- Email: [email protected]
leucovorin-based chemotherapy
Annals of Oncology 12 709-714. 2001 © 2001 Klimer Academic Publishers Printed in the Netherlands
Original article Second-line treatment with oxaliplatin + raltitrexed in patients with advanced colorectal cancer failing fluoropyrimidine/leucovorin-based chemotherapy W. Scheithauer,1 G.V. Kornek,1 B. Schuell,1 H. Ulrich-Pur,1 M. Penz,1 M. Raderer,1 F. Lang,2 B. Schneeweiss,3 A. Lenauer 4 & D. Depisch4 'Department ofInternal Medicine I. Division of Oncology, University Medical School, Vienna. 2 Department of Surgery, General Hospital of Neunkirchen, Neunkirchen; 3Department of Internal Medicine, General Hospital of Kirchdorf, Kirchdorf/Krems, ADepartment of Surgery. Wr Neustadt General Hospital, Wr Neustadt. Austria
Summary Background. To evaluate the efficacy and tolerance of combined raltitrexed and oxaliplatin in patients with advanced colorectal cancer pretreated with ftuoropyrimidine-leucovorin-based chemotherapy. Patients and methods: Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within six months after withholding palliative chemotherapy with fluoropyrimidines-leucovorin ± irinotecan, participated in this study. Treatment consisted of oxaliplatin 130 mg/m 2 and raltitrexed 3.0 mg/m 2 both given on day 1 every three weeks for a total of eight courses unless prior evidence of progressive disease. Results: The overall objective response rate was 33.3% for all 36 evaluable patients (95% confidence interval (CI): 18.6%51%). Seventeen additional patients (47.2%) had stable disease, and only seven (19.5%) progressed. The median progression-
Introduction Many patients with advanced colorectal cancer are candidates for therapeutic options after failure of 5-fiuorouracil (5-FU)-based therapy, because virtually all of them will experience disease progression after a median time of only about four to six months [1, 2]. Until recently, these patients had few options, but now regional treatments and various different systemic chemotherapy regimens exist [3]. The topoisomerase I inhibitor irinotecan has been proven to be of particular value in this treatment setting, and because of a significant survival advantage and a clinical benefit when compared to best supportive care or continuous infusional 5-FU, its use as single agent is now considered standard secondline therapy/new reference for forthcoming clinical trials [4, 5]. However, the survival gain in the latter study was only 2.3 months, and this small benefit, the rather high costs of treatment, and the fact that irinotecan is associated with significant toxicity (despite rigorous implementation of common guidelines for the management of adverse reactions) have been impediments to its universal Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/709/168972 by guest on 05 June 2018
free survival was 6.5 months (range 1.2-14.0). After a median follow-up time of 12 months, 23 patients (63.8%) are still alive. The tolerance of treatment was acceptable with only 8 of 36 patients (22%) experiencing grade 3 or 4 neutropenia. Grade 3 non-haematological adverse reactions included peripheral sensory neuropathy in three, asthenia in one, diarrhea in two, and clinically insignificant increase in serum transaminases in two patients, respectively. Conclusions Our data suggest that the combination of oxaliplatin and raltitrexed has substantial antitumour activity in patients with progressive fluoropyrimidine-leucovorin ± irinotecan pretreated colorectal cancer. Because of its favorable toxicity profile and convenient three-weekly outpatient administration schedule, further evaluation of this regimen seems warranted. Key words: colorectal cancer, oxaliplatin, raltitrexed, secondline chemotherapy
adoption [6, 7]. Another problem with the use of irinotecan in the second-line treatment setting is related to the expected increased use of its combination with 5-FU-LV in front-line therapy. In two recently published randomised controlled trials, such combination regimens have resulted in significantly higher objective response rates, progression-free and overall survival when compared with bolus or continuous infusional 5-FU-LV [8, 9]. Similarly, the combination of 5-FU and irinotecan is currently being evaluated in surgically resected patients, who will eventually recur after adjuvant treatment. Thus for various reasons, there is an urgent need for alternative, non-cross resistant, effective and non-toxic regimens for the treatment of patients failing 5-FU-LV ± irinotecan regimens. The specific thymidilate synthase inhibitor raltitrexed and the third-generation 1,2-diaminocyclohexane-platinum derivate oxaliplatin, which both exhibit incomplete cross-resistance with 5-FU, have demonstrated antitumour efficacy in previously untreated as well as 5-FULV pretreated patients with advanced colorectal cancer [10-14]. Since preclinical and clinical data indicate at
710 least an additive effect of raltitrexed and oxaliplatin in various tumour types [15-18], and the toxicity profile of these two drugs does not suggest a synergism when used in combination, the present study was undertaken. The specific aim of our study was to determine the antitumour potential of this combination in patients with advanced colorectal cancer failing 5-FU-LV ± irinotecan regimens, and to reconfirm its favorable toxicity profile as documented in two recently published studies in patients with previously untreated disease [17, 18].
Patients and methods
stimulating factor (G-CSF) was recommended in the former group of patients. Any patient who required more than two weeks for recovery of adverse reactions was taken off the study.
Pretreatment and follow-up evaluation Prior to initiating chemotherapy, all patients were assessed by physical examination, routine haematology and biochemistry analyses, chest X-ray, and CT scans to define the extent of the disease. Complete blood cell counts with platelet and differential counts were obtained weekly during chemotherapy, and serum chemistries were repeated at least once every course. Subjective symptoms, physical examination, performance status and all adverse reactions were recorded before each treatment cycle. Tumour size was measured every eight weeks by CTscan, X-ray, or any other technique that allows retrospective and independent reassessment.
Patient selection Patients with histologically confirmed metastatic or locally recurrent colorectal cancer and bidimensionally measurable disease (defined as presence of at least one index lesion capable of two-dimensional measurement by computed tomographic (CT) scan outside any irradiated zone and greater than 2 cm in diameter) were considered candidates for this study. All patients must have developed progressive disease while receiving or within six months after discontinuing palliative or adjuvant fluoropyrimidine-based chemotherapy. Eligibility criteria also included age between 19 and 75 years, a World Health Organisation (WHO) performance status of 0-2, a life expectancy of at least three months, adequate bone marrow reserve (leukocyte count >4000/ul, platelet count > 100,000/ul), adequate renal (serum creatinine concentration
Assessment of response The primary efficacy end point was response rate, which was evaluated according to WHO criteria [19]. A CR required the complete disappearance of all objective evidence of disease on two separate measurements at least 4 weeks apart. A PR was defined as a more than 50% reduction in the sum of the products of the perpendicular diameters of measurable bidimensional lesions without a CR, no progression of any lesion by more than 25% or the appearance of any new lesion, confirmed on two separate measurements that were four weeks apart. In case of bone metastases, CR was attributed only when there was complete disappearance of all lesions on X-ray, and PR was attributed when decrease in size and/or recalcification of lytic lesions occurred. Decreased density of blastic lesions or improvement in bone scan positive. X-ray negative disease were not taken into account. Progressive disease (PD) was defined as the enlargement of any existing measurable lesion by more than 25% or the development of new metastatic lesions. Stable disease (SD) was any measurement that did not fulfill the criteria for CR, PR or PD. All tumour measurements were reviewed and confirmed by an independent panel of oncologists and radiologists to confirm responses and the date of progression Secondary efficacy end points included the duration of response (measured from the onset of the best response to the date of disease progression), progression-free survival (calculated from the start of treatment to the time of progression or relapse), and overall survival time.
