Investigational New Drugs 2, 391-395 (1984) �9 1984, Martinus Nijhoff Publishers. Printed in the Netherlands

5-Fluorouracil and Folinic Acid: a Phase I - I I trial in gastrointestinal malignancy

James Cunningham, 1 R.M. Bukowski, G.T. Budd, J.K. Weick and J. Purvis Department o f Hematology and Medical Oncology, Cleveland Clinic Foundation, Cleveland, OH 44106 1Fairview General Hospital, Department o f i n ternal Medicine, 18099, Lorain A venue, Cleveland, OH 44111

Key words: 5-Fluorouracil, Folinic Acid, gastrointestinal malignancies

Summary

Fifty-one patients with metastatic adenocarcinoma received Folinic Acid (FA) combined with 5-Fluorouracil (5FU) in a Phase I - I I clinical trial. Two different schedules were used: (a) bolus infusion - 5FU 7 - 1 2 mg/kg /d I.V. d l - 5 , FA 1.6 mg/kg /d I.V. d l - 5 ; (b) continuous infusion - 5FU 600-1200 mg/mZ/d I.V. d l - 4 , FA 60 mg/m z /d I.V. d1 -4 . Mucositis and myelosuppression were dose-limiting, with recommended dose levels of 5FU for further trials being 10 mg/kg /d I.V. d l - 5 and 1000 mg/mZ/d I.V. d 1 - 4 on the bolus and continuous infusion schedules, respectively. Forty-one evaluable patients with measurable disease were treated. Thirty-six had metastatic colorectal carcinoma, and 14/36 patients responded (CR-1, PR-13), in- cluding responses in three patients who had previously failed 5FU treatment alone. In the two patients with unknown primary sites and three with gastric cancer, no response were seen. 5FU and FA have activity equi- valent to 5FU alone, and the responses in patients receiving prior 5FU suggest it may be superior. The pos- sibility that toxicity may be enhanced does exist. Further trials of these two agents are warranted.

Introduction

Fluoropyrimidines such as 5-flurouracil (5FU) are

among the oldest and most widely used agents available to treat solid tumors (1). Although they possess only modest antitumor activity (2), some optimism with regard to their usefulness has recent- ly arisen with an enhanced understanding of their mode of action. Thus the recognition that stable fluoropyrimidine inhibition of the enzyme thymi- dylate synthetase required the presence of a reduced folate cofactor raised the possibility that the avail- ability of intracellular reduced folates might be a limiting factor in achieving the prolonged thymidy- late depletion necessary for cytotoxicity (3). The demonstration that excess folinic acid (FA) could potentiate the growth inhibition by 5FU of human carcinoma cells in vitro (4) prompted the present study. A Phase I - I I trial of 5FU and FA was there-

fore initiated in November 1982 to determine the possible toxicity and clinical effectiveness of this combination. The purpose of this report is to de- scribe the results of the study.

Methods

Fifty-one patients were entered into the study. The clinical characteristics of this group of patients are outlined in Table 1. Patients were eligible for the study if they had biopsy-proven and metastatic adenocarcinoma arising from either the gastroin- testinal tract or an unknown primary site. Prior chemotherapy and /or radiotherapy were allow- able, and the presence of either clinically measur- able or nonmeasurable disease was acceptable. All obstructive lesions must have been bypassed surgi- cally, and a pretreatment white blood count of at

Address for reprints: R.M. Bukowski, M.D., 9500 Euclid Avenue, Cleveland, OH 44106, U.S.A.

392

least 4000 cells/#l and a platelet count of over 100 000//4 were required. All patients were inform- ed of the investigational nature of the study and in- formed consent obtained in accordance with insti- tutional policies.

Pretreatment evaluation included a complete his- tory and physical examination, complete blood count, BUN, creatinine, LDH, SGOT, total bili- rubin, alkaline phosphatase, and chest x-ray. Liver scans or computerized tomographic scans were ob- tained when appropriate for lesion measurement. Patients treated in the Phase I portion had complete blood counts every 7 days and those in the Phase II portion at least every 14 days. All biochemical studies were repeated before each course of treat- ment and patients examined to assess toxicity and response. X-rays and /or scans were repeated prior to each course, when appropriate, to assess re- sponse.

