80 -

Original Study

Phase I Trial of Weekly Docetaxel, TotalAndrogen Blockade, and Image-Guided Intensity-Modulated Radiotherapy for Localized High-Risk

Prostate AdenocarcinomaDavid T. Marshall,1 Stephen Ramey,1 Ali-Reza Golshayan,1 Thomas E. Keane,1

Andrew S. Kraft,1 Uzair Chaudhary2

AbstractThis phase I trial provided the maximum tolerated dose (MTD) of 25 mg/m2 for docetaxel when combined withandrogen deprivation therapy (ADT) and high-dose intensity-modulated radiotherapy (IMRT) to the prostateand seminal vesicles for high-risk localized prostate cancer. No patients had severe side effects at this dose,and it should be used in future trials to test the efficacy of this treatment paradigm.Background: This was a phase I study to find the maximum tolerable dose (MTD) of weekly docetaxel combined withhigh-dose intensity-modulated radiotherapy (IMRT) and androgen deprivation therapy (ADT). Patients and Methods:Men with localized high-risk prostate cancer (HRPC) were treated with weekly docetaxel at 10 to 30 mg/m2 concurrentwith IMRT of 77.4 Gy to the prostate and 45 Gy to the seminal vesicles. ADT consisted of a gonadotropin-releasinghormone agonist (GnRHa) and bicalutamide beginning 2 months before and during chemoradiation. GnRHa wascontinued for 24 months. Results: Nineteen patients were enrolled. No dose-limiting toxicity (DLT) was seen withdocetaxel doses up to 25 mg/m2. At the 30 mg/m2 level, 2 of 4 patients experienced DLTs of both grade 3 fatigue anddyspepsia. At 41 months’ median follow-up, 2 patients had died—1 from metastatic prostate cancer and the otherfrom heart failure. Two other patients experienced biochemical failure. One patient with bladder invasion at diagnosisexperienced late grade 2 urinary hesitancy 9 months after completion of radiotherapy, requiring short-term intermittentcatheterization. All patients had erectile dysfunction, but no late toxicities worse than grade 2 were identified.Conclusion: Weekly docetaxel may be combined with high-dose IMRT and long-term ADT up to a MTD of 25 mg/m2.Acute toxicities and long-term side effects of this regimen were acceptable. Future studies evaluating the efficacy ofdocetaxel, ADT, and IMRT for localized HRPC should use a weekly dose of 25 mg/m2 when limiting the irradiatedvolume to the prostate and seminal vesicles.

Clinical Genitourinary Cancer, Vol. 12, No. 2, 80-6 ª 2014 Elsevier Inc. All rights reserved.Keywords: Androgen deprivation therapy, Docetaxel, High-risk prostate cancer, Radiotherapy

IntroductionProstate cancer is the most common noncutaneous cancer and

the second most common cause of cancer death among men in theUnited States, with more than 240,000 new cases and 28,000deaths reported in 2012.1 High-risk prostate cancer (HRPC)

1Medical University of South Carolina, Charleston, SC2University of California, San Francisco, Fresno, CA

Submitted: Sep 18, 2013; Revised: Nov 7, 2013; Accepted: Nov 8, 2013; Epub:Nov 13, 2013

Address for correspondence: David T. Marshall, MD, MSC 318, 169 Ashley Avenue,Charleston, SC 29425E-mail contact: marshadt@musc.edu

Clinical Genitourinary Cancer April 2014

represents an area with considerable room for improvement inlong-term outcomes. D’Amico et al defined high-risk patients asthose having � T2c disease, Gleason score � 8, or prostate-specificantigen (PSA) levels > 20 and found that these patients had 8-yearPSA relapse-free survival of 40% after radiotherapy (RT).2 Zelefskyet al found a 5-year PSA relapse-free survival of 38%, although thisvalue varied from 21% to 67% depending on the dose of radiationused.3 Furthermore, among patients experiencing rising PSA valuesafter RT (“PSA failure”), patients with a Gleason score of � 8had higher rates of 5-year prostate cancerespecific mortality.4 Thesehigh rates of PSA failure and increased risk of prostate cancerespecificmortality after rising PSA levels indicate a need for improvedbiochemical control in high-risk localized prostate cancer.

