1965
`A Phase II Study of Continuous Infusion
`5-Fluorouracil in Advanced Hormone
`Refractory Prostate Cancer
`An Illinois Cancer Center Study
`Timothy M. Kuzel, M.D.,* Martin S. Tallman, M.D., Daniel Shevrin, M.D.,
`Edward Braud, M.D., L a 9 Kilton, M.D., Patricia Johnson, M.D., Ph.D.,
`James Kozlowski, M.D., Nicholas 1. Vogelzang, M.D.,
`Richard Blough, M.S., and A1 B. Benson, 111, M.D.
`
`Background. 5-Fluorouracil (5-FU) has been previ-
`ously associated with therapeutic benefit in hormone re-
`fractory prostate cancer. However, no previous study has
`administered 5-FU as a prolonged continuous infusion,
`which may be the optimal schedule for this cell-cycle spe-
`cific agent.
`Methods. Therefore, 25 patients were treated with
`5-FU administered as a continuous intravenous infusion
`at a dose of 1000 mg/m2/day for 5 days every 28 days.
`Eligibility required disease defined by bidimensionally
`measurable lesions or evaluable lesions on bone scan or
`radiograph with elevated serum levels of prostate-spe-
`cific antigen (PSA), no severe cytopenias, and an Eastern
`Cooperative Oncology Group performance status less
`than 3. Prior chemotherapy was not allowed. Dose modifi-
`cations were specified for mucositis and hematologic tox-
`icity.
`Results. Eighteen of 22 patients were evaluable for
`response and toxicity, whereas 4 were evaluable for toxic-
`ity alone. Toxicity was significant using this dose and
`schedule and included episodes of sudden death (one pa-
`tient), paroxysmal supraventricular tachycardia (one pa-
`tient), and congestive heart failure (one patient). Other
`Grade 3 toxicities included stomatitis (two patients) and
`
`From the Illinois Cancer Center, Chicago Illinois.
`Participating institutions: Northwestern University and Vet-
`erans Affairs Lakeside Medical Center (T.M.K., M.S.T., J.K., A.B.B.),
`Central Illinois CCOP (Springfield) (E.B.), Alexian Brothers Hospital
`and Northwest Oncology/Hematology (D.S.), Kilton Medical Prac-
`tice (L.K.), Carle Cancer Center CCOP (Urbana) (P.J.), the University
`of Chicago (N.J.V.), Highland Park Hospital, and the Rockford Clinic.
`* American Cancer Society Clinical Oncology Career Develop-
`ment Award recipient.
`Supported in part by grant #2P30-CA-21742 NCI NM.
`Address for reprints: Timothy M. Kuzel, M.D., Assistant Profes-
`sor of Medicine, Northwestern University Medical School, Room
`8524 Olson Pavilion, 303 E. Chicago Avenue, Chicago IL 60611.
`Accepted for publication May 7, 1993.
`
`diarrhea (one patient). Significant myelosuppression did
`not occur. Objective responses were not observed, but 12
`patients experienced stable disease with a median dura-
`tion of 4 months.
`Conclusions. Infusional 5-FU can not be recom-
`mended for the treatment of advanced hormone refrac-
`tory prostate cancer. Cancer 1993; 72:1965-8.
`
`Key words: continuous infusion, prostate cancer, chemo-
`therapy, 5-fluorouracil.
`
`The treatment of advanced hormone refractory prostate
`cancer is a common therapeutic dilemma faced by the
`medical oncologist. Although secondary hormonal ma-
`neuvers occasionally achieve clinically meaningful re-
`missions,'T2 the duration of remission is usually less
`than 6 months. Still, chemotherapy is frequently only
`administered after the failure of second-line hormone
`therapy. Many chemotherapeutic agents have been
`tested in this disease with stabilization and remission
`rates of approximately 25%.3 However, no chemothera-
`peutic agent alone or in combination has improved the
`survival of patients with this disease.
