Clinical report 211
`Phase I dose-finding study of biweekly irinotecan in
`combination with fixed doses of 5-fluorouracil/leucovorin,
`gemcitabine and cisplatin (G-FLIP) in patients with advanced
`pancreatic cancer or other solid tumors
`R. Rachamallaa, S. Malamudb, M. L. Grossbarda,b, S. Mathewa, M. Dietrichb and
`P. Kozucha
`This phase I trial was initiated based on encouraging
`clinical data with 5-fluorouracil (5-FU)/leucovorin (LV),
`gemcitabine and cisplatin (G-FLIP) in the therapy of solid
`tumors. In this trial, G-FLIP has been modified to facilitate
`outpatient administration and to optimize sequence-
`dependent synergistic activity. Treatment consisted of
`biweekly (once every 14 days) cycles of sequential
`gemcitabine 500 mg/m2, irinotecan per dose escalation
`schedule, bolus 5-FU 400 mg/m2 and LV 300 mg on day 1
`followed by a 24-h 5-FU infusion 1500 mg/m2, followed by
`cisplatin 35 mg/m2 on day 2. The irinotecan starting dose
`was 80 mg/m2 and escalated by 20 mg/m2 in cohorts of
`three patients until the maximum tolerated dose (MTD)
`was defined. Twenty-three patients were enrolled
`(13 men/10 women) with the following cancers: 11
`pancreatic, five gallbladder, three squamous cell carcinoma
`of the head and neck, one hepatocellular carcinoma, one
`melanoma, one gastric, and one breast cancer. Median
`patient age was 63 years (range 44–78) and median
`Karnofsky performance status (KPS) was 80. Patients
`received a median of 8 cycles (range 1–16) over five
`irinotecan dose levels (80, 100, 120, 140 and 160 mg/m
`2).
`Dose-limiting toxicity consisting of grade 3 nausea/
`vomiting despite aggressive anti-emetic therapy occurred
`in one patient at dose level 1 and three patients at dose
`level 3. Grade 3–4 hematological toxicities per patient
`consisted of thrombocytopenia (3%), anemia (6%),
`thrombosis (23%), neutropenia (16%) and neutropenic
`fever (10%). Of 18 patients evaluable for response, one
`complete response (pancreatic) and eight partial
`responses (three gallbladder, two pancreatic, two head and
`neck, and one breast) were attained. Seven patients had
`disease stabilization (five pancreatic, one hepatocellular
`and one gastric) for a median of 16 weeks (range 10–22).
`Median time to disease progression among all 23 patients
`enrolled to the phase I portion of the trial was 20.5 weeks
`(range 4–37). We conclude that G-FLIP is a novel outpatient
`chemotherapy regimen with acceptable toxicity at the
`maximum tolerated irinotecan dose of 120 mg/m
`2. The
`phase II trial of G-FLIP using an irinotecan dose of 120 mg/
`m
`2 for patients with metastatic pancreatic cancer is
`ongoing. Anti-Cancer Drugs15:211–217 /C13c 2004 Lippincott
`Williams & Wilkins.
`Anti-Cancer Drugs 2004, 15:211–217
`Keywords: 5-fluorouracil, cisplatin, gemcitabine, irinotecan, leucovorin,
`pancreatic cancer, phase I trial
`aSt Luke’s-Roosevelt Hospital Center, New York, NY, USA andbBeth Israel
`Medical Center, New York, NY, USA.
`Sponsorship: Study funded by Pharmacia Oncology.
`Correspondence to P. Kozuch, St Luke’s-Roosevelt Hospital Center, 1000 10th
`Avenue Suite 11G, l New York, NY 10019, USA.
`Tel: + 1 212 523-6769; fax: + 1 212 523-2004;
`e-mail: pkozuch@chpnet.org
`Received 25 July 2003Revised form accepted24 November 2003
`Introduction
`The novel combination of gemcitabine, 5-fluorouracil
`(5-FU) bolus plus infusion, irinotecan and cisplatin
`(G-FLIP) was developed to approximate known
`sequence-dependent activity while minimizing sequence-
`dependent toxicity among the four drugs. A retrospective
`analysis of a similar regimen containing these four drugs
`demonstrated encouraging activity and survival outcomes
`in heavily pretreated patients, all with metastatic pancrea-
`tic cancer, thereby encouraging phase I and II develop-
`ment of the regimen with a simplified 5-FU schedule [1].
