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Clinical Cancer Research Vol. 5, 2399-2408, September 1999
© 1999 American Association for Cancer Research

Clinical Trials

A Pilot Study of Interferon {alpha}-2a, Fluorouracil, and Leucovorin Given with Granulocyte-Macrophage Colony Stimulating Factor in Advanced Gastrointestinal Adenocarcinoma

Jeremy D. Shapiro, Nancy Harold, Chris Takimoto, J. Michael Hamilton, David Vaughn, Alice Chen, Seth M. Steinberg, David Liewehr, Carmen Allegra, Brian Monahan, Alex Lash, Frank Grollman, Donald Flemming, Katherine Behan, Patrick G. Johnston, Daniel Haller, Mary Quinn, Geraldine Morrison and Jean L. Grem1

Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Naval Medical Center, Bethesda, Maryland 20889 [J. D. S., N. H., C. T., J. M. H., A. C., C. A., F. G., K. B., P. G. J., M. Q., G. M., J. L. G.]; Department of Medical Oncology, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104 [D. V., D. H.]; Hematology/Oncology, Department of Internal Medicine, National Naval Medical Center, Bethesda, Maryland 20889 [B. M.]; Biostatistics and Data Management Section, Office of the Director, Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland 20892 [S. M. S., D. L.]; Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892 [A. L.]; and Department of Radiology, National Naval Medical Center, Bethesda, Maryland 20889 [D. F.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We reported previously that the addition of recombinant Escherichia coli human granulocyte-macrophage colony stimulating factor (GM-CSF) to a 5-fluorouracil (5-FU) and leucovorin (LV) regimen seemed to ameliorate diarrhea and permit increased 5-FU dose intensity (J. L. Grem et al., J. Clin. Oncol., 12: 560–568, 1994). We then tested the effect of GM-CSF given with a more toxic regimen of 5-FU/LV/IFN-{alpha} (IFN {alpha}-2a).

Thirty-one patients with a good performance status and no prior chemotherapy for systemic disease received IFN {alpha}-2a (5 MU/m2 s.c., days 1–7), 5-FU (370 mg/m2 i.v., days 2–6), LV (500 mg/m2 i.v., days 2–6), and GM-CSF (Saccharomyces cerevisiae 250 µg/m2 s.c., days 7–18) every 3 weeks. Toxicities and 5-FU dose intensity were compared with that observed in our prior Phase II trial with 5-FU/LV/IFN {alpha}-2a (J. L. Grem et al., J. Clin. Oncol., 11: 1737–1745, 1993).

In comparison with the prior Phase II study, the WBC and granulocyte nadirs in the present trial were significantly higher. When trends in toxicity grades for all cycles were compared, stratifying for 5-FU dose, the incidence and severity of mucositis, skin rash, WBC toxicity, and granulocyte toxicity were significantly lower in the present trial, whereas nausea/vomiting and fatigue were significantly worse. The delivered 5-FU dose intensity for all cycles of therapy appeared to be significantly higher in the present trial. Six of 28 evaluable patients had a partial response (21.4%), and 13 (46%) had stable disease for >=12 weeks. Despite treatment-related toxicity, patient quality of life did not worsen during the study. No correlation was observed between thymidylate synthase content in primary tumor specimens and response, time to treatment failure, or survival.

The addition of GM-CSF appeared to decrease the severity of leukopenia, granulocytopenia, mucositis, and skin rash when compared with our prior experience with this regimen of 5-FU/LV/IFN {alpha}-2a, at the cost of greater nausea/vomiting and fatigue. The potential impact of increased 5-FU dose intensity on clinical response, however, remains to be determined.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
5-FU2 remains an effective chemotherapy agent in the treatment of many advanced gastrointestinal malignancies (1) . An important mechanism of action occurs through the generation of 5-FdUMP, which combines with TS and the folate cofactor, 5–10 methylenetetrahydrofolate to form a covalent ternary complex. TS catalyzes the conversion of dUMP to TMP, a precursor of TTP, one of the four deoxyribonucleotides required for DNA synthesis. Inhibition of TS thus interferes with DNA synthesis and repair. Incorporation of the anabolites of 5-FU into RNA and DNA may also contribute to cytotoxicity (2) .

