Radiotherapy for Prostate Cancer

*****See Radiation Section in Management of Localized Disease in Prostate Cancer Chapter Notes*****

Hypofractionation

• The full dose of radiation is usually divided into a number of smaller doses called fractions
  • Fractionated radiotherapy has been used since the early days of radiation, when it was found that cure could be achieved with less normal tissue injury when the radiation dose was split into many small fractions
• Hypofractionation (i.e. fewer fractions) reduces the overall treatment course by delivering higher doses per fraction
• Prostate cancer is believed to be acutely sensitive to the amount of radiation delivered at each treatment, such that providing a few treatments of high dose is more effective at producing cell kill than many fractions of 2 Gy.
  • It is hypothesized that one could provide a lower total dose, thus lessening risk for normal organ injury, with similar prostate cancer control using higher than standard doses per fraction
  • Patient risk selection and biologically effective doses have resulted in excellent biochemical control reported up to 5 years, but it is not clear if moderate hypofractionation is more efficacious.
• Doses in the range of 2.6 to 3.1 Gy have been delivered in phase III trials with low morbidity.
  • Safe treatment delivery requires accurate patient setup and conformal treatment planning.
• Early studies of extreme fractionation (6.7 to 10 Gy) show good biochemical control rates but the duration of follow-up is limited.

External Beam Radiotherapy

• Most commonly involves the use of gamma radiation, usually photons
• Advances in Radiation Technology
  • In the era before CT [pre-1990s], RT technique was sometimes referred to as conventional radiation
  • 3D tumor visualization and treatment planning using CT scans began in the 1990s. The result is described as 3DCRT because the radiation beams conform to the shape of the treatment target
  • A major advance in the delivery of radiation came with the advent of intensity-modulated radiation therapy (IMRT). IMRT is a sophisticated way of treatment delivery in which the intensity of radiation can be varied from each beam angle.
    • IMRT requires the use of advanced software, specialized personnel, and hardware adaptations to linear accelerators
    • IMRT results in reduced radiation doses to the rectum, bladder, femoral heads, and small bowel compared to 3DCRT
  • Image-guided radiation therapy (IGRT) is a method in which imaging techniques are used to guide IMRT to the target area. Image guidance was development based on a realization that the
    1. Daily location of the prostate within the pelvis throughout the course of RT is not identical (interfraction motion)
    2. Prostate is mobile even during a single session of RT (intrafraction motion).
    • With image guidance, the location of the prostate can be verified daily before delivering radiation
  • Stereotactic body radiotherapy (SBRT, CyberKnife) defines an external-beam RT that delivers a high dose each treatment using precisely targeted and highly conformal radiation in a small number of fractions (hypofractionation).
    • Limited results have been published in a small number of patients with low-risk disease

Heavy-particle therapy

• Another form of 3D-CRT
• Difficult to produce and control
• Theoretical advantages over conventional x-ray and electron beams:  
  1. More densely destructive in tissue, and the damage they create is less easily repaired by tumour cells
  2. Can be easier to spare the normal tissues surrounding the cancerous target.
     • Travels differently in tissue and exhibits a Bragg peak, which refers to a sharp cutoff in dose at the end of the particle’s range in tissue. Beyond this depth, the tissue receives little or no radiation.
• Most commonly used particles are neutrons and protons
  • Neutrons
    • May cause more normal tissue damage than photon beam therapy
    • Few prostate cancer patients in the USA are treated with neutron RT
  • Protons
    • An expensive treatment option for prostate cancer that currently has not demonstrated a clinical benefit over standard IMRT.
      • Studies comparing proton therapy to modern IMRT for prostate cancer are mostly limited to treatment-planning studies which have shown that proton radiation can reduce the volumes of nearby organs that receive low to medium—but not high—doses of radiation compared to IMRT
      • Unknown if
        • Lowering of low-to-moderate doses of radiation to the rectum from proton therapy results in lower GI toxicity rates compared to IMRT
        • Protons cause higher rates of GU toxicity or pelvic fracture rates as a result of somewhat higher doses to the bladder (at high dose regions) and femoral heads
      • No clinical study has directly compared patient outcomes
        • Data suggest that proton therapy is safe and effective for prostate cancer treatment and likely results in cancer control and morbidity outcomes similar to that with IMRT.

