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Radiation Oncology and Prostate CancerCurrent Status and New Advances : Radiation Oncology and Prostate Cancer Current Status and New Advances Ajay Sandhu M.D. Associate Professor, Radiation Oncology UCSD Moores Cancer Center


Epidemiology : 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


Risk Factors : 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


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


Prostate specimen : Prostate specimen


Screening : Screening ACS and AUA Recommendation All men > 50 with an expected survival > 10 yrs should undergo an annual DRE and serum PSA


What is PSA? : What is PSA? Prostatic Specific Antigen (PSA) Protein, functions to liquefy seminal coagulum, made by both benign and cancerous prostate cells Normal levels < 4 ng/dl Biopsies of the prostate are recommended for PSA’s > 4 ng/dl


CAUTION ABOUT PSA : 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


TREATMENT OPTIONS : TREATMENT OPTIONS OBSERVATION SURGERY- Prostatectomy RADIOTHERAPY- conformal IMRT, Brachytherapy, combination HORMONES- Androgen deprivation CHEMOTHERAPY


Comparison of Therapies : 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


Risk Stratification of PC : Risk Stratification of PC Low risk: PSA <10, GS 2-6, T1-T2a Intermediate risk: PSA 10-20, GS 7, T2b High risk: PSA>20 or GS >7 or >T2b


Radiation Oncology : 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


Radiation Oncology : 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 Gy=100 rads)


Slide18 : 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


Slide19 : Radiation Therapy and Prostate Cancer First used to treat prostate cancer in 1909 (Pasteau) Radium capsules inserted into the urethra (intracavitary brachytherapy) Teletherapy machines of the day could not produce sufficiently penetrating beams London (1920)


Slide20 : External Beam Treatment Machines 1920’s 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


Slide21 : 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


Standard 4 field pelvic plan : Standard 4 field pelvic plan


Intensity Modulated RT : 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


Modern linear accelerator head : Modern linear accelerator head


Slide26 : 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


Slide27 : Intensity Modulated Radiation Therapy The intensity of each beam is modulated by moving the multi-leaf collimators in and out of the beam’s path The longer the leaves stay open in a particular position the higher the intensity of the radiation to that spot


Multiple angles used in IMRT : Multiple angles used in IMRT


Machine eye view : Machine eye view


Better conformity with IMRT : Better conformity with IMRT bladder prostate rectum Seminal vesicles


Slide31 : 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+ Conventional RT IMRT Plan bladder prostate rectum


Organ preservation : Organ preservation Breast Larynx Tongue GI cancers Extremity Prostate?


Early Stage Prostate CancerLong-term biochemical disease control : Early Stage Prostate Cancer Long-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 <2 µg/L 52% Washington University 925 PSA <6 µg/L 61% Johns Hopkins 2404 PSA <2 µg/L 74% *Defined as PSA <10 µg/L and absence of 2 rises after a nadir **Absence of 3 consecutive rises after a nadir ***8-year results


Slide34 : 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 n=275 Intermediate n=322 Unfavorable n=175


External Beam RT : 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 1991;21:935 Pilepich et al. Int J Radiat Oncol Biol Phys 1987;13:351


Slide36 : 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 < 0.0001


Slide37 : 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


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


Rising PSA after RP : 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, PSA<2.0 and longer PSA doubling time (>10 months)


RT after RP : 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


Palliative RT : 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 1982;50:893 Blitzer et al. Cancer 1985;55:1468 Turner et al. Br J Cancer 2002;84:297


Side Effects of Therapy : 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


Conclusions : 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