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Weekly therapy with folinic acid (FA) and high-dose 5-fluorouracil (5-FU) 24-hour infusion in pretreated patients with metastatic colorectal carcinoma
Annals of Oncology 5: 233-237, 1994. C 1994 Kluwer Academic Publishers. Printed in the Netherlands.
Original article Weekly therapy with folinic acid (FA) and high-dose 5-fluorouracil (5-FU) 24-hour infusion in pretreated patients with metastatic colorectal carcinoma A multicenter study by the Association of Medical Oncology of the German Cancer Society (MO) H. J. Weh,1 H. J. Wilke,2 J. Dierlamm,1 U. Klaassen,2 R. Siegmund,3 H. J. Illiger,3 A. Schalhorn,4 E. D. Kreuser,5 U. Hilgenfeld,5 B. Steinke,6 W. Weber,7 O. Burkhard,8 A. Zoller,9 J. Pfitzner,10 R. Subert,11 R. Kriebel12 & D. K. Hossfeld1 1
Department of Oncology and Hematology, Medical University Clinic, Hamburg; 2 University Clinic, Tumour Research, Essen; 3Department of Oncology and Hematology, Stddtische Kliniken, Oldenburg; 'Medical Clinic III, Ludwig Maximilians-University, Klinikum Grofihadem, Munich; 3Department of Oncology and Hematology, Medical University Clinic Steglitz, Berlin; 6Medical Clinic II, University Clinic, Tubingen; 1 Medical Clinic I, Hospital Barmherzige Briider, Trier; 8 Outpatient Clinic, Worms; 9Medical Clinic, Diakonie-Krankenhaus, Schwabisch Hall; i0Medical Clinic, St. Josefs-Hospital, Potsdam; "Department of Hematology and Oncology, Klinikum Schwerin; 12 Outpatient Clinic, Miinster, Germany
disease (PD) was documented. In all other patients therapy was stopped after one course (6 infusions). Background: No effective salvage therapy is known for paResults: 5/57 patients (9%) achieved PR, 32/57 (56%) tients with metastatic colorectal carcinoma progressive after SD, in 19/57 (33%) disease was progressive and one toxic chemotherapy with 5-fluorouracil (5-FU)/folinic acid (FA) death occured. 26/32 patients (81%) with SD or PR after the or 5-FU/alpha interferon (IFN) combinations. The aim of first chemotherapy again obtained SD or PR on high-dose the study was to test whether weekly FA/high-dose 5-FU is 5-FU/FA but only 8/18 (44%) of those with PD after first an effective therapy in pretreated patients with progressive chemotherapy did so. The median duration of SD/PR was 3 metastatic colorectal carcinoma months and the median survival for all patients 8 months Patients and methods: Between January and December (range 3-17+). Apart from one toxic death, toxicity consist1992, 57 patients with metastatic colorectal carcinoma were ing for the most part of mucositis (n = 24), nausea (n — 23), treated with weekly infusions of high-dose 5-fluorouracil diarrhoea (n — 18) and hand-foot syndrome (n = 12) was (5-FU) (2600 mg/m2 as 24-hour infusion) and folinic acid moderate. (FA) (500 mg/m2 as 1-hour infusion prior to 5-FU). All paConclusion: Pretreated patients with metastatic colorectal tients were pretreated with chemotherapy, most of them with carcinoma, notably those with a primary PR or SD, can probregimens containing 5-FU i.v. bolus/FA or 5-FU/alfa inter- ably benefit from weekly high-dose 5-FU/FA. feron (IFN), and all had documented progressive disease at the time of entering the study. In patients with partial remission (PR) or stable disease (SD) with improvement of their Key words: metastatic colorectal carcinoma, high-dose clinical condition, therapy was continued until progressive 5-FU/FA Summary
Introduction Treatment results of systemic chemotherapy in metastatic colorectal cancer are still poor. In previously untreated patients combinations of 5-fluorouracil/folinic acid, considered by most oncologists to be the therapy of choice, result in remission rates of about 23%-31% [1,2], with a median survival of about 12 months. Various phase II studies of 5-fluorouracil/alfa-interferon have yielded similar results [3-5]. In pretreated patients, notably those refractory to systemic chemotherapy, remission rates are much lower. The remission rate to 5-FU/FA in patients pretreated with 5-FU was only 12% [6] and 5-FU/alfa IFN resulted in no remissions in
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13 patients pretreated with 5-FU/FA, 5-FU/methotrexate of 5-FU alone [7]. However, Ardalan et al. [8], using a 24-hour infusion of high-dose 5-FU (2600 mg/ m2) with FA (500 mg/m2), recently reported the astonishingly high remission rate of 30% in 10 patients pretreated with 5-FU/FA. Prompted by these results, from January 1992 to December 1992, the Association of Medical Oncology of the German Cancer Society (AIO) conducted a multicenter study in pretreated patients with metastatic colorectal carcinoma. We used the regimen proposed by Ardalan et al., with the slight modification that FA was given as 1-hour infusion prior to 5-FU.