`5-Fluorouracil(5-FU) is a commonly used antineo-
`plastic agent with activity in tumors of the head and
`neck, breast, and gastrointestinal tract. In addition, 5-
`FU has been shown in vitro to inhibit deoxyribonucleic
`acid synthesis and 5-alpha reductase activity in the
`prostatic cell.4 Most studies of 5-FU for advanced hor-
`mone refractory prostate cancer have suggested only a
`modest benefit.5,6 However, 5-FU has usually been ad-
`ministered as an intravenous bolus either once per
`week or every 3 weeks. It is now recognized that 5-FU is
`a cell-cycle specific agent. Therefore, administration by
`continuous intravenous infusion may maximize the
`
`JANSSEN EXHIBIT 2054
`Mylan v. Janssen IPR2016-01332
`
`

`

`1966 CANCER September 25, 2993, Volume 72, No. 6
`
`therapeutic efficacy against a relatively indolent neo-
`plasm with a long doubling
`The Piedmont On-
`cology Association reported a Phase I1 trial using a high
`dose (4000 mg/m2) of 5-FU administered via a 24-hour
`continuous infusion.' Objective responses were not ob-
`served, but 33% of patients had stable disease. More
`commonly, 5-FU is administered as a 5-day infusion at
`more modest doses (1000 mg/m2/day). This dose and
`schedule in colorectal carcinomas yields similar re-
`sponse rates as the bolus 5-FU schedules combined
`with the modulators leucovorin or alpha-interferon."
`Thus, the Illinois Cancer Center performed a Phase I1
`study of continuous infusion 5-FU in patients with hor-
`mone refractory prostate cancer.
`
`Methods
`
`Patients with histologically documented metastatic
`prostate carcinomas refractory to hormonal therapy
`were eligible. Patients were required to have bidimen-
`sionally measurable lesions or evaluable lesions on
`bone scan or radiograph with elevated serum levels of
`prostate-specific antigen (PSA), no pre-existing severe
`cytopenias, and an Eastern Cooperative Oncology
`Group performance status less than or equal to 2. Prior
`chemotherapy was not permitted. Patients with symp-
`tomatic coronary artery disease or those who had re-
`ceived radiation therapy within 28 days of study entry
`were not eligible. Concurrent chemotherapy or steroid
`therapy was not permitted.
`5-FU was administered as a 5-day continuous infu-
`sion via a peripheral vein or through a central indwell-
`ing catheter at a dosage of 1000 mg/m2/day every 28
`days. Patients were to be examined at least monthly so
`that response and toxicity could be assessed. Complete
`blood counts, serum chemistries, prostatic acid phos-
`phatase, and serum PSA levels were to be obtained be-
`fore study and before each cycle. Lesion measurements
`or bone scan/radiographs documenting evaluable dis-
`ease were to be obtained every other month. Toxicity
`was graded using the National Cancer Institute Com-
`mon Toxicity Criteria.
`Response criteria for the study were based on East-
`ern Cooperative Oncology Group criteria for measur-
`able lesions and on National Prostatic Cancer Project
`criteria for evalucble lesions. Complete response re-
`quired complete disappearance of all clinically detect-
`able tumor and osteoblastic lesions for at least 28 days,
`return to normal of elevated levels of serum prostatic
`acid phosphatase and serum PSA, recalcification of all
`osteolytic lesions, normalization of any abnormal bio-
`chemical markers, and absence of cancer-related
`weight loss greater than or equal to 10%. Partial re-
`sponse required at least a 50% reduction in the product
`
`of the longest diameters of the indicator lesions or sums
`of the products of multiple indicator lesions for a mini-
`mum of 28 days (for patients with measurable disease),
`return to normal of elevated levels of serum prostatic
`acid phosphatase and PSA, no increase in size of osteo-
`blastic lesions, recalcification of one osteolytic lesion if
`any present, a 50% reduction in number of abnormal
`foci of uptake on bone scan, and no cancer-related
`weight loss greater than or equal to 10% and no deterio-
`ration of performance status from baseline. Progressive
`disease was defined as (1) the appearance of new areas
`of malignant disease by bone scan or radiograph; (2)
`death attributed to neoplastic disease after a minimum
`of one cycle of chemotherapy (5 days); (3) for measur-
`able disease an increase in product of longest diameters
`or sum of products greater than 25% over smallest size
`documented earlier; (4) for evaluable disease an in-
`crease in extent of disease judged to exceed 25% over
`minimum tumor burden previously; (5) development of
`ureteral obstruction; or (6) an increase in bone pain re-
`quiring radiation therapy. Stable disease included pa-
`tients with tumor indicator changes less than those de-
`fined for partial response or not as great as for progres-
`sive disease. PSA levels were monitored, but increases
`alone did not constitute progressive disease.
