Capecitabine in the treatment of metastatic renal cell carcinoma

To evaluate the therapeutic effects and systemic toxicities of a capecitabine-based home therapy regimen in patients with metastatic renal cell carcinoma, 30 patients were enrolled in a phase II clinical trial. Treatment consisted of oral capecitabine combined with subcutaneous recombinant human interferon-α 2a, recombinant human interleukin-2 and oral 13-cis-retinoic acid. There were two (7%) complete responses (CRs) and eight (27%) partial remissions (PRs), for an overall objective response rate of 34% (95% CI 17–53%). Except one, all responses are ongoing, with a median duration of 9+ and 8+ months for CRs and PRs, respectively. Additionally, 12 patients (40%) reached stable disease. Eight patients (27%) showed continued disease progression despite treatment. Therapy was well tolerated and was given in the outpatient setting. Capecitabine-related World Health Organization (WHO) grade 2 and 3 toxicities were observed in five and two patients respectively, and were limited to fatigue, nausea/vomiting, diarrhoea, stomatitis, dermatitis and hand-and-foot syndrome. The substitution of capecitabine for 5-FU in the pre-existing biochemotherapy regimen did not result in a reduced therapeutic efficacy and showed significant anti-tumour activity in patients with advanced renal cell carcinoma. © 2000 Cancer Research Campaign


PATIENTS AND METHODS
The study protocol was approved by the Clinical Institutional Ethical Review Board of the University of Hannover. Between June 1998 and December 1998 we entered 30 patients in a phase II clinical trial, (Table 1). All patients presented with histologically confirmed metastatic renal cell carcinoma in advanced state, aged 18-75 years, expected survival of more than 3 months, Karnofsky status of ≥ 70%, and signed informed consent.
Patients received the following capecitabine-based outpatient chemo-immunotherapy regimen. Interferon-α was administered subcutaneously at 5 MIU m -2 on day 1 of weeks 5-8. Interleukin-2 was administered subcutaneously at 10 MIU m -2 on days 3, 4 and 5 of weeks 1 and 4, and at 5 MIU m -2 on days 1, 3 and 5 of weeks 2 and 3. Capecitabine was administered orally on days 1-5 of weeks 5-8 at 1000 mg m -2 twice daily. In addition, oral 13-cisretinoic acid was given at 34 mg m -2 daily during weeks 1-8. Concomitant medication was given as needed to control adverse effects of immunotherapy. Patients were treated on an outpatient basis. Table 2 summarizes the therapy regimen used in this study. 8-week treatment cycles were repeated for up to three courses. Number of treatment cycles varied exclusively based on progressive disease of the patients. Re-evaluation of the patients' tumour status was performed between treatment cycles.
Response to therapy was evaluated according to World Health Organization (WHO) criteria: complete response = disappearance of all signs of disease for a minimum of 8 weeks; partial response = 50% or more reduction in sum of products of the greatest perpendicular diameters of measurable lesions, no increase in lesion size and no new lesions; stable disease = less than a partial response with no disease progression for at least 8 weeks; progressive disease = 25% and more increase in sum of the products in the Capecitabine in the treatment of metastatic renal cell carcinoma longest perpendicular diameters of measurable lesions, or development of new lesions.
Systemic toxicity was evaluated at weekly intervals using a grading system adapted from the World Health Organization (WHO).
Treatment efficacy was assessed on intent-to-treat basis.

Median follow-up and survival
Median follow-up of all patients is 8 months; except for three patients, all patients are still alive.

Toxicity
In all patients, capecitabine therapy was completed without modification of dosage or change of time-interval. 25 of 30 patients reported capecitabine-associated, mostly mild sideeffects (Table 5). No grade 4 toxicity was observed and only two patients reported grade 3 malaise, one of them with concomitant grade 3 nausea/vomiting and stomatitis. Grade 2 stomatitis, dermatitis, hand-and-foot syndrome, anorexia, diarrhoea and malaise were observed in four, two, two, two, one and one patients, respectively. Mild grade 1 gastrointestinal side-effects were reported in 16, and mild anorexia in nine patients with moderate dermatitis, five showed early stages of hand-and-foot syndrome in the upper extremity and/or nail disorders. Few patients (n = 9) developed grade 1 neurological symptoms including transient paraesthesiasis, headache and dizziness; eight patients reported mild myalgia. Grade 1 neutropenia was seen in one patient. No cardiac toxicity was noted; one patient with a history of severe aortic stenosis tolerated capecitabine without treatment-associated cardiac symptoms. In all patients treatmentrelated toxicities resolved after cessation of therapy. No toxic death occurred.

