Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer

Capecitabine is an orally administered prodrug of fluorouracil which is indicated in the US and Europe, in combination with docetaxel, for the treatment of patients with metastatic breast cancer failing anthracycline therapy, and as monotherapy for metastatic breast cancer resistant to paclitaxel and anthracycline therapy (US) or failing intensive chemotherapy (Europe). Capecitabine is also approved for use in metastatic colorectal cancer. Capecitabine is metabolically activated preferentially at the tumour site, and shows antineoplastic activity and synergy with other cytotoxic agents including cyclophosphamide or docetaxel in animal models. Bioavailability after oral administration is close to 100%. In patients with pretreated advanced breast cancer, capecitabine is effective as monotherapy and also in combination with other agents. Combination therapy with capecitabine 1,250 mg/m(2) twice daily for 2 weeks of every 3-week cycle plus intravenous docetaxel 75 mg/m(2) on day one of each cycle was superior to intravenous monotherapy with docetaxel 100 mg/m(2) on day one of each cycle. Capecitabine plus docetaxel significantly reduced the risks of disease progression and death by 35% (p = 0.0001) and 23% (p < 0.05), respectively, and significantly increased median survival (p < 0.05) and objective response rates (p < 0.01). Efficacy has also been demonstrated with capecitabine monotherapy and combination therapy in previously untreated patients in preliminary trials. The most common adverse effects occurring in patients receiving capecitabine monotherapy include lymphopenia, anaemia, diarrhoea, hand-and-foot syndrome, nausea, fatigue, hyperbilirubinaemia, dermatitis and vomiting (all >25% incidence). While gastrointestinal events and hand-and-foot syndrome occurred more often with capecitabine than with paclitaxel or a regimen of cyclophosphamide, methotrexate and fluorouracil (CMF), neutropenic fever, arthralgia, pyrexia and myalgia were more common with paclitaxel, and nausea, stomatitis, alopecia and asthenia were more common with CMF. The incidence of adverse effects and hospitalisation was similar in patients receiving capecitabine plus docetaxel and those receiving docetaxel monotherapy. In conclusion, capecitabine, an oral prodrug of fluorouracil which is activated preferentially at the tumour site, is an effective and convenient addition to the intravenous polychemotherapeutic treatment of advanced breast cancer in pretreated patients, and also has potential as a component of first-line combination regimens. Combined capecitabine plus docetaxel therapy resulted in similar rates of treatment-related adverse effects and hospitalisation to those seen with docetaxel monotherapy. Capecitabine is also effective as monotherapy in pretreated patients and phase II data for capecitabine as first-line monotherapy are also promising. While gastrointestinal effects and hand-and-foot syndrome occur often with capecitabine, the tolerability profile was comparatively favourable for other adverse effects (notably, neutropenia and alopecia).     

Docetaxel: a review of its use in metastatic breast cancer

Docetaxel (Taxotere), a cytotoxic taxane, is an antimicrotubule agent effective in the treatment of patients with breast cancer. The clinical profile of docetaxel as an effective cytotoxic agent in the treatment of metastatic breast cancer is well established. As yet, no single standard regimen has been identified as optimal for the treatment of patients with metastatic breast cancer after failure of prior chemotherapy. However, the efficacy of docetaxel monotherapy administered every 3 weeks as a 1-hour infusion is similar to or better than that of doxorubicin, paclitaxel and fluorouracil plus vinorelbine, and better than that of methotrexate plus fluorouracil or mitomycin plus vinblastine. Although docetaxel is associated with neutropenia and other adverse events, its overall tolerability profile is generally acceptable in the majority of patients. Docetaxel, therefore, is an effective option in the treatment of patients with metastatic breast cancer after failure of prior chemotherapy.     