1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.clgc.2013.11.019

If localized prostate cancer does recur and becomes metastaticafter definitive therapy, treatment has traditionally been androgendeprivation therapy (ADT), which is successful in inducing diseasecontrol for 2 to 3 years. Unfortunately, treatment ultimately failswhen the cancer becomes castrate resistant.5 In 2008, Berthold et alshowed that for castrate-resistant disease, docetaxel improved me-dian survival to 19.2 months, compared with 16.3 months withmitoxantrone, and this survival benefit came with an improvementin quality of life.6,7 A similar increase in overall survival was notedby Petrylak et al when comparing combined docetaxel and estra-mustine vs. mitoxantrone.8

Docetaxel’s potential utility in prostate cancer springs from itsability to phosphorylate Bcl-2, leading to apoptosis of prostatecancer cells,9 and its potential to enhance tumor responsiveness toradiation in both docetaxel-sensitive and docetaxel-insensitive tis-sues.10 Docetaxel has been shown to have less radiosensitizing effecton normal tissue compared with tumor. Mason et al have shown animprovement in the therapeutic ratio by demonstrating that theradiosensitizing effect of the combination of radiation and docetaxelon a variety of tumors grown in mice is greater than the radio-sensitization of the jejunal cells of the mice.10 They calculated thetherapeutic gain (defined as the ratio of the enhancement effect ofcombining docetaxel with irradiation for tumor to that of jejunum)to range from 1.13 to 2.04. Docetaxel radiosensitizes tissues byarresting cells in the radiosensitive G2 and M phases of the cellcycle.11 In addition, the overexpression of Bcl-2 in many cancers,including prostate cancers, has been well documented and alsocontributes to the increased tumor response to docetaxel whencompared with normal tissues.9

In light of these promising biochemical properties and clinicalefficacy in metastatic prostate cancer, the tolerance of docetaxel hasbeen tested in the initial treatment of high-risk prostate cancer.12-17

However, some of these studies have not used intensity-modulatedradiotherapy (IMRT) or have included large irradiated vol-umes,12,14,15 increasing the risk of gastrointestinal (GI) toxicity.Others have combined docetaxel with estramustine, increasing therisk of neutropenia when compared with docetaxel administrationalone.16,17

In addition to early chemotherapy, high-dose RT and early ADThave received considerable attention as methods to improvebiochemical control and overall survival in patients with HRPC.Pilepich et al showed significantly improved 10-year overall survival(49% vs. 39%) and rates of no evidence of disease (37% vs.23%) when comparing indefinite gonadotropin-releasing hormoneagonist (GnRHa) and no adjuvant ADT, noting that a statisticallysignificant difference in overall survival was seen specifically inpatients with a Gleason score � 7.18 Bolla et al also showedincreased overall survival and freedom from disease at 5 years whencomparing 3-year GnRHa therapy and RT with RT alone.19

Subsequent trials have demonstrated an improved disease-freesurvival20 and overall survival21 when comparing long-term ADT(2.5-3 years) and short-term ADT (4-6 months). Several trials havealso shown improved freedom from failure when comparing high-dose RT (78-79.2 Gy) vs. lower dose RT (68-70.2 Gy), althougha benefit in overall survival was not demonstrated, and GI toxicitywas increased.22-24 IMRT has been found to mitigate some of theGI toxicity associated with high-dose RT.3,25

Because of the potential benefits of docetaxel, high-dose RT, andADT, this phase I study was designed to find the maximumtolerable dose (MTD) of weekly docetaxel when combined withhigh-dose image-guided IMRT (77.4 Gy) and ADT in patients withHRPC.