234
Patients and methods
Results
Between January and December 1992, 57 eligible pretreated patients entered the study. In 42 patients pretreatment consisted of 5-FU/FA combinations. Most of these patients were treated according to three regimens: A monthly regimen, as proposed by Machover et al. [9], with 5-FU (340-400 mg/m2) and FA (200 mg/m2) for 5 consecutive days; a weekly regimen of high-dose FA (500 mg/m2) and 5-FU (600 mg/m2) as used by the Gastrointestinal Tumour Study Group [10]; a continuous infusion for 14 days with 5-FU (200 mg/m2) [11]. Thirteen patients were pretreated with 5-FU/alfa-interferon according to Wadler et al. [7]. The main inclusion criteria were: histologically-proven metastatic colorectal cancer, bidimensionally measurable disease, pretreatment with chemotherapy, progressive disease at the time of study entry, age <75 years, Karnofsky performance status >60%, adequate bone marrow (WBC >4.0 x 1071, platelets > 100 x 1071), liver (serum bilirubine level <2.0 mg/dl) and renal (serum creatinine level <2.0 mg/dl) function.
Clinical data of the 57 patients are given in Table 1. All patients had progressive disease at the time of entering the study. In 29 patients progress was diagnosed while on chemotherapy, and high-dose 5-FU/FA was therefore started immediately. In 27 additional patients progress occurred during a therapy-free interval after achievement of SD or PR by the previous treatment. These patients were treated with high-dose 5-FU/FA after documentation of PD. Response to the first chemotherapy cannot be evaluated in 6 patients. Five patients were pretreated in an adjuvant manner with various combinations of 5-FU/FA. After a median of 10 months (range 5-14) all developed metastatic disease. In one patient response to first therapy and time interval to high-dose 5-FU/FA are unknown.
Treatment and study design
Prior to therapy all patients underwent a subcutaneous port insertion and most patients received the 5-FU infusions via portable infusion pumps (Baxter Healthcare Corporation, Deerfield, USA) on an outpatient basis. One course of therapy consisted of 6 weekly infusions of highdose 5-FU (2600 mg/m2 as 24-hour infusion) and FA (500 mg/m2 as 1-hour infusion prior to 5-FU). Treatment was identical to that used by Ardalan et al. [8] with the exception that FA was not given as a 24-hour infusion but as a 1-hour infusion prior to 5-FU. For practical reasons the FA was given as a 1-hour infusion instead of the 24-hour infusion used by Ardalan et al. 5-FU doses, in most patients within the range of 4 to 5 g, had to be filled into two portable pumps. Administration of FA over 24 hours would have necessitated the use of an impractical third pump. After a therapy-free interval of 2 weeks the second course was administered. Patients with no hematological recovery at that time were withdrawn from the study. In instances of toxicity, reduction of the 5-FU doses, but not of the FA doses, were planned. In instances of grade 3 diarrhoea or mucositis, grade 4 leukopenia, or grade 3 thrombocytopenia, 5-FU doses were reduced to 80% of the previous infusion. If leucocytes had not recovered to >3 x 1071 and thrombocytes to > 100 x 1071 treatment was postponed for one week. In case of life-threatening cardiotoxicity therapy had to be stopped. After each course of therapy, response to treatment was evaluated. In instances of clinical suspicion of PD during treatment, response to therapy was evaluated immediately. After discontinuation of therapy, disease status was evaluated every 6 weeks. In the presence of PR or SD with improvement of the patients' clinical condition, therapy was continued until progressive disease was diagnosed. In instances of SD without (further) improvement of the patients' clinical condition, or PD, therapy was stopped. The WHO criteria for response and toxicity were applied [12]. PR was defined as a 50% or greater decrease in the sum of the products of the largest perpendicular diameters of all measurable lesions for at least 4 weeks without progression of any lesion or the appearance of new lesions. SD was defined as a decrease of lesions for at least 4 weeks which did not reach the criteria of PR, or a less than 25% increase of lesions. PD was defined as a 25% or greater increase in the size of one or more measurable lesions, or the appearance of new lesions. Response rates were compared by using a two-sided chi-square test Survival curves were established by the method of Kaplan and Meier [13]. Factors of independent prognostic value were determined by multivariate analysis according to the Cox model [14].
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Table 1. Clinical data of the 57 patients. No. of patients Median age (range) Male/female Karnofsky performance status 80%-100% 60%-70% Primary site of tumour Colon Rectum Time interval: Primary tumour/ metastatic disease <1 year >1 year Metastatic sites Liver Lung Peritoneum Local relapse Bone Lymph nodes No. of metastatic sites 1 >2 First-line chemotherapy 5-FU/FA regimens 5-FU/alfa IFN No. of different preceding forms of chemotherapy 1 2 3 or more Preceding metastasectomy Response to first chemotherapy Partial remission Stable disease Progressive disease Unknown (adjuvant) Time interval: Preceding chemotherapy/ high-dose 5-FU/FA Median <1 month 2-4 months 5-10 months >10 months Unknown
57 (31-74) yrs 36/21 40 17 37 20 36 21 47 17 5 4 4 3 27 30 42 13 41 11 5 10 13 20 18 6 3.6 (0-24) months 29 12 10 5 1
235
A total of 119 chemotherapy courses were given, 1 course to 28 patients, 2 courses to 15 patients, 3 courses to 6 patients, 4 courses to 2 patients, 5 courses to 2 patients, 6 courses to 3 patients and 7 courses to one patient.