Docetaxel: a review of its use in non-small cell lung cancer

Docetaxel, a semisynthetic member of the taxoid class of antineoplastic agents, is effective in the treatment of patients with locally advanced and metastatic non-small cell lung cancer (NSCLC). In noncomparative trials in patients with NSCLC, docetaxel 75 or 100 mg/m2 produced objective response rates of 20 to 38% and 14 to 25% as a first-line or second-line monotherapy, respectively. In Japan, docetaxel 60 mg/m2 produced objective response rates of 19 to 25% in previously untreated patients. Docetaxel 100 or 75 mg/m2 produced significantly higher response rates than either vinorelbine or ifosfamide in previously treated patients; patients treated with docetaxel 75 mg/m2 had an improved 1-year survival rate compared with those who received vinorelbine or ifosfamide. Docetaxel monotherapy in chemotherapy-naive patients produced survival rates that are similar to those reported for most platinum-containing standard combinations such as cisplatin plus vinorelbine. Combination of docetaxel with one other antineoplastic resulted in objective response rates of 20 to 54% in chemotherapy-naive patients; triple chemotherapy combinations produced responses in 51 and 60% of patients. Promising results from a few small studies and one large phase II study have also indicated a potential role for docetaxel as neoadjuvant therapy. The main dose-limiting adverse event associated with docetaxel is neutropenia, and fluid retention is common in many patients. The tolerability profile is generally acceptable in the majority of patients, although extra care has to be taken in patients with impaired liver function to minimise the risk of severe or febrile neutropenia. Conclusions. Docetaxel is generally well tolerated by patients receiving treatment for locally advanced and metastatic NSCLC, and produces response and survival rates equivalent to many current standard treatment options. Comparative studies have shown that docetaxel monotherapy provides significant survival benefits over best supportive care or treatment with vinorelbine or ifosfamide. Response and 1-year survival rates with docetaxel monotherapy are particularly encouraging in patients refractory or resistant to cisplatin or carboplatin, for whom treatment options are few. Neoadjuvant docetaxel has produced improved survival compared with local treatment alone. Combinations of docetaxel with other antineoplastic agents have produced relatively high response and 1-year survival rates; however, further comparative studies are required to confirm these benefits. In the meantime, docetaxel is a welcome addition to the options available for patients with advanced NSCLC.     

多西紫杉醇加顺铂及氟尿嘧啶化疗辅助治疗进展期胃癌

目的研究多西紫杉醇加顺铂及氟尿嘧啶(5-FU)/亚叶酸钙方案联合新辅助化疗治疗局部进展期胃癌,并评价此方案的疗效和毒副作用。方法2003-10～2004-10收治的18例局部进展期胃癌患者加入研究。入组患者术前接受的新辅助化疗方案为:多西紫杉醇75mg/m2,第1天静脉滴注;顺铂30mg/m2,第1～3天静脉滴注;5-FU500mg/m2,第1～5天静脉滴注;亚叶酸钙100mg于5-FU前30min静脉冲入;每3周为1周期,共3个周期。观察新辅助化疗后肿瘤原发病灶的缓解情况、手术后病理缓解情况以及新辅助化疗的毒副反应。结果新辅助化疗后所有患者进行了根治性手术治疗,有效10例,其中完全缓解3例,部分缓解7例;疾病稳定5例,疾病进展3例。术后病理检查2例病理水平达到完全缓解。不良反应主要为白细胞减少、恶心、脱发、呕吐及黏膜炎,其中有4例患者发生了Ⅲ～Ⅳ级的白细胞减少,但未有因此而发生严重感染和病死者。结论多西紫杉醇加顺铂及5-FU/亚叶酸钙的化疗方案在进展期胃癌的治疗中近期疗效显著,患者耐受性良好。     

Polyethylene glycol-liposomal doxorubicin: a review of its use in the management of solid and haematological malignancies and AIDS-related Kaposi's sarcoma