Treatment protocol Statistical methods The treatment regimen was based on two previously published phase I — II studies, indicating that a dose-intensity as high as the sum of the Using standard statistical methods, an optimal two-stage design was recommended doses of each agent given alone can be safely adminisemployed in the protocol [20]. If no CR or PR was noted in the first tered [16, 18] Chemotherapy thus consisted of raltitrexed 3.0 mg/m 2 cohort of 14 patients, a response rate of > 15% could be excluded with administered as a 15 min intravenous (i.v.) infusion, plus oxaliplatin 95% confidence and accrual would stop. If at least one CR or PR was 130 mg/m 2 , diluted in 250 ml of 5% glucose, administered as a twoobserved, more than 30 patients were to be entered in the study to hour i.v. infusion. Treatment courses were repeated every three weeks determine the response rate more accurately For the response rates. fora total of eight courses unless prior evidence of progressive disease 95% CIs were calculated as previously described [21] The distribution Concomitant medications routinely given before cytotoxic drug adminof time to death from date of study entry was estimated using the istration included 8 mg ondansetron and S mg dexamethasone Kaplan-Meier product-limit method [22]. Toxicity and dosage modification guidelines
Adverse reactions were evaluated according to WHO criteria [19] In the event of grade 4 haematological or any other severe ( > grade 2) organ toxicity in individual patients, the dose of oxaliplatin and raltitrexed was reduced by 25% for subsequent courses. Oxaliplatin was discontinued if paraesthesia associated with pain or functional impairment persisted between treatment cycles, or if a patient had experienced any other severe neurotoxicity. Treatment could be delayed for up to two weeks if symptomatic toxicity persisted and/or the neutrophil count ( A N Q was lower than 1000/jJ and/or the platelet count lower than 75.000/|jl. Administration of granulocyte colony-
Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/709/168972 by guest on 05 June 2018
Results Patient characteristics Between January 1999 and March 2000, a total of 36 patients took part in this trial, all of whom were considered evaluable for response and toxicity assessment. The demographic data, sites of metastatic tumor, and prior
711 therapies are listed in Table 1. The patients' median age was 66 years. Almost two-thirds of the study population (61%) were male, and the large majority (81%) had a WHO performance status of 0 or 1. Except for 10 patients, all had multiple metastases involving 2 or more organ systems. The predominant sites of metastases were liver in 30, lung in 12, abdominopelvic mass in 23, and soft-tissue and/or bone in 10 patients. Two patients had tumour recurrence while receiving adjuvant therapy with FU-LV, all others progressed while receiving (n = 14) or within six months after discontinuing palliative fluoropyrimidine-leucovorin-based first-line chemotherapy. The median duration off first-line chemotherapy was 2.5 months (range 1-6 months). Previous therapy consisted of i.v. bolus 5-FU-LV (NCCTG/Mayo-regimen) in 17 patients, bi-monthly continuous infusional doublemodulated 5-FU-LV (deGramont regimen) without (n — 6) or combined with irinotecan (n - 11), and regional intra-arterial 5-FU-LV in 2 patients, respectively. Two patients with rectal cancer had received prior palliative pelvic radiation therapy. A total of 219 courses were administered to the 36 patients. The median number of treatment cycles was 6 (range 1-8), and the median duration of follow-up at the time of this analysis was 12 months (range 6-20 months). Response to therapy Antitumour responses according to the patients' pretreatment results are shown in Table 2. The overall response rate was 33.3% for all 36 patients (95% CI: 18.6%-51%). All responses were partial; the median time to response was 3 months (range 2.5^4 months), and their median duration was 6.2 months (range 3—10.5 months). Seventeen additional patients (47.2%) showed stabilization of disease lasting more than three months (median 5, range 3.5-11.8 months), and in only seven patients (19.5%) was the disease progression not influenced by chemotherapy. The median progression-free survival in all 36 patients was 6.5 months, within a range of 1.2-14.0 months. As shown in Table 2, the subset of patients who were most likely to benefit from secondline therapy with oxaliplatin + raltitrexed were those with prior response. In this subgroup of patients, 6 of 10 exhibited PR as compared to 1 out of 10 among those who had failed first-line 5-FU-LV-based chemotherapy. The difference in terms of objective response rate, median progression-free and overall survival time between patients who experienced disease progression while off previous 5-FU-based therapy and those who progressed while on previous 5-FU-based therapy (defined as clinically resistant 5-FU disease), however, did not reach the level of statistical significance. Response rates in these two subsets of patients were 9 of 20 (45%) and 3 of 16 (18.8%; P = 0.192). The corresponding values for median progression-free and overall survival were 7.1 vs. 5.35 months (P - 0.108), and > 12.5 vs. > 10.8 months (P - 0.231), respectively. Similarly, no difference in response activity was noted between the 25 patients Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/709/168972 by guest on 05 June 2018
Table I. Patient characteristics Variable
Number of patients
Number of patients Sex Male Female Age (years) Median Range WHO performance status 0 1 2 Location of primary tumour Colon Rectum Histologic grading Grade 1 Grade 2 Grade 3 Location of metastases Liver Lung Abdominopelvic mass Soft-tissue Bone Number of metastatic sites Single Multiple First-line chemotherapy Bolus 5-FU-LV Continuous inf. 5-FU-LV Cont inf 5-FU-LV-irinotecan Regional intrahepatic 5-FU-LV
36 22 14 66 41-75 15 14 7 20 16 4 27 5 30 12 23 6 4 10 26 17 6 11 2
Table 2. Response rate according to prior treatment response Response to treatment
first-line
Number of patients
PR n (%)
SD n (%)
PD n (%)
Partial response (PR) Stable disease (SD) Progression (PD)
10 16 10
6(16.6) 5(13.9) 1(2.8)
3(8.3) 9(25.0) 5(13.9)
1(2.8) 2(5.6) 4(11.1)
Total
36
12(33.3)
17(47.2)
7(19.5)
who had received 5-FU-LV (36%) and those (n = 11) pretreated with 5-FU-LV + irinotecan (27.3%; P - 0.769). Toxicity All 36 patients, who received a total of 219 courses of therapy, were assessable for toxicity. Side effects associated with treatment are listed in Table 3. Haematological toxicity was commonly observed, though it was generally mild to moderate and fully reversible within one week in all patients. Leukopenia occurred in 24 patients (67%), and was grade 3 or 4 in only 5 cases (14%). The median nadir WBC count was 3850/ml (range 8008600/ml). The variations in neutrophil counts paralleled those of WBCs; the median nadir of ANCs was 2180/ml (range 420-5670/ml). Thrombocytopenia was relatively
712 Table 3 Highest grade of treatment-associated toxicity (n = 36). Toxicity
WHO grade 1 n (%)
2 n (%)
3 n (%)
