High activity and reduced neurotoxicity of bi-fractionated oxaliplatin plus 5-fluorouracil/leucovorin for elderly patients with advanced colorectal cancer

R. Mattioli1, C. Massacesi2, F. Recchia3, F. Marcucci2, C. Cappelletti1, L. Imperatori1, A. Pilone2, M. Rocchi4, A. Cesta3, G. Laici1, M. Bonsignori2 and P. Lippe1,*

1 S. Croce Hospital, Medical Oncology Unit, Fano; 2 Torrette Regional Hospital, Department of Oncology and Radiotherapy, Ancona; 3 Civilian Hospital, Medical Oncology Department, Avezzano; 4 Biomathematics Department, University of Urbino, Urbino, Italy

* Correspondence to: Dr P. Lippe, Medical Oncology Unit, S.Croce Hospital 61032 Fano (PU), Italy. Tel: +39-0721-88-23-96; Fax: +39-02-700-54-71-56; Email: paolippe{at}libero.it


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:: The proportion of elderly within the general population is increasing and the incidence of colorectal cancer increases with age. Oxaliplatin and 5-fluorouracil (FU) combination is active in this disease.

Patients and methods:: This multicenter phase II study was designed to investigate feasibility, efficacy, activity of daily living (ADL) and instrumental activity of daily living (IADL) in elderly patients with metastatic colorectal cancer treated, as first-line chemotherapy, with a bi-fractionated oxaliplatin/5-FU based regimen. Treatment was oxaliplatin 45 mg/m2, leucovorin 200 mg/m2, 5-FU 400 mg/m2 and 22 h continuous infusion of 5-FU 600 mg/m2, all given intravenously on days 1 and 2, every 2 weeks.

Results:: Seventy-eight patients were enrolled; median age was 75 years (range 70–85). Among 77 evaluable patients, we observed seven complete responses and 32 partial responses, for an overall response rate of 51% (95% confidence interval 40% to 62%). A stabilization of disease was observed in 25% of patients while 19 patients progressed. Canadian NCI grade 3/4 toxicities were: neutropenia in 32% of patients (febrile in two), diarrhea in 10%, mucositis in 4%, and fatigue in 4%. Sensory neuropathy was mild and occurred as grade 3 in 6% of patients. ADL and IADL scores did not change significantly during treatment.

Conclusions:: The bi-fractionated delivery of oxaliplatin plus 5-FU/leucovorin demonstrated high antitumor activity in elderly patients with advanced colorectal cancer. Splitting oxaliplatin administration might reduce incidence of severe neuropathy, although this has to be confirmed by further studies.

Key words: elderly, first line chemotherapy, colorectal cancer, phase II trial, oxaliplatin, neuropathy


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The incidence of colorectal cancer increases in patients over the age of 70 and the proportion of the elderly population is rising year by year. Therefore the number of elderly patients with colon cancer is likely to increase as well [1Go].

In the advanced colorectal cancer setting, combination regimens of oxaliplatin or irinotecan and 5-fluorouracil (FU)/leucovorin have recently shown an impressive efficacy as front-line chemotherapy for advanced colorectal cancer [2Go]. However, the median age for patients included in these trials did not exceed 65 years old, with elderly cancer patients generally excluded. Therefore, it is difficult to evaluate whether efficacy and tolerability data obtained in clinical studies are reproducible for the elderly.

Oxaliplatin (Eloxatin®; Sanofi-Synthelabo, Paris, France) is a third-generation platinum-analog. Neurotoxicity is dose-limiting and occurs in two distinct forms, an acute neurological symptom complex that occurs within hours or days of therapy and a chronic, cumulative sensory neuropathy [3Go]. Although various strategies and several neuromodulatory agents have been proposed to prevent or treat oxaliplatin-induced neurotoxicity, no evidence-based recommendation has been established [4Go]. The administration of oxaliplatin over 2 days intended to maximize the synergistic effect with 5-FU, has also been reported to be associated with a low rate of cumulative sensory neuropathy [5Go, 6Go].

In this study, we assessed the safety and efficacy of a bi-fractionated oxaliplatin and 5-FU/levo-folinic acid regimen specifically in elderly advanced colorectal cancer patients.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
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Patient selection and treatment plan
Patients enrolled in the study had to fulfill the following inclusion criteria: histologically or cytologically confirmed metastatic or locally advanced colorectal carcinoma; at least one bi-dimensionally measurable lesion (>10 mm); age 70 years or more; no previous chemotherapy-lines for advanced setting; 0–2 performance status on the Eastern Cooperative Oncology Group (ECOG) scale; life expectancy >3 months; adequate bone marrow reserve (neutrophil count >1500/µl, platelet count >100 000/µl); renal and hepatic functional markers within the following range (bilirubin <2 times the normal upper limit (ULN); transaminase levels <5 ULN in the case of hepatic metastases; alkaline phosphatase levels <10 times ULN with hepatic or bone metastases, <2.5 if not; serum creatinine <1.5 times ULN); normal cardiac function. Patients who had received previous radiotherapy (with at least 4 weeks interval) were included if their assessable disease was outside the radiation field. The main exclusion criteria were: symptomatic central nervous system metastases, second primary malignancy, and serious systemic disorders. Upon informed consent, all patients gave their written permission in conformity with EEC regulations governing the ‘Good Clinical Practice’. The study protocol was approved by the Institutional Review Board of the coordinating center.

