Radiation Oncology and Prostate Cancer Current Status and New Advances

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Radiation Oncology and Prostate CancerCurrent
Status and New Advances

• Ajay Sandhu M.D.
• Associate Professor,
• Radiation Oncology
• UCSD Moores Cancer Center

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Epidemiology

• 200,000 cases/yr in US
• 40,000 deaths
• 15 lifetime risk of developing disease
• Risk increases with age
• 80 chance of () bx by 80 yrs
• Most men die with prostate cancer, not of
  prostate cancer

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Risk Factors

• Family history of PCA (RR 2.0) 10 of all
  cases
• Race not an independent risk factor
• Unproven risk factors
• High dietary fat
• BPH (benign prostatic hypertrophy)
• Smoking
• Occupational factors

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Pathology Histology

• Digital Rectal Exam
• limitations
• Prostatic biopsy (sampling issues)
• Gleason score
• Graded 1-5 based on microscopic patterns
• Scores range from 2-10

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Prostate specimen
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Screening

• ACS and AUA Recommendation
• All men gt 50 with an expected survival gt 10 yrs
  should undergo an annual DRE and serum PSA

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What is PSA?

• Prostatic Specific Antigen (PSA)
• Protein, functions to liquefy seminal coagulum,
  made by both benign and cancerous prostate cells
• Normal levels lt 4 ng/dl
• Biopsies of the prostate are recommended for
  PSAs gt 4 ng/dl

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CAUTION ABOUT PSA

• 25 men with progressive cancer have NO rise in
  PSA
• ? PSA threshold for biopsy more so for younger
  men
• Free PSA for higher sensitivity and specificity

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TREATMENT OPTIONS

• OBSERVATION
• SURGERY- Prostatectomy
• RADIOTHERAPY- conformal
• IMRT, Brachytherapy, combination
• HORMONES- Androgen deprivation
• CHEMOTHERAPY

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Comparison of Therapies

• No Modern randomized trials
• 1982 randomized trial demonstrating advantage of
  RP never widely accepted and criticized
• Nonrandomized comparison showed similar results
  for similar cohorts of patients with uniform
  selection criteria

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Risk Stratification of PC

• Low risk PSA lt10, GS 2-6, T1-T2a
• Intermediate risk
• PSA 10-20, GS 7, T2b
• High risk
• PSAgt20 or GS gt7 or gtT2b

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Radiation Oncology

• Radiation therapy has a long
• in the treatment of cancer
• 1st patient treated in 1896
• within 2 months of the
• discovery of X-rays

Wilhelm Roentgen (1845-1923) Discovers X-rays in
1895
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Radiation Oncology

• Radiation kills tumor cells by damaging DNA
• Radiation?Free radicals (OH?) ? DNA breaks
• DNA breaks prevent the replication of DNA
• Irradiated cells ultimately die when attempting
  to divide
• (reproductive death)
• Radiation dose was given previously in rads
• Today it is given in Gray (1 Gy100 rads)

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Radiation Modalities
Teletherapy ? Therapy at a distance (external
beam RT) Involves the use of photons and
electrons

• Brachytherapy
• Close therapy
• The use of radioactive sources (Cs137, Ir192,
  I125) placed either in a cavity (intracavitary)
  or within (interstitial) a tumor

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Radiation Therapy and Prostate Cancer
First used to treat prostate cancer in 1909
(Pasteau) Radium capsules inserted into the
urethra (intracavitary brachytherapy) Teletherap
y machines of the day could not produce
sufficiently penetrating beams
London (1920)
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External Beam Treatment Machines
1920s Low energy Poor penetration Unable to
treat the prostate without skin toxicity
1950s Moderate Energy Improved penetration Less
skin toxicity
1990s Computer controlled Linear
accelerators Multiple high energy beams IMRT
capable
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External Beam Prostate RT

• Initially a four field technique was used
  (anterior-posterior
• and 2 lateral fields)
• Field edges were shaped to minimize the dose to
• bladder and rectum
• Daily treatments lasting 8 weeks

Conventional 4 field prostate RT
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Standard 4 field pelvic plan
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Intensity Modulated RT

• Unlike conventional RT, IMRT conforms the dose to
  the shape of the target in 3 dimensions
• IMRT uses a sophisticated planning software to
  divide each beam into thousands of beamlets
  with different intensities
• IMRT is delivered using machines equipped with
  multi-leaf collimators which move in and out of
  the beams path

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Modern linear accelerator head
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Conventional RT field with shaped edges The beam
has equal intensity across its surface
IMRT field divided into different beamlets Each
pixel has a different intensity
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Intensity Modulated Radiation Therapy
The intensity of each beam is modulated by moving
the multi-leaf collimators in and out of the
beams path The longer the leaves stay open in
a particular position the higher the intensity
of the radiation to that spot
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Multiple angles used in IMRT
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Machine eye view
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Better conformity with IMRT
Seminal vesicles
bladder
rectum
prostate
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IMRT in Prostate Cancer
Reduces the dose to the bladder, rectum and
femoral heads thereby minimizing the risk of
injury to those organs Moreover, it provides
the ability to dose escalate to 80 Gy
bladder
prostate
rectum
IMRT Plan
Conventional RT
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Organ preservation

• Breast
• Larynx
• Tongue
• GI cancers
• Extremity
• Prostate?

