• Information
  1. Introduction
  2. Effects of Radiation on Cells
  3. Use of Radiosensitizing Agents
  4. Practical Issues
  5. Radiotherapy as Curative Treatment
  6. Brachytherapy
  7. Radiation and Surgery
  8. Radiolabelled Monoclonal Antibodies
  9. Palliation
  10. Radiation Proctitis

A. Introduction

1. Approximately 50% of cancer patients will undergo radiation therapy
2. Some tumors are cured by radiation therapy, but most therapy is palliative
3. Excellent modality for reducing local recurrence of tumors [6]
4. Types of Therapy
   1. High energy radiation beams for deep penetration
   2. Lower energy beams for more superficial tumors
   3. Proton beam therapy - spares normal tissue with minimal exit effects [12]
   4. Brachytherapy - implanted radioactive solids for local effects [3]
   5. Combinations with chemotherapies and radiosensitizing agents

B. Effects of Radiation on Cells

1. DNA strand breakage - usually with effects on cell cycle progression
2. Double strand DNA (dsDNA) breaks probably lead to cell death
   1. Most normal cells have excellent DNA repair systems
   2. Many tumor cell types cannot repair extensive DNA damage
   3. ~240 hours are required for repair of DNA by normal cells
   4. Therefore, small daily doses of radiation are preferred over larger doses
3. Some cells are induced to undergo apoptosis (programmed cell death)
   1. Intact tumor suppressor protein p53 is probably required for this response
   2. Lymphocytes, intestinal crypt, germ, and salivary gland cells are usually susceptible
4. Induction of (abnormal) growth factor and signal transduction pathways
5. Small (~10%) increases in radiation dose may increase tumor responses significantly
6. Radiation for Hodgkin's Lymphoma increases risk of breast cancer in involved fields [11]

C. Use of Radiosensitizing Agents

1. Selective uptake and/or binding of specific agents on tumor cells
   1. These agents render target cells more susceptible to radiation
   2. Similar to use of Psoralein in ultraviolet therapy for skin disease (PUVA)
2. DNA Damaging and Repair Damaging Agents are used
3. Monoclonal Antibodies with chemical tags show some promise
4. Cell Cycle Specific Sensitizers
5. Many currently used chemotherapeutic agents increase cell radiosensitivity
   1. 5-FU, platinum agents, paclitaxel
   2. Metronidazole (Flagyl®) also increases sensitivity

D. Practical Issues

1. Goal is targetting of tumor tissue
2. Three-dimensional Computed Tomographic (CT) guided targetted beams are now used
3. Multiple beams are used with focus at a single point / area
4. With separately controlled beam attenuators, treatment areas of any shape can be created
5. Often used as a combined modality therapy
6. Goal is sparing of normal tissue, with focus on tumor tissue
7. Smaller daily dosing, rather than larger less frequent doses, is safer for normal tissue
8. Conformal techniques reduce damage to normal tissues compared with conventional [4]

E. Radiotherapy as Curative Treatment

1. Depends on stage as well as tumor type
2. Localized Hodgkin's Disease and Non-Hodgkin's Lymphomas
3. Cervical Carcinoma
4. Prostate Cancer
5. Central Nervous System (CNS) Tumors
6. Head and Neck Cancers
7. Seminoma
8. Choroidal Melanoma and Retinoblastoma
9. Thyroid Carcinoma (iodine-131)
10. Breast Cancer
    1. Reduces recurrence from 27% to 9% with 2-4% mortality reduction [6]
    2. Lesion-targeted additional radiation (after standard doses) reduces local recurrence 40-50% [10]
    3. Radiation schedule of 40 Gy in 15 fractions provides similar control and tolerability as the standard schedule of 50 Gy in 25 fractions for early breast cancer after sugical resection [15]
11. Reduces recurrence of and mortality from rectal cancer used preoperatively [8]
12. Palliation only for various unresectable tumors, including sarcomas, pancreatic, lung, brain
13. Radiotherapy in patients >70 years with glioblastoma increased survival from 16.9 weeks with supportive care to 29.1 weeks [14]

F. Brachytherapy [3]

1. Use of radioactive source placed into the patient
2. Local effects; may be left in temporarily or permanently
3. Older problems included exposure of personnel to radiation
4. Newer systems use robotic arms for implanting through catheters
5. Many treatments are now temporary, and the implants can be removed
6. This allows patient to lead a more normal life as outpatient