First-line therapy
Response rates
PR"
13
PR: SD: PD:
2 7 3
SD
20
PR: SD: PD:
1 16 3
PD
18
SD: PD:
8 10
6
PR: SD: PD:
2 1 3
One patient is not evaluable for response because she died of therapy-induced toxic effects. Therapy led to 5/57 (9%) PR, 32/57 (56%) SD and 19/57 (33%) PD. Median duration of SD/PR was 3 months. Several clinical variables, such as response to intial chemotherapy, Karnofsky performance status, time interval: primary tumour/diagnosis of metastatic disease, number of metastatic sites, number of different preceding chemotherapy forms, and time interval: previous chemotherapy/start of high-dose 5-FU/FA were tested for their influence on treatment results. As shown in Table 2, only response to previous chemotherapy and number of metastatic sites influenced response rates of high-dose 5-FU/FA in the univariate analysis. However, in the multivariate analysis, possibly due to the small number of patients, none of these parameters were still of independent prognostic. In Table 3 response rates are listed in detail according to response to first-line chemotherapy. Again, it is evident that most patients with PR or SD after high-dose 5-FU/FA had had PR or SD after the first chemotherapy. On the other hand, PD was noted in only 6/33 patients with a previous SD or PR, but in 10/18 patients with previous PD (p - 0.01). The best response rates were achieved Table 2. Treatment results (PR/SD) and survival according to clinical variables'. Clinical variables
Response to previous chemotherapy PR or SD PD
Karnofsky performance status 80%-100% 60%-70% Time interval: Primary tumour/metastatic disease <1 year >1 year No. of metastatic sites 1
>2 No. of preceding forms of chemotherapy 1 >2
Time interval: Preceding chemotherapy/start of high-dose 5-FU/FA <1 month >2 months
No. of patients p-value with PR or SD
Median survival (months)
p-value
26/32 - 81% 8/18-44%
0.01
10 4
0.001
26/35 - 74% 8/15-53%
NS
10 4
0.01
19/31 - 6 1 % 15/19-79%
NS
8 11
NS
20/24 - 83% 14/26-54%
0.03
10 7
NS
25/34 - 74% 9/16-56%
NS
9 6
NS
18/28-64% 16/22-73%
NS
8 9
NS
• Excluded were the 6 patients in whom response to primary therapy could not be evaluated and the patient with toxic death.
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Table 3. Treatment results according to first-line chemotherapy. high-dose 5-FU/FA No of pts.
No of pts.
Unknown (adjuvant)
* One toxic death after 4 infusions of high-dose 5-FU/FA.
in 13 patients in whom primary therapy had resulted in PR or SD, who had had no further chemotherapy and in whom high-dose 5-FU/FA was started after documentation of progressive disease during a therapy-free interval. Two of these patients achieved PR, 10 SD and one patient died of therapy-induced toxic effects. Survival
As of July 1993,37 patients have died and 20 are alive. The median survival from the start of first-line chemotherapy for all patients is 19 months (range 5-41+). Median survival from start of weekly high-dose 5-FU/ FA for all patients is 8 months (range 1—17+), for those with PD 4 months (range 1-9) and for those with SD or PR 12 months (range 3-17+). In the univariate analysis, shown in Table 2, PR or SD after first-line chemotherapy and good performance status favorably influenced survival. In the multivariate analysis, again possibly due to the small number of patients, these two parameters lost their independent prognostic value. Toxicity
Data on toxicity in 48 patients are available (Table 4). One toxic death occurred. This patient developed diarrhoea, grade 4, with severe dehydration, leukopenia, grade 3, and thrombocytopenia grade 1 after 4 infusions. Despite rehydration therapy the patient died some hours after admission. In all other patients diarrhoea, mucositis and nausea were the most frequent toxic effects. They were seen in roughly one-third of the patients. In most patients these toxicities were moderate, but in one patient therapy had to be stopped because of grade 4 nausea. Cardiotoxicity was observed in two patients. One patient developed reversible angina pectoris and another myocardial infraction. In this patient, therapy also had to be stopped. Handfoot syndrome and neurotoxicity, side effects rarely observed in regimens with conventional doses of 5-FU,
236 Survival of 8 months from the start of weekly highdose 5-FU/FA in this prognostically unfavorable group WHO grade of patients is also encouraging. In previously untreated 1 2 0 3 4 patients the median survival of those treated with 5-FU/FA or 5-FU/alfa IFN regimens is generally Leukopenia 1 1 44 2 0 about 10 to 12 months [1, 5, 10, 17]. This suggests that Thrombocytopenia 47 1 0 0 0 therapy with high-dose 5-FU/FA had a favorable influDiarrhoea 28 9 6 3 2 ence on survival in most patients. Favorable response Mucositis 24 14 8 2 0 Nausea 24 11 8 4 1 to previous therapy and, as in other studies [1, 18], Hair loss 41 4 3 0 0 good performance status were predictive of prolonged Hand-foot syndrome 7 36 3 2 0 survival. Neurotoxicity 45 1 1 1 0 As in many other 5-FU/FA or 5-FU/alfa IFN studCardiotoxicity* 46 0 0 1 1 ies one therapy-induced toxic death was observed. In 1 One patient developed angina pectoris and another a myocardial all other patients toxic effects were generally moderate. infarction. Apart from the patient with toxic death, nearly no hematotoxicity was observed. Diarrhoea, mucositis and were observed in 15 patients. Toxicities resulted