Bolus administration of 5-FU as a single agent has modest clinical activity in advanced colorectal cancer with response rates of 10–15% (3 , 4) . In an attempt to increase the clinical effectiveness of fluoropyrimidines, agents capable of modulating fluoropyrimidine cytotoxicity in the laboratory have been tested in the clinical setting. Administration of the reduced folate LV (5-formyltetrahydrofolate) increases intracellular folate pools and promotes greater stability of the ternary complex and more prolonged TS inhibition (2) . Several clinical studies have demonstrated that the addition of LV increases response rates, at the cost of greater toxicity (5) . The IFNs have also been tested in the clinic after the demonstration by several laboratories that each of the IFNs ({alpha}, ß, and {gamma}) can enhance the cytotoxicity of 5-FU in a variety of human cancer cell lines (6, 7, 8, 9, 10) . The basis of the interaction has varied in different model systems, but augmentation of DNA-directed cytotoxic effects of 5-FU is a common theme (6, 7, 8, 9, 10, 11) . Phase II studies with 5-FU/IFN combinations have reported response rates ranging from 26 to 63%, potentially higher than would be expected with 5-FU alone (12, 13, 14, 15) .

Because LV and IFN modulate 5-FU by complementary mechanisms, combination therapy appeared to be a rational therapeutic strategy (16) . We developed a regimen combining IFN {alpha}-2a with a daily for 5-days schedule of LV (500 mg/m2 i.v. over 30 min) and 5-FU (370 mg/m2/day i.v. push 1 h after LV; Ref. 17 ). In the pilot study, IFN {alpha}-2a at a dose of 5 MU/m2 days 1–7 was associated with a biological effect relevant to 5-FU (decreased 5-FU clearance leading to increased 5-FU exposure) and produced toxicity similar to that seen with a lower IFN {alpha}-2a dose (3 MU/m2). In a subsequent Phase II study in advanced colorectal cancer patients, objective responses were seen in 54% of 44 assessable patients, with a median survival of 16.3 months (18) . We also observed an apparent association between delivered 5-FU dose intensity and clinical response.

Colony-stimulating factors have been able to reduce the hematological toxicity of many combination chemotherapy regimens, and there is some suggestion that mucosal toxicity may also be reduced (19 , 20) . We have demonstrated previously that the addition of GM-CSF (Escherichia coli) to a 5-day 5-FU/LV regimen seemed to ameliorate diarrhea and permit increased 5-FU dose intensity (21) . We therefore wished to determine whether toxicity could be ameliorated and 5-FU dose intensity could be increased by the addition of GM-CSF to our previously reported 5- FU/LV/IFN {alpha}-2a regimen (18) . Because TS is a crucial intracellular target of 5-FU, an additional goal of this study was to examine whether baseline intratumoral TS content in resected primary tumors predicted for outcome.

Given the degree of nonhematological toxicity observed with the 5-FU/LV/IFN {alpha}-2a regimen and the fact that the treatment is palliative, the impact of treatment on the patient’s quality of life is an important consideration. We therefore planned to measure the quality of life of patients using the FACT scale 2 for colorectal cancer because it combines functional and satisfaction items and incorporates disease specificity and subjectivity into the assessment (22 , 23) . We wished to test two alternate hypotheses. Because patients entering this trial were required to have minimal cancer-related symptoms, quality of life might worsen due to recurrent treatment-related toxicities such as mucositis, diarrhea, and constitutional symptoms. Alternatively, patient satisfaction and quality of life might improve after the initial three cycles of therapy when appropriate dose adjustments have been made, the patients become more familiar with the expected side effects, and clinical restaging has been performed to indicate whether they are receiving benefit from therapy.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Eligibility.
This pilot study was activated in April 1994 and closed in October 1995 after accruing 31 patients. The final patient was taken off study in January 1999 for disease progression. The major objectives of this trial were to characterize the incidence and severity of clinical toxicities associated with the addition of GM-CSF to our our previously reported IFN {alpha}-2a and LV-modulated 5-FU regimen and to compare the delivered 5-FU dose intensities on the present and prior study. The planned sample size was 30 patients, with the expectation that 80% of these patients would receive three or more courses of therapy. This sample size was felt to be adequate to allow comparison of the toxicities and delivered 5-FU dose intensity in patients receiving 5-FU/LV/IFN {alpha}-2a/GM-CSF with that observed in our prior Phase II trial. Twenty-eight patients were enrolled at the NCI-Medicine Branch, National Naval Medical Center, and three were entered at the University of Pennsylvania Cancer Center. Adult patients with a diagnosis of unresectable primary, recurrent or metastatic adenocarcinoma arising in the gastrointestinal tract, an ECOG performance state of 0–1, and no prior chemotherapy for metastatic or recurrent disease were eligible. Prior adjuvant therapy with 5-FU alone or with levamisole, LV, or IFN must have been completed >12 months before study entry, and patients were not permitted to have received prior radiotherapy to the aerodigestive tract or to more than one-third of bone marrow reserve. Additional eligibility criteria included an absolute granulocyte count >2,000/µl, platelets >100,000/µl, bilirubin <2.0 mg/dl, aspartate aminotransferase <5 times upper normal limit, creatinine <2.0 mg/dl, no known cerebral metastases, and no other concurrent serious medical illness. Because the major end points were analysis of clinical toxicity and delivered 5-FU dose intensity, measurable disease was not required. The study had the approval of the Cancer Therapy Evaluation Program, National Cancer Institute and the Institutional human subjects review boards at both participating institutions. All patients gave written informed consent.

