
to radiotherapy (odds ratio 0.73; P = .005).

18. SENSITISATION OF
HYPOXIC CELLS
• MISONIDAZOLE
• ETANIDAZOLE
• NIMORAZOLE
• CHEMOTHERAPY DRUGS

19. MISONIDAZOLE-
• The Danish Head and Neck Cancer Study-2 (DAHANCA-2) performed a
double-blind randomized trial evaluating the effect of misonidazole given in two
drug schedules with split-course irradiation in the treatment of carcinoma of the
larynx and pharynx.
• Patients were stratified according to
• tumor site (larynx vs. pharynx),
• nodal status, and
• institution.
• The total misonidazole dose was 11 g/m2.
• 626 patients.
• Overall, the misonidazole group did not have significantly better local tumor
control than the placebo group.

20. • The European Organisation for Research and
Treatment of Cancer conducted a randomized study
of conventional fractionation RT versus modified
fractionation RT (three fractions per day) with or
without misonidazole.
• 523 advanced head and neck cancer patients.
• No differences were seen in treatment outcome.
• Serious peripheral neuropathy, the dose-limiting
toxicity.

21. ETANIDAZOLE-
• Analog of misonidazole
• Lower lipid solubility and
• Less neurotoxicity.

22. • A Radiation Therapy Oncology Group (RTOG) phase III
study with etanidazole in head and neck tumors (521
patients).
• conventionally fractionated irradiation with or without
etanidazole
• 2 mg/m2 THREE times per week.
• No grade III or IV central nervous system or peripheral
neuropathy was observed.
• The 2-year actuarial local tumor control was 40% in each
arm, and the survival was 41% and 43%, respectively, in the
irradiation alone and the irradiation plus etanidazole arms.

23. NIMORAZOLE-
• 5-nitroimidazole of the same structural class as metronidazole.
• Its dose-limiting toxicity is nausea and vomiting;
• The drug can be administered with each radiation treatment.
• DAHANCA conducted a phase III trial of nimorazole (1.2 g/m2 vs.
placebo) for squamous cell cancer of the supraglottic larynx and
pharynx.
• There was a statistically significant improvement in locoregional
tumor control (49% vs. 33% at 5 years; P = .002) but not for
survival.
• The use of nimorazole has become the standard of care in
Denmark but has not been adopted in other countries.

26. HYPOXIC
CYTOTOXINS
• MITOMYCIN-C (MMC)
• PORFIROMYCIN
• TIRAPAZAMINE

27. MITOMYCIN-C
• An antibiotic antineopastic drug.
• Metabolized in regions of low oxygen
concentration.
• Preferentially cytotoxic to hypoxic cells.

28. • Yale University examined the concurrent use of
MMC in 195 head and neck cancer patients treated
on two randomized trials.
• 68 Gy with or without MMC on days 1 and 43 of RT.
• Local regional recurrence-free survival was
improved with the addition of MMC from 54% to
76% (P = .003).
• Overall survival improved from 42% to 48%, but this
was not statistically significant.

29. PORFIROMYCIN
• The Yale investigators conducted a phase III study.
• Conventionally fractionated radiation plus MMC versus radiation plus
porfiromycin.
• Hematologic and nonhematologic toxicity was equivalent in the two treatment
arms.
• With a median follow-up >6 years, MMC was superior to porfiromycin with
respect to
1. 5-year local relapse-free survival (91.6% vs. 72.7%; P = .01),
2. local-regional relapse-free survival (82% vs. 65.3%; P = .05), and
3. disease-free survival (72.8% vs. 52.9%; P = .03).
• There were no significant differences between the two arms with respect to
overall survival (49% vs. 54%) or distant metastasis-free rate (80% vs. 76%).

30. TIRAPAZAMIN
E
• Under hypoxic conditions, a free radical one-
electron reduction product rapidly forms and is
believed to be the toxic species, causing oxidative
damage to pyrimidines and inducing DNA strand
breaks.