4 n (%)
12(33) 11 (31) 5(14) 10(28) 1(3) 6(17) 5(14) 3(8) 10(28) 5(14) 8(22) 7(19) 5(14)
7(19) 7(19) 4(11) 6(17) 1(3) 5(14) 4(11) 1(3) 8(22) 13(36) 4(11) -
4(11) 6(17) 1(3) 1(3) _
M3)
The mean dose of oxaliplatin was 40.34 mg/m2/week, (range 12.37-43.3 mg/m2/week), and the mean dose of raltitrexed was 0.986 mg/m2/week (range 0.87-1.0 mg/m2/week). Survival
Leukopenia Granulocytopenia Thrombocytopenia Anaemia Infection Nausea/emesis Diarrhea Stomatitis Liver function Alopecia Peripheral neuropathy Asthenia Pain at injection site
2(6) _ K3) _ 3(8) 1(3) -
2(6) _ _ _ _ _ _ _ _ _ -
As of September 2000, with a median follow-up duration of 12 months (range 6-20 months), 13 of all 36 patients entered had died because of progressive disease. Twenty-three patients (64%) are still alive with metastatic disease, of whom twenty (56%) had received or currently undergo other cytotoxic chemotherapy (irinotecan: n - 13, capecitabine: n - 7). The median survival duration has not been reached yet and was >11.0 months (range 1.5-17.5+ months) at the time of this report.
uncommon and generally mild; it was noted in a total of Discussion 10 patients (28%), and only one of them had WHO grade 3 (1%). Accordingly, there were no episodes of In agreement with the study rationale, i.e., in vitro and in bleeding. The median nadir platelet count was 168,000/ml vivo evidence of an at least additive effect of raltitrexed (range 45,000—418,000/ml) with no evidence of a cumu- and oxaliplatin [15-18], therapeutic results achieved in lative nature of this side effect. Only 1 patient (3%) this multicenter phase II trial suggest an encouraging developed grade 3 anaemia requiring packed RBC antitumour activity of this combination in patients with transfusion, whereas mild anaemia was recorded in 16 metastatic, 5-FU-LV ± irinotecan pretreated colorectal patients (47%). The median nadir of haemoglobin was cancer. The objective response rate was 33% (95% CI: 12.3 g/dl (range 7.2-16.9 g/dl). Two patients developed 19%-51%), and partial responses lasted for a median documented infection, both without the requirement of duration of 6.2 months. Together with 17 additional hospitalisation. patients achieving stable disease, tumour progression Among non-haematological adverse reactions, tran- could be abrogated in as many as 80%. Even if one is sient mild to moderate gastrointestinal toxicities were not willing to accept objective response as a valid end frequently encountered. Grade 3 diarrhea, however, was point in clinical trials, the therapeutic potential of this noted only in two patients. Other non-myelosuppressive combination regimen is supported by the observed protoxicities included peripheral sensory neuropathy and gression-free and overall survival time of 6.5 and > 11 asthenia, which were rated severe in 3 and 1 case, months, respectively. Comparable therapeutic results in respectively. Clinically insignificant elevations in liver pretreated patients with advanced colorectal cancer, in functional parameters occurred in 20 patients, partial fact, have only been reported in a few studies using alopecia and pain at the injection site in 5 patients each. chronomodulated 5-FU plus oxaliplatin [23] or irinoteSix patients (17%) had at least one treatment delay of can plus oxaliplatin [24]. Our data seem to compare one week at some time during therapy, and the total favorably with most other salvage regimens [3], includnumber of delayed courses was nine (4.1%). The reasons ing irinotecan monotherapy that has been postulated as for delayed courses were haematological in five (neutro- new standard and reference second-line treatment for penia and/or thrombocytopenia), non-haematological in future trials [9]. Median PFS was reported to be 4.2 two (infection, port-a-cath implantation), and personal months and median survival 10.8 months in the irinotecan winner arm in this trial [9]. Because of differences in reasons in two. patients' pretreatment characteristics, however, a selecFour patients (11%) had a 25% dose reduction of tion bias can not be ruled out, and any superiority of cytotoxic drugs during treatment according to the study combined raltitrexed + oxaliplatin remains to be deterprotocol, because of grade 4 neutropenia (n - 2) or mined in future randomised trials. grade 3 diarrhea (n = 2). Oxaliplatin was discontinued in three patients because of progressive sensory neuroAdditional potential advantages of the investigated pathy (after four, six, and seven courses), and in one combination regimen may represent its comfortable patient due to reproducible laryngopharyngeal dysaes- administration schedule, i.e., a 2'/2-hour outpatient treatthesia. One patient warranted early discontinuation of ment without the requirement of technically complex treatment for personal reasons after four courses. Dose and cost-intensive infusional devices plus the favorable intensity was calculated for each patient and for each toxicity profile: severe adverse events requiring a 25% drug. The mean given dose intensity of oxaliplatin was dose attenuation of both chemotherapeutic drugs and/or 93.1% of the projected dose, and 98.6% for raltitrexed. early discontinuation of oxaliplatin (due to progressive Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/709/168972 by guest on 05 June 2018
713 cumulative sensory neuropathy) were observed in only six patients, and < 5% of all treatment courses were to be delayed for toxicity reasons, both resulting in an approximately 95% mean dose intensity of the projected drug doses. Despite its use as second-line therapy, the raltitrexed-oxaliplatin combination regimen seems to be less myelosuppressive and associated with less nonhaematological adverse reactions including diarrhea and vomiting compared to irinotecan [8, 9], as well as oxaliplatin plus bolus [25], flat continuous infusion [26], and even chronomodulated FU [27]. As noted by others [16] and in our previous first-line therapy trial [18], apart from transient and clinically insignificant elevations in liver functional parameters, it seems possible that raltitrexed exhibits the lowest incidence of severe toxicities of all fluoropyrimidine-based regimens when combined with oxaliplatin. Due to its cumulative nature and the limited duration of treatment according to our study protocol, even oxaliplatin-induced neurotoxicity did not represent a problem: in all three patients who had experienced grade 3 peripheral sensory neuropathy, functional impairment regressed to ^ grade 2 after 2.54 months. In conclusion, our results suggest that this combination may be considered as effective salvage regimen in leucovorin-modulated fluoropyrimidine pretreated patients with progressive metastatic colorectal cancer. Although the number of patients failing 5-FU-LV + irinotecan might have been too small to firmly extend this conclusion to this subpopulation, objective responses were noted in 3 of 11 (27%) of these patients. In view of its major response activity, acceptable toxicity profile, and convenient administration schedule, this combination regimen should be investigated further in randomised trials.