Polyethylene glycol (PEG)-liposomal doxorubicin is a formulation of the anthracycline doxorubicin in which the drug is encapsulated in PEG-coated liposomes. This alters the pharmacokinetic properties of doxorubicin, prolonging circulation time and enhancing localisation to tumours. In a large randomised trial, intravenous PEG-liposomal doxorubicin was at least as effective as topotecan in patients with ovarian cancer refractory or sensitive to first-line platinum-based chemotherapy. Overall response rates of patients with ovarian cancer refractory to platinum- and paclitaxel-based chemotherapy who received the drug ranged from 18.3 to 27.6% in noncomparative clinical trials. PEG-liposomal doxorubicin also has antitumour activity in patients with metastatic breast cancer pretreated with other chemotherapeutic agents. Overall response rates were similar in patients with pretreated metastatic breast cancer who had received PEG-liposomal doxorubicin or two comparator salvage chemotherapy regimens (vinorelbine or mitomycin C plus vinblastine) in an interim analysis of a large randomised study. In patients with advanced AIDS-related Kaposi's sarcoma, PEG-liposomal doxorubicin monotherapy produced overall response rates ranging from 46 to 77% in randomised trials. The drug was significantly more effective than bleomycin plus vincristine alone or in combination with standard doxorubicin, as measured by tumour response. As a replacement for standard doxorubicin in commonly used combination therapies, PEG-liposomal doxorubicin has shown activity in multiple myeloma and aggressive non-Hodgkin's lymphoma in small, preliminary trials. The most common adverse events associated with PEG-liposomal doxorubicin are myelosuppression, palmar-plantar erythrodysaesthesia, stomatitis and nausea. These can be managed by delaying or reducing dosages. Although preliminary trials are promising, the relative cardiotoxicity of PEG-liposomal doxorubicin compared with the standard formulation has not been clearly established. CONCLUSIONS: Monotherapy with PEG-liposomal doxorubicin is effective as a second-line chemotherapy in patients with platinum-refractory ovarian cancer and in patients with metastatic breast cancer. However, as with all chemotherapeutic agents, the benefits of treatment need to be weighed against the agent's tolerability profile. Strong comparative data have helped to establish PEG-liposomal doxorubicin as the first-line treatment option in patients with advanced Kaposi's sarcoma. Anticancer activity has also been observed in studies conducted in small numbers of patients with multiple myeloma or non-Hodgkin's lymphoma receiving PEG-liposomal doxorubicin instead of standard doxorubicin in combination regimens, although further data are needed to confirm the clinical relevance of these findings.     

Primary chemotherapy with gemcitabine, liposomal doxorubicin and docetaxel in patients with locally advanced breast cancer: results of a phase I trial

The primary objective was to determine the optimal doses for gemcitabine (prolonged infusion), liposomal doxorubicin (Myocet) and docetaxel as primary (neoadjuvant) chemotherapy for locally advanced breast cancer. Secondary objectives included evaluation of the safety and efficacy of the regimen. Patients (n=19) with histologically confirmed stage II or III breast cancer were treated with liposomal doxorubicin (50-60 mg/m2) and docetaxel (60-75 mg/m2) on day 1, and gemcitabine as 4-h infusion (350-400 mg/m2) on day 4. Treatment was repeated every 3 weeks for a maximum of 6 cycles. The maximum tolerated doses were gemcitabine 350 mg/m2, liposomal doxorubicin 60 mg/m2 and docetaxel 75 mg/m2. Dose-limiting toxicities were stomatitis, diarrhea and infection. The predominant hematologic toxicity was mild-to-moderate myelosuppression with grade 3/4 neutropenia in 20% of cycles. Non-hematologic toxicity was generally mild, with no grade 4 toxicities being observed. Predominant non-hematologic toxicity was stomatitis, which occurred in 95% of patients. Grade 3 toxicities were reported for stomatitis, nausea, diarrhea, infection and constipation. No cases of cardiac, renal, pulmonary or neurotoxicity were observed. The clinical response rate was 83% and histologically confirmed, clinically complete remissions occurred in two patients (11%). We conclude that the combination of gemcitabine (prolonged infusion), liposomal doxorubicin and docetaxel is safe and highly effective in patients with locally advanced breast cancer as defined by maximum tolerated doses. The evaluated schedule is suitable for phase II studies.     