Treatment Plan.
5-FU was obtained from commercial sources. IFN {alpha}-2a (Roferon; Hoffman La-Roche, Nutley, NJ), calcium LV (Ben Venue Laboratories, Bedford, OH), and GM-CSF (Leukine; Immunex Corp., Seattle, WA) were provided by the Cancer Therapy Evaluation Program, Division of Cancer Treatment, NCI. IFN {alpha}-2a was administered as a s.c. injection at a dosage of 5 million units/m2 on days 1–7. Calcium leucovorin (500 mg/m2) was administered as a 30-min i.v. infusion on days 2–6, immediately after IFN {alpha}-2a, and was followed 1 h later by 370 mg/m2 5-FU by i.v. push over 5 min. GM-CSF (250 µg/m2/day) was given by s.c. injection starting on day 7 and was continued until day 18 or longer if necessary to permit granulocyte recovery. GM-CSF was discontinued a minimum of 2 days before the start of the next cycle of therapy. Oral cryotherapy and an oral hygiene program were used as described previously (18) . Treatment cycles were repeated at 21-day intervals provided the granulocyte count was >1,200/µl, the platelet count >80,000/µl, and the patient had recovered from nonhematological toxicities. The dose of 5-FU was reduced by 15% if the granulocyte nadir was <500/µl for >5 days, a platelet nadir <25,000/µl, and for grades 3 and 4 mucositis, diarrhea, or other nonhematological toxicity. Patients requiring regular treatment delays also had a dose reduction of 5-FU in an attempt to restore 21 day cycles and thereby maximize 5-FU dose intensity. The dose of 5-FU was increased by 15% if the granulocyte nadir was >1,000/µl and the platelet nadir was >50,000/µl, other nonhematological toxicities were <= grade 1 in severity, and treatment could be repeated at 3- or 4-week intervals. The dose of GM-CSF was reduced by 50% if the patient experienced acute dyspnea or hypotension, pleurisy, weight gain >10% body weight, asymptomatic pleural effusions, severe myalgias, arthralgias, bone pain, and extreme fatigue or malaise. GM-CSF was discontinued if patients developed >= grade 3 nonhematological toxicity attributed to it, hypersensitivity reactions, or a thromboembolic event. Dose reductions of IFN {alpha}-2a in 25% increments were guided by the patient’s perception of the severity of these constitutional symptoms and if these symptoms were accompanied by a decline in performance status. In addition, a change in the IFN {alpha}-2a schedule was planned if the concurrent administration of IFN {alpha}-2a and GM-CSF on day 7 appeared to result in greater constitutional side effects (fever, malaise, and myalgias).

Patients were continued on treatment until disease progression. All patients are evaluable for toxicity, and all with measurable disease are included in the response assessment. Previously reported response criteria were used (18) , and toxicity was graded using the NCI Common Toxicity Criteria version one.

Quality of Life.
Quality of life was measured using the FACT-C self report instrument. This tool was developed to measure the multidimensional aspects of health-related quality of life among colon cancer patients participating in clinical trials (22 , 23) . It consists of five general subscales (physical well being, social/family well being, relationship with doctor, emotional well being, and functional well being) as well as a nine-item Colorectal Cancer subscale that offers assessment of a variety of disease-, treatment-, symptom-, and condition-specific quality of life assessments. All patients enrolled in the protocol were asked to complete the FACT-C on day 1 of cycle 1 prior to the administration of drugs (baseline) and prior to treatment on day 1 of cycles 3, 6, and 12. The scoring algorithm requires that all responses to "negative" items be reversed so that a higher score always indicates a higher quality of life. Scoring of each subscale is described in the manual published by the author (23) .

TS Expression.
Determination of TS protein content in primary tumor samples was performed immunohistochemically with the TS-106 monoclonal antibody to human TS (24) . Paraffin-embedded tissue sections 6-µm thick were deparaffinized in xylene, rehydrated through graded alcohols, and washed in PBS. The TS 106 monoclonal antibody was applied using the avidin-biotin complex immunohistochemical technique (25) . A pathologist confirmed that the slides represented primary tumor tissue. The slides were scored for the intensity of TS protein staining by the consensus of two observers using a visual grading system based on the intensity of staining (0 or 1, low; 2 or 3, high) as well as its extent (focal, <25% tumor staining positive; diffuse, >25% tumor); these two individuals were blinded to the identity and outcome of the patients in question.