5
6. 7.
8.
9.
10 11
12. 13
14.
15.
16.
17.
Acknowledgement 18.
This study was supported in part by the Austrian Gesellschaft zur Erforschung der Biologie und Behandlung von Tumorkrankheiten.
19. 20
References 21. 1. de Gramont A, Bosset JF. Milan C et al. Randomised trial comparing monthly low-dose leucovonn and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil plus continuous infusion for advanced colorectal cancer. A French Intergroup study. J Clin Oncol 1997: 15 808-15. 2. Schmoll HJ, Kohne CH, Lorenz M et al. Weekly 24h infusion of high-dose (HD) 5-fiuorouracil (5-FU 24h) with or without fohnic acid (FA) versus bolus 5-FU/FA (NCCTG/Mayo) in advanced colorectal cancer (CRC): A randomized phase III study of the EORTC GITCCG and the AIO. Proc Am Soc Clin Oncol 2000; l9:24la(Abstr). 3. Henderson CA. Therapeutic options for the treatment of colorectal cancer following 5-fluorouracil failure Semin Oncol 1998; 25(Suppl II): 29-38 4 Cunningham D, Pyrhonen S, James RD et al. Randomised trial Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/709/168972 by guest on 05 June 2018
22. 23.
24.
25.
of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998. 352. 1413-8. Rougier P. Van Cutsem E, Bajetta E et al. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 1998: 352: 1407-12. O'Connell MJ. Irinotecan for colorectal cancer: A small step forward Lancet 1998; 352: 1402. Chester JD. Dent JT. Wilson G et al Protracted infusional 5-fluorouracil (5-FU) with bolus mitomycin in 5-FU resistant colorectal cancer. Ann Oncol 2000; II: 235-7. Saltz LB. Cox JV. Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000; 343: 905-14 Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as firstline treatment for metastatic colorectal cancer: A multicenter randomised trial. Lancet 2000; 355: 1372-8. Cvitkovic E. Bekradda M. Oxaliplatin' A new therapeutic option in colorectal cancer Semin Oncol 1999; 26. 647-62. Brienza S, Bensmaine MA, Soulie P et al. Oxaliplatin added to 5-fluorouracil-based therapy (5-FU + FA) in the treatment of 5-FU-pretreated patients with advanced colorectal carcinoma (ACRC): Results from the European compassionate-use program. Ann Oncol 1999; 10: 1311-6. Danenberg PV, Malli H, Swenson S. Thymidilate synthase inhibitors. Semin Oncol 1999; 26: 621-31. Harstrick A. Vanhoefer U, Seeber S. New drugs in colorectal cancer. A review of antitumor activity and cross-resistance patterns of topoisomerase I inhibitors, thymidilate synthase inhibitors, and oxaliplatin. Onkologie 1998; 21: 95-103 Horikoshi N, Alba K, Kurihara M et al. Phase II study of 'Tomudex' in chemotherapy pretreated patients with advanced colorectal cancer. Proc Am Soc Clin Oncol 1999, 18: 257a (Abstr). Fizazi K, Viala J, Daniel C et al. Raltitrexed (Tomudex) and oxaliplatin: An active out-patient regimen in malignant mesothehoma. Eur J Cancer 1999; 35 (Suppl 4): S252 (Abstr). Fizazi K, Ducreux M, Ruffle Pet al. Phase-I, dose-finding, and pharmacokinetic study of raltitrexed combined with oxaliplatin in patients with advanced cancer. J Clin Oncol 2000; 18- 2293-300 Douillard JY, Michel P, Gamelin E et al. Raltitrexed ('Tomudex') plus oxaliplatin An active combination for first-line chemotherapy in patients with metastatic colorectal cancer Proc Am Soc Clin Oncol 2000; 19- 250a (Abstr). Scheithauer W, Kornek GV. Ulnch-Pur H et al Promising therapeutic potential of oxaliplatin + raltitrexed in patients with advanced colorectal cancer (ACC): Results of a phase I — 11 trial. Proc Am Soc Clin Oncol 2000; 19: 257a (Abstr). Miller AB, Hoogstraten B, Staquet M, Winkler V. Reporting results of cancer treatment. Cancer 1981; 47: 207-14 Gehan EA. The determination of the number of patients required in a follow-up trial of a new chemotherapeutic agent. J Chron Dis 1961; 13:346-53. Anderson JR, Bernstein L, Pike MC. Approximate confidence intervals for probabilities of survival and quantiles in life-table analysis. Biometrics 1982, 38: 407-16. Kaplan EL. Meier P. Non-parametric estimation from incomplete observations J Am Stat Assoc 1958, 53: 458-81. De Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938 47. Scheithauer W, Kornek GV, Raderer M et al. Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer J Clin Oncol 1999; 17: 902-6. Zori Comba A, Blajman C, Richardet E et al. Bimonthly oxaliplatin (L-OHP) with (A) or without (B) fluorouracil (FU) and leucovorin (FA): Proven evidence of synergism in a phase II randomised trial. Proc Am Soc Clin Oncol 1999; 18: 248a (Abstr)
714 26
27
de Gramont A, Figer A, Seymour M el al. Leucovonn and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer J Clin Oncol 2000; 18: 2938—47. Levi F, Zidani R, Misset JL. Randomised multicenter trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer: International Organization for Cancer Chronotherapy. Lancet 1997; 350: 681-6.
Received 9 November 2000; accepted 7 February 2001.
Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/709/168972 by guest on 05 June 2018
Correspondence to. W. Scheithauer, MD Department of Internal Medicine I Division of Oncology Vienna University Medical School Waehringer Guertel 18-20 1090 Vienna Austria E-mail: werner scheithauer(S;akh-wien.ac.at
Original article Second-line treatment with oxaliplatin + raltitrexed in patients with advanced colorectal cancer failing fluoropyrimidine/leucovorin-based chemotherapy W. Scheithauer,1 G.V. Kornek,1 B. Schuell,1 H. Ulrich-Pur,1 M. Penz,1 M. Raderer,1 F. Lang,2 B. Schneeweiss,3 A. Lenauer 4 & D. Depisch4 'Department ofInternal Medicine I. Division of Oncology, University Medical School, Vienna. 2 Department of Surgery, General Hospital of Neunkirchen, Neunkirchen; 3Department of Internal Medicine, General Hospital of Kirchdorf, Kirchdorf/Krems, ADepartment of Surgery. Wr Neustadt General Hospital, Wr Neustadt. Austria
Summary Background. To evaluate the efficacy and tolerance of combined raltitrexed and oxaliplatin in patients with advanced colorectal cancer pretreated with ftuoropyrimidine-leucovorin-based chemotherapy. Patients and methods: Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within six months after withholding palliative chemotherapy with fluoropyrimidines-leucovorin ± irinotecan, participated in this study. Treatment consisted of oxaliplatin 130 mg/m 2 and raltitrexed 3.0 mg/m 2 both given on day 1 every three weeks for a total of eight courses unless prior evidence of progressive disease. Results: The overall objective response rate was 33.3% for all 36 evaluable patients (95% confidence interval (CI): 18.6%51%). Seventeen additional patients (47.2%) had stable disease, and only seven (19.5%) progressed. The median progression-
Introduction Many patients with advanced colorectal cancer are candidates for therapeutic options after failure of 5-fiuorouracil (5-FU)-based therapy, because virtually all of them will experience disease progression after a median time of only about four to six months [1, 2]. Until recently, these patients had few options, but now regional treatments and various different systemic chemotherapy regimens exist [3]. The topoisomerase I inhibitor irinotecan has been proven to be of particular value in this treatment setting, and because of a significant survival advantage and a clinical benefit when compared to best supportive care or continuous infusional 5-FU, its use as single agent is now considered standard secondline therapy/new reference for forthcoming clinical trials [4, 5]. However, the survival gain in the latter study was only 2.3 months, and this small benefit, the rather high costs of treatment, and the fact that irinotecan is associated with significant toxicity (despite rigorous implementation of common guidelines for the management of adverse reactions) have been impediments to its universal Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/709/168972 by guest on 05 June 2018
free survival was 6.5 months (range 1.2-14.0). After a median follow-up time of 12 months, 23 patients (63.8%) are still alive. The tolerance of treatment was acceptable with only 8 of 36 patients (22%) experiencing grade 3 or 4 neutropenia. Grade 3 non-haematological adverse reactions included peripheral sensory neuropathy in three, asthenia in one, diarrhea in two, and clinically insignificant increase in serum transaminases in two patients, respectively. Conclusions Our data suggest that the combination of oxaliplatin and raltitrexed has substantial antitumour activity in patients with progressive fluoropyrimidine-leucovorin ± irinotecan pretreated colorectal cancer. Because of its favorable toxicity profile and convenient three-weekly outpatient administration schedule, further evaluation of this regimen seems warranted. Key words: colorectal cancer, oxaliplatin, raltitrexed, secondline chemotherapy
adoption [6, 7]. Another problem with the use of irinotecan in the second-line treatment setting is related to the expected increased use of its combination with 5-FU-LV in front-line therapy. In two recently published randomised controlled trials, such combination regimens have resulted in significantly higher objective response rates, progression-free and overall survival when compared with bolus or continuous infusional 5-FU-LV [8, 9]. Similarly, the combination of 5-FU and irinotecan is currently being evaluated in surgically resected patients, who will eventually recur after adjuvant treatment. Thus for various reasons, there is an urgent need for alternative, non-cross resistant, effective and non-toxic regimens for the treatment of patients failing 5-FU-LV ± irinotecan regimens. The specific thymidilate synthase inhibitor raltitrexed and the third-generation 1,2-diaminocyclohexane-platinum derivate oxaliplatin, which both exhibit incomplete cross-resistance with 5-FU, have demonstrated antitumour efficacy in previously untreated as well as 5-FULV pretreated patients with advanced colorectal cancer [10-14]. Since preclinical and clinical data indicate at
710 least an additive effect of raltitrexed and oxaliplatin in various tumour types [15-18], and the toxicity profile of these two drugs does not suggest a synergism when used in combination, the present study was undertaken. The specific aim of our study was to determine the antitumour potential of this combination in patients with advanced colorectal cancer failing 5-FU-LV ± irinotecan regimens, and to reconfirm its favorable toxicity profile as documented in two recently published studies in patients with previously untreated disease [17, 18].
Patients and methods
stimulating factor (G-CSF) was recommended in the former group of patients. Any patient who required more than two weeks for recovery of adverse reactions was taken off the study.
Pretreatment and follow-up evaluation Prior to initiating chemotherapy, all patients were assessed by physical examination, routine haematology and biochemistry analyses, chest X-ray, and CT scans to define the extent of the disease. Complete blood cell counts with platelet and differential counts were obtained weekly during chemotherapy, and serum chemistries were repeated at least once every course. Subjective symptoms, physical examination, performance status and all adverse reactions were recorded before each treatment cycle. Tumour size was measured every eight weeks by CTscan, X-ray, or any other technique that allows retrospective and independent reassessment.
Patient selection Patients with histologically confirmed metastatic or locally recurrent colorectal cancer and bidimensionally measurable disease (defined as presence of at least one index lesion capable of two-dimensional measurement by computed tomographic (CT) scan outside any irradiated zone and greater than 2 cm in diameter) were considered candidates for this study. All patients must have developed progressive disease while receiving or within six months after discontinuing palliative or adjuvant fluoropyrimidine-based chemotherapy. Eligibility criteria also included age between 19 and 75 years, a World Health Organisation (WHO) performance status of 0-2, a life expectancy of at least three months, adequate bone marrow reserve (leukocyte count >4000/ul, platelet count > 100,000/ul), adequate renal (serum creatinine concentration
Assessment of response The primary efficacy end point was response rate, which was evaluated according to WHO criteria [19]. A CR required the complete disappearance of all objective evidence of disease on two separate measurements at least 4 weeks apart. A PR was defined as a more than 50% reduction in the sum of the products of the perpendicular diameters of measurable bidimensional lesions without a CR, no progression of any lesion by more than 25% or the appearance of any new lesion, confirmed on two separate measurements that were four weeks apart. In case of bone metastases, CR was attributed only when there was complete disappearance of all lesions on X-ray, and PR was attributed when decrease in size and/or recalcification of lytic lesions occurred. Decreased density of blastic lesions or improvement in bone scan positive. X-ray negative disease were not taken into account. Progressive disease (PD) was defined as the enlargement of any existing measurable lesion by more than 25% or the development of new metastatic lesions. Stable disease (SD) was any measurement that did not fulfill the criteria for CR, PR or PD. All tumour measurements were reviewed and confirmed by an independent panel of oncologists and radiologists to confirm responses and the date of progression Secondary efficacy end points included the duration of response (measured from the onset of the best response to the date of disease progression), progression-free survival (calculated from the start of treatment to the time of progression or relapse), and overall survival time.