Pegylated liposomal doxorubicin: a review of its use in metastatic breast cancer, ovarian cancer, multiple myeloma and AIDS-related Kaposi's sarcoma

Pegylated liposomal doxorubicin (Caelyx?, Doxil?) represents an improved formulation of conventional doxorubicin, with reduced cardiotoxicity and an improved pharmacokinetic profile. This article reviews the efficacy and tolerability of pegylated liposomal doxorubicin in metastatic breast cancer, progressive ovarian cancer, relapsed or refractory multiple myeloma and AIDS-related Kaposi's sarcoma, as well as summarizing its pharmacological properties. In three randomized, open-label, multicentre trials, monotherapy with pegylated liposomal doxorubicin was as effective as doxorubicin or capecitabine in the first-line treatment of metastatic breast cancer, and as effective as vinorelbine or combination mitomycin plus vinblastine in taxane-refractory metastatic breast cancer. Pegylated liposomal doxorubicin alone was as effective as topotecan or gemcitabine alone in patients with progressive ovarian cancer resistant or refractory to platinum- or paclitaxel-based therapy, according to the results of three randomized multicentre trials. In addition, in patients with progressive ovarian cancer who had received prior platinum-based therapy, progression-free survival was significantly longer with pegylated liposomal doxorubicin plus carboplatin than with paclitaxel plus carboplatin, according to the results of a randomized, open-label multicentre trial. Combination therapy with pegylated liposomal doxorubicin plus bortezomib was more effective than bortezomib alone in patients with relapsed or refractory multiple myeloma, according to the results of a randomized, open-label, multinational trial. Randomized multinational trials also demonstrated the efficacy of pegylated liposomal doxorubicin in patients with advanced AIDS-related Kaposi's sarcoma. Pegylated liposomal doxorubicin exhibited a relatively favourable safety profile compared with conventional doxorubicin and other available chemotherapy agents. The most common treatment-related adverse events included myelosuppression, palmar-plantar erythrodysesthesia and stomatitis, although these are manageable with appropriate supportive measures. To conclude, pegylated liposomal doxorubicin is a useful option in the treatment of various malignancies, including metastatic breast cancer, ovarian cancer, multiple myeloma and AIDS-related Kaposi's sarcoma.     

Capecitabine: new indication. In breast cancer: inadequately assessed

There is no consensus on treatment of locally advanced or metastatic breast cancer after failure of first-line cytotoxic chemotherapy. Common options are continuous infusion of a taxane (docetaxel or paclitaxel), vinorelbine or fluorouracil. Capecitabine is now licensed for use in breast cancer, both in combination with IV docetaxel after anthracycline failure, and as single-agent therapy after failure of anthracyclines and taxanes. The clinical evaluation dossier on capecitabine fails to answer the most important questions about comparative efficacy and safety. In second-line treatment, after anthracycline failure, the only available comparative trial showed that the capecitabine + docetaxel combination increased median survival time by about three months relative to placebo + docetaxel, but caused more adverse events. There are no trials comparing capecitabine with other options. There is no evidence that capecitabine increases the length or quality of survival, relative to intravenous vinorelbine, in women with breast cancer that is resistant to both anthracyclines and taxanes. The classical adverse effects of capecitabine are also observed in women with breast cancer, namely palmoplantar erythrodysesthesia, diarrhoea, nausea and vomiting, and major hyperbilirubinemia. Capecitabine can be taken by mouth and this may be an advantage. However, current evidence is too limited to justify using capecitabine outside of clinical trials.     

Docetaxel (Taxotere) - an update

The development of docetaxel, a member of the taxoid family, has been recent and rapid. Phase I studies recommend that a dose of 100 mg/m(2) be administered every three weeks in a 1-h infusion. These studies have also demonstrated that the major dose-limiting toxicity is neutropenia. Major clinical research projects are now being carried out for breast cancer, non-small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN) and gastric cancer. In advanced and metastatic NSCLC, Phase II studies have shown a response rate of 30 - 40%, and responses have been obtained in cis-platinum failures. In advanced and metastatic breast cancer, first-line treatment has yielded a response rate of 54 - 68%, and the rate for second-line response is only slightly lower, indicating an absence of cross-resistance. Phase II combination studies with docetaxel are in progress, and preliminary results are promising. The first Phase III study demonstrated preliminary response rates significantly higher than seen with doxorubicin, although survival data have not yet been published. Fewer results are available from SCCHN studies, but response rates have been encouraging (around 40%). Although further long-term data are needed to determine the precise role of docetaxel in combination with other drugs, it is apparent that this promising drug shows one of the best response rates for monotherapy in NSCLC and breast cancer.     