Patients and MethodsEligibility Criteria and Pretreatment Workup

All patients had high-risk localized prostate cancer as defined bythe presence of 1 or more of the following: (1) stage � cT2c(American Joint Committee on Cancer, 1997), (2) pretreatmentPSA level � 20, and (3) Gleason score � 8. Patients were ineligibleif they had evidence of nodal or metastatic disease. No previous RT,surgery, chemotherapy, immunotherapy, or alternative treatmentfor prostate cancer was allowed, with the exception of ADT of 4weeks or less. Participants were required to be at least 18 years ofage, have an Eastern Cooperative Oncology Group performancestatus of 2 or less, and have no peripheral neuropathy greaterthan grade 1. They also had to have a bilirubin level less thanor equal to the upper limit of normal (ULN), creatinine level< 1.5 times the ULN, granulocyte count � 1500/mL, and plateletcount � 100,000/mL. Patients with any of the following enzymelevels were also ineligible: (1) alkaline phosphatase, alanine trans-aminase (ALT), or aspartate aminotransferase (AST) > 5 times theULN; (2) alkaline phosphatase > 2.5 times the ULN and AST orALT > ULN; (3) AST or ALT > 1.5 times the ULN and alkalinephosphatase greater than the ULN. Men of childbearing potentialhad to be willing to consent to using effective contraception whilereceiving treatment and for at least 3 months thereafter. Patientswith a history of severe hypersensitivity reaction to docetaxel orother drugs formulated with polysorbate 80 were excluded. Pre-treatment evaluation included history, physical examination, com-plete blood count with differential, serum creatinine determination,liver function tests, serum testosterone determination, prostate bi-opsy, chest radiograph, bone scan, histologic review, and magneticresonance imaging or computed tomography of the abdomen andpelvis. Patients were required to document informed consent on aninstitutional review board (IRB)-approved informed consent docu-ment. All research was done in compliance with Medical Universityof South Carolina IRB rules and regulations.

Androgen Deprivation Therapy and ChemotherapyThe overall treatment schema is shown in Figure 1. ADT was

administered with a GnRHa and an antiandrogen (bicalutamide, 50mg/d by mouth) beginning 2 months before docetaxel treatmentand radiation and continuing for an additional 2 months concurrentwith this therapy. The GnRHa was then continued for an additional24 months alone.

Docetaxel was administered weekly concurrent with RT in adose-escalation scheme requiring a minimum of 3 patients percohort. It was originally planned that cohorts would start at10 mg/m2, increasing to 25 mg/m2 with 5 mg/m2 increases betweeneach cohort; however, after 6 patients had been treated at 25 mg/m2

with no DLT, an additional cohort was treated at 30 mg/m2.Docetaxel in each cohort was administered as a 30-minute intra-venous infusion with 10 mg of dexamethasone and 25 mg ofdiphenhydramine HCl weekly beginning on day 1 of RT for a total

Clinical Genitourinary Cancer April 2014 - 81

Figure 1 Schema for Combined Modality Treatment

Abbreviation: D ¼ docetaxel (weekly).

Docetaxel, ADT, IMRT for Prostate Cancer

82 -

of 9 weekly doses. To reduce the incidence of fluid retentionand hypersensitivity reactions, 3 doses of 4 mg dexamethasonewere also given with the first dose the night before each docetaxelinfusion, and the second and third doses were given every 12 hoursover the next day. Antiemetic use was optional.