Chemotherapy consisted of 5FU and FA. Two different schedules of 5FU were employed; namely, I.V. bolus infusion daily for 5 days and a 96-h con- stant I.V. infusion. In the Phase I portion of the study, three to five patients were treated at each dose level of 5FU and, if toxicity was acceptable, the dose escalated. The dose levels of 5FU used for the bolus schedule were 7.0, 8.0, 10.0, 11.0, and 12.0 mg/kg I.V. d l - 5 . FA was given at a dose of 1.6 mg/kg I.V. d l - 5 prior to each 5FU infusion and was not escalated. Dose levels of 5FU employ- ed for the continuous infusion schedule were 600, 800, 1000, and 1200 mg/m 2 I.V. d l - 4 . FA was given daily (d1-4) at a dose of 60 mg/m 2 . When the Phase I portion of the study was completed, pa-

Table 1. Patient characteristics.

No. patients - 51

F / M - 23/28

Median age (range):

Female - 64 (21-76)

Male - 58 (37-73)

Performance status (median) - 2

Pr imary tumor sites:

Colon - 36

Rectum - 10

Gastric - 3

Unknown primary - 2

tients were then treated at appropriate dose levels. Courses were repeated at intervals of 28 days if toxi- city allowed.

In patients with clinically measurable disease, the following response criteria were employed: a com- plete response was defined as complete disappear- ance of tumor for at least one month with no symp- toms related to the malignancy present. A partial response was defined in one of two ways. For le- sions with bidirectional measurements, a 50% or greater decrease in the sum of the products of the diameters of measured lesions was employed. In patients with palpable hepatomegaly, a 30% or greater decrease in the sum of measurements below the xiphoid and both midclavicular lines was em- ployed. In either case, the improvement had to last at least one month, with no increase in size of other lesions or appearance of new lesions. Progressive disease was defined as the appearance of new le- sions or a 25% increase in any measured lesion. Survival duration was calculated from the time a patient entered the trial, and median survival of various groups was estimated directly from the Kaplan-Meier survival curves (5).

Results

Fifty-one patients participated in the study. Hema- tologic toxicity was evaluable following 38 courses

Table 2. Hematologic toxicity - intermittent infusion schedule.

)

5FU dose* No. p t s . / Median WBC Median platelet

levels no. nadir x 103//~1 nadir x 103/#1

D 1 - 5 courses (range) (range)

7.0 mg /kg 1/1 4.4 113 (-) (-)

8.0 mg /kg 5/5 3.9 226

(2.6-8.9) (142-439)

10.0 mg /kg 14/21 4.8 249

(0.3-11.7) (29-450)

11.0 mg /kg 5/6 2.8 181

(1.3-6.4) (140-223)

12.0 mg /kg 3/6 2.1 238

(1.7-9.3) (236-500)

* FA dose - 1.6 m g / k g / d .

of treatment with continuous infusion and in 39 courses of treatment employing the intermittent

bolus infusion schedule. Myelosuppression was found regularly with either schedule of treatment and is outlined in Tables 2 and 3. The leukocyte nadir appeared to be doserelated, occurring be- tween 10 to 22 days following intermittent bolus in- fusions and between 15 to 17 days following con- tinuous infusion treatment. Cumulative myelosup- pression was not observed and allowed for repeated cycles of treatment to be given at 28-day intervals. No toxic deaths occurred following treatment.

Gastrointestinal toxicity in the form of stomati- tis, diarrhea, or proctitis was frequently encounter- ed and tended to parallel the degree of leukopenia. This toxicity is outlined in Table 4. Miscellaneous toxicity included superficial phlebitis following

Table 3. Hematologic toxicity - continuous infusion schedule.

