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Hypofractionated Adaptive Image-Guided Radiation Therapy for Localized Adenocarcinoma of the Prostate

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00809991
Recruitment Status : Active, not recruiting
First Posted : December 17, 2008
Last Update Posted : March 12, 2021
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:
This will be a Phase II study evaluating the effectiveness and toxicity of a specific radiation therapy regimen. This choice of daily dose is based on the prior published experience showing safety and efficacy of hypofractionated regimens. The total dose is calculated to be effective for late effects which has been shown to be effective and safe in a large prospective Phase II study. If the hypothesis for the prostate is is true, then this regimen should be at least as effective or more effective for tumor control than the current conventional therapy.

Condition or disease Intervention/treatment Phase
Prostate Cancer Radiation: hypofractionation Phase 2

Detailed Description:

Radiation therapy is an effective and frequently utilized modality for the treatment of clinically localized prostate cancer. Traditionally, external beam radiation has been delivered in a fractionated manner using daily doses of 1.8-2.0 Gy. This daily dose was derived from early animal experiments and clinical experience, supported by mathematical models of normal tissue and tumor response to fraction size. The most widely used of these models is the linear-quadratic formula, which predicts responses to different fraction sizes based on the alpha/beta ratio of any given tissue.

One of the main motivations for delivering a treatment at low dose rate or with many fractions is that late-responding normal tissue are generally more sensitive than early-responding tissues (i.e. tumor) to increases in fraction size. So increasing the number of fractions generally spares late-responding tissues more than the tumor. This can be quantified in terms of the alpha/beta ratio:

  • Small alpha/beta ratio (2-4 Gy), typical of late sequelae, means high sensitivity to fractionation changes.
  • Large alpha/beta ratio (>8 Gy), typical of tumor control, means low sensitivity to fractionation changes.

It is generally assumed that the mechanistic basis for the different fractionation response of tumors and late-responding normal tissues relates to the larger proportion of cycling cells in tumors. But prostate tumors contain unusually small fractions of cycling cells. Brenner and Hall as well as Duchesne and Peters have reasoned that prostate tumors might not respond to changes in fractionation in the same way as other cancers; both papers hypothesize that prostate tumors might respond to changes in fractionation or dose rate more like a late-responding normal tissue. , In mathematical terms, the suggestion is that the alpha/beta ratio for prostate cancer might be low, comparable to that for late-responding tissues or even lower. Previous estimates of alpha/beta ratios of normal tissue and tumor tissue have generally been 3 and 10, respectively. Recent evidence has estimated the alpha/beta ratio of prostate cancer to be as low as 1.5. If these hypotheses are true, then the optimal therapeutic ratio for prostate cancer would be achieved using daily doses higher than 2 Gy.

Several preliminary clinical reports have found reasonable PSA control rates and no increase in late toxicity using doses of 2.5 to 3 Gy. Kupelian from the Mayo Clinic found PSA-free survival rates of 97%, 88%, and 70% in low-, intermediate-, and high-risk patients, respectively. The dose regimen used was 70 Gy in 2.5 Gy daily fractions. Both acute and late toxicity were not higher than seen with typical dose regimens. A group from Christie Hospital reported 82%, 56%, and 39% 5-year biochemical disease free survival rates (low, intermediate, and high risk, respectively) in patients treated with 50 Gy in 16 fractions (3.125 Gy per fraction), with acceptable bowel and bladder toxicity.

These results, although promising, require further validation. If the hypothesis that prostate cancer alpha/beta ratio is lower than normal tissue is correct, then the optimal fractional dose is likely to be even higher than the doses tested thus far, but if incorrect, the result may be increased normal tissue toxicity.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 188 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Hypofractionated Adaptive Image-Guided Radiation Therapy for Localized Adenocarcinoma of the Prostate
Actual Study Start Date : December 22, 2008
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : September 2025

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Hypofractionated radiation therapy in prostate adenocarcinoma
Participants with histologically confirmed, locally confined adenocarcinoma of the prostate receive 3.6 Gy per day to a total dose of 57.6 Gy (16 fractions).
Radiation: hypofractionation
3.6 Gy per day to a total dose of 57.6 Gy (16 fractions). T

Primary Outcome Measures :
  1. Assess the incidence of grade 2 or greater GU and GI toxicity and self-reported quality of life data with image-guided radiation therapy in doses of 3.6 Gy per day to a total dose of 57.6Gy (16 fractions). [ Time Frame: 7 years ]

Secondary Outcome Measures :
  1. Assess biochemical and clinical control rates associated with the hypofractionated dose regimen for both low-risk and intermediate-risk groups. Assessment will be performed at median 4 years and again at median 7 years' follow-up. [ Time Frame: 7 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically confirmed, locally confined adenocarcinoma of the prostate
  • Clinical stages T1a to T2b PSA of less than 10 ng per ml
  • Gleason score of less than 3+4=7
  • The patient has decided to undergo external beam radiation as treatment choice for his prostate cancer
  • Signed study-specific consent form prior to registration

Exclusion Criteria:

  • Stage T3 to 4 disease
  • Gleason 4+3=7 or higher score
  • PSA greater than 10 ng per ml
  • Clinical or Pathological Lymph node involvement N1
  • Evidence of distant metastases M1
  • Radical surgery for carcinoma of the prostate
  • Previous Chemotherapy or pelvic radiation therapy
  • Previous or concurrent cancers other than basal or squamous cell skin cancers or superficial bladder cancer unless disease free for at least 5 years
  • History of inflammatory bowel disease
  • Major medical or psychiatric illness which, in the investigator's opinion, would prevent completion of treatment and would interfere with follow up

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00809991

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United States, Maryland
The Johns Hopkins University School of Medicne
Baltimore, Maryland, United States, 21231
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
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Principal Investigator: Danny Song, MD The Johns Hopkins University School of Medcine
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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Identifier: NCT00809991    
Other Study ID Numbers: J0859
NA_00019393 ( Other Identifier: JHM IRB )
First Posted: December 17, 2008    Key Record Dates
Last Update Posted: March 12, 2021
Last Verified: March 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
Prostate Cancer
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Prostatic Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type