Statistical Methods.
The study describing our prior Phase II study included data collected through November 1992, and the report was published in 1993 (18) . The final patient was taken off that study in the Spring 1996 for disease progression. The database for the 46 patients enrolled in this prior trial was, therefore, updated to include the toxicities and doses of 5-FU received for all cycles administered. The Wilcoxon rank sum test was used to compare the WBC, AGC, and platelet nadirs between the two trials, as well as the delivered 5-FU dose intensity for all patients. Comparison of the worst grades of toxicity experienced by patients on the present and prior study was performed by Lehmann’s method that tests for differences in trends of toxicity grades (26) . Comparisons of trends in toxicity grades between the two studies for all cycles, stratified for 5-FU dose, were performed using the stratified version of the Cochran-Armitage trend test (27) . The Breslow-Day statistic was used to test for the homogeneity of the odds ratio for constitutional toxicities between strata of IFN {alpha}-2a and GM-CSF doses (27) . A paired Student’s t test was used to evaluate the change in quality of life scores from baseline to treatment cycles 3, 6, and 12. The probability of treatment failure and overall survival were computed actuarially using the Kaplan-Meier method beginning with the patient’s on-study date, and differences in these parameters according to TS levels were compared using the Mantel-Haenszel technique (28 , 29) . All Ps are two-sided.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Demographics.
The characteristics of the 31 patients entering this trial are listed in Table 1Citation . All patients were asymptomatic or had minimal cancer-related symptoms. Only two patients had received prior adjuvant chemotherapy. All patients are evaluable for toxicity, and 28 are assessable for response. Three patients were excluded from response assessment because their disease was not measurable. Two patients declined further therapy for personal reasons after their initial cycle of treatment; although neither had evidence of disease progression, they are included in the response assessment. All patients are included in the analysis of time to treatment failure and survival. The characteristics of the 46 patients treated on our prior Phase II trial are shown for comparison.


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  		Table 1 Patient characteristics

 
Clinical Toxicity.
During the first cycle of therapy, no patient experienced worse than grade 2 hematological toxicity (Table 2)Citation . Mucositis, diarrhea, fatigue, and nausea/vomiting were the most frequent toxicities. One of two patients who withdrew after one cycle experienced grade 4 diarrhea, grade 3 fatigue, and grade 3 nausea and vomiting, whereas the other patient experienced grade 2 mucositis, grade 1 diarrhea, and grade 1 nausea and vomiting. Nine patients required a dose reduction of 5-FU to 315 mg/m2 for their second cycle of therapy due to mucositis of either grade 3 (four patients) or grade 4 (one patient) severity, and/or diarrhea of grade 3 or 4 severity (three patients each). One additional patient who experienced grade 2 mucositis after only three doses of 5-FU received a "double" dose reduction to 270 mg/m2 for cycle 2. Thus, one-third of patients required a dose reduction after one cycle. All clinical toxicity had resolved by day 21 or day 28 in 68 and 94% of patients, respectively, whereas two patients required a 2-week delay to allow resolution of toxicities. When compared with cycle one toxicity seen in our prior trial, the WBC and AGC nadirs were significantly higher with the GM-CSF-containing regimen (Table 2)Citation . However, the grades of nausea/vomiting and fatigue seemed to be higher in the present trial (Table 3)Citation .


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  		Table 2 Hematological toxicity during initial cycle of therapy

The total number of patients was 31 for the present study and 46 for the prior study; the number of patients with hematological values are indicated in the table. The distribution of values was compared by the Wilcoxon rank sum test, and two-sided Ps are shown.

 

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  		Table 3 Frequency of nonhematological toxicities during the initial cycle of therapy

A comparison of worst nonhematologic toxicity while on study between the present study and the prior Phase II study was performed with Lehmann’s method that tests for differences in trends of toxicity grades. Two-sided Ps are presented.

 
A total of 335 courses of chemotherapy were delivered, and each patient received a median of seven cycles (range, 1 to 42). Eight patients (26%) who experienced minimal toxicity at the starting dose of 5-FU received an escalation to 425 mg/m2, and the dose was subsequently escalated to 490 mg/m2 in three patients. The worst grade of toxicity experienced by patients across all cycles is shown in Table 4Citation . Severe or life-threatening mucositis or diarrhea occurred in 26 and 42% of patients. Prophylactic antiemetics were not used in this trial, and 19% of patients experienced at least one cycle of therapy complicated by nausea and vomiting of grade 3 or worse severity. These patients generally responded well to antiemetic therapy. Skin rash occurred in a minority of patients and was manifested by either palmar-plantar erythrodysesthesia (three patients) or a generalized rash (four patients). Hematological toxicity was generally mild. Grade 2 anemia and thrombocytopenia was seen in 29 and 3% of patients, respectively, and grade 3–4 toxicity was not seen. Grade 4 neutropenia was seen in only 13% of patients. Fourteen patients (45%) ultimately required a 5-FU dose reduction.