`Irinotecan (CPT-11, Camptosar) is a water-soluble
`topoisomerase I inhibitor with a unique mechanism of
`action of reversible inhibition of DNA topoisomerase I
`and a broad range of antitumor activity as a single agent
`[2]. T opoisomerase I inhibitors also may interfere with
`processes involved in DNA repair and enhance cytotoxi-
`city when combined with DNA-damaging agents such as
`cisplatin. Overlapping single-agent activity, non-overlap-
`ping toxicities, and a lack of cross-resistance and potential
`synergism in preclinical studies provide the rationale for
`combining irinotecan and cisplatin [3–5]. Several phase I
`trials have demonstrated the feasibility of combining
`these two drugs in a variety of dosages, schedules and
`sequences. Phase I and II data support total monthly
`cisplatin doses of 60–80 mg/m2, and monthly irinotecan
`doses between 180 and 280 mg/m 2 independent of
`0959-4973 /C13c 2004 Lippincott Williams & Wilkins DOI: 10.1097/01.cad.0000119740.70602.67
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`dose scheduling (i.e. weekly, biweekly, monthly dosing)
`[6]. There is clinical evidence suggesting reversal
`of cisplatin resistance when it is combined with
`irinotecan [7].
`Gemcitabine is a cell-cycle-specific pyrimidine nucleo-
`side analog that undergoes intracellular phosphorylation
`to form active di- and triphosphates. This process is dose
`rate dependent so the effectiveness of gemcitabine may
`be improved by altering the standard infusion schedule to
`a fixed-dose rate [8]. Gemcitabine cytotoxicity correlates
`with its incorporation into genomic DNA thereby
`inhibiting DNA synthesis.
`5-FU is an anti-metabolite that also requires intracellular
`activation to inhibit DNA synthesis. Preclinical and
`clinical data have reported cytotoxic synergy between
`gemcitabine and 5-FU in pancreatic and ovarian cancers
`[9]. Several phase I–II studies using different infusion
`schedules of 5-FU in combination with gemcitabine have
`reported potentially additive activity for the combination
`in pancreatic and renal cell carcinoma with tolerable
`toxicity profile [10–13].
`Irinotecan can be combined safely with gemcitabine and
`the doublet has demonstrated response rates of 20–30%
`in patients with locally advanced or metastatic pancreatic
`cancer. T oxicities include grade 3–4 neutropenia and
`grade 3 diarrhea [14,15]. Combinations of cisplatin with
`either 5-FU or gemcitabine have been studied exten-
`sively in various malignancies including esophageal, lung,
`cervix, head and neck, and urothelium.
`The G-FLIP regimen is based on laboratory evidence of
`disease-specific drug synergism with irinotecan. A retro-
`spective analysis of 34 heavily pretreated metastatic
`pancreatic cancer patients treated with G-FLIP combina-
`tion (irinotecan dose = 80 mg/m
`2) reported a partial
`response rate of 24%, disease stabilization rate of 21%
`and a median survival of 10.3 months. The regimen was
`well tolerated with most observed toxicities being grade
`1–2 mucositis, nausea/vomiting, neurotoxicity, nephro-
`toxicity and diarrhea [1]. A review of 15 patients receiving
`the four-drug regimen as initial treatment of metastatic
`pancreatic cancer documented a 33% response rate [17].
`Based on this encouraging clinical activity, a phase I dose-
`finding study was initiated to determine the maximum
`tolerated dose (MTD) of irinotecan in combination with
`fixed doses of gemcitabine, 5-FU/leucovorin (LV) and
`cisplatin in metastatic solid tumors.