5FU dose* No. pts . / Median WBC Median platelet levels no. nadir • 103//xl nadir • 103/#1

D1-5 courses (range) (range)

600 mg/m z 3/3 6.2 445 (5.0-8.5) (411-481)

800 mg/m 2 5/7 6.0 340 (2.1-9.0) (274-460)

100 mg/m z 12/15 5.0 192 (1.6-9.0) (147-297)

1200 mg/m z 11/13 4.0 260 (0.8-10.0) (160-435)

* FA dose - 60 mg/mZ/d.

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5FU and FA in 75~ of patients. One episode of ataxia and one of transient delirium occurred, both being self-limited. Alopecia was mild and observed in 12~ of patients.

The dose-limiting toxicity of the continuous schedule was mucositis and that for the intermittent schedule, leukopenia and mucositis. Based on hemotologic and gastrointestinal toxicity, the dose levels recommended for Phase II trials are as fol- lows: (a) continuous infusion schedule - 5FU 1000 mg/m 2 I.V. d l - 4 , FA 60 mg/m z I.V. d l - 4 ; (b)

bolus infusion schedule - 5FU 10 mg/kg I.V. d l - 5 , FA 1.6 mg/kg I.V. d l - 5 . Forty-four pa- tients were considered evaluable for response since they had measurable disease, and 40 patients were evaluable. Nonevaluable patients included three patients who were lost to follow-up. The results in the 41 evaluable patients are outlined in Table 5. The overall response rate was 34~ (14/41 patients) with the majority of responses being partial. The median response duration was likewise brief, being 4.0 months. In patients with colorectal carcinoma 14/36 (39%) responded, and in patients with no prior chemotherapy, 11/25 (44%) demonstrated re- sponses. The sites of measurable disease in these pa- tients were as follows: liver (four), lung (three), liver and lung (two), abdominal mass (one), lymph node (one). The performance levels (SWOG crite- ria) in this group varied, with six patients having levels of 0 or 1 and five patients 2 or greater. Final- ly, the median number of courses to a response was one, with the range being one to three.

Table 4. Gastrointestinal toxicity 5FU & FA.

Type Intermittent infusion (mg/kg d l - 5 )

7.0 8.0 10.0 11.0

Mucositis 0* 40 57.1 83.3 (0/1)** (2/5) (12/21) (5/6)

Nausea, 0 20 5 0 vomiting (0/1) (1/5) (2/21) (0/6) Diarrhea 0 60 48 66.6

(0/1) (3/5) (10/21) (4/6)

Continuous infusion (mg/m 2 d l - 4 )

12.0 600 800 1000 1200

100 33 100 100 100 (6/6) (1/3) (7/7) (15/15) (13/13) 0 33 0 0 0 (0/6) (1/3) (0/7) (0/15) (0/13) 66.6 0 57.1 40 15.4 (4/6) (0/3) (4/7) (6/15) (2/13)

* Percent incidence. ** Incidence/no. courses.

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Table 5. Response data*.

1) Response evaluable patients - 41 CR - 1 (2~ PR - 13 (32%) NR - 27

2) Responses according to previous treatment status in pa- tients with colorectal carcinoma: a) No prior chemotherapy - 25

CR - 1 (4070) PR - 10 (40~ N R - 14

b) Prior chemotherapy - 11 CR - 0 PR - 3 (27~ N R - 8

3) Responses in patients with other than colorectal carcino- ma: a) Gastric cancer (prior chemotherapy)

NR - 3 b) Unknown primary (prior chemotherapy)

NR - 2 4) Median response duration - 4.0 mos.

(1.5-7.0+) 5) Responses according to dose levels and schedule in pre-

viously untreated patients: Continuous schedule Bolus schedule

Level CR + PR Level CR + PR

600 mg/m 2 0/1 7 mg/kg 0/1 800 mg/m z 0/4 8 mg/kg 2/2

1000 mg/m 2 2/4 10 mg/kg 3/4 1200 mg/m 2 2/4 11 mg/kg 2/2

4/13 (30%) 7/12 (58~

*CR - complete response; PR - partial response; NR - no re- sponse.