The current status of docetaxel for advanced non-small cell lung cancer

Docetaxel is an active single agent in both first- and second-line therapy of patients with advanced non-small cell lung cancer (NSCLC). Randomized trials versus best supportive care have documented an improvement in overall survival for docetaxel therapy in both settings. Docetaxel also produced a significant 1-year survival rate improvement when compared with vinorelbine or ifosfamide as second-line therapy. Docetaxel has been extensively investigated in phase I/II studies in combination with cisplatin, carboplatin, irinotecan and gemcitabine. Substantial activity has been demonstrated. In a randomized phase II trial comparing docetaxel plus cisplatin with docetaxel plus gemcitabine, the efficacy of the two regimens was almost identical (response rates 32 and 34%; 1-year survival rates 42 and 38%). However, the combination of docetaxel with gemcitabine was associated with significantly less grade III/IV neutropenia, diarrhea and nausea/vomiting. Three drug regimens combining docetaxel with, for example, gemcitabine and carboplatin or with ifosfamide and cisplatin, are producing very high response rates in phase II trials. Whether three-drug combinations including docetaxel will result in an improved outcome for patients with advanced NSCLC remains to be determined.     

Therapeutic applications of medicinal plants in the treatment of breast cancer: a review of their pharmacology, efficacy and tolerability

Various active compounds (or their semi-synthetic derivatives) derived from medicinal plants have been assessed for their efficacy and tolerability in the treatment of breast cancer. Some of these plant species, including Taxus baccata (paclitaxel, docetaxel), Podophyllum peltatum (etoposide), Camptotheca acuminata (camptothecin) and Vinca rosea (vinblastine, vinorelbine) have well recognized antitumour activity in breast cancer, and have been evaluated in clinical trials. For example, results from recent Phase II/III trials have established docetaxel as the most active single agent in the treatment (first or second-line) of advanced metastatic breast cancer. For other plant species such as Panax ginseng and Allium sativum, antitumour activity has been evaluated in experimental studies using cultured cells and animal models, but the therapeutic potential in patients remains to be determined. Antitumour activity derived from medicinal plants may produce results via a number of mechanisms, including effects on cytoskeletal proteins which play a key role in mitosis (paclitaxel), inhibition of activity of topoisomerase enzymes I (camptothecin) or II (etoposide), stimulation of the immune system (Viscum album), or antiprotease-antioxidant activity. Medicinal plant-derived antineoplastic agents may be used in single agent or in combinational therapies, and have been used in first-line or second-line (including anthracycline-refractory patients) treatment of localized or metastatic breast cancer. Adverse effects resulting from the use of these agents include neutropenia and peripheral neuropathies.     

Expanding options in breast cancer

In metastatic breast cancer, docetaxel is the only drug to have shown superior activity to doxorubicin [objective response rates (ORRs) 48 versus 33%] by direct comparison in a randomized trial. Importantly, this greater activity was accompanied by a lower risk of cardiotoxicity. Docetaxel has also proved superior to various combination regimens in patients who had previously failed anthracyclines. In the comparison versus mitomycin C plus vinblastine, survival was significantly prolonged in the docetaxel arm. The combination of paclitaxel with doxorubicin has achieved remarkably high rates of response. However, the combination is cardiotoxic (with the highest response rates reporting an incidence of clinical congestive heart failure in the region of 18%). In comparison, the combination of docetaxel with doxorubicin, while also highly active (ORR > 70%), is relatively non-cardiotoxic (with only one case of clinical congestive heart failure in 96 patients treated). Given that docetaxel appears to be the most active single agent in metastatic breast cancer, there is a compelling case for the drug to be evaluated in the adjuvant setting and such studies are ongoing.     