`Materials and methods
`Patient selection
`Patients with a histologically or cytologically confirmed
`diagnosis of a solid tumor refractory to conventional
`treatment or for which no standard therapy existed were
`eligible for this phase I study. Once MTD was defined,
`accrual was transitioned to the phase II trial and
`enrollment was limited to patients with metastatic
`pancreatic cancer. Other eligibility criteria included the
`following: age Z 18 years, Karnofsky performance status
`(KPS) of Z 60, life expectancy of at least 12 weeks; no
`chemotherapy, immunotherapy or radiotherapy for at
`least 4 weeks prior to entry into the study (6 weeks for
`nitrosureas or mitomycin C); no concurrent therapy
`including chemotherapy, immunotherapy, radiotherapy
`or any other investigational drug; no prior therapy with
`a topoisomerase I inhibitor; measurable or evaluable
`disease; adequate hematopoietic (absolute granulocyte
`count of Z 1500/mm
`3 and platelet count Z 100 /C2109/
`l), renal (creatinine ofr1.5 mg/dl) and hepatic function
`(bilirubin r2.0 mg/dl); negative pregnancy test docu-
`mented prior to study entry for premenopausal women;
`men and women who were fertile must have used
`adequate contraception. Exclusion criteria included
`patients with brain involvement or leptomeningeal
`disease; progressive sensory neuropathy or hearing loss;
`serious illnesses or medical conditions including uncon-
`trolled diabetes, hypertension or arrhythmias, congestive
`heart failure or unstable angina, active infection, prior
`invasive malignancies within 5 years with an exception of
`curatively treated basal or squamous cell carcinoma of
`skin or carcinoma in situ of the cervix. A signed informed
`consent was obtained from all patients before study entry.
`The protocol had approval of a local IRB.
`Dosage and drug administration
`Therapy was administered in an outpatient setting every
`2 weeks and consisted of gemcitabine 500 mg/m2 i.v. in
`100 cm3 normal saline at 10 mg/m2/min, followed by
`irinotecan (per dose escalation schema) in 500 cm 3
`D5W over 90 min, followed by LV 300 mg in 50 cm3
`normal saline i.v. over 10 min, followed by 5-FU 400 mg/
`m2 in 50 cm3 normal saline over 10 min, followed by 5-FU
`1500 mg/m2 via an AIM pump (Ambulatory Infusion
`Manager; Abbott, Chicago, IL) over 24 h on day 1. On day
`2, 24 h after the day 1 5-FU bolus, patients received
`35 mg/m2 of cisplatin in 50 cm3 normal saline i.v. over
`45 min.Prior to receiving cisplatin, mannitol 12.5 g was
`administered i.v. in 500 cm
`3 D5 0.5 normal saline over
`30 min and an additional 25 g of mannitol in 1000 cm3 0.5
`normal saline with 30 meq of potassium chloride
`(KCl) and magnesium sulfate 2 g was administered
`upon completion of cisplatin infusion. Cisplatin
`infusion was started once urine output reached at least
`100 cm3/h with 10–20 mg of lasix given immediately
`before cisplatin infusion. The starting irinotecan dose was
`80 mg/m
`2 and was escalated stepwise by 20 mg/m 2
`increments in successive cohorts of three patients until
`the MTD was reached. Additional patients could be
`enrolled at a particular dose level to further evaluate toxic
`side-effects.
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`At each dose level, the initial patient was observed for 4
`weeks (2 biweekly cycles) prior to entry of subsequent
`patients. Subsequent patients at each dose level were
`evaluated weekly for at least 2 weeks before accrual at the
`next dose level could take place. Weekly evaluations
`consisted of a toxicity check, physical examination and
`laboratory evaluation (complete blood count, chemistry
`profile including serum creatinine, electrolytes and
`hepatic function).
`Assessment of toxicity and response
`Dose-limiting toxicity (DLT) was defined as grade 3 or
`greater non-hematologic toxicity (including nausea/vo-
`miting despite aggressive antiemetic therapy) or inability
`of the patient to take 75% or more of planned
`chemotherapy. If DLT developed in one of three
`patients, then three additional patients were to be
`enrolled at that dose level. If two or three out of three
`initial patients or more than one out of three additional
`patients treated at a dose level developed DLT , dose
`escalation was to be stopped. MTD was defined as the
`dose level below the dose that produced unacceptable
`toxicity. Additional patients were to be enrolled at the
`MTD in the phase II portion of the study to further
`characterize disease specific efficacy and toxicity.