Oxaliplatin was administered at 45 mg/m2 i.v. (as a 90-min infusion), followed by levo-folinic acid 200 mg/m2 i.v. (as a 2-h infusion), bolus 5-FU 400 mg/m2 i.v. (10-min infusion) and 22-h infusion 5-FU, 600 mg/m2 i.v., given for 2 consecutive days. Cycles were repeated every 2 weeks. Intravenous ondansetron 8 mg or granisetron 3 mg and i.v. dexamethasone 8 mg were administered as prophylactic antiemetics.

Whenever hematological or gastrointestinal (diarrhea or mucositis) toxicity grade 2 or more was present at day 21, treatment infusion was delayed for a maximum of 2 weeks until the toxicity had resolved. In cases of the reappearance of grade 3/4 hematological or gastrointestinal toxicity during the following courses, oxaliplatin was to be administered at 75% of the original dose. In cases of paresthesia with pain or functional decrease, 5-FU was infused unchanged, while every oxaliplatin infusion was reduced by 25% for an event lasting more than 7 days, or discontinued if paresthesia with functional impairment became persistent. Study treatment was discontinued when grade 2/3 hematological or gastrointestinal toxicity persisted for more than 2 weeks, and in every case of grade 4 diarrhea, mucositis, neurotoxicity or thrombocytopenia.

The use of granulocyte-colony stimulating factors was allowed during treatment for patients with febrile neutropenia (neutrophil count <1000/mm3 and temperature >38 °C), or grade 3/4 neutropenia, according to the investigator's decision. Supportive care, including blood transfusions, administration of erythropoietin, antibiotics, antiemetics and analgesics, was provided when appropriately indicated by the investigators. The use of neuromodulatory agents, antiepileptic drugs, amifostine or glutathione was not allowed to prevent oxaliplatin-induced neurotoxicity, while patients who developed chronic neurotoxicity received gabapentin and the following cycles of chemotherapy were preceded by intravenous administration of glutathione.

Patients received chemotherapy until progression of disease or until the ‘treatment period’ was completed (at least 12 cycles).

Efficacy, tolerability and self-maintenance assessments
Staging assessments included a physical examination, complete blood count, serum tumor markers (CEA, CA 19.9), electrocardiogram, abdomen-chest computed tomography (CT) scan or chest X-ray and abdomen MRI or, when appropriate, brain CT scan, bone scan, abdominal ultrasounds and other radiological investigations. Routine blood tests were repeated prior to each chemotherapy administration. Response was assessed with CT scan or other staging methods, using WHO objective response criteria. A complete clinical, radiological and functional re-staging for assessing tumor response was performed every six courses or earlier if clinical or biochemical progression (on CEA, CA 19.9 values) was suspected. Moreover serum tumor markers were re-assessed monthly in those patients with high baseline values. Re-staging was also performed every 3 months after treatment discontinuation until death. Toxicity was graded according to Canadian NCI CTC criteria (http://ctep.cancer.gov) and was assessed before each chemotherapy administration by physical examination, direct questioning and measurement of hematological and biochemical parameters. Safety was assessed for at least 1 month after treatment discontinuation and in any case until the beginning of second-line chemotherapy.

For the assessment of patient self-maintenance, every patient was evaluated before chemotherapy, after six and 12 cycles, through a geriatric multidimensional evaluation method, including Activity of Daily Living (ADL) [7Go] and Instrumental Activity of Daily Living (IADL) [8Go].

Statistical plan and analysis
The primary end points were the analysis of safety and tumor response. A two-staged Simon accrual design was adopted for this phase II study [9Go]. Considered of interest was a response rate of 45% for p(1) and a response rate of 30% for the lower limit of activity, p(0). If less than nine responses (partial or complete) were observed in the first 27 assessable patients, the activity of the combination therapy could be excluded with 95% confidence, and accrual would stop. With the second stage of the study to confirm the planned level of activity, 30/81 responses should be recorded.

