Trial Information

The ELDORADO (Eligard®, Docetaxel and Radiotherapy) Study: A Phase II Study of Chemo - Hormonal Therapy and Radiation in High Risk Prostate Cancer

1.0 Objectives

1.1 Primary objective

To investigate if the inversion of sequencing of multi - phase, intensity - modulated
radiotherapy (IMRT), for the treatment of patients with high - risk prostate cancer, can
improve the delivery of concurrent, weekly Docetaxel chemotherapy, in concert with long -
term androgen deprivation (LTAD).

1.2 Secondary objective

To investigate if the inversion of sequencing of multi - phase IMRT can improve the time to
grade 2 or 3 gastrointestinal toxicity, the total amount of Docetaxel that can be delivered,
or the quality of life in patients receiving concurrent, weekly Docetaxel chemotherapy, in
concert with long - term androgen deprivation (LTAD).

2.0 Background

2.1 Rationale to investigate chemo - radiation in high - risk, non - metastatic prostate
cancer

Concurrent chemotherapy and radiotherapy, compared to radiotherapy alone, has resulted in
improvements in overall survival and cure in patients with locally advanced head and neck ,
cervix , and lung cancer . Long - term androgen deprivation (LTAD) and radiotherapy results
in modest 10 year overall and biochemical - free relapse rates in patients with "High risk"
disease . Treatment intensification, in the form of escalation of radiotherapy dose, the
addition of chemotherapy, or the addition of radical prostatectomy, in highly - selected
patients, has been proposed in the literature , . Given the success of combining concurrent
chemotherapy with radiotherapy in other solid tumor sites, it would seem reasonable to
investigate this in patients with high - risk, non - metastatic prostate cancer, as defined
in the Canadian consensus document , who are in the worst prognostic category.

2.2 Choice of chemotherapy agent and regimen

The optimal chemotherapy to combine with radiation therapy is unknown for the treatment of
prostate cancer. A recent phase III study has, however, shown the superiority of Docetaxel
and prednisone chemotherapy over the previous standard regimen, Mitoxantrone and prednisone
, in men with metastatic prostate cancer, who demonstrated progression on androgen
deprivation. For the first time, an improvement in overall median survival was seen for the
regimen containing Docetaxel (18.9 vs 16.5 months, p = 0.009), with 48% of men having a 50%
or greater reduction in PSA, and improved HRQOL. Toxicity was felt to be acceptable, with
the main toxicities (>30% probability) being: fatigue, alopecia, nausea and/or vomiting,
neutropenia, nail changes, sensory neuropathy, and diarrhea. The results of this study were
supported by a similar phase III study showing superiority of Docetaxel, estramustine and
prednisone over Mitoxantrone and prednisone in patients with progressive, hormone -
refractory prostate cancer.

Literature review reveals that there is only one published study of concurrent Docetaxel
chemotherapy and external beam radiation. The study by Kumar describes a phase I, dose -
escalation study designed to determine the maximum tolerated dose (MTD) of weekly Docetaxel.
The patient population included twenty - two patients with localized, "high risk" prostate
cancer, and used modern external beam radiotherapy to a conventional dose of 70.2 Gray in 39
fractions, including treatment of the pelvic lymph nodes to a dose of 45 Gray in 25
fractions. They determined that the maximum weekly-tolerated dose of Docetaxel was 20 mg/m2,
and that at a dose level of 25 mg/m2, the dose - limiting toxicity was grade 3 diarrhea
(using the NCI common toxicity criteria, version 2.0 ), which occurred in 2 patients,
necessitating a 25% dose reduction. In addition to clinical feasibility, additional studies
suggest that Docetaxel may be a reasonable agent to study. There is evidence from in vitro
studies that Docetaxel increases the radio - responsiveness by 2.5 to 3 times , , .
Docetaxel inhibits the action of Bcl-2, through the phosphorylation of serine residues on
the Bcl-2 molecule, promoting apoptosis via the caspase cascade , a pathway of cell
apoptosis also utilized by ionizing radiation. Docetaxel is also felt to inhibit the growth
of Bcl-2 negative tumors through overexpression of p27, a protein often lost in androgen -
insensitive prostate cancer cells.

A comparison of predictors of radiation and androgen therapy resistance, compared to the
dominant targets of docetaxol also highlights why docetaxol may be an ideal agent. A small
study by Rossner examined patients who underwent salvage radical prostatectomy after
biochemical failure from external beam radiotherapy . Fifty - five percent of patient's
salvage radical prostatectomy specimens, that showed viable prostate cancer, demonstrated
Bcl-2 overexpression, whereas in a comparison group who underwent radical prostatectomy,
matched for known prognostic factors, who had no previous exposure to radiation, there was
no detectable Bcl-2 overexpression.