Treatment protocol Statistical methods The treatment regimen was based on two previously published phase I — II studies, indicating that a dose-intensity as high as the sum of the Using standard statistical methods, an optimal two-stage design was recommended doses of each agent given alone can be safely adminisemployed in the protocol [20]. If no CR or PR was noted in the first tered [16, 18] Chemotherapy thus consisted of raltitrexed 3.0 mg/m 2 cohort of 14 patients, a response rate of > 15% could be excluded with administered as a 15 min intravenous (i.v.) infusion, plus oxaliplatin 95% confidence and accrual would stop. If at least one CR or PR was 130 mg/m 2 , diluted in 250 ml of 5% glucose, administered as a twoobserved, more than 30 patients were to be entered in the study to hour i.v. infusion. Treatment courses were repeated every three weeks determine the response rate more accurately For the response rates. fora total of eight courses unless prior evidence of progressive disease 95% CIs were calculated as previously described [21] The distribution Concomitant medications routinely given before cytotoxic drug adminof time to death from date of study entry was estimated using the istration included 8 mg ondansetron and S mg dexamethasone Kaplan-Meier product-limit method [22]. Toxicity and dosage modification guidelines
Adverse reactions were evaluated according to WHO criteria [19] In the event of grade 4 haematological or any other severe ( > grade 2) organ toxicity in individual patients, the dose of oxaliplatin and raltitrexed was reduced by 25% for subsequent courses. Oxaliplatin was discontinued if paraesthesia associated with pain or functional impairment persisted between treatment cycles, or if a patient had experienced any other severe neurotoxicity. Treatment could be delayed for up to two weeks if symptomatic toxicity persisted and/or the neutrophil count ( A N Q was lower than 1000/jJ and/or the platelet count lower than 75.000/|jl. Administration of granulocyte colony-
Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/709/168972 by guest on 05 June 2018
Results Patient characteristics Between January 1999 and March 2000, a total of 36 patients took part in this trial, all of whom were considered evaluable for response and toxicity assessment. The demographic data, sites of metastatic tumor, and prior
711 therapies are listed in Table 1. The patients' median age was 66 years. Almost two-thirds of the study population (61%) were male, and the large majority (81%) had a WHO performance status of 0 or 1. Except for 10 patients, all had multiple metastases involving 2 or more organ systems. The predominant sites of metastases were liver in 30, lung in 12, abdominopelvic mass in 23, and soft-tissue and/or bone in 10 patients. Two patients had tumour recurrence while receiving adjuvant therapy with FU-LV, all others progressed while receiving (n = 14) or within six months after discontinuing palliative fluoropyrimidine-leucovorin-based first-line chemotherapy. The median duration off first-line chemotherapy was 2.5 months (range 1-6 months). Previous therapy consisted of i.v. bolus 5-FU-LV (NCCTG/Mayo-regimen) in 17 patients, bi-monthly continuous infusional doublemodulated 5-FU-LV (deGramont regimen) without (n — 6) or combined with irinotecan (n - 11), and regional intra-arterial 5-FU-LV in 2 patients, respectively. Two patients with rectal cancer had received prior palliative pelvic radiation therapy. A total of 219 courses were administered to the 36 patients. The median number of treatment cycles was 6 (range 1-8), and the median duration of follow-up at the time of this analysis was 12 months (range 6-20 months). Response to therapy Antitumour responses according to the patients' pretreatment results are shown in Table 2. The overall response rate was 33.3% for all 36 patients (95% CI: 18.6%-51%). All responses were partial; the median time to response was 3 months (range 2.5^4 months), and their median duration was 6.2 months (range 3—10.5 months). Seventeen additional patients (47.2%) showed stabilization of disease lasting more than three months (median 5, range 3.5-11.8 months), and in only seven patients (19.5%) was the disease progression not influenced by chemotherapy. The median progression-free survival in all 36 patients was 6.5 months, within a range of 1.2-14.0 months. As shown in Table 2, the subset of patients who were most likely to benefit from secondline therapy with oxaliplatin + raltitrexed were those with prior response. In this subgroup of patients, 6 of 10 exhibited PR as compared to 1 out of 10 among those who had failed first-line 5-FU-LV-based chemotherapy. The difference in terms of objective response rate, median progression-free and overall survival time between patients who experienced disease progression while off previous 5-FU-based therapy and those who progressed while on previous 5-FU-based therapy (defined as clinically resistant 5-FU disease), however, did not reach the level of statistical significance. Response rates in these two subsets of patients were 9 of 20 (45%) and 3 of 16 (18.8%; P = 0.192). The corresponding values for median progression-free and overall survival were 7.1 vs. 5.35 months (P - 0.108), and > 12.5 vs. > 10.8 months (P - 0.231), respectively. Similarly, no difference in response activity was noted between the 25 patients Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/709/168972 by guest on 05 June 2018
Table I. Patient characteristics Variable
Number of patients
Number of patients Sex Male Female Age (years) Median Range WHO performance status 0 1 2 Location of primary tumour Colon Rectum Histologic grading Grade 1 Grade 2 Grade 3 Location of metastases Liver Lung Abdominopelvic mass Soft-tissue Bone Number of metastatic sites Single Multiple First-line chemotherapy Bolus 5-FU-LV Continuous inf. 5-FU-LV Cont inf 5-FU-LV-irinotecan Regional intrahepatic 5-FU-LV
36 22 14 66 41-75 15 14 7 20 16 4 27 5 30 12 23 6 4 10 26 17 6 11 2
Table 2. Response rate according to prior treatment response Response to treatment
first-line
Number of patients
PR n (%)
SD n (%)
PD n (%)
Partial response (PR) Stable disease (SD) Progression (PD)
10 16 10
6(16.6) 5(13.9) 1(2.8)
3(8.3) 9(25.0) 5(13.9)
1(2.8) 2(5.6) 4(11.1)
Total
36
12(33.3)
17(47.2)
7(19.5)
who had received 5-FU-LV (36%) and those (n = 11) pretreated with 5-FU-LV + irinotecan (27.3%; P - 0.769). Toxicity All 36 patients, who received a total of 219 courses of therapy, were assessable for toxicity. Side effects associated with treatment are listed in Table 3. Haematological toxicity was commonly observed, though it was generally mild to moderate and fully reversible within one week in all patients. Leukopenia occurred in 24 patients (67%), and was grade 3 or 4 in only 5 cases (14%). The median nadir WBC count was 3850/ml (range 8008600/ml). The variations in neutrophil counts paralleled those of WBCs; the median nadir of ANCs was 2180/ml (range 420-5670/ml). Thrombocytopenia was relatively
712 Table 3 Highest grade of treatment-associated toxicity (n = 36). Toxicity
WHO grade 1 n (%)
2 n (%)
3 n (%)