Single-agent capecitabine maintenance therapy after response to capecitabine-based combination chemotherapy in patients with metastatic breast cancer

We performed an analysis of the efficacy of capecitabine monotherapy as maintenance treatment for metastatic breast cancer (MBC) after response to capecitabine-based chemotherapy [capecitabine plus docetaxel (XT) or vinorelbine (XN)] as a first-line or a second-line treatment. Sixty-four Chinese patients with histologically confirmed MBC received capecitabine maintenance therapy after disease stabilization or maximal response to capecitabine-based combination chemotherapy. Single-agent capecitabine was administered at a dose of 1000 mg/m(2) twice daily for 14 days, followed by a 7-day rest period, every 3 weeks. The median time to progression, the primary endpoint of the study, was 4.4 months (95% confidence interval, 3.4-5.4 months). Fifty-nine patients were evaluable for response. Capecitabine maintenance therapy produced an objective response rate of 5.1% (95% confidence interval, 3.9-6.3%). The incidence of grade 3/4 leukopenia (3.1%) and neutropenia (4.7%) was significantly lower (P<0.001) with capecitabine monotherapy than with combination chemotherapy (46.9 and 54.7%, respectively). Conversely, the incidence of grade 3 hand-foot syndrome was higher with capecitabine maintenance therapy than with combination therapy (14.1 vs. 0%, respectively; P=0.003). Capecitabine monotherapy is an effective maintenance treatment after response to capecitabine-based combination chemotherapy in MBC with a favorable safety profile.     

DOF与DCF方案治疗进展期胃癌的临床对照观察

目的:本研究旨在评价多西他赛联合奥沙利铂、氟脲嘧啶(DOF方案)与多西他赛联合顺铂、氟脲嘧啶(DCF方案)组成的5天联合方案一线治疗进展期胃癌的有效性和安全性。方法:75例患者分为A、B两组。A组38例,接受DOF方案:多西他赛75mg/m2第2天,奥沙利铂130mg/m2第1天,氟脲嘧啶500mg/m2第1～5天;B组37例,接受DCF方案:多西他赛75mg/m2第2天,顺铂25mg/m2第1～3天,氟脲嘧啶500mg/m2第1～5天。均每3周重复,至少应用2周期。结果:A组患者临床控制率、完全缓解率、部分缓解、中位治疗至进展时间、中位生存期以及1年生存率和2年的生存率分别为65.78%、5.26%、42.10%、5.9月、11.2月、52.63%、18.42%。B组分别为54.06%、2.70%、35.14%、5.8月、10.8月、48.64%、13.51%。治疗前两组生活质量(QOL)分值相当,但是治疗后1月、2月的QOL分值有差异(P<0.05)。两组生存期比较无显著差异(P>0.05)。两组主要毒副反应为骨髓抑制、恶心呕吐,但不严重。结论:多西他赛联合奥沙利铂、氟脲嘧啶和多西他赛联合顺铂、氟脲嘧啶一线治疗进展期胃癌疗效均确切、毒副反应均可以接受。与最好的支持治疗相比联合化疗可延长患者生存期,提高生活质量。特别是前者对生活质量的影响比后者轻。     

多西紫杉醇联合顺铂二线化疗对进展期晚期胃癌患者临床疗效研究

目的：观察多西紫杉醇联合顺铂二线化疗治疗晚期胃癌一线药物化疗后病情进展患者的疗效及安全性。方法将80例晚期胃癌一线奥沙利铂联合氟尿嘧啶类药物化疗后病情进展患者纳入研究,其中单药组32例：给予多西紫杉醇75～100 mg／m2治疗,21 d 为1个周期;联合组48例：给予多西紫杉醇60～75 mg／m2 d1,顺铂针25 mg／m2 d1～3,21 d 为1个周期。结果80例均可评价客观疗效及不良反应,单药组和联合组的有效率（RR）分别为12．5％和33．3％,疾病控制率（DCR）分别为43．8％和75．0％,联合组较单药组的 RR 及 DCR 均明显提高（P ＜0．05）。单药组的无疾病进展时间（PFS）为3．1月,联合组的 PFS 为3．9月,联合组较单药组有延长,但差异无统计学意义（P ＞0．05）。最常见的不良反应为血液学毒性、恶心呕吐和脱发,差异均无统计学意义（P ＞0．05）。结论晚期胃癌一线化疗进展患者采用多西紫杉醇联合顺铂方案有效率及疾病控制率较高,不良反应可耐受,仍需进一步研究。     

Oxaliplatin: a review of its use in the management of metastatic colorectal cancer.