31. • The HeadSTART study
• 861 patients
• compared standard fractionation RT (70 Gy) with concurrent
cisplatin/tirapazamine versus concurrent cisplatin alone.
• overall survival, at 2-year rates of 65.7% in the cisplatin alone arm
and 66.2% in the cisplatin/tirapazamine cohort.
• No differences were seen in failure-free survival, time to
locoregional failure, or quality of life.
• The patients in this study were not selected based on the presence of
tumor hypoxia. Moreover, 12% had major RT planning deficiencies,
with those patients having significantly worse locoregional control and
overall survival compared to those in protocol compliance.

32. BIOLOGIC MODIFIERS
• Overexpression of the epidermal growth factor receptor-1
(EGFR-1) is associated with an adverse outcome in
squamous head and neck cancer.
• An open-label phase III trial tested the impact of weekly
injections of cetuximab added to a course of RT alone.
• Two-year local regional increased from 48% with RT to
56% with RT and cetuximab (P = .02).
• The initial survival advantage seen with the addition of
cetuximab to RT has persisted, with updated 5-year overall
survival rates of 45.6% versus 36.4% (P = .018).

33. • Phase III study, RTOG-0522, randomized patients
with locally advanced head and neck cancer to
receive RT and concurrent cisplatin with or without
cetuximab.
• Results of the study were presented at the
American Society of Clinical Oncology annual
meeting in 2011. Treatment intensification with the
addition of cetuximab to CRT did not improve 2-
year progression-free or overall survival.

34. CHEMICAL
RADIOPROTECTION

35. 1. PROTECTION
2. MITIGATION
3. TREATMENT

36. PROTECTION
• Cytotoxicity of ionizing irradiation results from the
generation of free radicals that cause DNA strand
breaks and lead to mitotic cell death.
• Amifostine is the prototype pharmacologic
radioprotector that functions via free radical
scavenging.

37. • An open-label phase III randomized trial was conducted from 1995 to 1997
to assess the ability of this drug to reduce the incidence of grade 2 or higher
acute and late xerostomia and grade 3 or higher acute mucositis.
• Patients enrolled in this trial received curative intent or adjuvant
postoperative irradiation without concurrent chemotherapy.
• 1.8 to 2.0 Gy/#.
• Curative intent - 66 to 70 Gy, and
• postoperative irradiation - 50 to 60 Gy
• IMRT was not utilized, and inclusion of >75% of both parotid glands was
required for inclusion in the study.
• 200 mg/m2 intravenously for 15 to 30 minutes every day prior to each
fraction of radiotherapy.

38. • Amifostine did not reduce the incidence of grade
3 mucositis
• Significantly reduced the incidence of acute and
long-term grade >2 xerostomia.

39. • TOXICITY-
• Nausea and vomiting and
• Transient hypotension.
• Subcutaneous administration- Reduces toxicity
• Severe cutaneous toxicity, including
A. Erythema multiforme,
B. Stevens-Johnson syndrome, and
C. Toxic epidermal necrolysis.

40. • Amifostine is approved by the U.S. Food and Drug
Administration for xerostomia in the setting of RT
alone.
• Cytoprotective benefit in the chemoradiation
setting, level 1 evidence is lacking.

41. MITIGATION
• Palifermin is a recombinant human keratinocyte
growth factor that belongs to the fibroblast growth
factor (FGF-7) family of cytokines.
• It stimulates cellular proliferation and differentiation
in a variety of epithelial tissues including mucosa
throughout the alimentary tract, salivary glands, and
type II pneumocytes.
• Palifermin also regulates intrinsic glutathione-
mediated cytoprotective mechanisms.