in dose nausea, the most frequent toxicities, were seen in about reductions of 20% in 6 patients and delay of therapy in 30%-40% of the patients. Frequency and severity were comparable to or even lower than in 5-FU/FA regi4 patients. mens with conventional doses [9,10,17]. However, two types of toxic side effects, hand-foot syndrome and neurotoxicity, observed in 15 patients, seem to be Discussion strongly correlated to high-doses of 5-FU [19-21]. Because of the moderate toxicity of this form of At present no effective systemic chemotherapy is known for patients with metastatic colorectal carci- treatment, the high rate of SD and the relatively favornoma refractory to the 5-FU/FA or 5-FU/TPN regi- able survival, weekly FA/high-dose 5-FU 24-hour inmens. In Wadler's study [7] 5-FU/alfa IFN resulted in fusion may be offered as a reasonable salvage chemono partial remissions among 12 patients pretreated therapy to pretreated patients with progressive metawith 5-FU/FA or methotrexate. In another report no static colorectal carcinoma. Particularly those patients major responses were seen with 5-FU/FA/alfa IFN in with a response to prior chemotherapy have a good 15 patients refractory to 5-FU/FA [15]. For patients chance of again achieving SD. with hepatic metastases alone hepatic arterial perfusion A randomized trial comparing weekly high-dose may be a reasonable treatment with a partial response 5-FU/FA as a 1-hour infusion with 5-FU/FA as a 24rate of 39% and a median survival of 16.8 months, as hour infusion and with optimal supportive care alone reported in a recent paper by Kemeny et al. [16]. Week- seems worthwhile to us. ly therapy with FA/high-dose 5-FU as a 24-hour infusion has recently been reported to result in a remission rate of 30% in patients pretreated with conventional References doses of FA/5-FU [8]. If such a high remission rate could be confirmed this type of therapy would be an 1. Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced excellent salvage treatment option. colorectal cancer Evidence in terms of response rate. J Clin In our larger multicenter study the remission rate of Oncol 1992; 10:896-903. 9% was clearly inferior to that reported by Ardalan et 2. Kemeny N, Lokich JI, Anderson N et al. Recent advances in al. [8]. A possible explanation for our lower remission the treatment of advanced colorectal cancer. Cancer 1993; 71: 9-18. rate is the modified application of FA in our study 3. Kemeny N, Younes A, Seiter K et al. Interferon alpha-2a and (1-hour versus 24-hour infusion in the study of 5-fluorouracil for advanced colorectal carcinoma. Cancer Ardalan et al.). On the other hand, our patients were 1990; 66: 2470-5. probably not completely comparable to those treated 4. Pazdur R, Ajani JA, Patt YZ et al. Phase II study of fluoroin the above-mentioned study. Sixteen out of 57 of our uracil and recombinant interferon alfa-2a in previously untreated advanced colorectal carcinoma. J Clin Oncol 1990; 8: patients were very heavily pretreated with two or more 2027-31. types of different systemic chemotherapy, and in addi5. Weh HJ, Platz D, Braumann D et al. Phase II trial of 5-fluorotion, in 10 patients previous metastasectomy had been uracil and recombinant interferon alfa-2b in metastatic coloperformed, 17 patients had poor performance statuses rectal carcinoma. Eur J Cancer 1992; 28A: 1820-3. and 30 had had at least two metastatic sites. Neverthe6. Arbuck SG. Overview of clinical trials using 5-fluorouracil and less, the achievement of SD in 56% of patients with leucovorin in the treatment of colorectal cancer. Cancer 1989; 63 (Suppl. 6): 1036-44. progressive disease is encouraging. Favourable re7. Wadler S, Schwartz EL, Goldman M et al. Fluorouracil and sponse to previous chemotherapy and only one site of recombinant alfa-2a-interferon: An active regimens against metastatic disease were factors indicating a favourable advanced colorectal carcinoma. J Clin Oncol 1989; 7: 1769response to high-dose 5-FU/FA. 75. Table 4. Main toxicities in 48 patients.
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237 8. Ardalan B, Chua L, Tian E et al. A phase II study of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma. J Clin Oncol 1991; 9: 625-30. 9. Machover D, Goldschmidt E, Chollet P et al. Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid. J Clin Oncol 1986; 4: 68596. 10. Petrelli N, Douglass Jr HO, Herrera L et al. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: A prospective randomized phase III trial. J Clin oncol 1989; 7: 1419-26. 11. Sinnige HAM, Nanninga AG, Verschueren RCJ et al. A phase I-II study of 14-days continuous infusion of 5-fluorouracil with weekly bolus leucovorin in metastatic colorectal carcinoma. Eur J Cancer 1992; 28 A: 885-8. 12. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207-14. 13. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-81. 14. Cox DR. Regression models and life tables. J R Stat Soc (B) 1972; 34:187-200. 15. Bernhard H, Klein O, Meyer zum Biischenfelde KH et al. Treatment of refractory colorectal carcinoma with fluorouracil, folinic acid, and interferon alfa-2a. Sem Oncol 1992; 19 (Suppl. 3): 204-7. 16. Kemeny N, Cohen A, Seiter K et al. Randomized trial of hepatic arterial floxuridine, mitomycin, and carmustine versus floxuridine alone in previously treated patients with liver
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17. 18.