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  		Table 4 Worst grade of toxicity across all cycles for each patient

A comparison of worst nonhematologic toxicity while on study between the present study and the prior Phase II study was performed with Lehmann’s method that tests for differences in trends of toxicity grades. Two-sided Ps are presented.

 
When the worst toxicities experienced by the patients were considered, the leukocyte and granulocyte nadirs in patients treated with the present GM-CSF-containing regimen were significantly higher than that observed in the prior Phase II trial (Fig. 1)Citation . As might be expected, no significant difference in platelet nadirs was noted. Differences in trends of toxicity for the nonhematolgical toxicities were compared between the two studies (Table 4)Citation . There appeared to be a trend for higher grades of diarrhea and skin rash in the prior trial without GM-CSF. In contrast, fatigue, myalgias/arthralgias, and nausea/vomiting tended to be more severe in the present trial with GM-CSF.



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  		Fig. 1. Worst hematological toxicity across all cycles of therapy. The lowest leukocyte (WBC), granulocyte (AGC), and platelet nadirs for each patient while on protocol therapy were compared for the present study (n = 31 patients) and the prior Phase II study (n = 46 patients). The data are presented as a box plot, in which the median value is represented by a horizontal line; the 25th and 75th percentiles are shown by the bar; the 10th and 90th percentiles are depicted by the whiskers; and the 5th and 95th percentiles are shown by the solid circle. The distribution of values for each category was compared by the Wilcoxon rank sum test, and two-sided Ps are shown.

 
The incidence and grade of clinical toxicities for all cycles at 5-FU doses of 315, 370, and 425 mg/m2 are shown in Fig. 2Citation . The trends in toxicity grades between the present and prior trial, stratifying for 5-FU dose, were compared using the stratified version of the Cochran-Armitage trend test. The analyses were performed using three groupings: grades 0+1 versus grade 2 versus grades 3+4. The incidence of toxicity was significantly lower in patients on the present study for the following categories: mucositis (P2 < 0.0001); skin rash (P2 = 0.016); WBC (P2 < 0.0001); and AGC (P2 < 0.0001). No differences in toxicity grades for diarrhea were apparent (P2 = 0.85). In contrast, the incidence of nausea/vomiting (P2 < 0.0001) and fatigue (P2 < 0.0001) were significantly higher in patients treated on the present study. To test for a possible interaction between the doses of IFN {alpha}-2a and GM-CSF and the severity of constitutional toxicities, the likelihood of experiencing either fatigue or aches with different doses of one drug at a fixed dose of the second agent was calculated (Table 5)Citation . Patients receiving a lower dose of IFN {alpha}-2a (<=3.75 MU/m2) and full doses of GM-CSF were 6.0-fold more likely to experience grade 2–3 fatigue compared with those receiving a reduced dose of GM-CSF. Among patients receiving full doses of IFN {alpha}-2a, however, the odds of experiencing grade 2–3 fatigue was similar for each of the two GM-CSF dose strata. The odds ratios for these two comparisons were significantly different (P2 = 0.02), suggesting a differential effect according to IFN {alpha}-2a dose. Similarly, when stratified according to GM-CSF dose, patients receiving lower doses of GM-CSF and 5 MU/m2 IFN {alpha}-2a were 4.3-fold more likely to have grade 2–3 fatigue compared with patients receiving lower IFN doses. With full-dose GM-CSF, however, the incidence of grade 2–3 fatigue was high for both IFN dose strata. The odds ratios were again significantly different, suggesting a differential effect according to GM-CSF dose. No such interaction, however, was evident for aches and pains (P2 = 0.25).



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  		Fig. 2. Percentage of cycles complicated by clinical toxicities. The incidence of toxicity of various types is shown for all cycles at 315, 370, and 425 mg/m2 of 5-FU for both the present and prior Phase II studies. The number of assessable cycles per dose for each trial are shown in parentheses. The data are presented as a stacked bar graph with three groupings: grade 1, grade 2, and grade 3–4.