G. Radiation and Surgery

1. Rectal Carcinoma [9]
2. Positive Margins in Mastectomy - chest wall irradiation
3. Adjuvent for Lumpectomy for breast cancers
4. Whole brain radiation with stereotactic radiosurgery boost for patients with 1-3 brain metastases (mainly with lung adenocarcinoma) improved performance, mortality [13]

H. Radiolabelled Monoclonal Antibodies [3]

1. Radioimmunotherapy
   1. Most therapeutics use Iodine-131 (I-131)
   2. However, ß-emissions are therapeutic, not gamma-emissions
   3. Only ~35% of I-131 emissions are ß-rays
   4. Gamma rays contribute to non-specific irradiation to patient and surroundings
   5. Therefore, patients must usually spend several days in a shielded room
   6. More favorable radionuclides are being developed (rhenium-186, -188, curium-57)
   7. alpha ray emitters are also effective therapeutically (astatine-211, bismuth-213)
2. Anti-CD20 Monoclonal Antibody (Ab) labelled with I-131
   1. For treatment of Non-Hodgkin's Lymphoma
   2. Unlabelled (non-radioactive) Ab showed 9% complete and 50% partial responses
   3. Radiolabelled Ab showed 50% complete and 79% partial responses
   4. Using myeloablative levels of radiolabelled Ab, 79% complete and 86% partial responses were observed
3. Anti-CD22 Radiolabelled Abs
4. Anti-HLA-DR Radiolabelled Abs

I. Palliation

1. Bone Pain [3]
   1. Especially in prostate cancer, multiple myeloma, breast and lung cancers
   2. External beam therapy palliates in ~70% of cases
   3. Strontium-89 (Metastron®)
   4. Rhenium-186 etidronate: beta/gamma emitter; 3.8 day half-life
   5. Samarium-153 EDTM phosphonate: beta/gamma emitter; 1.95 day half-life
   6. Response rates similar to external beam therapy without the skin and tissue destruction
2. Strontium-89 (Metastron®)
   1. Pure beta-ray emitter with 50.5 day half life
   2. Intravenous reduces pain in ~80%, complete relief ~10% in prostate Ca [5]
   3. Less effective in breast cancer
3. Spinal Cord Compression
4. CNS Tumors
   1. Radiation used only after reduction of edema
   2. Especially effective for CNS lymphomas
   3. Standard therapy for CNS metastases of any type

J. Radiation Proctitis

1. Associated with radiation given for malignant pelvic disease
2. Risk of chronic proctitis 5-20% 5 years within radiation therapy
3. Higher incidence of acute radiation proctitis which is usually self limited
4. Topical glucocorticoids and sucralfate have been used with minimal efficacy
5. Butyrate stimulates vasodilation, mucosal proliferation and mucosal repair
6. Topical butyrate improves symptoms and healing rates in acute radiation proctitis [7]

References

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2. Koka A and Macklis RM. 1995. Clev Clin J Med. 62(4):254
3. Chatal JF and Hoefnagel CA. 1999. Lancet. 354(9182):931
4. Dearnaly DP, Khoo VS, Norman AR, et al. 1999. Lancet. 353(9149):267
5. Robinson RG, Preston DF, Schiefelbein M, Baxter KG. 1995. JAMA. 274(5):420
6. Early Breast Cancer Trialists' Collaborative Group. 2000. Lancet. 355(9217):1757
7. Zornberg GL and Jick H. 2000. Lancet. 356(9237):1219
8. Camma C, Giunta M, Fiorica F, et al. 2000. JAMA. 284(8):1008
9. Kapiteijn E, Marijnen CAM, Nagtegaal ID, et al. 2001. NEJM. 345(9):638
10. Bartelink H, Horiot JC, Poortmans P, et al. 2001. NEJM. 345(19):1378
11. Travis LB, Hill DA, Dores GM, et al. 2003. JAMA. 290(4):465
12. Friedmann Am, Tarbell NJ, Schaefer PW, Hoch BL. 2004. NEJM. 350(5):494 (Case Record)
13. Andrews DW, Scott CB, Sperduto PW, et al. 2004. Lancet. 363(9422):1665
14. Keime-Guibert F, Chinot O, Taillandier L, et al. 2007. NEJM. 356(15):1527
15. START Trialists' Group. 2008. Lancet. 371(9618):1098