Oxaliplatin is a cytotoxic agent which, like other platinum compounds, acts primarily by causing inter- and intra-strand cross-links in DNA, thereby inhibiting DNA synthesis. Oxaliplatin has a bulky carrier ligand which is thought to enhance cytotoxicity and abolish cross-resistance between oxaliplatin and other platinum compounds. Phase II and III clinical trials have found oxaliplatin combined with fluorouracil/calcium folinate (leucovorin/folinic acid) to be an effective first- and second-line treatment for patients with metastatic colorectal cancer. First-line triple therapy with oxaliplatin and fluorouracil/calcium folinate achieved significantly higher response rates than fluorouracil/calcium folinate alone in 2 phase III studies (objective response rates 59 vs 23% and 50.7 vs 22.3%). In addition, median progression-free survival was longer with triple therapy in both studies (8.9 vs 5.2 and 8.75 vs 6.0 months). However, there was no significant difference in median duration of survival between treatment groups, although this may be a consequence of the subsequent use of oxaliplatin and/or surgery in patients who relapsed during therapy with fluorouracil/calcium folinate alone. About 30 to 45% of patients (whose disease progressed during or after fluorouracil-based therapy) responded to second-line combination therapy with oxaliplatin and fluorouracil/calcium folinate. Median progression-free survival ranged from 7 to 10 months and the median duration of survival from 10 to 17 months. Objective responses were achieved in 20 and 24% of patients in 2 small trials of first-line oxaliplatin monotherapy and in about 10% of patients given the drug as a second-line option. Peripheral sensory neuropathy is the dose-limiting toxicity associated with oxaliplatin. Severe neurotoxicity has been estimated to occur in 10% of patients after 6 treatment cycles and in 50% after 9 cycles of an oxaliplatin dosage of 130 mg/m2 once every 3 weeks. It is cumulative, but reversible on discontinuation of therapy. Nausea, vomiting and diarrhoea are common, but are usually mild to moderate. Myelosuppression is also observed, but is usually mild. Conclusion: oxaliplatin is a promising treatment option for patients with metastatic colorectal cancer. It appears to be particularly advantageous (in terms of response rate and duration of progression-free survival) when used in combination with fluorouracil/calcium folinate as both a first- and second-line option, although preliminary studies have failed to show any survival advantage over fluorouracil/calcium folinate alone. Promising results have been found in studies of the drug as monotherapy, and oxaliplatin may also prove useful in the neoadjuvant setting in patients with unresectable liver metastases; however, data are limited at present.     

Oxaliplatin. A review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies

Oxaliplatin is a platinum compound that inhibits DNA synthesis, primarily by causing intrastrand cross-links in DNA. Oxaliplatin has a broad spectrum of antineoplastic activity and has demonstrated a lack of cross-resistance with other platinum compounds. In patients with metastatic colorectal cancer, intravenous oxaliplatin has been trialled as a monotherapy and in combination with other agents. The highest response rates were achieved when oxaliplatin was used in combination with fluorouracil/folinic acid (leucovorin; calcium folinate), typically > or = 50% in the first-line setting and 13 to 45% as a second-line therapy. First-line triple therapy with oxaliplatin and fuorouracil/folinic acid achieved significantly higher response rates and longer median progression-free survival than fluorouracil/folinic acid therapy alone. However, no significant difference in the median duration of overall survival was found. This may be a consequence of the subsequent use of oxaliplatin and/or surgery after disease progression in patients who relapsed after fluorouracil/folinic acid therapy alone. Neoadjuvant therapy with oxaliplatin/fluorouracil/folinic acid has proven beneficial in enabling surgical removal of previously unresectable liver metastases. In 2 studies, surgery with curative intent was performed in 16 and 51% of patients with initially unresectable liver metastases following oxaliplatin/fluorouracil/folinic acid therapy; the 5-year survival rates were 40 and 50%, respectively. In patients with advanced ovarian cancer, first-line therapy with oxaliplatin/cyclophosphamide achieved an objective response rate which did not differ significantly from that of cisplatin/cyclophosphamide (33 vs 42%). In addition, oxaliplatin has shown efficacy in patients with platinum-pretreated ovarian cancer and achieved objective response rates similar to paclitaxel in this setting (16 vs 17%). Promising results have also been found with oxaliplatin in patients with non-Hodgkin's lymphoma, breast cancer, mesothelioma and non-small cell lung cancer. Reversible, cumulative, peripheral sensory neuropathy is the principle dose-limiting factor of oxaliplatin therapy. Haematological and gastrointestinal toxicities occur frequently but are generally mild to moderate in intensity. CONCLUSION: Oxaliplatin in combination with fluorouracil/folinic acid is an effective treatment option for patients with metastatic colorectal cancer, both as a first-line therapy and in patients refractory to previous chemotherapy. Although preliminary results failed to show any overall survival advantage of this regimen over fluorouracil/folinic acid alone, this may be a consequence of trial design and requires further examination. Additional clinical investigation of oxaliplatin in patients with other cancers is warranted given the promising results achieved in early trials, most notably in patients with platinum-pretreated ovarian cancer.     