`T oxicity was graded using the National Cancer Institute
`Common T oxicity Grading Criteria (version 2.0). Drug
`specific dose adjustments were made prior to subsequent
`cycles in case of toxicity. Cisplatin dose was decreased by
`25% for neutropenic fever, platelet countsr100 000/m
`3
`or for grade 1–2 persistent sensory neuropathy. Cisplatin
`was discontinued for grade 3–4 sensory neuropathy.
`Cisplatin dose was reduced to 20 mg/m2 and administra-
`tion changed to a continuous infusion if serum creatinine
`rose to 1.5–3 mg/dl. Infusional 5-FU dose was reduced by
`25% for grade 3–4 stomatitis or grade 2 or greater hand–
`foot syndrome. Irinotecan-associated acute or delayed
`diarrhea was treated symptomatically with atropine and
`loperamide, and irinotecan dose was reduced by 25% for
`grade 3–4 diarrhea.
`T umor responses were evaluated every 8 weeks by
`objective, two-dimensional measurements of evaluable
`tumors along the longest diameter according to RECIST
`criteria, employing imaging studies such as computed
`tomography scans or magnetic resonance imaging. A
`complete response (CR) was defined as the disappear-
`ance of all measurable and evaluable disease for at least 4
`weeks without appearance of new lesions. A partial
`response (PR) was defined as at least 30% decrease in the
`sum of longest diameter of all measurable lesions from
`baseline without appearance of new lesions. Progressive
`disease (PD) corresponded to at least 20% increase in the
`sum of the longest diameter of the measurable lesions or
`the appearance of new lesions. Stable disease (SD) was
`defined as insufficient decrease in tumor to qualify for a
`PR or insufficient increase in size to qualify for PD.
`T oxicity was evaluated in patients who received at least
`two G-FLIP cycles. Patients who achieved a CR could
`continue treatment for up to 6 months beyond the
`documentation of complete response. All patients with
`PR or with SD were continued until documentation of
`disease progression. Patients were withdrawn from the
`therapy in case of progressive disease, patient refusal,
`physician’s preference or development of any toxicity that
`would preclude further therapy. Response durations were
`measured from the time of documented radiographic
`response to the first observation of progressive disease.
`Time to disease progression was measured from the start
`of the treatment to first documentation of disease
`progression.
`Study design
`This study was designed as a phase I–II, open label, non-
`randomized dose finding study. In the phase I study, the
`first three eligible patients were assigned to receive
`treatment at dose level 0. At least three patients were
`studied for 28 days at each dose level before starting
`additional patients on escalated doses of irinotecan. In
`the event that the MTD was less than irinotecan 100 mg/
`m
`2 biweekly the dose of cisplatin was to be reduced to
`30 mg/m2 biweekly and irinotecan dose escalation would
`resume at one dose level below the previous MTD. When
`the MTD of irinotecan was determined, accrual was to be
`transitioned to the phase II aspect of the trial. Accrual to
`the phase II study was limited to patients with metastatic
`pancreatic cancer in order to fully define disease specific
`efficacy as well as to further characterize the toxicity
`profile of this novel regimen.
`Results
`Patient characteristics
`T wenty-three patients were enrolled in the phase I study
`between March 2002 and February 2003. Patient
`characteristics are illustrated in Table 1. Thirteen men
`and 10 women with a median age of 63 years and median
`KPS of 80 were enrolled. T en patients (43%) received
`prior treatment: two patients received surgery alone, two
`patients received either chemotherapy alone or in
`combination with surgery, one patient received che-
`motherapy and radiation, and five patients received
`surgery, chemotherapy and radiation. All 23 patients
`enrolled into the phase I study were assessable for
`toxicity after completing a minimum 2 cycles of therapy.