Secondary end points were the evaluation of time to disease progression (TTP), overall survival (OS), duration of response, and assessment of patient self-maintenance. TTP and OS were measured from the date of enrollment to the beginning of disease progression and death from cancer, respectively, and were both determined by the Kaplan–Meier product–limit method [10Go]. The duration of response and stable disease were measured from the date of the beginning of the treatment to a documented disease progression. All analyses were performed following an intention to treat analysis.


    Results
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 Patients and methods
 Results
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 References
 
Characteristics of patients
Patients' characteristics are summarized in Table 1. From August 2001 to July 2004, 78 patients entered the study and 77 of them are now evaluable for response. There was one protocol violation: one patient could not be assessed for response because after resection of liver metastases no measurable lesions were present at start of chemotherapy. Among those patients with stage Dukes' B or C at diagnosis, the median disease-free interval before relapse was 18 months, and 24 (31%) of them had previously received 5-FU-based adjuvant chemotherapy.


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Table 1. Patients' characteristics

 
In total, 657 courses of chemotherapy were administered, with a median of eight cycles per patient (range 1–19). Two patients received only 1 and 2 courses, respectively, discontinuing chemotherapy due to early progression of disease. All reported cycles included oxaliplatin. Of interest, 25 (32%) patients received 12 or more cycles. The mean dosage of oxaliplatin was 34 mg/m2 per week, which represented 76% of the planned dose. Treatment delays were mainly caused by hematologic and gastrointestinal toxicity.

Thirty-four patients discontinued chemotherapy due to progression of disease, whilst 17 patients concluded the planned ‘treatment period’ of at least 12 cycles. The remaining patients stopped treatment early because of the following events: refusal of treatment continuation in 12 patients, unacceptable toxicity in eight, local treatment of metastases in four, and worsening of comorbidities in one. Two patients are still receiving treatment.

The best objective responses were achieved as follows: seven (9%) complete responses (CR), 32 (42%) partial responses (PR), 19 (25%) stable diseases (SD), and 19 (25%) failures. Therefore, the overall response rate was 51% (95% CI 41% to 63%), while the tumor control rate (response or disease stabilization) was 75%. The median duration of response and stabilization was 9 and 7.5 months, respectively.

As of October 2004, 61 (78%) patients progressed and 31 (40%) of them died of disease. Among those patients still alive, the median follow-up time was 12.5 months. The median time to disease progression and overall survival was 8 (range 0.5–22) and 20 (range 1–29) months, respectively (Figure 1). One- and 2-year survival rates were 76% and 24%, respectively.



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Figure 1. Time to progression and overall survival (Kaplan–Meier method).

 
Among patients who progressed to chemotherapy, a second line was delivered to 29/61 (47%) of them. This consisted of irinotecan-based regimens in 13, infusional 5-FU in 10 and oral fluoropyrimidines in six patients. Eight patients also received a third line of chemotherapy. After chemotherapy, four patients with metastatic disease confined to the liver received locoregional treatments (surgery and/or radiofrequency) of the residual disease. Also, two patients with an inoperable locoregional relapse as the only site of disease, underwent pelvic external beam radiotherapy.

Toxicity data for the 78 patients are summarized in Table 2. Neutropenia was the most common hematological side-effect: grade 3 and 4 in 11% of patients, but only two episodes of neutropenic fever. Anemia and thrombocytopenia were mild. No patients required red blood or platelet transfusions. Neurotoxicity, diarrhea, mucositis, fatigue and emesis were the most common non-hematological side-effects. In particular, severe neurotoxicity was assessed in five patients, diarrhea in five and fatigue in three patients (6%, 6% and 5%, respectively). Acute laryngopharyngeal dysesthesias occurred in one patient. As expected, chronic neurotoxicity resulted in a cumulative dose-related toxicity: patients with grade 0 neurotoxicity received a mean cumulative oxaliplatin dose of 491 mg/m2; patients with grade 1, a mean cumulative dose of 792 mg/m2; patients with grade 2 and 3, a mean cumulative dose of 942 mg/m2.


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Table 2. NCI-CTC toxicities (by patient)

 
Treatment was discontinued due to toxicity in eight (10%) cases; three of them developed moderate or severe ipersensitivity reaction to oxaliplatin, which disappeared after the infusion of chlorpheniramine 20 mg and dexamethasone 16 mg. The other reasons for discontinuation were grade 4 diarrhea in two patients, persistent grade 3 neurotoxicity in two patients, and deep venous thrombosis of the right femoral vein in another patient. The case of a 79-year-old man with a previous history of cardiac attacks, who after the first cycle had a complete atrial-ventricular blockage of electric stimulus and required a pacemaker, was not judged related to chemotherapy. Over all there were no treatment-related deaths.