4 n (%)
12(33) 11 (31) 5(14) 10(28) 1(3) 6(17) 5(14) 3(8) 10(28) 5(14) 8(22) 7(19) 5(14)
7(19) 7(19) 4(11) 6(17) 1(3) 5(14) 4(11) 1(3) 8(22) 13(36) 4(11) -
4(11) 6(17) 1(3) 1(3) _
M3)
The mean dose of oxaliplatin was 40.34 mg/m2/week, (range 12.37-43.3 mg/m2/week), and the mean dose of raltitrexed was 0.986 mg/m2/week (range 0.87-1.0 mg/m2/week). Survival
Leukopenia Granulocytopenia Thrombocytopenia Anaemia Infection Nausea/emesis Diarrhea Stomatitis Liver function Alopecia Peripheral neuropathy Asthenia Pain at injection site
2(6) _ K3) _ 3(8) 1(3) -
2(6) _ _ _ _ _ _ _ _ _ -
As of September 2000, with a median follow-up duration of 12 months (range 6-20 months), 13 of all 36 patients entered had died because of progressive disease. Twenty-three patients (64%) are still alive with metastatic disease, of whom twenty (56%) had received or currently undergo other cytotoxic chemotherapy (irinotecan: n - 13, capecitabine: n - 7). The median survival duration has not been reached yet and was >11.0 months (range 1.5-17.5+ months) at the time of this report.
uncommon and generally mild; it was noted in a total of Discussion 10 patients (28%), and only one of them had WHO grade 3 (1%). Accordingly, there were no episodes of In agreement with the study rationale, i.e., in vitro and in bleeding. The median nadir platelet count was 168,000/ml vivo evidence of an at least additive effect of raltitrexed (range 45,000—418,000/ml) with no evidence of a cumu- and oxaliplatin [15-18], therapeutic results achieved in lative nature of this side effect. Only 1 patient (3%) this multicenter phase II trial suggest an encouraging developed grade 3 anaemia requiring packed RBC antitumour activity of this combination in patients with transfusion, whereas mild anaemia was recorded in 16 metastatic, 5-FU-LV ± irinotecan pretreated colorectal patients (47%). The median nadir of haemoglobin was cancer. The objective response rate was 33% (95% CI: 12.3 g/dl (range 7.2-16.9 g/dl). Two patients developed 19%-51%), and partial responses lasted for a median documented infection, both without the requirement of duration of 6.2 months. Together with 17 additional hospitalisation. patients achieving stable disease, tumour progression Among non-haematological adverse reactions, tran- could be abrogated in as many as 80%. Even if one is sient mild to moderate gastrointestinal toxicities were not willing to accept objective response as a valid end frequently encountered. Grade 3 diarrhea, however, was point in clinical trials, the therapeutic potential of this noted only in two patients. Other non-myelosuppressive combination regimen is supported by the observed protoxicities included peripheral sensory neuropathy and gression-free and overall survival time of 6.5 and > 11 asthenia, which were rated severe in 3 and 1 case, months, respectively. Comparable therapeutic results in respectively. Clinically insignificant elevations in liver pretreated patients with advanced colorectal cancer, in functional parameters occurred in 20 patients, partial fact, have only been reported in a few studies using alopecia and pain at the injection site in 5 patients each. chronomodulated 5-FU plus oxaliplatin [23] or irinoteSix patients (17%) had at least one treatment delay of can plus oxaliplatin [24]. Our data seem to compare one week at some time during therapy, and the total favorably with most other salvage regimens [3], includnumber of delayed courses was nine (4.1%). The reasons ing irinotecan monotherapy that has been postulated as for delayed courses were haematological in five (neutro- new standard and reference second-line treatment for penia and/or thrombocytopenia), non-haematological in future trials [9]. Median PFS was reported to be 4.2 two (infection, port-a-cath implantation), and personal months and median survival 10.8 months in the irinotecan winner arm in this trial [9]. Because of differences in reasons in two. patients' pretreatment characteristics, however, a selecFour patients (11%) had a 25% dose reduction of tion bias can not be ruled out, and any superiority of cytotoxic drugs during treatment according to the study combined raltitrexed + oxaliplatin remains to be deterprotocol, because of grade 4 neutropenia (n - 2) or mined in future randomised trials. grade 3 diarrhea (n = 2). Oxaliplatin was discontinued in three patients because of progressive sensory neuroAdditional potential advantages of the investigated pathy (after four, six, and seven courses), and in one combination regimen may represent its comfortable patient due to reproducible laryngopharyngeal dysaes- administration schedule, i.e., a 2'/2-hour outpatient treatthesia. One patient warranted early discontinuation of ment without the requirement of technically complex treatment for personal reasons after four courses. Dose and cost-intensive infusional devices plus the favorable intensity was calculated for each patient and for each toxicity profile: severe adverse events requiring a 25% drug. The mean given dose intensity of oxaliplatin was dose attenuation of both chemotherapeutic drugs and/or 93.1% of the projected dose, and 98.6% for raltitrexed. early discontinuation of oxaliplatin (due to progressive Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/709/168972 by guest on 05 June 2018
713 cumulative sensory neuropathy) were observed in only six patients, and < 5% of all treatment courses were to be delayed for toxicity reasons, both resulting in an approximately 95% mean dose intensity of the projected drug doses. Despite its use as second-line therapy, the raltitrexed-oxaliplatin combination regimen seems to be less myelosuppressive and associated with less nonhaematological adverse reactions including diarrhea and vomiting compared to irinotecan [8, 9], as well as oxaliplatin plus bolus [25], flat continuous infusion [26], and even chronomodulated FU [27]. As noted by others [16] and in our previous first-line therapy trial [18], apart from transient and clinically insignificant elevations in liver functional parameters, it seems possible that raltitrexed exhibits the lowest incidence of severe toxicities of all fluoropyrimidine-based regimens when combined with oxaliplatin. Due to its cumulative nature and the limited duration of treatment according to our study protocol, even oxaliplatin-induced neurotoxicity did not represent a problem: in all three patients who had experienced grade 3 peripheral sensory neuropathy, functional impairment regressed to ^ grade 2 after 2.54 months. In conclusion, our results suggest that this combination may be considered as effective salvage regimen in leucovorin-modulated fluoropyrimidine pretreated patients with progressive metastatic colorectal cancer. Although the number of patients failing 5-FU-LV + irinotecan might have been too small to firmly extend this conclusion to this subpopulation, objective responses were noted in 3 of 11 (27%) of these patients. In view of its major response activity, acceptable toxicity profile, and convenient administration schedule, this combination regimen should be investigated further in randomised trials.