 

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  		Table 5 Interaction between GM-CSF and IFN dose and fatigue

 
IFN {alpha}-2a therapy was reasonably well tolerated, and full doses were administered in 77% of cycles. Eight patients (26%) received an IFN {alpha}-2a dose reduction for the following reasons: fatigue, five patients; fever, two patients; and shortness of breath, one patient. As planned in the protocol, after evaluating the toxicities of the first 14 patients, we decided to omit the seventh daily dose of IFN {alpha}-2a in an attempt to reduce the constitutional toxicities associated with the regimen. Full doses of GM-CSF (250 µg/m2/day) were administered in 84% of the cycles. Eleven patients (35%) ultimately required a dose reduction for the following reasons: fatigue, 3 patients; shortness of breath, WBC >20,000/µl during the prior treatment cycle, and bone pain/myalgias, 2 patients each; local skin reaction and peripheral edema, 1 patient each.

5-FU was administered at or above 370 mg/m2 in 71% of all cycles. For patients receiving four cycles of 5-FU, full dose was maintained in 62% of patients. This percentage decreased slightly to 53 and 54% of patients at cycles 8 and 12, respectively. Cycles were given at 3-week intervals 62% of the time, and 91% were given at 4-week intervals. The delivered dose intensity for all cycles of therapy appeared to be higher in the present trial compared with the prior study without GM-CSF (Fig. 3)Citation . Although the 5-FU dose intensity for patients on the present trial who achieved a partial response was slightly higher than in those with stable disease (median 591 versus 491 mg/m2/week), the difference was not significant.



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  		Fig. 3. 5-FU dose intensity. The delivered 5-FU dose intensity in patients receiving 5-FU/LV/IFN {alpha}-2a/GM-CSF is shown as a box plot in comparison with that delivered in our prior study using the same 5-FU/LV/IFN {alpha}-2a regimen without GM-CSF. Arrow, intended dose intensity of a standard 5-FU regimen with high-dose LV (370 mg/m2, days 1–5 every 4 weeks).

 
Clinical Response.
Six partial responses (21%) were seen in the 28 patients evaluable for response. The responses were observed in colorectal cancer (5 of 17 patients) and gall bladder cancer (1 patient). Thirteen patients had stable disease for >=12 weeks, and 8 of these had minor tumor shrinkage (>25% but <50%). Neither performance status nor age appeared to influence clinical response. All patients have progressed, and the median time to treatment failure was 5.2 months. The time to progression was 12 months or longer in 10 patients (32%). Twenty-seven of 31 patients have died at the time of analysis. The median survival was 14.9 months, and the proportion of patients surviving at 1 and 2 years was 53 and 30%, respectively.

Quality of Life.
Compliance with the FACT-C questionnaire was good, and completed questionnaires were obtained from 94% of study participants at baseline, 89% of 19 patients remaining on study at cycle 6, and 85% of 13 remaining patients at cycle 12. Assessment of the validity of the FACT-C was performed by evaluating its ability to discriminate among patients with different ECOG performance status ratings, using a t test for independent groups. All FACT-C subscale scores, except those that do not measure physical or functional well being, were significantly (P < 0.05) higher at study entry for patients with ECOG 0 as compared with patients with an ECOG performance score of 1. No gender or age differences were evident in any of the FACT-C subscale scores. In addition, the mean (and SD) values at baseline for all subscales were similar to those obtained from three different groups of colorectal cancer patients enrolled on clinical trials at a different institution.3

Paired baseline and during-therapy quality of life data were available for cycle 3 in 24 patients, for cycle 6 in 17 patients, and for cycle 12 in 11 patients. The overall scores for the five general and the colorectal cancer-specific subscales were essentially the same prior to cycles 3, 6, and 12 compared with baseline (data not shown), and a slight improvement in the emotional well being subscale was noted after 3 (P = 0.01) and 6 (P = 0.003) cycles of therapy. Among the cohort of patients who remained on study for 12 cycles, no differences in the various subscales were evident compared with their baseline (Fig. 4)Citation . Thus, despite the toxicity associated with this regimen, patients did not report a decline in their quality of life. Patients receiving 6 days of IFN {alpha}-2a tended to have improved quality of life scores compared with patients receiving IFN {alpha}-2a for 7 days: mean change in overall quality of life scores at cycle 3, -7.6 versus 11.0 (P = 0.01).



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  		Fig. 4. FACT-C quality of life scores. The baseline FACT-C quality of life scores and those obtained prior to the twelfth cycle are shown in the subset of eleven patients who completed 12 cycles of therapy.