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Early Stage Prostate CancerLong-term biochemical
disease control
n Endpoint 10-year Result External Beam
RT Mass General 1396 PSA Control 42 MD
Anderson 643 PSA Control 61 Fox
Chase 408 PSA Control 59 Radical
Prostatectomy Mayo Clinic 3170 PSA lt2
µg/L 52 Washington University 925 PSA lt6
µg/L 61 Johns Hopkins 2404 PSA lt2
µg/L 74 Defined as PSA lt10 µg/L and absence of
2 rises after a nadir Absence of 3 consecutive
rises after a nadir 8-year results
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Prostate IMRT

• Higher doses possible with IMRT may even result
  in
• better PSA control rates

Zelefsky et al. (Memorial Sloan Kettering)Int J
Radiat Oncol Biol Phys (2002)
Favorable n275 Intermediate n322 Unfavorable n
175
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External Beam RT

• Toxicity data compiled from 526 patients treated
  with external beam RT on two national protocols
• Most toxicities involve the rectum and bladder
• Any Moderate-Severe
• Diarrhea 12.7 7.8
• Proctitis 9.9 6.3
• Rectal Bleed 8.7 3.1
• Rectal-anal stricture 4.4 1.5
• Rectal Ulcer 1.1 1.1
• SBO 0.6 0.6
• Cystitis 11.4 4.6
• Hematuria 5.7 3.6
• Any severe GI-related (3.3) and GU-related
  (7.7)

Lawton et al. Int J Radiat Oncol Biol Phys
199121935 Pilepich et al. Int J Radiat Oncol
Biol Phys 198713351
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Prostate IMRT

• IMRT may help to further ?risk of GI toxicity
  especially in patients treated to high doses
• Total dose 81 Gy
• Grade ? 2
• Bladder Rectum
• Acute Chronic Acute Chronic
• 3DCRT 37 7 61 13
• IMRT 44 9 45 0.5
• p-value NS NS 0.05 0.0001

Zelefsky et al. (Memorial Sloan
Kettering)Radiotherapy Oncology (2000)
Update J Urology (2001) 3-yr g2 chronic rectal 2
vs 14, p lt 0.0001
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Prostate IMRT

• IMRT can also ?high doses to the penile bulb
• Sethi et al. (Loyola)
• Red J (2003)
• Dose (mean)
• Corpora cavernosa
• ?51
• Penile Bulb
• ?47
• without compromising
• prostate dose
• Clinical data needed to determine whether this
• approach reduces the risk of impotency

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Androgen Deprivation

• Combined Androgen Blockade
• Intermittent ADT
• Neoadjuvant ADT
• Concurrent ADT
• Long-term Androgen Deprivation

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Rising PSA after RP

• RP therapeutic goal undetectable PSA
• 25-50 develop PSA elevation after RP with 77 of
  these within first 2 years
• Salvage RT more effective for positive margins,
  PSAlt2.0 and longer PSA doubling time (gt10 months)

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RT after RP

• Capsule perforation, positive margins or invasion
  of seminal vesicle
• Adjuvant or Salvage
• Two randomized trials have shown earlier the
  better
• Improved biochemical disease free survival and
  local control not overall survival
• Long term quality of life not adverse with RT

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Palliative RT

• Beneficial in controlling painful metastatic
  sites
• Improvement is seen in 80-90 of patients, many
  experience complete relief
• Treatment lasts 10 days (total dose, 30 Gy)
• An alternative is the radionuclide strontium-89
• Sr-89 is given i.v. and is useful in pts with
  multiple painful sites
• Benefit is seen in 80-85 of patients

Tong et al. Cancer 198250893 Blitzer et al.
Cancer 1985551468 Turner et al. Br J Cancer
200284297
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Side Effects of Therapy

• Urinary incontinence 9.6 vs 3.5
• Erectile Dysfunction 80 vs 60 for surgery vs RT
• Diarrhea, bowel urgency, painful hemorrhoids
  double in RT vs S
• Source PCOS

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Conclusions

• Radiation therapy has a long history in the
  treatment of prostate cancer
• Many of its early pioneers were famous urologists
  including Hugh Hampton Young
• Older techniques were not effective, modern
  brachytherapy and external beam approaches are
  associated with high cure rates with low rates of
  toxicity (IMRT)
• RT is also an effective approach in patients who
  relapse following surgery and those with painful
  metastatic disease sites