`
`Results
`
`Between February 1990 and June 1992, 25 patients
`were enrolled in this study. All patients were required
`to give written informed consent, as approved by the
`institutional review boards at all participating institu-
`tions. Three patients were found to be ineligible be-
`cause of either previous chemotherapy (two patients) or
`withdrawal before receiving chemotherapy (one pa-
`tient). Characteristics of eligible patients are summa-
`rized in Table 1. All patients had failed systemic hor-
`monal therapy with either orchiectomy or gonadotro-
`pin releasing hormone (GRH) agonists. Patients who
`had not undergone orchiectomy were required to con-
`tinue the GRH agonist therapy during this tial. Of the
`22 eligible patients, 18 were evaluable for both toxicity
`and response (received one full cycle of 5-FU), and 4
`were only evaluable for toxicity (did not complete one
`cycle).
`
`Toxicity
`
`Mild anemia, nausea/vomiting, leukopenia, and sto-
`matitis were common side effects. Table 2 lists the spec-
`trum and extent of side effects observed during the trial.
`Hematologic toxicity was not a major toxicity. Severe
`neutropenia (less than 500/pl) or thrombocytopenia
`(less than 20,0OO/pl) did not develop in any patient.
`
`

`

`Continuous Infusion 5-Fluorouracil/Kuzel et al.
`
`1967
`
`22
`
`69
`54-79
`
`Table 1. Patient Characteristics
`No.
`Age (yr)
`Median
`Range
`ECOG performance status
`0
`1
`2
`Previous hormonal therapy
`Orchiectomy
`Orchiectomy + flutamide
`Orchiectomy + diethylstilbesterol
`GRH
`GRH + flutamide
`Unknown
`Site of disease
`Bone only
`Entry PSA
`88
`Median
`8.9-11.700
`Ranee
`ECOG: Eastern Cooperative Oncology Group; GRH: gonadotropin releasing
`hormone aeonist: PSA: urostate-suecific antieen.
`
`3
`16
`3
`
`11
`2
`1
`1
`1
`2
`
`22
`
`Several patients received erythrocyte transfusions dur-
`ing the course of the trial. The most common side effect
`requiring dose adjustment was Grade 2-4 stomatitis.
`Two of the four patients evaluable only for toxicity
`were removed from study because of Grade 3 or 4 car-
`diac toxicity. One patient developed a supraventricular
`arrhythmia with hypotension during the administra-
`tion of the first cycle of 5-FU, and one patient devel-
`oped congestive heart failure requiring termination of
`the first cycle of chemotherapy. A third patient died
`unexpectedly 3 weeks after the first cycle of 5-FU. The
`exact cause of death was not determined, and no au-
`topsy was performed.
`
`Response
`
`Eighteen patients were assessable for response. No
`complete responses and no partial responses were ob-
`served. Twelve patients experienced stable disease with
`a median duration of 4 months as determined by symp-
`toms and objective results of bone scans. Only three of
`these patients experienced a decline in their PSA levels
`during their treatment, none as great as 50% of pre-
`treatment levels. All others had gradual increases
`in PSA.