 
Intratumoral TS Content.
Paraffin-embedded blocks or unstained slides of tumor tissue were available in 23 patients. The specimens were from primary tumor tissue in 19 patients and from a metastatic site in 1 patient. No tumor was seen in three specimens. Of the 20 specimens in which tumor was seen, only one sample was not interpretable because of a high level of nonspecific staining. Among the 19 informative samples, TS staining was of low intensity (0 or 1) in 11 patients and of high intensity (2 or 3) in 8 patients, whereas the staining pattern was diffuse in 17 tumor samples. No correlation was observed between TS content and prognosis for the 18 patients with low (0–1) and high (2–3) intensity staining in primary tumor samples: median time to progression, 4.9 versus 6.2 months; survival, 14.9 versus 16.2 months, respectively. Fifteen of these 18 patients were evaluable for response. A minor or partial tumor response was seen in three of six patients with low TS content and six of nine patients with high TS expression. The one patient with a biopsy from a liver metastasis had low TS staining; although the patient had nonmeasurable disease, the time to disease progression was prolonged (29 months). Because a long interval between initial biopsy of primary tumor and development of systemic disease is a potential explanation for the lack of predictive information, we recorded the date of tumor biopsy for all patients. The median time (25th and 75th percentiles) from biopsy to study entry was 38 days (20 and 61days, respectively).


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The principal aim of this study was to evaluate whether the addition of GM-CSF to a 5-FU/LV/IFN {alpha}-2a regimen might reduce toxicity and preserve cycle intervals of 3 weeks compared with our previous study using an identical schedule of 5-FU/LV/IFN {alpha}-2a in colorectal cancer patients. Because this is not a randomized study, we recognize that any toxicity comparisons must be viewed with caution. With this caveat in mind, however, the addition of GM-CSF appeared to be associated with significantly less leukopenia and granulocytopenia when either the first cycle, worst grade per patient across all cycles, or all cycles at 5-FU doses of 315–425 mg/m2, were considered. In addition, the severity of mucositis and skin rash also seemed to be lower than expected in the present study. In contrast, fatigue was significantly worse in the present study and is presumed to be due, at least in part, to the combined constitutional effects of IFN {alpha}-2a and GM-CSF. Nausea and vomiting also appeared to be of greater severity in the present study and generally occurred during the administration of 5-FU/LV/IFN-{alpha}. Prophylactic antiemetics were not used in either the present or previous trial. The incidence of grade 2 or worse nausea and vomiting was similar in patients with colorectal primaries versus other gastrointestinal primaries (79% versus 67%) on this trial, and we cannot provide an explanation.

In our previous trial of GM-CSF/5-FU/LV given without IFN {alpha}-2a, grade 3–4 diarrhea was observed in only 6% of patients, arguably much less than expected (21) . The type of GM-CSF used in that trial was an E. coli-derived preparation from Schering Corp. The yeast-derived GM-CSF from Immunex was used in the present trial at the request of the Cancer Therapy Evaluation Program, NCI. The incidence of grade 3–4 diarrhea in the present study was similar to that observed in our Phase II study of 5-FU/LV/IFN {alpha}-2a in the absence of GM-CSF (18) . It is unclear whether the differences between the two preparations of GM-CSF might provide an explanation for this, or if the presence of IFN offset any potential ameliorative effects of GM-CSF. Wadler et al. (30) reported recently the potential effect of G-CSF given with thrice weekly IFN {alpha}-2a and a weekly schedule of 5-FU given either by bolus injection or a high-dose infusion over 24 h. 5-FU dose escalation was feasible with the 24-h infusion schedule but not with the bolus schedule. In that trial, G-CSF clearly ameliorated the granulocytopenia associated with the regimen, but it was unclear if the mucosal toxicities were affected.

Our clinical interest in 5-FU/IFN combinations followed the demonstration that IFN potentiated 5-FU cytotoxicity in cancer cell lines. This synergism was greatest with extended exposure to both 5-FU and IFN {alpha} (16 , 31) . The results of several Phase II studies, including our own, appeared promising, and numerous randomized studies were conducted to evaluate the potential benefit of adding IFN to different 5-FU schedules. While waiting for the completion of these studies, we sought to improve upon our results by adding GM-CSF to our previous regimen, in an attempt to ameliorate toxicity, while maximizing 5-FU dose intensity. The results of several randomized trials in metastatic colorectal cancer have now been published (32, 33, 34, 35, 36, 37) . Unfortunately, none of the studies demonstrated a substantive benefit in favor of the IFN-containing arms, and the latter were generally more toxic. Most of these studies administered IFN {alpha} three times per week, an empirically derived schedule that may not duplicate the experimental conditions associated with maximal 5-FU cytotoxicity. The National Surgical Adjuvant Breast and Bowel Project has reported recently the results of their adjuvant colon cancer protocol C-05 that compared six cycles of LV-modulated 5-FU with or without IFN {alpha}-2a on the NCI schedule (38) . This very large, randomized trial also failed to show a benefit for the IFN {alpha} arm, although clinical toxicity was higher. Therefore, additional studies with 5-FU/LV/IFN {alpha} on this schedule do not appear warranted.