Docetaxel dose reductions of 25% were planned for gran-ulocyte counts of 1000 to 1499/mL, platelet counts of 75,000to 99,999/mL, or febrile neutropenia (absolute neutrophil count(ANC) of < 500/mm3 with a concomitant temperature� 38.5�C). In the case of febrile neutropenia, the 25% dosereduction was continued in subsequent doses, and if anotherinstance of febrile neutropenia occurred, the patient was removedfrom the study. Doses were held for patients with granulocytecounts of < 1000/mL or platelet counts < 75,000/mL. Patientswere also removed from the study for neutropenia with counts notrecovering to ANC > 1000/mm3 within 3 weeks or thrombo-cytopenia with counts not recovering to a platelet count> 100,000/mL within 3 weeks. Dose reductions of 25% were alsoplanned for AST or ALT levels between 1.5 and 5 times theULN with a concomitant alkaline phosphatase level between1 and 2.5 times the ULN and for alkaline phosphatase level be-tween 2.5 and 5 times the ULN with a concomitant AST or ALTlevel between 1 and 1.5 times the ULN. Doses were held for AST,ALT, or alkaline phosphatase levels > 5 times the ULN or for acombination of AST or ALT levels between 1.5 and 5 times theULN and alkaline phosphatase levels between 2.5 and 5 times theULN. Any bilirubin level greater than the ULN also resulted inholding the scheduled dose with retreatment at 25% dosereduction when the level recovered to less than or equal to theULN. Any delay of � 3 weeks led to the patient’s removal fromthe study. Any grade 2 stomatitis would result in a 25% dosereduction, whereas grade 3 or 4 stomatitis would result in holdingthe planned dose until resolution, with a 25% dose reduction ofsubsequent doses. Dose reductions of 25% were also planned forany grade 2 neuropathy, and the planned dose would be held forany grade 3 or 4 neuropathy, with patients continuing theprotocol at the investigator’s discretion. Grade 4 hypersensitivityreactions would result in treatment discontinuation. For other

Clinical Genitourinary Cancer April 2014

grade 3 or 4 toxicities, treatment was withheld until the toxicityresolved to grade 1 or less and then was reinstituted (if medicallyappropriate) with a 25% dose reduction. Patients were alsoremoved from the protocol at first evidence of disease progression.

RadiotherapyExternal-beam RT was administered using IMRT to a total

dose of 77.4 Gy in 43 fractions of 1.8 Gy per fraction. The firstplanning target volume (PTV1) included the prostate and proximalseminal vesicles and received 45 Gy in 25 fractions. The secondplanning target volume (PTV2) included the prostate and receivedan additional 32.4 Gy in 18 fractions. The gross tumor volume(GTV) included the prostate and any identifiable primary tumorextension. The first clinical target volume included the GTV and anallowance of 3 mm for extracapsular extension (excluding therectum) and proximal 2.5 cm of the seminal vesicles. The PTV1 wasdefined as the first clinical target volume plus setup error (S) andorgan motion (M). An allowance of 0.5 cm was made for S ifnoneimage guided planning was used or 0.2 cm for S if fiducialswere placed in the prostate and daily image guidance was used. Theallowance for M was based on individualized measurements definedby full-breathing cycle computed tomography (4-dimensional),individualized measurements based on observing prostate fiducialsmotion under fluoroscopy, uniform expansions of 7 mm in alldirections except 3 mm posteriorly if a rectal balloon was not used,or uniform expansions of 3 mm in all directions if a rectal balloonwas used. CTV2 was equal to the GTV. PTV2 was defined asCTV2 plus similar allowances for S and M. PTV1 was planned for adose of 45 Gy in 25 fractions, with an additional 32.4 Gy in18 fractions to PTV2. Total dose to PTV2 was 77.4 Gy in43 fractions. No more than 25% of the rectal wall or bladder wallshould have received 70 Gy, and maximal doses to 0.1 cc of smallbowel, large bowel, and femoral heads were 50, 60, and 45 Gy,respectively.

AnalysisThe primary objective of the study was to determine the MTD of

docetaxel in combination with high-dose RT and long-term ADT in

Table 1 Patient Characteristics

Total No. of Patients 19

Age, years

Median 68

Range 45-80

TNM No. of Patients

T1cN0M0 9

T2aN0M0 4

T3aN0M0 1

T3bN0M0 4

T4N0M0 1

Gleason Score, No. of Patients

3 þ 4 3

4 þ 3 2

8 7

9 5

10 2

PSA at Diagnosis (ng/mL)

�10 6

10.01-20 3

>20 10

Range 1.8-280.7

Abbreviation: PSA ¼ prostate specific antigen.