`
`Discussion
`
`5-FU is a commonly used antineoplastic agent for the
`treatment of adenocarcinomas. Prolonged infusions
`
`have been associated with significant response rates in
`neoplasms of the breast, head and neck, and gastroin-
`testinal tract. In vitro, there is evidence for alteration in
`deoxyribonucleic acid synthesis and 5-alpha reductase
`activity in prostate cell lines.* Early trials using 5-FU as
`a single agent with bolus administration suggested re-
`sponse rates of 20-25%.3 These trials were performed
`before the kinetic advantages of prolonged infusions of
`5-FU were recognized and before the availability of
`PSA monitoring. Thus, this trial was carried out to fur-
`ther study 5-day infusions of 5-FU in hormone refrac-
`tory prostate cancer.
`No objective responses were observed in the 18 pa-
`tients assessable for response. The lack of even as much
`as a 50% decrease in PSA levels further suggests that
`this agent has no clinical activity in this disease. Stable
`disease was observed based on bone scan findings and
`symptom control, but the relatively short duration sug-
`gests that these patients may simply have had biologi-
`cally more indolent disease, rather than a benefit from
`the therapy.
`Toxicity was significant in this population. In partic-
`ular, cardiotoxicity was frequently observed. Cardio-
`toxicity has been associated previously with infusions
`of 5-FU.",'* The incidence of significant adverse car-
`diac events of all types reported from a recent large
`prospective trial was approximately 7.6%.'* In this trial
`the incidence of cardiotoxicity ranged from 9.1 Yo to pos-
`sibly as high as 13.6% if the patient with sudden death
`is included. The mechanism(s) by which 5-FU effects
`the heart have not been clearly elucidated, but may in-
`volve
`thrombogenic complications,'3 vasospastic
`changes14 or direct antimyocardial effects." This trial
`was designed for older male patients, a population at
`
`Table 2. Toxicitv Observed During Any Cycle
`Grade
`
`Symptoms
`
`2
`
`3
`
`4
`
`1
`7
`4
`5
`2
`5
`4
`
`4
`1
`3
`
`2
`
`Anemia
`Nausea/vomiting
`Stomatitis
`Diarrhea
`Leukopenia
`Thrombocytopenia
`Cardiac
`PSVT
`CHF
`1
`Dysuria
`1
`Anorexia
`1
`Altered sensorium
`1
`Alovecia
`PSVT uaroxvsmal suuraventricular tachycardia; CHF: congestive heart failure.
`
`1
`
`2
`1
`
`1
`
`1
`
`1
`
`

`

`1968 CANCER September 15, 2993, Volume 72, No. 6
`
`significant risk for underlying cardiac disease. Thus, the
`higher incidence in this trial may be related to subclini-
`cal pre-existent atherosclerotic disease. Alternatively,
`there may be a greater risk of inducing a hypercoagu-
`able state due to the underlying metastatic adenocarci-
`noma which is further exacerbated by 5-FU.
`Attempts to enhance bolus 5-FU efficacy in colorec-
`tal tumors using combinations of 5-FU with alpha-in-
`terferon or leucovorin recently have been described.
`Using these strategies, bolus 5-FU appears to be as ef-
`fective as infusional 5-FU. Furthermore, long-term
`low-dose infusions of 5-FU may be the most dose-in-
`tense way to administer the agent. These approaches
`may warrant further study in prostate cancer, but there
`is little reason to be encouraged. Synergistic benefits are
`unlikely, as a recent Phase I1 trial of recombinant hu-
`man alpha-interferon in hormone refractory prostate
`carcinoma demonstrated little antitumor effect and
`substantial t~xicity.'~ Additionally, the mechanism of
`enhanced antitumor effect using the combinations ap-
`pears to relate to alterations in metabolism and clear-
`ance of 5-FU, similar to infusing 5-FU. Therefore, given
`the lack of response, and the development of significant
`toxicity, infusional 5-FU can not be recommended for
`the treatment of hormone refractory prostate cancer.
`New drugs with novel mechanisms of action or combi-
`nations of drugs exploiting the biology of hormone re-
`fractory prostate cancer cell need to be developed.
`
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