ADL and IADL analysis during treatment is shown in Table 3. After six cycles, IADL indexes increased in 11/56 (19%), remained stable in 34/56 (61%) and decreased in 11/56 (19%) evaluable patients. Regarding ADL scores, after six cycles, they improved in 4/56 (7%), no change in 47/56 (84%), and worsened in 5/56 (9%) patients. After 12 chemotherapy cycles, IADL and ADL indexes improved or were maintained in 96% and 100% of evaluated cases, respectively. No significant correlation was observed between ADL and IADL indexes after six and 12 cycles and the disease response to the treatment.


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Table 3. Activity of daily living (ADL) and instrumental activity of daily living (IADL)

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Treating an old patient with advanced colorectal cancer with chemotherapy requires a clear balance to be made between positive and negative effects, especially evaluating patient symptoms and tolerability. As previously underlined by some authors [11Go], 5-FU-based chemotherapy seems to be well tolerated and to lead to overlapping outcomes, even in patients aged 70 or older, with good performance status, when compared with younger patients. The aim of this study was to assess if a combined regimen of oxaliplatin and 5-FU/levo-folinic acid could be feasible and effective in an elderly population of patients with advanced colorectal cancer patients.

The treatment was well tolerated. No unexpected adverse event or toxic deaths occurred. Although we observed a relevant rate of severe haematologic toxicity, this has been as frequent as expected considering previous reports [2Go, 12Go–14Go]. Oxaliplatin peripheral neurological toxicity has been characterized by symptoms, triggered or aggravated by exposure to cold, including paresthesias, dysesthesias, cold hypersensitivity and pain in the arm used for drug infusion. This reversible acute neurotoxicity is related to a peripheral-nerve hyperexcitability [15Go]. A persistent sensory peripheral neuropathy may also develop with prolonged treatment, eventually causing sensory loss and functional impairment, and possibly related axonal neuropathy similar to other platinum-based chemotherapeutic agents [15Go]. In our series, the incidence of grade 3 peripheral neuropathy was 6.4%, a rate lower than that previously reported with ‘Folfox’ regimens [2Go, 12Go–14Go]. Considering that a mean weekly dose intensity of oxaliplatin of 34 mg/m2 was administered, and that 30 patients (40%) received a cumulative dose of oxaliplatin greater than 800 mg/m2, one possible reason of the recorded low rate of severe neuropathy could be found in the fractionated administration over 2 days of the drug. Moreover, neuromodulatory agents have not been administered to patients to prevent oxaliplatin-induced neurotoxicity. Only patients who developed chronic symptomatic neurotoxicity received gabapentin and the following cycles of chemotherapy were preceded by intravenous administration of glutathione. It is possible that this drug influenced the interpretation of the neurotoxicity and partially impaired the reliability of our results in terms of reduced neurotoxicity.

Although the regimen we employed may be considered as ‘aggressive’ because of the potential side-effects it could cause, in most of the patients, ADL and IADL indexes evaluated during the treatment were maintained stable.

The results in term of efficacy of this phase II study are encouraging because the 51% objective response rate reported here in a setting of elderly patients is quite similar to the objective response rates reported in previous larger trials in younger patients [2Go]. The median time to disease progression is in line with values observed in studies that employed FOLFOX-like regimens.

In conclusion, our data confirm that the combination regimen of oxaliplatin and 5-FU/leucovorin achieves noteworthy activity for elderly patients with advanced colorectal cancer, with response rates similar to that observed for younger patients. Furthermore, bi-fractionated delivery of oxaliplatin might reduce neurotoxicity, although further data based on randomized trials are needed to confirm this hypothesis.

Received for publication January 1, 2005. Revision received February 21, 2005. Accepted for publication February 21, 2005.


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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3. Wilson RH, Lehky T, Thomas RR, Quinn MG, Floeter MK, Grem JL. Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol 2002; 20: 1767–1774.[Abstract/Free Full Text]

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11. Popescu RA, Norman A, Ross PJ et al. Adjuvant or palliative chemotherapy for colorectal cancer in patients 70 years or older. J Clin Oncol 1999; 17: 2412–2418.[Abstract/Free Full Text]

12. Andrè T, Bensmaine MA, Louvet C et al. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 1999; 17: 3560–3568.[Abstract/Free Full Text]

13. Maindrault-Goebel F, de Gramont A, Louvet C et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Oncology Multidisciplinary Research Group (GERCOR). Ann Oncol 2000; 11: 1477–1483.

14. Andrè T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350: 2343–2351.[Abstract/Free Full Text]

15. Lehky TJ, Leonard GD, Wilson RH, Grem JL, Floeter MK. Oxaliplatin-induced neurotoxicity: acute hyperexcitability and chronic neuropathy. Muscle Nerve 2004; 29: 387–392.[CrossRef][ISI][Medline]





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