David T. Marshall et al

patients with high-risk locally advanced adenocarcinoma of theprostate.

DLT was defined as any of the following: grade 4 gran-ulocytopenia or thrombocytopenia possibly or probably related toprotocol therapy, grade 3 or greater nonhematologic toxicity, or theinability to deliver weekly chemotherapy on 2 successive occasionsbecause of ANC < 1000/mL or platelet count < 50,000/mL ordelayed grade � 3 proctitis, cystitis, or diarrhea � 3 months aftertreatment. If none of the first 3 patients in a cohort experienced aDLT, the dose was to be escalated by 5 mg/m2 in the next cohort;however, if 1 of the first 3 patients in a cohort experienced a DLT,an additional 3 patients received the dose of this cohort. If anyadditional patients experienced a DLT in the second set of 3 pa-tients, the MTD would have been exceeded, and 3 additional pa-tients would have been treated at the next lower dose. The MTDwas defined as the dose level at which none or 1 of 6 patientsexperienced DLTs and that was immediately below the level atwhich 2 of the first 3 patients in any cohort or at least 2 of 6 patientsin any expanded cohort experienced a DLT.

Biochemical failure was initially defined by 2 different methodsaccording to the protocol: (1) American Society for RadiationOncology criteria—3 consecutive rises in PSA levels after an irra-diation nadir with date of PSA failure taken as the midpoint be-tween the post-irradiation nadir PSA level and the first of 3consecutive rises; (2) two consecutive rises of PSA levels by at least0.2 ng/mL > 1.0 ng/mL. However, when the Phoenix consensusdefinition of biochemical failure was accepted as the optimalmethod of defining relapse of PSA levels after RT, especially withthe use of hormone therapy, this method was implemented in thisstudy, with PSA failure being designated as the date of the first PSAvalue � 2.0 ng/mL more than the posttreatment nadir. Also, asingle rise in PSA level was considered a biochemical failure ifaccompanied by an abnormal bone scan, an abnormal pelvic mag-netic resonance image or computed tomographic scan, reinitiationof androgen suppression, or other objective evidence of disease. PFSwas defined as the absence of biochemical relapse or other radio-graphic or objective evidence of disease or reinitiation of androgensuppression. The National Cancer Institute Common TerminologyCriteria for Adverse Events, version 3.0, was used to record toxic-ities. Time to PSA failure was measured from radiation start date todate of PSA elevation.

Patients underwent examinations including history, physical,performance status assessment, and PSA measurement every 3weeks during chemoradiation, at completion of chemoradiation,at least every 3 months for 2 subsequent years, and at least every6 months for 4 subsequent years. During chemoradiation and atthe completion of treatment, visits also included a completeblood count with differential, kidney function tests, liver functiontests, serum electrolyte determinations, and drug toxicity assess-ments. The posttreatment visits included assessments for late radi-ation toxicity including the American Urologic AssociationSymptom Score26 and the Urinary Quality of Life score,27 theMerrick Dysuria Score28 and the Mount Sinai Erectile FunctionScore,29 the International Index of Erectile Function,30 and serumPSA and testosterone measurements. After disease progression wasnoted, patients would be followed only for survival and secondmalignancies.

ResultsNineteen patients were enrolled from February 2006 to

September 2010 and were treated with concurrent docetaxel andIMRT, with docetaxel doses ranging from 10 mg/m2 to 30 mg/m2.Initial patient characteristics are shown in Table 1. Three patientswere treated in each cohort, with the dose increasing from 10 mg/m2