5
6. 7.
8.
9.
10 11
12. 13
14.
15.
16.
17.
Acknowledgement 18.
This study was supported in part by the Austrian Gesellschaft zur Erforschung der Biologie und Behandlung von Tumorkrankheiten.
19. 20
References 21. 1. de Gramont A, Bosset JF. Milan C et al. Randomised trial comparing monthly low-dose leucovonn and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil plus continuous infusion for advanced colorectal cancer. A French Intergroup study. J Clin Oncol 1997: 15 808-15. 2. Schmoll HJ, Kohne CH, Lorenz M et al. Weekly 24h infusion of high-dose (HD) 5-fiuorouracil (5-FU 24h) with or without fohnic acid (FA) versus bolus 5-FU/FA (NCCTG/Mayo) in advanced colorectal cancer (CRC): A randomized phase III study of the EORTC GITCCG and the AIO. Proc Am Soc Clin Oncol 2000; l9:24la(Abstr). 3. Henderson CA. Therapeutic options for the treatment of colorectal cancer following 5-fluorouracil failure Semin Oncol 1998; 25(Suppl II): 29-38 4 Cunningham D, Pyrhonen S, James RD et al. Randomised trial Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/709/168972 by guest on 05 June 2018
22. 23.
24.
25.
of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998. 352. 1413-8. Rougier P. Van Cutsem E, Bajetta E et al. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 1998: 352: 1407-12. O'Connell MJ. Irinotecan for colorectal cancer: A small step forward Lancet 1998; 352: 1402. Chester JD. Dent JT. Wilson G et al Protracted infusional 5-fluorouracil (5-FU) with bolus mitomycin in 5-FU resistant colorectal cancer. Ann Oncol 2000; II: 235-7. Saltz LB. Cox JV. Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000; 343: 905-14 Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as firstline treatment for metastatic colorectal cancer: A multicenter randomised trial. Lancet 2000; 355: 1372-8. Cvitkovic E. Bekradda M. Oxaliplatin' A new therapeutic option in colorectal cancer Semin Oncol 1999; 26. 647-62. Brienza S, Bensmaine MA, Soulie P et al. Oxaliplatin added to 5-fluorouracil-based therapy (5-FU + FA) in the treatment of 5-FU-pretreated patients with advanced colorectal carcinoma (ACRC): Results from the European compassionate-use program. Ann Oncol 1999; 10: 1311-6. Danenberg PV, Malli H, Swenson S. Thymidilate synthase inhibitors. Semin Oncol 1999; 26: 621-31. Harstrick A. Vanhoefer U, Seeber S. New drugs in colorectal cancer. A review of antitumor activity and cross-resistance patterns of topoisomerase I inhibitors, thymidilate synthase inhibitors, and oxaliplatin. Onkologie 1998; 21: 95-103 Horikoshi N, Alba K, Kurihara M et al. Phase II study of 'Tomudex' in chemotherapy pretreated patients with advanced colorectal cancer. Proc Am Soc Clin Oncol 1999, 18: 257a (Abstr). Fizazi K, Viala J, Daniel C et al. Raltitrexed (Tomudex) and oxaliplatin: An active out-patient regimen in malignant mesothehoma. Eur J Cancer 1999; 35 (Suppl 4): S252 (Abstr). Fizazi K, Ducreux M, Ruffle Pet al. Phase-I, dose-finding, and pharmacokinetic study of raltitrexed combined with oxaliplatin in patients with advanced cancer. J Clin Oncol 2000; 18- 2293-300 Douillard JY, Michel P, Gamelin E et al. Raltitrexed ('Tomudex') plus oxaliplatin An active combination for first-line chemotherapy in patients with metastatic colorectal cancer Proc Am Soc Clin Oncol 2000; 19- 250a (Abstr). Scheithauer W, Kornek GV. Ulnch-Pur H et al Promising therapeutic potential of oxaliplatin + raltitrexed in patients with advanced colorectal cancer (ACC): Results of a phase I — 11 trial. Proc Am Soc Clin Oncol 2000; 19: 257a (Abstr). Miller AB, Hoogstraten B, Staquet M, Winkler V. Reporting results of cancer treatment. Cancer 1981; 47: 207-14 Gehan EA. The determination of the number of patients required in a follow-up trial of a new chemotherapeutic agent. J Chron Dis 1961; 13:346-53. Anderson JR, Bernstein L, Pike MC. Approximate confidence intervals for probabilities of survival and quantiles in life-table analysis. Biometrics 1982, 38: 407-16. Kaplan EL. Meier P. Non-parametric estimation from incomplete observations J Am Stat Assoc 1958, 53: 458-81. De Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938 47. Scheithauer W, Kornek GV, Raderer M et al. Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer J Clin Oncol 1999; 17: 902-6. Zori Comba A, Blajman C, Richardet E et al. Bimonthly oxaliplatin (L-OHP) with (A) or without (B) fluorouracil (FU) and leucovorin (FA): Proven evidence of synergism in a phase II randomised trial. Proc Am Soc Clin Oncol 1999; 18: 248a (Abstr)
714 26
27
de Gramont A, Figer A, Seymour M el al. Leucovonn and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer J Clin Oncol 2000; 18: 2938—47. Levi F, Zidani R, Misset JL. Randomised multicenter trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer: International Organization for Cancer Chronotherapy. Lancet 1997; 350: 681-6.
Received 9 November 2000; accepted 7 February 2001.
Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/709/168972 by guest on 05 June 2018
Correspondence to. W. Scheithauer, MD Department of Internal Medicine I Division of Oncology Vienna University Medical School Waehringer Guertel 18-20 1090 Vienna Austria E-mail: werner scheithauer(S;akh-wien.ac.at