Of pa r t i cu la r interest was the g roup o f 11 pa-

t ients with colorec ta l cancer who had received pr ior

c hemo the rapy which included 5FU or a 5FU com-

b ina t ion . Responses occurred in 3/11 pat ients and

las ted for a med ian o f 2.0 months . In one pa t ien t ,

progress ive disease occurred with hepat ic ar ter ia l

infus ion o f 5FU, and a subsequent response to 5FU

and F A was documen ted . In this g roup , two re-

sponses occur red with the con t inuous in fus ion

schedule and one with the in te rmi t ten t schedule.

The med ian survival o f all 41 pat ients evaluable

for response was 6.5 months . The m e d i a n survival

o f all r e spond ing pat ients (CR + PR) was 9.5

months . Final ly , the med ian survivals of the nonre-

sponding pat ients was 3.75 months .

D i s c u s s i o n

5FU has l imited effect iveness as an an t i t umor agent

in gas t ro in tes t ina l cancer. In the present s tudy we

have shown that dai ly bolus infusions o f F A can be

admin i s t e red safely in c o m b i n a t i o n with ei ther o f

two conven t iona l schedules o f 5FU. A l t h o u g h the

toxic effects o f this c o m b i n a t i o n were qual i ta t ively

similar to tha t o f 5FU alone, they a p p e a r e d to be

more severe in degree, indica t ing poss ible synergis-

tic toxici ty o f the two agents. Both gas t ro in tes t ina l

toxic i ty and myelo tox ic i ty were f o u n d to be dose-

l imit ing. The r e c o m m e n d e d dose levels o f 5FU for

future trials are 10 m g / k g I.V. d l - 5 bolus infu-

sion, or 1000 m g / m Z / d I .V. over 96 hours . The F A

dosage was held cons tan t and is much lower than

employed in o ther tr ials with these two agents.

The overal l effect iveness o f 5FU and F A appears

to be at least equivalent to 5FU a lone and may in

fact be super ior . Fur the r tr ials , including a ran-

domized c o m p a r i s o n o f 5FU with 5FU and F A , are

needed to demons t r a t e this. The responses seen in

pat ients with colorec ta l cancer who fai led previous

5FU, a l though brief , are interest ing and suppor t

the a ugme n ta t i on o f 5FU act ivi ty by F A . Responses

were observed at var ious dose levels and with bo th

schedules o f 5FU admin i s t r a t ion . In view of the

small series o f pat ients involved, super ior i ty o f

ei ther schedule cannot be demons t r a t ed . Machove r

et al. (6) have recent ly r epor ted their experience

with the c o m b i n a t i o n o f 5FU and F A . A response

rate o f 40% (12/30) was no ted in pat ients with colo-

rectal cancer and 60% (3/5) in pat ients with gastr ic

cancer. The schedule employed involved high dose

F A (200 m g / m 2) and 5FU ( 3 7 0 - 4 0 0 m g / m 2) I .V.

d l - 5 by r ap id in t ravenous infus ion repea ted every

four weeks. F ina l ly , a second tr ial using this com-

b ina t ion was r epor t ed by Bruckner et al. (7). This

was a Phase I t r ial with F A admin i s t e red at a dose

of 25 mg I .V. , and 5FU dosage was escala ted f rom

17.5 m g / k g to 35 m g / k g I .V. on d l and 2, repea ted

at three-week intervals . In 27 pat ients with colorec-

tal c a r c i n o m a 1 CR, 2 PRs, and 9 m i n o r responses

were noted. In bo th these trials, responses occurred

in both previously treated and unt rea ted patients.

The results in our trial and the experience of

others (6, 7) are sufficiently encouraging to warran t

further trials of this combina t ion in tumors where

5FU has some therapeutic effectiveness. The op-

t imal schedule is unclear, and further biochemical

and pharmacologic studies will be required to clari-

fy this issue. Should future trials conf i rm the activi-

ty of 5FU and FA, a randomized compar i son with

5FU alone will be necessary.

References

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395

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5. Thomas DG, Breslow N, Gart JJ: Trend and homogeneity analysis of proportions and lifetable data. Comput Biomed Res 10:373-381, 1977

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