`Eighteen of these patients were evaluable for response.
`Five patients were withdrawn from the trial prior to
`response evaluation for the following reasons: one patient
`had severe asthenia necessitating withdrawal from study
`after 1 cycle and four patients had early disease
`progression after 1 or 2 cycles of G-FLIP . The initial
`seven patients with metastatic pancreatic cancer enrolled
`in the phase II portion of this trial are evaluable for
`Phase I study of biweekly G-FLIPRachamalla et al. 213
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`toxicity. Four were men and three women; median age
`was 54. Five of these patients previously were untreated
`and two had received prior gemcitabine-based regimens.
`Treatment administration and toxicity
`A total of 134 cycles were administered and each patient
`received a median of 8 cycles (1–16). From a starting dose
`of 80 mg/m2 of irinotecan, dose escalation proceeded until
`dose level 4 (160 mg/m2). Hematologic and non-hemato-
`logic toxicities are summarized in Table 2. No DLTs were
`identified at dose level 0, and one out of three patients at
`dose level 1 required hospitalization for nausea and
`vomiting. Subsequently, three additional patients were
`enrolled at dose level 1 without additional DLTs. All
`patients at dose level 2 tolerated therapy without DLTs.
`Six patients initially were enrolled at dose level 3, per
`protocol, permitting accrual of additional patients at a
`particular dose level to further evaluate toxic side-effects.
`One of these six patients developed grade 3 nausea and
`vomiting requiring hospitalization and i.v. hydration.
`Therefore, an additional three patients were enrolled at
`dose level 3, two of whom developed refractory grade 3–4
`nausea/vomiting requiring hospitalization in spite of
`aggressive antiemetic therapy. At the principal investiga-
`tor’s discretion, one patient was entered at dose level 4
`before the DLT and MTD were determined. Grade 2
`nausea and vomiting occurred at that dose. In light of the
`above events, dose level 2 was identified as the MTD. Per
`study design, accrual was then transitioned to the phase
`II part of the study. The initial seven patients enrolled
`onto the phase II trial were evaluable for toxicity and
`none experienced DLT .
`Outside of the DLT , therapy was well tolerated and grade
`3–4 toxicities per patient were largely hematological, and
`consisted of anemia (6%), thrombocytopenia (3%),
`neutropenia (16%) and neutropenic fever (10%). Hema-
`tologic toxicities were consistent throughout all dose
`levels. Grade 3–4 thrombosis occurred in seven patients
`(23%), so the protocol was amended with prophylactic
`coumadin 1 mg daily recommended. Grade 3–4 non-
`hematologic toxicities were limited to nausea/vomiting
`and fatigue in four (13%) and seven patients (23%),
`respectively. Grade 3–4 nausea/vomiting was observed in
`one patient at dose level 1 and three patients at dose
`level 3. Other non-hematologic toxicities were mainly
`grade 1–2 nausea/vomiting (60%), diarrhea (40%), con-
`stipation (16%) and fatigue (30%). Grade 1–2 ototoxicity
`and neurotoxicity was seen in two patients. T wo patients
`developed cisplatin hypersensitivity, during cycles 5 and
`11, respectively. These hypersensitivity reactions were
`characterized by intense chest pressure and light-head-
`edness in one patient, and chest pressure and diffuse skin
`erythema in the other patient. Both of these reactions
`Table 2 Toxic side-effects (event per patient)
`Dose level 0 (n = 4) Dose level 1 ( n = 6) Dose level 2 ( n = 10) Dose level 3 ( n =9 )
`Grade 3–4 Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4 Grade 1–2
`Hematological
`n e u t r o p e n i a 00321010
`thrombocytopenia 0 0 1 10100
`anemia 1 NR 1 NR 0 NR 0 NR
`neutropenic fever 0 NA 2 NA 0 NA 1 NA
`thromboembolism 1 NA 4 NA 1 0 1 NA
`Non-hematological
`neuropathy 0 0 0 10100
`o t o t o x i c i t y 00020000
`c o n s t i p a t i o n 00030101
`n a u s e a / v o m i t i n g 02150734
`fatigue 0 1 2 23323
`diarrhea 0 0 0 20505
`NR, not reported; NA, not applicable.