DISCUSSION
The use of biologic therapies has an established role in the treatment of metastatic renal cell carcinoma (Quesada, 1988;Belldegrun et al, 1991;Atzpodien et al, 1995a;Hofmockel et al, 1997). Potentially better results can be obtained using combination therapies with cytokines and 5-fluorouracil (Lopez et al, 1996;Hofmockel et al, 1997). Retinoids are known to control many important biological processes, including differentation, morphogenesis, growth and tissue homeostasis (Warrel, 1994). Clinical and pre-clinical results provide evidence for an antiproliferative effect of 13-cis-retinoic acid in IFN-α-treated patients with renal cell carcinoma (Buer et al, 1995;Motzer et al, 1995). Furthermore, it seems to have a favourable effect in the treatment of renal  Tumour thrombus, soft tissue, pericardium, myelon (n = 2); b Good prognosis was defined by the presence of lung metastases and the absence of bone metastases, ESR < 70 mm after 1 h, serum lactic dehydrogenase < 280 units l -1 , neutrophilic granulocytes < 6000 µl -1 and haemoglobin > 100 gm l -1 poor prognosis patients included all others Patients were entered between June 1998 and December 1998. Patients received cytokines and chemotherapy at home. Treatment cycles were repeated every 2 months for an average of 1.5 cycles (range 1-3) unless disease progression occurred cancer, when added to immuno-chemotherapy regimens (Atzpodien et al, 1995b). Capecitabine, as a novel fluoropyrimidine carbamate which is converted to 5-fluorouracil by three enzymes located in the liver and in tumours, shows promising response rates and remission durations while being very well tolerated in patients with metastatic renal cell carcinoma. Due to four-fold higher thymidine phosphorylase (5-DFUR to 5-FU) activity in tumour compared to adjacent healthy tissue (Frings, 1998), capecitabine allows for a more specific anti-tumour therapy than conventional i.v. fluorouracil.
In the present home-therapy trial, we treated 30 patients with progressive metastatic renal cell carcinoma with a combination of p.o. capecitabine, s.c. IFN-α, s.c. IL-2 and 13-cis-RA. The dose of capecitabine was adapted on an empirical basis from the recommend dose (Roche Laboratories Inc, 1998). The continued administration over an extended treatment interval of 4 weeks in combination with s.c. IFN-α, as opposed to an administration for 2 weeks followed by a 1-week rest period, required both a reduction in the daily dose of capecitabine and a > 50% reduction in cumulative 8-week capecitabine dosages. Capecitabine shows promising objective response rates in various solid tumours (Frings, 1998).
We report first clinical results of capecitabine in the treatment of advanced renal cancer.
In the patients reported here, the rate of capecitabine-related toxicity was low, and side-effects were moderate overall. Predominant side-effects included gastrointestinal toxicities with diarrhoea, nausea/vomiting, dyspepsia and stomatitis, and cutaneous symptoms including dermatitis and early stages of handand-foot syndrome. A few patients experienced mild malaise and mild neurological/musculoskeletal side-effects.
Capecitabine-associated systemic toxicities were mostly limited to WHO grade 1, rarely grade 2. Only two patients experienced WHO grade 3 effects. It should be noted that in addition to capecitabine all patients were simultaneously treated with s.c.  This confirmed the excellent tolerability reported in other malignancies at various dosages and treatment intervals of  myelon; e Good Prognosis was defined by the presence of lung metastases and the absence of bone metastases, ESR < 70 mm after 1 h, serum lactic dehydrogenase < 280 units l -1 neutrophilic granulocytes < 6000 µl -1 and haemoglobin > 100 gm l -1 , poor prognosis patients included all others Good prognosis was defined by the presence of lung metastases and the absence of bone metastases, ESR < 70 mm after 1 h, serum lactic dehydrogenase < 280 units l -1 neutrophilic granulocytes < 6000 µ l -1 and haemoglobin > 100 gm l -1 , poor prognosis patients included all others; b This patient developed brain metastases capecitabine (Budman et al, 1998;Mackean et al, 1998). Per oral administration of capecitabine, in contrast to most chemotherapeutic agents that are applied intravenously, allows treatment in an outpatient or home therapy setting. This advantage will reduce expenses and could enhance quality of life in the palliative setting. Unless randomized data become available, the contribution of capecitabine and its potential therapeutic feasibility cannot be definitively assessed. Therefore, we have initiated a prospectively controlled randomized clinical trial to investigate the role of capecitabine in patients with advanced renal cell carcinoma.
Capecitabine associated toxicities were evaluated during weeks 5-8 of each treatment cycle according to WHO criteria and were observed in 25 of 30 patients. Grade 2 toxicity was seen in five patients and grade 3 toxicity occured in two patients; b Patients may have had several side-effects.