to 25 mg/m2; no DLT was seen in these groups. At level 4 (docetaxel25 mg/m2), 1 patient required discontinuation of docetaxel for grade2 hyperbilirubinemia in cycle 1; however, this event was notconsidered a DLT, as specified by the protocol. This patient wasretrospectively identified as having a history of elevated bilirubinbefore being diagnosed with prostate cancer. His bilirubin level wasnormal at the time of enrollment to this study. He completed RTwith ADT without further docetaxel. Therefore, an additional3 patients were treated at the 25 mg/m2 dose with no DLT.Because there was no DLT at the planned maximum dose level of25 mg/m2, and 5 of 6 patients at this level completed all protocolchemotherapy and radiotherapy, another cohort of patients wasadded at a 30 mg/m2 dose level. This change was reviewed andapproved by the IRB before implementation. Two of the 4 patientsin this group experienced DLTs. Both experienced grade 3 fatigueand grade 3 upper GI toxicity in the form of dyspepsia (Table 2).Because no patients had experienced a DLT among the 6 patientstreated at the 25 mg/m2 level, and because 5 of 6 patients at thislevel completed all protocol chemotherapy and radiotherapy, andbecause 2 of the 4 patients at the 30mg/m2 level experienced DLTs,the MTD was defined as 25 mg/m2. All patients received the fullcourse of RT to 77.4 Gy.

Grade � 2 acute toxicities included genitourinary (11 patients)and GI toxicities (6 patients), fatigue (4 patients), hematologic

Clinical Genitourinary Cancer April 2014 - 83

Table 2 Acute Toxicitya by Docetaxel Dose

DocetaxelDose(mg/m2)

No. ofPatients

Hematologic Toxicity Gastrointestinal Toxicity Genitourinary Toxicity Fatigue Other

Grade Occurrences Grade Occurrences Grade Occurrences Grade Occurrences Grade Occurrences10 3 1 5 1 3 1 2 0 0 1 Sodium 1

2 1 2 1 2 1 1 Potassium 1

1 Neuropathy 1

15 3 1 5 1 3 1 2 2 1 1 Muscle Ache 1

2 1 2 1 1 Creatinine 1

1 Potassium 2

1 AST 1

1 Sodium 1

20 3 1 4 1 1 1 1 0 0 1 AST 1

2 1 2 2 1 ALT 1

1 Potassium 1

25 6 1 6 1 2 1 2 1 3 1 Hot flashes 1

2 1 2 1 2 4 1 Hyperbilirubinemia 1

2 Hyperbilirubinemia 1

1 Sodium 1

1 Creatinine 1

2 Creatinine 1

1 Skin 1

1 Alkaline phosphatase 1

1 Potassium 1

30 4 1 1 1 2 1 1 1 1 1 Alopecia 2

3a 2 2 3 2 1 1 Nail change 1

3b 2 1 Hot flashes 2

2 Creatinine 1

Abbreviations: ALT ¼ alanine transaminase; AST ¼ aspartate aminotransferase.aNational Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. Toxicities are recorded by number of occurrences; thus more occurrences are often reported than number of patients in the group. This finding is especially true of hematologic toxicities for whichpatients often had 2 or even 3 separate hematologic toxicities (eg, low hemoglobin, platelets, and absolute neutrophil count).bThese events were considered dose-limiting toxicities.

Docetaxel,

ADT,IM

RTfor

Prostate

Cancer

84 -ClinicalGenitourinary

CancerApril2014

Table 3 Overall Acute Toxicitya of Docetaxel, Intensity-Modulated Radiotherapy, and Androgen Deprivation

Toxicity

Occurrences Per Grade

1 2 3 4Gastrointestinal

Upper 3 e 2 e

Lower 8 4 e e

Genitourinary 8 11 e e

Hematologic

Hemoglobin 11 1 e e

Platelet 4 e e e

Leukocytes 1 1 e e

Absolute neutrophils 5 e e e

Hepatobiliary

Alkaline phosphatase 1 e e e

Alanine aminotransferase 1 e e e

Aspartateaminotransferase

2 e e e

Hyperbilirubinemia 1 1 e e

Electrolyte

Potassium 5 e e e

Sodium 3 e e e

Other

Creatinine 2 2 e e

Fatigue 4 2 2 e

Muscle ache 1 e e e

Neuropathy 1 e e e

Skin 2 e e e

Alopecia 2 e e e

Nail change 1 e e e

Hot flashes 3 e e e

aNational Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0.