The chemotherapy of head and neck cancer

Studies of combination therapy [with agents such as cisplatin, 5-fluorouracil (5-FU) and methotrexate] have shown some improvements in response rate; however, no obvious survival advantage over monotherapy in the treatment of patients with metastatic or advanced locoregional cancer of the head and neck have been observed. In the neoadjuvant setting, chemotherapy is helpful in preserving the larynx and hypopharynx but has no proven impact (positive or negative) on survival. New treatment options are needed to improve survival in head and neck cancer. Among the new options for chemotherapy in metastatic/recurrent disease is docetaxel. With monotherapy, response rates of 23-42% are seen, and, when used in combination with cisplatin and 5-FU, response rates of 52-100% have been reported in phase I/II trials. A phase III trial of the addition of docetaxel to standard neoadjuvant therapy with cisplatin and 5-FU is now underway.     

Vandetanib with docetaxel as second-line treatment for advanced breast cancer: a double-blind, placebo-controlled, randomized Phase II study

Purpose The aim of this Phase II study was to assess the efficacy and safety of vandetanib in combination with docetaxel in patients with pretreated advanced breast cancer. Methods The primary study objective was to compare the number of progression events in patients receiving once-daily oral vandetanib (100 mg) in combination with docetaxel (100 mg/m² iv every 21 days) versus placebo plus docetaxel. Sixty-four patients were randomized to receive study treatment (n = 35, vandetanib; n = 29, placebo). Results A slightly greater number of patients had experienced a progression event by the data cut-off in the vandetanib group (24 [69%]) compared with the placebo group (18 [62%]); HR = 1.19, two-sided 80% CI: 0.79–1.81; two-sided P = 0.59), suggesting that the addition of vandetanib to docetaxel did not affect the risk of disease progression compared with placebo plus docetaxel. The safety and tolerability profile of the combination therapy reflected those of both drugs as monotherapy agents. Conclusions In patients with advanced breast cancer, vandetanib plus docetaxel was generally well tolerated. Clinical benefit was not different to that observed with placebo plus docetaxel. However, due to the small patient number it was not possible to yield robust results, further research is required to identify predictive factors for patient selection.     

Preoperative chemotherapy with epidoxorubicin, docetaxel and capecitabine plus pegfilgrastim in patients with primary breast cancer

The objective of this pilot trial was to evaluate the safety and activity profile of epidoxorubicin, docetaxel and oral capecitabine plus pegfilgrastim (TEX+P) as preoperative first-line treatment for patients with breast cancer. Eleven consecutive patients were enrolled in this prospective clinical pilot trial. Preoperative treatment consisted of epidoxorubicin [75 mg/m2 body surface area (BSA)] and docetaxel (75 mg/m2 BSA) administered sequentially on day 1 in combination with oral capecitabine 2000 mg/m2 daily divided into two doses on days 1-14 of each 3-week treatment cycle. Pegfilgrastim 6 mg fixed dose was administered s.c. on day 2 of every treatment cycle. Patients received a total of 58 cycles (median 6 cycles, range 1-6) of this therapeutic regimen. Outpatient TEX+P was well tolerated. No WHO grade IV toxicity was observed. A pathological major response to this preoperative therapy regimen could be demonstrated in eight of nine evaluable patients leading to breast-conserving surgery in seven of nine evaluable patients. We conclude that outpatient TEX+P is safe in the neoadjuvant treatment of patients with primary breast cancer. Thus, this regimen can be considered for further clinical trials.