It would also appear that Bcl-2 overexpression is also prognostic for recurrence after
radical prostatectomy. In a study by Stackhouse, patients whose radical prostatectomy
specimens' demonstrated Bcl-2 overexpression had a 27% versus 69% actuarial probability of
relapse - free survival at 100 months, compared to patients whose surgical specimens did not
overexpress Bcl-2 (Stackhouse 1999).

In summary, the scientific rationale of using concurrent Docetaxel include: providing
biological dose enhancement to tumor cells through radio - sensitization, independent cell
kill, aid in the destruction of prostate cancer cells that have radio - resistant
phenotypes, and to help overcome cells that have an androgen - insensitive phenotype. It is
not anticipated that sufficient drug can be delivered to eradicate distant micro -
metastases, therefore we are intentionally targeting patients who are 'high - risk', but not
at a very high risk of harboring distant micro - metastases. In personal communication with
Dr. Ian Tannock (email correspondence available at request), he supports the idea of weekly,
as opposed to every 3 weekly Docetaxel, when the intent is to enhance the efficacy of
radiotherapy.

The rationale for utilizing weekly Docetaxel, from a side - effect profile, instead of every
3 weekly Docetaxel, is to avoid the hematological toxicity and Myelosuppression of every 3
weekly Docetaxel, as with weekly administration, myelosuppression is only seen rarely
(<3%), even in heavily - pretreated patients with metastatic, hormone - refractory prostate
cancer8.

2.3 Rationale for radiotherapy sequence inversion

The standard sequence of radiation therapy portals used to treat prostate cancer, is to
treat a large volume first, encompassing regional lymphatics, as well as the primary tumor
site, and then treat the prostate, and any local extension of tumor that may be
extraprostatic, which is usually a small volume. The major reason is to address all the
tumor, both microscopic and grossly evidence tumor, so that areas that harbour tumor do not
re - seed an area that has been irradiated, and to prevent progression of tumor. In the case
of prostate cancer, the initial radiation portals that encompass the regional lymphatics and
prostate also encompass small bowel, large portions of bladder and bone marrow. Whereas IMRT
can reduce the volume of small bowel, bladder and bone marrow in the high dose radiation
volume, it cannot avoid these organs completely. The smaller volume, which only treats the
prostate, can completely avoid the small bowel, largely by treating patients with a full
bladder, which pushes the small bowel away from the high dose radiation area. When small
bowel, or any organ, can be completely avoided by radiation, it will not result in side
effects to that organ.

By treating a small volume first, which avoids small bowel and bone marrow, and knowing that
the toxicity of Docetaxel is cumulative, it may be possible to deliver more Docetaxel, in
full - doses, without delays, because the small bowel will not be irradiated at the same
time as the initiation of Docetaxel, as opposed to the tradition sequence of radiotherapy,
where the small bowel will be irradiated at the same time as the initiation of Docetaxel. if
the order of the large and boost portals were reversed, as well as, employing IMRT, to
sculpt the radiation dose away from the small bowel, for the larger fields.

The reason that a sequence inversion is possible for the treatment of prostate cancer, is
that neo - adjuvant and concurrent androgen deprivation results in stasis of prostate cancer
cells in the radiation volumes, so that there is virtually no added risk of prostate cancer
cells migrating from the pelvic lymphatics while the prostate is being irradiated.

2.4 Overlapping treatment - related toxicities and rationale for sequence inversion

The anticipated dose - limiting acute toxicity, common to both modalities is, treatment -
related diarrhea. A recent study by Ashman retrospectively examined 27 patients who
underwent whole pelvic radiotherapy using 2D, 3D conformal techniques and IMRT. Overall, 9
patients (33%) experienced acute Grade 2 gastrointestinal toxicity, and only 1 of these
patients was treated with IMRT. Antidiarrheal medication was required for 6 patients (22%).
However, 5 of these 6 patients also received chemotherapy (either concurrent
vinblastine/estramustine or neoadjuvant carboplatin, estramustine and paclitaxel, breakdown
by chemotherapy regiment not specified in publication), and none were treated with IMRT. No
Grade 3 or higher acute or late GI toxicities were observed. No cases of late radiation
enteritis were observed.