19. 20. 21.
metastases from colorectal cancer. J Clin Oncol 1993; 11: 330-5. Erlichman C, Fine s, Wong A et al. A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 1988; 6: 469-75. Ardalan B, Singh G, Silberman H. A randomized phase I and II study of short-term infusion of high-dose fluorouracil with or without N-(phosphonacetyl)-L-aspartic acid in patients with advanced pancreatic and colorectal cancers. J Clin Oncol 1988; 6: 1053-8. Diaz-Rubio E, Aranda E, Martin M et al. Weekly high-dose infusion of 5-fluorouracil in advanced colorectal cancer. Eur J Cancer 1990; 26: 727-9. O'Dwyer PJ, Paul AR, Waleczak J et al. Phase II study of biochemical modulation of fluorouracil by low dose PALA in patients with colorectal cancer. J Clin Oncol 1990; 8:1497-503. Steinberg J, Erlichman C, Gadalla T et al. Prognostic factors in patients with metastatic colorectal cancer receiving 5-fluorouracil and folinic acid. Eur J Cancer 1992; 28 A: 1817-20.
Received 18 August 1993; accepted 10 November 1993. Correspondence to: H. J. Weh, M.D. Department of Oncology and Hematology Medical University Clinic Martinistr. 52 20246 Hamburg, Germany
Original article Weekly therapy with folinic acid (FA) and high-dose 5-fluorouracil (5-FU) 24-hour infusion in pretreated patients with metastatic colorectal carcinoma A multicenter study by the Association of Medical Oncology of the German Cancer Society (MO) H. J. Weh,1 H. J. Wilke,2 J. Dierlamm,1 U. Klaassen,2 R. Siegmund,3 H. J. Illiger,3 A. Schalhorn,4 E. D. Kreuser,5 U. Hilgenfeld,5 B. Steinke,6 W. Weber,7 O. Burkhard,8 A. Zoller,9 J. Pfitzner,10 R. Subert,11 R. Kriebel12 & D. K. Hossfeld1 1
Department of Oncology and Hematology, Medical University Clinic, Hamburg; 2 University Clinic, Tumour Research, Essen; 3Department of Oncology and Hematology, Stddtische Kliniken, Oldenburg; 'Medical Clinic III, Ludwig Maximilians-University, Klinikum Grofihadem, Munich; 3Department of Oncology and Hematology, Medical University Clinic Steglitz, Berlin; 6Medical Clinic II, University Clinic, Tubingen; 1 Medical Clinic I, Hospital Barmherzige Briider, Trier; 8 Outpatient Clinic, Worms; 9Medical Clinic, Diakonie-Krankenhaus, Schwabisch Hall; i0Medical Clinic, St. Josefs-Hospital, Potsdam; "Department of Hematology and Oncology, Klinikum Schwerin; 12 Outpatient Clinic, Miinster, Germany
disease (PD) was documented. In all other patients therapy was stopped after one course (6 infusions). Background: No effective salvage therapy is known for paResults: 5/57 patients (9%) achieved PR, 32/57 (56%) tients with metastatic colorectal carcinoma progressive after SD, in 19/57 (33%) disease was progressive and one toxic chemotherapy with 5-fluorouracil (5-FU)/folinic acid (FA) death occured. 26/32 patients (81%) with SD or PR after the or 5-FU/alpha interferon (IFN) combinations. The aim of first chemotherapy again obtained SD or PR on high-dose the study was to test whether weekly FA/high-dose 5-FU is 5-FU/FA but only 8/18 (44%) of those with PD after first an effective therapy in pretreated patients with progressive chemotherapy did so. The median duration of SD/PR was 3 metastatic colorectal carcinoma months and the median survival for all patients 8 months Patients and methods: Between January and December (range 3-17+). Apart from one toxic death, toxicity consist1992, 57 patients with metastatic colorectal carcinoma were ing for the most part of mucositis (n = 24), nausea (n — 23), treated with weekly infusions of high-dose 5-fluorouracil diarrhoea (n — 18) and hand-foot syndrome (n = 12) was (5-FU) (2600 mg/m2 as 24-hour infusion) and folinic acid moderate. (FA) (500 mg/m2 as 1-hour infusion prior to 5-FU). All paConclusion: Pretreated patients with metastatic colorectal tients were pretreated with chemotherapy, most of them with carcinoma, notably those with a primary PR or SD, can probregimens containing 5-FU i.v. bolus/FA or 5-FU/alfa inter- ably benefit from weekly high-dose 5-FU/FA. feron (IFN), and all had documented progressive disease at the time of entering the study. In patients with partial remission (PR) or stable disease (SD) with improvement of their Key words: metastatic colorectal carcinoma, high-dose clinical condition, therapy was continued until progressive 5-FU/FA Summary
Introduction Treatment results of systemic chemotherapy in metastatic colorectal cancer are still poor. In previously untreated patients combinations of 5-fluorouracil/folinic acid, considered by most oncologists to be the therapy of choice, result in remission rates of about 23%-31% [1,2], with a median survival of about 12 months. Various phase II studies of 5-fluorouracil/alfa-interferon have yielded similar results [3-5]. In pretreated patients, notably those refractory to systemic chemotherapy, remission rates are much lower. The remission rate to 5-FU/FA in patients pretreated with 5-FU was only 12% [6] and 5-FU/alfa IFN resulted in no remissions in
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13 patients pretreated with 5-FU/FA, 5-FU/methotrexate of 5-FU alone [7]. However, Ardalan et al. [8], using a 24-hour infusion of high-dose 5-FU (2600 mg/ m2) with FA (500 mg/m2), recently reported the astonishingly high remission rate of 30% in 10 patients pretreated with 5-FU/FA. Prompted by these results, from January 1992 to December 1992, the Association of Medical Oncology of the German Cancer Society (AIO) conducted a multicenter study in pretreated patients with metastatic colorectal carcinoma. We used the regimen proposed by Ardalan et al., with the slight modification that FA was given as 1-hour infusion prior to 5-FU.
