CHEMICAL MODIFIERS OF RADIATION

RESPONSE

Dr. SAADVIK R YJR-2

• CHEMICAL RADIOSENSITISATION

• CHEMICAL RADIOPROTECTORS

CHEMICAL RADIOSENSITISATION

• THE OXYGEN EFFECT

• TUMOUR HYPOXIA

THE OXYGEN EFFECT

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.

• Increased delivery of oxygen to tumor,

• Preferential sensitization of hypoxic cells with oxygen mimetic agents,

• Cytotoxic agents that selectively target hypoxic tumor cells.

INCREASED DELIVERY OF OXYGEN TO TUMOUR

• HYPERBARIC OXYGEN

• CARBOGEN

• NICOTINAMIDE

• EFAPROXIRAL

• ANAEMIA

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.

CARBOGEN

• 95% O2 & 5% CO2

• With or without NICOTINAMIDE.

• 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.

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.

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.

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.

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.

• 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).

SENSITISATION OF HYPOXIC CELLS

• MISONIDAZOLE

• ETANIDAZOLE

• NIMORAZOLE

• CHEMOTHERAPY DRUGS

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.

• 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.

ETANIDAZOLE-

• Analog of misonidazole

• Lower lipid solubility and

• Less neurotoxicity.

• 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.

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.

HYPOXIC CYTOTOXINS

• MITOMYCIN-C (MMC)

• PORFIROMYCIN

• TIRAPAZAMINE

MITOMYCIN-C

• An antibiotic antineopastic drug.

• Metabolized in regions of low oxygen concentration.

• Preferentially cytotoxic to hypoxic cells.

• 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.

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%).

TIRAPAZAMINE

• 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.

• 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.

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).

• 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.

CHEMICAL RADIOPROTECTION

1. PROTECTION

2. MITIGATION

3. TREATMENT

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.

• 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.

• Amifostine did not reduce the incidence of grade 3 mucositis

• Significantly reduced the incidence of acute and long-term grade >2 xerostomia.

• 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.

• 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.

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.

• 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).

• 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.

TREATMENT

• SUCRALFATE

• BENZYDAMINE HYDROCHLORIDE

• ISEGANAN

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.

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.

• 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.

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.

• 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.

• 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.

• 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.

THANK YOU