David T. Marshall et al

toxicities (2 patients), rising creatinine levels (2 patients), andhyperbilirubinemia (1 patient) (Table 3). At a median follow-up of41 months, no patient had late toxicity of any grade > 2. There wasno late GI toxicity greater than grade 1 and no genitourinarytoxicity greater than grade 2. One patient with T4 disease withinvolvement of the bladder required short-term intermittent urinarycatheterization 9 months after treatment. All patients had grade2 erectile dysfunction.

With a median follow-up of 41 months, 17 of 19 patients are stillliving and 15 of 19 (78.9%) are alive and free of biochemical relapseby Phoenix criteria. One patient died of congestive heart failure 16months after initiating chemoradiation, with no evidence of prostatecancer at last follow-up. The second deceased patient died of prostatecancer 46 months after starting chemoradiation. He experiencedbiochemical relapse at 12 months by Phoenix criteria and was diag-nosed with bone metastases at 15 months. He received multiple linesof chemotherapy and radiation to bone and brain metastases beforeultimately choosing to discontinue treatment. Using the Phoenixcriteria, 2 other patients experienced recurrence with biochemicalfailure, 1 at 46.2 months and 1 at 46.9 months after treatment.

DiscussionConcurrent weekly docetaxel at 25 mg/m2 (9 weekly infusions)

with complete androgen blockade and image-guided IMRT to theprostate (77.4 Gy) and seminal vesicles (45 Gy) is well toleratedand considered theMTD in this setting. No DLTwas experienced inthe 6 patients treated at this level, and 5 of 6 completed all chemo-therapy and RT at this level. The only DLTs were at the 30 mg/m2

level, with 2 of 4 patients experiencing both grade 3 upper GI toxicityand grade 3 fatigue. Rather than being limited by the increased RTdose or concurrent ADT, the MTD was actually higher than the 20mg/m2 previously reported by Kumar et al.12 In contrast to thecurrent study, Kumar et al administered 45 Gy to the pelvis before anadditional 25.2Gywas given to the prostate; thus, this trial resulted ina lower total dose to the prostate (70.2 Gy vs. 77.4 Gy) but with alarger volume of rectum and bowel exposed to 45 Gy through thepelvic fields and the use of 3-dimensional RT rather than IMRT.

Several other trials have confirmed the feasibility of docetaxel as acomponent of the treatment of high-risk localized prostate cancer.Perrotti et al treated 20 patients with 20 mg/m2 weekly docetaxel,IMRT of 72 Gy, and concurrent ADT (17 of 20 patients).13 Grade 3toxicities included 1 patient with a nonsteroidal antiinflammatorydrugeinduced GI bleeding and 2 patients with dehydration. Despiteacknowledging the potential benefits of high-dose RT, the authors ofthis study reported a reticence to exceed a dose of 72 Gy basedon the potential for increased effective radiation dose because ofradiosensitization by docetaxel.13 Although docetaxel can potentiallyincrease the GI toxicity of RT,10 our study showed that this effectdoes not seem to be great enough to necessitate a significant reduc-tion in docetaxel dose, particularly when the RT is directed onlyat the prostate and seminal vesicles and not to the pelvic lymphnodes. Another study also examined weekly docetaxel (20 mg/m2 for6 cycles) administered concurrently with RT; however, adjuvantdocetaxel of 60 mg/m2 was also administered for 3 cycles given every3 weeks beginning 3 weeks after RT of 70 Gy in 35 fractions to theprostate and seminal vesicles. This study also included 46 Gy tothe interiliac and lower common iliac nodes. Grade 3 toxicitiesamong the 50 patients included neutropenia (1 patient), diarrhea(2 patients), proctitis (1 patient), anal ulcer (1 patient), and dysuria(2 patients), whereas grade 4 toxicities were myocardial infarction(1 patient) and proctitis (1 patient).14