234
Patients and methods
Results
Between January and December 1992, 57 eligible pretreated patients entered the study. In 42 patients pretreatment consisted of 5-FU/FA combinations. Most of these patients were treated according to three regimens: A monthly regimen, as proposed by Machover et al. [9], with 5-FU (340-400 mg/m2) and FA (200 mg/m2) for 5 consecutive days; a weekly regimen of high-dose FA (500 mg/m2) and 5-FU (600 mg/m2) as used by the Gastrointestinal Tumour Study Group [10]; a continuous infusion for 14 days with 5-FU (200 mg/m2) [11]. Thirteen patients were pretreated with 5-FU/alfa-interferon according to Wadler et al. [7]. The main inclusion criteria were: histologically-proven metastatic colorectal cancer, bidimensionally measurable disease, pretreatment with chemotherapy, progressive disease at the time of study entry, age <75 years, Karnofsky performance status >60%, adequate bone marrow (WBC >4.0 x 1071, platelets > 100 x 1071), liver (serum bilirubine level <2.0 mg/dl) and renal (serum creatinine level <2.0 mg/dl) function.
Clinical data of the 57 patients are given in Table 1. All patients had progressive disease at the time of entering the study. In 29 patients progress was diagnosed while on chemotherapy, and high-dose 5-FU/FA was therefore started immediately. In 27 additional patients progress occurred during a therapy-free interval after achievement of SD or PR by the previous treatment. These patients were treated with high-dose 5-FU/FA after documentation of PD. Response to the first chemotherapy cannot be evaluated in 6 patients. Five patients were pretreated in an adjuvant manner with various combinations of 5-FU/FA. After a median of 10 months (range 5-14) all developed metastatic disease. In one patient response to first therapy and time interval to high-dose 5-FU/FA are unknown.
Treatment and study design
Prior to therapy all patients underwent a subcutaneous port insertion and most patients received the 5-FU infusions via portable infusion pumps (Baxter Healthcare Corporation, Deerfield, USA) on an outpatient basis. One course of therapy consisted of 6 weekly infusions of highdose 5-FU (2600 mg/m2 as 24-hour infusion) and FA (500 mg/m2 as 1-hour infusion prior to 5-FU). Treatment was identical to that used by Ardalan et al. [8] with the exception that FA was not given as a 24-hour infusion but as a 1-hour infusion prior to 5-FU. For practical reasons the FA was given as a 1-hour infusion instead of the 24-hour infusion used by Ardalan et al. 5-FU doses, in most patients within the range of 4 to 5 g, had to be filled into two portable pumps. Administration of FA over 24 hours would have necessitated the use of an impractical third pump. After a therapy-free interval of 2 weeks the second course was administered. Patients with no hematological recovery at that time were withdrawn from the study. In instances of toxicity, reduction of the 5-FU doses, but not of the FA doses, were planned. In instances of grade 3 diarrhoea or mucositis, grade 4 leukopenia, or grade 3 thrombocytopenia, 5-FU doses were reduced to 80% of the previous infusion. If leucocytes had not recovered to >3 x 1071 and thrombocytes to > 100 x 1071 treatment was postponed for one week. In case of life-threatening cardiotoxicity therapy had to be stopped. After each course of therapy, response to treatment was evaluated. In instances of clinical suspicion of PD during treatment, response to therapy was evaluated immediately. After discontinuation of therapy, disease status was evaluated every 6 weeks. In the presence of PR or SD with improvement of the patients' clinical condition, therapy was continued until progressive disease was diagnosed. In instances of SD without (further) improvement of the patients' clinical condition, or PD, therapy was stopped. The WHO criteria for response and toxicity were applied [12]. PR was defined as a 50% or greater decrease in the sum of the products of the largest perpendicular diameters of all measurable lesions for at least 4 weeks without progression of any lesion or the appearance of new lesions. SD was defined as a decrease of lesions for at least 4 weeks which did not reach the criteria of PR, or a less than 25% increase of lesions. PD was defined as a 25% or greater increase in the size of one or more measurable lesions, or the appearance of new lesions. Response rates were compared by using a two-sided chi-square test Survival curves were established by the method of Kaplan and Meier [13]. Factors of independent prognostic value were determined by multivariate analysis according to the Cox model [14].