42. • Phase III double-blind placebo-controlled trial of patients with non-Hodgkin
lymphoma undergoing bone marrow transplantation(n=212).
• The bone marrow ablative regimen consisted of 12 Gy of total-body irradiation
(TBI) given at 1.5 Gy twice a day. Thereafter, etoposide (VP-16) and
cyclophosphamide were administered.
• Palifermin was delivered prior to the initiation of TBI and again after the
completion of chemotherapy, which also corresponded to 5 days after the
completion of TBI.
• DOSE- 60 mcg/kg/d 3 times for both administrations.
• Grade 3 or 4 mucositis approached 90%-placebo arm vs approximately 60% in
the palifermin arm.
• For those patients who developed this level of toxicity, the duration was
significantly reduced from 10.4 days in the placebo arm to 3.7 days in the
palifermin arm (P <.001).

43. • Phase III study examined a higher dose of palifermin at 180
mcg/kg to reduce oral mucositis in 188 patients with locally
advanced head and neck cancer treated with CRT.
• Palifermin was administered prior to starting CRT and once
weekly for 7 weeks.
• The incidence of severe oral mucositis in the palifermin arm
compared to placebo (54% vs. 69%; P = .041). Both overall
survival and progression-free survival were similar as well.
• The precise role for palifermin in the management of head
and neck cancer remains to be established.

44. TREATMENT
• SUCRALFATE
• BENZYDAMINE HYDROCHLORIDE
• ISEGANAN

45. SUCRALFATE
• Sucralfate, a basic aluminum salt of sucrose, is used in
the treatment of peptic ulcer disease.
• It provides a protective coating to ulcerated tissue by
means of binding to exposed proteins in damaged cells.
• It also stimulates mucus production, mitosis, and
surface migration of cells.
• The clinical data do not show any benefit from
sucralfate.

46. BENZYDAMINE
HYDROCHLORIDE
• Benzydamine hydrochloride is a nonsteroidal anti-inflammatory drug that
also possesses antimicrobial activity.
• It is a potent inhibitor of TNF-α
• Benzydamine therapy resulted in a 30% reduction in mucosal erythema
and ulceration.
• Most of this benefit was observed once doses >25 Gy had been delivered.
• One-third of the benzydamine patients did not develop any mucosal
ulceration, compared with only 18% of the placebo-treated patients (P =
.04).
• There was a nonsignificant trend toward reduction in mouth pain at rest for
the patients who received benzydamine.

47. • Importantly, benzydamine was no more effective than
placebo with respect to the reduction of pain during
meals.
• Cumulative weight loss during RT was equivalent in the
two treatment groups.
• There was no difference in the proportion of patients who
required enteral nutritional support between the two
treatment arms.
• The clinical value of benzydamine has not been proven
for patients receiving high-dose RT with or without
concurrent chemotherapy.

48. ISEGANAN
• Protegrins are naturally occurring peptides that
have broad-spectrum antimicrobial activity.
• Iseganan is a synthetic analog of this class of
compounds.
• A placebo-controlled trial in patients receiving
chemotherapy suggested that iseganan reduced the
incidence of ulcerative stomatitis and decreased
both mouth pain and swallowing difficulty.

49. • A phase III double-blind, placebo-controlled trial was
subsequently conducted to test this concept in patients receiving
head and neck RT.
• Minimum dose of 60 Gy but different fractionation schemes.
• Forty percent of the patients enrolled received concurrent
chemotherapy.
• The study contained three treatment arms:
• standard-of-care (SOC) oral hygiene only,
• placebo plus SOC, and
• iseganan plus SOC.

50. • Iseganan and placebo were equivalent to one another with respect
to all end points in the trial.
• Both iseganan and placebo arms were superior to SOC oral hygiene
alone.
• Two-thirds of the patients in both arms had confluent mucositis
compared with 79% in the SOC alone arm (P = .02).
• Only 2% of the SOC patients had no mucosal ulceration versus 9%
in both the iseganan and placebo arms (P = .04).
• Peak mouth pain and difficulty swallowing were also significantly
worse for the patients assigned to SOC alone.
• RT dose reductions were also significantly more common in the
SOC patients.

51. • This trial provides an important foundation in the
evaluation of new therapies for mucositis through its
demonstration of the value of organized and
systematic attention to the maintenance of good
oral hygiene throughout a course of head and
neck CRT.

52. THANK YOU