We found no association between tumoral TS content in primary tumor tissue and either response, progression-free survival, or overall survival. Several investigators have evaluated TS content in tumor specimens as a possible prognostic marker in patients with advanced gastrointestinal tumors (39, 40, 41, 42, 43, 44, 45) . Some studies have demonstrated an inverse relationship between TS content, as measured in biopsies from locally advanced primary tumors (40 , 44 , 45) or metastatic disease (39 , 41) , and clinical response and/or survival. In contrast, a British study, in which TS content was evaluated in archival primary tumor tissue, did not show any relationship with response or survival to 5-FU-based therapy (42) . Benson et al. (43) reported recently the preliminary results of a much larger retrospective study that evaluated archival primary tumor samples from patients treated on an advanced colorectal cancer intergroup trial. This study failed to demonstrate any association between TS expression in the primary tumor and survival. Because the British and ECOG studies used archival tissues that were obtained months to years prior to the patient’s subsequent entry into the advanced disease studies, a possible explanation of the lack of association between clinical outcome and TS levels may have been the time difference between tissue procurement and treatment. Because the time difference between primary tissue procurement and treatment in this study was quite short (median, 38 days), this variable is unlikely to contribute to the lack of association between TS levels and outcome. Although patient numbers in our study were small, the results are consistent with the British and ECOG studies. Taken together, the data suggest that once a patient has developed metastatic disease, TS staining of the primary tumor may not provide useful prognostic information. This hypothesis should be tested in prospective studies, with particular emphasis on evaluating the prognostic importance of intratumoral TS expression in both primary and metastatic disease.

An additional aspect to this study was the measurement of quality of life by patient questionnaire. Although the amount and duration of antitumor responses retain their importance in the evaluation of palliative chemotherapy regimens, assessment of quality of life broadens the perspective of the practicing clinician who is attempting to evaluate the toxicity:benefit ratio of new therapies. Quality of life can be difficult to define and measure, and interpretation of results can be problematic. In this study, we used the FACT-C questionnaire, which has been designed to evaluate patients with advanced malignancies in general and patients with colorectal cancer in particular (22) . The FACT-C has demonstrated reliability and validity, is sensitive to change in performance status, and provides consistent results across different colorectal cancer populations (23) . Because patients enrolled in this study had a very good performance status with few cancer-related symptoms, an increase in quality of life was not expected. Our initial hypothesis was that the combined toxicity of 5-FU, LV, IFN {alpha}, and GM-CSF might outweigh any treatment benefits and result in an overall decline in quality of life. There was no discernible decline in overall quality of life from baseline to measurements prior to cycles 3, 6, and 12.

In summary, this formulation of GM-CSF given with 5-FU/LV/IFN {alpha}-2a appeared to substantially reduce the magnitude of the leukocyte and granulocyte toxicity, as might be expected. In addition, however, the severity of mucositis and skin rash seemed to be appreciably less than we observed in our prior Phase II study of 5-FU/LV/IFN {alpha}-2a. We were able to maintain 21-day treatment intervals for most patients, and the delivered 5-FU dose intensity was higher compared with our prior study using the same regimen without GM-CSF. Patients remaining on treatment did not have any measurable reduction in quality of life. The mixed population of patients enrolled in this study precludes assessment of the relative activity of this four-drug regimen as compared with a standard monthly schedule of 5-FU/LV. The question of the impact of 5-FU dose intensity on clinical response, however, remains uncertain.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at National Cancer Institute-Medicine Branch, National Naval Medical Center, 8901 Wisconsin Avenue, Building 8, Room 5101, Bethesda Maryland 20889. Phone: (301) 496-0901; Fax: (301) 480-1683; E-mail: jgrem{at}helix.nih.gov Back

2 The abbreviations used are: 5-FU, 5-fluorouracil; 5-FdUMP, 5-fluoro-2'-deoxyuridine monophosphate; TS, thymidylate synthase; LV, leuco9667vorin; GM-CSF, granulocyte-macrophage colony stimulating factor; FACT, Functional Assessment of Cancer Therapy; NCI, National Cancer Institute; ECOG, Eastern Cooperative Oncology Group; AGC, absolute granulocyte count. Back

3 E. Hahn, Division of Psychosocial Oncology, Rush Cancer Institute, personal communication. Back

Received 8/14/98; revised 4/13/99; accepted 5/18/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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