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Table 1. Clinical data of the 57 patients. No. of patients Median age (range) Male/female Karnofsky performance status 80%-100% 60%-70% Primary site of tumour Colon Rectum Time interval: Primary tumour/ metastatic disease <1 year >1 year Metastatic sites Liver Lung Peritoneum Local relapse Bone Lymph nodes No. of metastatic sites 1 >2 First-line chemotherapy 5-FU/FA regimens 5-FU/alfa IFN No. of different preceding forms of chemotherapy 1 2 3 or more Preceding metastasectomy Response to first chemotherapy Partial remission Stable disease Progressive disease Unknown (adjuvant) Time interval: Preceding chemotherapy/ high-dose 5-FU/FA Median <1 month 2-4 months 5-10 months >10 months Unknown
57 (31-74) yrs 36/21 40 17 37 20 36 21 47 17 5 4 4 3 27 30 42 13 41 11 5 10 13 20 18 6 3.6 (0-24) months 29 12 10 5 1
235
A total of 119 chemotherapy courses were given, 1 course to 28 patients, 2 courses to 15 patients, 3 courses to 6 patients, 4 courses to 2 patients, 5 courses to 2 patients, 6 courses to 3 patients and 7 courses to one patient.
First-line therapy
Response rates
PR"
13
PR: SD: PD:
2 7 3
SD
20
PR: SD: PD:
1 16 3
PD
18
SD: PD:
8 10
6
PR: SD: PD:
2 1 3
One patient is not evaluable for response because she died of therapy-induced toxic effects. Therapy led to 5/57 (9%) PR, 32/57 (56%) SD and 19/57 (33%) PD. Median duration of SD/PR was 3 months. Several clinical variables, such as response to intial chemotherapy, Karnofsky performance status, time interval: primary tumour/diagnosis of metastatic disease, number of metastatic sites, number of different preceding chemotherapy forms, and time interval: previous chemotherapy/start of high-dose 5-FU/FA were tested for their influence on treatment results. As shown in Table 2, only response to previous chemotherapy and number of metastatic sites influenced response rates of high-dose 5-FU/FA in the univariate analysis. However, in the multivariate analysis, possibly due to the small number of patients, none of these parameters were still of independent prognostic. In Table 3 response rates are listed in detail according to response to first-line chemotherapy. Again, it is evident that most patients with PR or SD after high-dose 5-FU/FA had had PR or SD after the first chemotherapy. On the other hand, PD was noted in only 6/33 patients with a previous SD or PR, but in 10/18 patients with previous PD (p - 0.01). The best response rates were achieved Table 2. Treatment results (PR/SD) and survival according to clinical variables'. Clinical variables
Response to previous chemotherapy PR or SD PD
Karnofsky performance status 80%-100% 60%-70% Time interval: Primary tumour/metastatic disease <1 year >1 year No. of metastatic sites 1
>2 No. of preceding forms of chemotherapy 1 >2
Time interval: Preceding chemotherapy/start of high-dose 5-FU/FA <1 month >2 months
No. of patients p-value with PR or SD
Median survival (months)
p-value
26/32 - 81% 8/18-44%
0.01
10 4
0.001
26/35 - 74% 8/15-53%
NS
10 4
0.01
19/31 - 6 1 % 15/19-79%
NS
8 11
NS
20/24 - 83% 14/26-54%
0.03
10 7
NS
25/34 - 74% 9/16-56%
NS
9 6
NS
18/28-64% 16/22-73%
NS
8 9
NS
• Excluded were the 6 patients in whom response to primary therapy could not be evaluated and the patient with toxic death.
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Table 3. Treatment results according to first-line chemotherapy. high-dose 5-FU/FA No of pts.
No of pts.
Unknown (adjuvant)
* One toxic death after 4 infusions of high-dose 5-FU/FA.
in 13 patients in whom primary therapy had resulted in PR or SD, who had had no further chemotherapy and in whom high-dose 5-FU/FA was started after documentation of progressive disease during a therapy-free interval. Two of these patients achieved PR, 10 SD and one patient died of therapy-induced toxic effects. Survival
As of July 1993,37 patients have died and 20 are alive. The median survival from the start of first-line chemotherapy for all patients is 19 months (range 5-41+). Median survival from start of weekly high-dose 5-FU/ FA for all patients is 8 months (range 1—17+), for those with PD 4 months (range 1-9) and for those with SD or PR 12 months (range 3-17+). In the univariate analysis, shown in Table 2, PR or SD after first-line chemotherapy and good performance status favorably influenced survival. In the multivariate analysis, again possibly due to the small number of patients, these two parameters lost their independent prognostic value. Toxicity
Data on toxicity in 48 patients are available (Table 4). One toxic death occurred. This patient developed diarrhoea, grade 4, with severe dehydration, leukopenia, grade 3, and thrombocytopenia grade 1 after 4 infusions. Despite rehydration therapy the patient died some hours after admission. In all other patients diarrhoea, mucositis and nausea were the most frequent toxic effects. They were seen in roughly one-third of the patients. In most patients these toxicities were moderate, but in one patient therapy had to be stopped because of grade 4 nausea. Cardiotoxicity was observed in two patients. One patient developed reversible angina pectoris and another myocardial infraction. In this patient, therapy also had to be stopped. Handfoot syndrome and neurotoxicity, side effects rarely observed in regimens with conventional doses of 5-FU,