The only completed phase III trial of initial docetaxel chemo-therapy combined this agent with estramustine.16 Patients wererandomized to docetaxel/estramustine (DE) and 3 years of ADTvs. 3 years of ADT alone. Local therapy was at the discretion ofa multidisciplinary team and included RT of 70 to 78 Gy tothe prostate in 87% of the DE þ ADT arm and 86% of theADT-alone arm. Pelvic fields to 46 to 50 Gy were used in 58% and59%, respectively. Docetaxel was administered at 70 mg/m2 every3 weeks for 4 cycles. Acute grade 3 and grade 4 toxicity was increasedbefore local treatment in the chemotherapy arm, with the mostcommon toxicity being neutropenia (grade 3 ¼ 14%; grade4 ¼ 13%) vs. no grade 3 or 4 toxicities in the arm withoutchemotherapy. Chemotherapy also had a negative impact on qualityof life at 3 months, although not at 1 year. A positive impact onPSA response, defined as a PSA level � 0.2 ng/mL after 3 monthsof treatment, was seen in 34% of patients in the DE þ ADT

Clinical Genitourinary Cancer April 2014 - 85

Docetaxel, ADT, IMRT for Prostate Cancer

86 -

arm vs. 15% in the ADT-only arm (P < .0001).16 These resultsindicate that a docetaxel-based chemotherapy regimen, althoughcausing increased toxicity and decreased quality of life in the shortterm, may have a beneficial effect on disease control as indicated byPSA control. Furthermore, the most common grade 3 to 4 toxicity inthis trial was neutropenia, an adverse effect that has not been seen inany of the sole-agent docetaxel/RT trials using a weekly schedule withmaximum doses of 30 mg/m2 or less, including the current study.12,13

ConclusionThis trial showed that weekly docetaxel administration concur-

rent with high-dose IMRT (77.4 Gy to the prostate and 45 Gy to theseminal vesicles) and ADT has a MTD for docetaxel of 25 mg/m2.This MTD is actually higher than that reported by Kumar et al,who reported that a lower RT dose of 70.2 Gy was used.12 Thisincrease in MTD of docetaxel likely results in part from thebeneficial effects on genitourinary and GI toxicities of using IMRTand smaller ports in the current study.3,25 The MTD of 25 mg/m2

found in this dose-escalation study should be used in future trials toevaluate the potential benefits of adding weekly docetaxel tohigh-dose RT and ADT for treatment of localized HRPC whenlimiting the irradiated volume to the prostate and seminal vesicles.

Clinical Practice Points

� Docetaxel has been shown to lengthen survival in patients withcastrate-resistant metastatic prostate cancer.

� Currently, localized HRPC is often treated with ADT and IMRT.The combination of modern high-dose IMRT, ADT, and doce-taxel therefore seems a reasonable approach for localized HRPC.

� This study was a phase I dose-escalation trial of docetaxel incombination with ADT and IMRT, consisting of 45 Gy to theseminal vesicles and 77.4 Gy to the prostate. Patients received aGnRHa and an antiandrogen beginning 2 months before startingand during 9 weeks of IMRT. GnRHa therapy was continuedfor 24 months after IMRT. Docetaxel was administered in9 weekly infusions during IMRT at dose levels of 10 to 30 mg/m2, at 5-mg/m2 increments.

� Nineteen patients were treated in this study and the MTD wasdefined as 25 mg/m2. No severe side effects were identified at orbelow this level. Two of 4 patients at the 30 mg/m2 level hadgrade 3 fatigue and dyspepsia.

� The 25 mg/m2 MTD is higher than the 20 mg/m2 dose iden-tified previously in a study that delivered RT to the pelvic lymphnodes in addition to the prostate and seminal vesicles. Thissuggests that limiting the volume of radiation to the prostate andseminal vesicles increases the MTD of concurrent docetaxel.

� Future studies evaluating the efficacy of docetaxel, ADT, and IMRTfor localized HRPC should use a weekly dose of 25 mg/m2 whenlimiting the irradiated volume to the prostate and seminal vesicles.

DisclosureThe authors have stated that they have no conflicts of interest.

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