`Table 1 Phase I patient characteristics
`Characteristic No. of patients %
`No. entered 23 100
`Sex
`male 13 56
`female 10 44
`Age (years)
`median 63
`range 44–78
`Performance status (KPS)
`60 1 4
`70 3 13
`80 11 48
`90 6 26
`100 2 8
`Prior therapya
`none 13 56.5
`surgery alone 2 8.6
`surgery, chemotherapy and radiation 5 21.7
`chemotherapy and radiation 1 4
`surgery and chemotherapy 1 4
`chemotherapy alone 1 4
`Primary site
`pancreas 11 47
`gallbladder 5 21
`hepatocellular 1 4
`head and neck 3 13
`gastric 1 4
`melanoma 1 4
`breast 1 4
`aOther prior treatments included interferon in one patient.
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`occurred within the first minute of cisplatin infusion, and
`recurred despite appropriate premedication with steroids
`and diphenhydramine upon rechallenge. Cisplatin was,
`therefore, discontinued in these two patients.
`Tumor response
`Eighteen of 23 patients were evaluable for response. One
`patient with locally advanced pancreatic cancer attained a
`radiological CR after 4 cycles of therapy and remained in
`CR following 8 cycles. Eight patients (44%) had PRs:
`three patients with gallbladder cancer, two with pancrea-
`tic cancer, one patient with adriamycin/taxane refractory
`breast cancer, and two patients with platinum/taxane
`refractory head and neck cancer (tongue and sinus).
`Seven patients (39%) attained disease stabilization: five
`pancreatic, one hepatocellular and one gastric cancer.
`Median time to disease progression among all 23 patients
`was 20.5 weeks (range 4–37 weeks).
`Discussion
`The chemotherapy agents in G-FLIP all have proven
`single-agent activity in a wide variety of malignancies. A
`clear rationale exists for combining these drugs based on
`preclinical and clinical data. Three drug and four drug
`regimens have been evaluated in pancreatic cancer. A
`retrospective analysis of 49 patients with advanced
`pancreatic cancer treated with gemcitabine, 5-FU/LV
`and cisplatin reported a median survival of 10.6 months
`and a 1-year survival of 46%. Grade 3–4 toxicities were
`hematological [18]. A four-drug combination of cisplatin
`and epirubicin on day 1, gemcitabine on days 1and 8, and
`5-FU continuous infusion daily for 28 days given to
`patients 49 with advanced pancreatic cancer (43 patients
`had metastatic disease) reported an objective response
`rate of 58% and clinical benefit in 22 (78%) of 28
`assessable patients. The median survival was 10 months
`in the intent-to-treat population [19].
`Table 3 illustrates the increasing response rates and
`overall survival associated with combination chemother-
`apy, providing the rationale for multidrug combinations in
`pancreatic cancer. Most phase II trials of gemcitabine-
`based doublets have reported median survivals of 7.5–8.5
`months, but these modest advances did not withstand
`analysis in phase III trials [20–23]. However, median
`survivals of 10–11 months are consistently reported in
`phase II trials of three- and four-drug regimens. These
`survival outcomes may represent a threshold that will
`translate into clinically meaningful advances in phase III
`testing.
`This trial was a phase I dose escalation study designed to
`determine the MTD of irinotecan in combination with
`fixed doses of gemcitabine, 5-FU/LV and cisplatin given
`as an outpatient regimen on an every-2-weeks schedule in
`patients with advanced solid tumors. The DLT was 5-
`HT
`3 antagonist-refractory nausea and vomiting occurring
`at irinotecan dose level 3 (irinotecan = 140 mg/m2).
`Cisplatin was dose reduced by 25% in only two patients
`due to delayed emesis. The subsequent FDA approval of
`aprepitant for delayed chemotherapy-associated nausea
`and vomiting may improve the tolerability of this
`regimen. Other non-hematologic toxicities were mild.