236 Survival of 8 months from the start of weekly highdose 5-FU/FA in this prognostically unfavorable group WHO grade of patients is also encouraging. In previously untreated 1 2 0 3 4 patients the median survival of those treated with 5-FU/FA or 5-FU/alfa IFN regimens is generally Leukopenia 1 1 44 2 0 about 10 to 12 months [1, 5, 10, 17]. This suggests that Thrombocytopenia 47 1 0 0 0 therapy with high-dose 5-FU/FA had a favorable influDiarrhoea 28 9 6 3 2 ence on survival in most patients. Favorable response Mucositis 24 14 8 2 0 Nausea 24 11 8 4 1 to previous therapy and, as in other studies [1, 18], Hair loss 41 4 3 0 0 good performance status were predictive of prolonged Hand-foot syndrome 7 36 3 2 0 survival. Neurotoxicity 45 1 1 1 0 As in many other 5-FU/FA or 5-FU/alfa IFN studCardiotoxicity* 46 0 0 1 1 ies one therapy-induced toxic death was observed. In 1 One patient developed angina pectoris and another a myocardial all other patients toxic effects were generally moderate. infarction. Apart from the patient with toxic death, nearly no hematotoxicity was observed. Diarrhoea, mucositis and were observed in 15 patients. Toxicities resulted in dose nausea, the most frequent toxicities, were seen in about reductions of 20% in 6 patients and delay of therapy in 30%-40% of the patients. Frequency and severity were comparable to or even lower than in 5-FU/FA regi4 patients. mens with conventional doses [9,10,17]. However, two types of toxic side effects, hand-foot syndrome and neurotoxicity, observed in 15 patients, seem to be Discussion strongly correlated to high-doses of 5-FU [19-21]. Because of the moderate toxicity of this form of At present no effective systemic chemotherapy is known for patients with metastatic colorectal carci- treatment, the high rate of SD and the relatively favornoma refractory to the 5-FU/FA or 5-FU/TPN regi- able survival, weekly FA/high-dose 5-FU 24-hour inmens. In Wadler's study [7] 5-FU/alfa IFN resulted in fusion may be offered as a reasonable salvage chemono partial remissions among 12 patients pretreated therapy to pretreated patients with progressive metawith 5-FU/FA or methotrexate. In another report no static colorectal carcinoma. Particularly those patients major responses were seen with 5-FU/FA/alfa IFN in with a response to prior chemotherapy have a good 15 patients refractory to 5-FU/FA [15]. For patients chance of again achieving SD. with hepatic metastases alone hepatic arterial perfusion A randomized trial comparing weekly high-dose may be a reasonable treatment with a partial response 5-FU/FA as a 1-hour infusion with 5-FU/FA as a 24rate of 39% and a median survival of 16.8 months, as hour infusion and with optimal supportive care alone reported in a recent paper by Kemeny et al. [16]. Week- seems worthwhile to us. ly therapy with FA/high-dose 5-FU as a 24-hour infusion has recently been reported to result in a remission rate of 30% in patients pretreated with conventional References doses of FA/5-FU [8]. If such a high remission rate could be confirmed this type of therapy would be an 1. Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced excellent salvage treatment option. colorectal cancer Evidence in terms of response rate. J Clin In our larger multicenter study the remission rate of Oncol 1992; 10:896-903. 9% was clearly inferior to that reported by Ardalan et 2. Kemeny N, Lokich JI, Anderson N et al. Recent advances in al. [8]. A possible explanation for our lower remission the treatment of advanced colorectal cancer. Cancer 1993; 71: 9-18. rate is the modified application of FA in our study 3. Kemeny N, Younes A, Seiter K et al. Interferon alpha-2a and (1-hour versus 24-hour infusion in the study of 5-fluorouracil for advanced colorectal carcinoma. Cancer Ardalan et al.). On the other hand, our patients were 1990; 66: 2470-5. probably not completely comparable to those treated 4. Pazdur R, Ajani JA, Patt YZ et al. Phase II study of fluoroin the above-mentioned study. Sixteen out of 57 of our uracil and recombinant interferon alfa-2a in previously untreated advanced colorectal carcinoma. J Clin Oncol 1990; 8: patients were very heavily pretreated with two or more 2027-31. types of different systemic chemotherapy, and in addi5. Weh HJ, Platz D, Braumann D et al. Phase II trial of 5-fluorotion, in 10 patients previous metastasectomy had been uracil and recombinant interferon alfa-2b in metastatic coloperformed, 17 patients had poor performance statuses rectal carcinoma. Eur J Cancer 1992; 28A: 1820-3. and 30 had had at least two metastatic sites. Neverthe6. Arbuck SG. Overview of clinical trials using 5-fluorouracil and less, the achievement of SD in 56% of patients with leucovorin in the treatment of colorectal cancer. Cancer 1989; 63 (Suppl. 6): 1036-44. progressive disease is encouraging. Favourable re7. Wadler S, Schwartz EL, Goldman M et al. Fluorouracil and sponse to previous chemotherapy and only one site of recombinant alfa-2a-interferon: An active regimens against metastatic disease were factors indicating a favourable advanced colorectal carcinoma. J Clin Oncol 1989; 7: 1769response to high-dose 5-FU/FA. 75. Table 4. Main toxicities in 48 patients.
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Received 18 August 1993; accepted 10 November 1993. Correspondence to: H. J. Weh, M.D. Department of Oncology and Hematology Medical University Clinic Martinistr. 52 20246 Hamburg, Germany