Radiation Therapy and Androgen Suppression Therapy

• See 2017 AUA Localized Prostate Cancer Guideline Notes and Management of Localized Disease Chapter Notes and Management of Locally Advanced Disease Chapter Notes

Radiation Therapy after Prostatectomy

• See Management of Locally Advanced Prostate Cancer Chapter Notes and 2019 AUA Guideline Notes on Radiation after Prostate Cancer Treatment

Radiation therapy for palliation

• Bone metastases
  • Management options for the management of bone metastases include surgery, medical management, and radiation.
    • RT can treat most patients with highly effective symptom relief.
  • A single-fraction regimen (800 cGy × 1) is the preferred regimen for patients with uncomplicated non-spinal bone metastasis
    • Appears to be as effective as other, more protracted regimens, is more cost-effective and less time-consuming for patients
  • Metastasis to a weight-bearing region can be painful and disabling, both functionally and psychologically.
  • Pathologic fracture is infrequent because prostate cancer produces primarily blastic metastases
    • Radiographic and clinical factors that warrant consideration of prophylactic surgical fixation (3):
      1. Intramedullary lytic lesion length ≥ 50% of the cross-sectional diameter of the bone
      2. Cortical lytic lesion length ≥ than the cross-sectional diameter of the bone
      3. Lytic lesion > 2.5 cm in axial length
      • These patients should be evaluated by an orthopedic surgeon.
    • If a pathologic fracture has occurred in a weight-bearing region, surgical fixation is required for pain control and to promote adequate healing.
      • Postoperative radiation is required after surgical fixation.
  • Spinal cord compression
    • Most serious complication of bone metastases
      • Epidural cord compressions arising from vertebral bodies accounts for the majority of spinal cord compressions; less frequently they are associated with soft-tissue masses involving the paravertebral region.
    • Diagnosis and Evaluation
      • Medical emergency; early diagnosis and therapy are critical
        • Failure to diagnose and treat promptly can lead to significant morbidity, including paraplegia and autonomic dysfunction
      • History and Physical Exam
        • The clinical syndrome often includes ≥1 of the following (3):
          1. Back pain
             • Pain is predominant symptom (≈95% of patients).
             • Back pain in a patient with a history of bone metastases should prompt an evaluation for epidural cord compression.
          2. Focal neurologic deficit (leg weakness, sensory levels)
          3. Changes in bladder or bowel control
          • Most of these patients have abnormalities on bone scintigraphs and/or abnormal findings on radiography at the time of diagnosis. However, a deficit on neurologic examination may be the only finding in patients who exhibit soft-tissue epidural metastasis in the paravertebral region.
      • Imaging
        • MRI is diagnostic modality of choice
    • Management
      • When the diagnosis of cord compression is made or even suspected, all patients should receive corticosteroid therapy (e.g., dexamethasone).
        • Steroids can decrease vasogenic edema and provide analgesic benefit
        • Loading dose of dexamethasone is 4-10 mg, followed by maintenance dose of 4-24 mg q6h
      • Definitive treatment should include radiation therapy, surgical decompression, or both
        • Situations in which surgery should be considered as an option before radiation (3):
          1. Unknown tissue diagnosis
          2. History of previous radiation to the same area
          3. Pathologic fracture with spinal instability or compression of the spinal cord by bone

Molecular Therapies and Radiation for Prostate Cancer

• Targeted RNA-Based Therapy
  • Chemical or short-interfering RNA (siRNA) inhibition of DNA repair proteins, such as DNA-dependent protein kinase ATM, results in cellular hypersensitivity to irradiation. Although these approaches have potential, they lack a means to selectively target cancer cells to avoid sensitization of surrounding non-cancerous tissues.
  • RNA interference (RNAi) is a promising new therapeutic approach, but the challenge for translating RNAi therapy is delivery, particularly for specific cell types.

Questions

1. What is the dose of palliative radiation for bone metastases?
2. What are the indications for surgical fixation of a bone metastasis?

Answers

1. What is the dose of palliative radiation for bone metastases?
   • 800cGy
2. What are the indications for surgical fixation of a bone metastasis?
   • Lesion ≥ 50% of diameter of bone
   • Cortex lesion > diameter of bone
   • Lesion ≥2.5cm in axial

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 116