`Except at dose level 0 (irinotecan 80 mg/m2), grade 3–4
`neutropenia occurred at a rate of 33% of patients/dose
`level. Grade 3 anemia requiring transfusions occurred in
`9% of patients. Hematopoietic colony stimulating factors
`like filgrastim or sargramostim and erythropoietin were
`administered according to the indications set forth by
`American Society of Clinical Oncology [24]. Grade 3
`thrombocytopenia was seen in two patients and was self
`limiting without bleeding complications or need for
`platelet transfusion. Hypersensitivity reactions to i.v.
`cisplatin are a rare, but life-threatening, complication that
`may occur even in patients who have received prior
`treatment with cisplatin. The appearance of hypersensi-
`tivity reactions was reported in patients treated with
`concomitant pelvic radiation and weekly i.v. cisplatin for
`gynecologic malignancies [25].
`The 31% incidence of thrombotic events with five
`patients developing deep venous thrombosis and two
`patients presenting with uncomplicated pulmonary em-
`bolism is notable. All patients with thrombotic events
`were treated with therapeutic doses of low-molecular-
`weight heparin. Hypercoagulability in cancer patients
`Table 3 Phase II reports of two-, three- and four-drug regimens for locally advanced and metastatic pancreatic cancer
`Treatment No. patients LA/M (%) RR (%) Median PFS
`(months)
`Median OS
`(months)
`Reference
`Gem (phase III) 163 5.6 2.2 5.4 20
`Gem/5-FU bolus 164 10/90 6.9 3.4 6.7
`Gem 10 mg/m2/min/5-FU bolus 34 24/76 17 3.7 5.7 29
`Gem + 5-FU bolus and infusion (FOLFUGEM) 62 35/65 26 4.8 9.0 30
`Gem + cisplatin biweekly 35 15/85 11.5 4.3 8.3 31
`Gem + oxaliplatin 34 0/100 31 4.1 8.7 32
`Gem + irinotecan 45 28/72 20 2.8 5.7 14
`Gem/5-FU/cisplatin 49 0/100 16.3 2.1 10.6 18
`Gem/5-FU/irinotecan/cisplatin 34 0/100 23.5 2.5 10.3 1
`Gem/cisplatin/epirubicin/5-FU 49 0/100 58 7 .5 10 19
`Iriotecan/oxaliplatin/5-FU 23 0/100 50 7 .5 NS 33
`LA, locally advanced disease; M, metastatic disease; Gem, gemcitabine; NS, not specified.
`Phase I study of biweekly G-FLIPRachamalla et al. 215
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`remains a complex and poorly understood problem.
`Activation of factor X, increased fibrinogen and platelet
`catabolism, decreased protein C, S and antithrombin III
`as well as direct generation of thrombin have been
`implicated in this process [26]. In one series from the
`UK, the estimated prevalence of venous thromboembo-
`lism in advanced pancreatic cancer patients was over 50%
`[27]. It is not known to what extent irinotecan, 5-FU, LV
`and drug administration schedule contribute to the rate
`of thromboembolism observed in this trial. During the
`panel review of CPT-11 trials in colorectal cancer,
`Rothenberg et al. reported a 16% incidence of throm-
`boembolic events with a combination of irinotecan,
`infusional 5-FU and LV compared to 9% with infusional
`5-FU and LV [28]. All subsequently enrolled patients
`were started on low-dose coumadin for thromboprophy-
`laxis.
`Significant antitumor activity in a wide variety of solid
`tumors including pancreas, gall bladder, hepatocellular,
`head and neck, and anthracycline/taxane refractory breast
`cancer was observed. In summary, G-FLIP is a well-
`tolerated regimen, administered in an outpatient setting
`on a biweekly basis. This regimen appears to be
`particularly active in pancreatic and gallbladder cancers.
`The DLT was intractable nausea and vomiting requiring
`hospitalization and i.v. fluid support. The recommended
`dose of irinotecan for phase II study is 120 mg/m
`2 in
`combination with fixed doses of gemcitabine, 5-FU/LV
`and cisplatin. Phase II testing in pancreatic cancer
`patients is ongoing.
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