Summary

Bevacizumab is a humanized recombinant antibody that prevents vascular endothelial growth factor (VEGF) receptor binding, and inhibits angiogenesis and tumor growth.

In patients receiving an irinotecan plus fluorouracil/leucovorin (IFL) regimen for first-line treatment of metastatic colorectal cancer, the addition of bevacizumab significantly increased overall survival by 4.7 months relative to IFL plus placebo. In the second-line treatment of advanced colorectal cancer, patients who received bevacizumab in combination with a fluorouracil/leucovorin plus oxaliplatin (FOLFOX4) regimen had an overall survival time that was 2 months longer than that in patients receiving FOLFOX4. Preliminary results indicated that bevacizumab significantly extended progression-free survival by 4.9 months in patients receiving paclitaxel for the first-line treatment of locally recurrent or metastatic breast cancer. The addition of bevacizumab to paclitaxel plus carboplatin in the first-line treatment of advanced NSCLC significantly prolonged overall survival by >2 months.

Bevacizumab has acceptable tolerability in patients with advanced colorectal cancer, breast cancer, or NSCLC, with the majority of adverse events being generally mild and clinically manageable. Thus, bevacizumab provides a highly effective addition to standard chemotherapeutic regimens for advanced colorectal cancer, breast cancer, and NSCLC.

Pharmacological Properties

Bevacizumab binds to soluble VEGF, preventing receptor binding, and inhibits VEGF-induced endothelial cell proliferation and migration in vitro. In vivo in murine xenografts, bevacizumab decreased tumor growth by ≈70–95% compared with control animals. In patients with rectal adenocarcinoma or inflammatory or locally advanced breast cancer, intravenous bevacizumab displayed antiangiogenic and antitumor effects.

The single-dose pharmacokinetic profile of bevacizumab 0.1–10 mg/kg is linear, and an accumulation index of 1.4–2.9 has been observed after multiple doses of 3–20 mg/kg. The mean central volume of distribution of bevacizumab was 37.9–48.6 mL/kg during monotherapy, 34.3–56.8 mL/kg during coadministration with other antineoplastic agents, and was 22% greater in males than in females after correction for bodyweight.

The clearance of bevacizumab is low (2.8–5.1 mL/kg/day with doses of 0.3–10 mg/kg) and varies with bodyweight, sex, and tumor burden. Bevacizumab 0.3–20 mg/kg has a long terminal elimination half-life (up to 22 day across a range of doses in multiple studies and ≈20 days in a population pharmacokinetic analysis), permitting administration at 2- or 3-week intervals.

Therapeutic Efficacy

In chemotherapy-naive patients with metastatic colorectal cancer, the addition of bevacizumab to IFL treatment significantly increased median values for overall survival by 4.7 months, progression-free survival by 4.4 months, and response duration by 3.3 months and the objective response rate (ORR) 1.3-fold relative to IFL plus placebo. In addition, bevacizumab plus fluorouracil/leucovorin significantly improved median progression-free survival, although not overall survival, in patients with a poor prognosis who were unlikely candidates for irinotecan therapy. Bevacizumab combined with FOLFOX4 significantly increased median overall survival by 2 months, median progression-free survival by >2 months, and the ORR by 2-fold relative to FOLFOX4 alone in chemotherapy-experienced patients with advanced colorectal cancer.

In preliminary results, first-line therapy with bevacizumab plus paclitaxel in patients with locally recurrent or metastatic breast cancer significantly increased median progression-free survival by 4.9 months and the ORR by almost 2-fold relative to paclitaxel monotherapy. In heavily pretreated patients, however, despite a significant 2-fold increase in ORR, the addition of bevacizumab to capecitabine did not demonstrate any significant increase in median progression-free or overall survival times relative to capecitabine alone.

Bevacizumab combined with paclitaxel plus carboplatin significantly increased median overall survival by >2 months, median progression-free survival at 1 year by almost 2 months, and more than doubled the ORR relative to paclitaxel plus carboplatin in chemotherapy-naive patients with advanced nonsquamous cell NSCLC. as|Tolerability

The tolerability profile of bevacizumab was generally acceptable in clinical trials in patients with advanced colorectal cancer, breast cancer, or NSCLC. In pooled analysis, the most common adverse events of any severity in patients receiving bevacizumab were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria. Most adverse events were mild to moderate in severity, and events such as hypertension, hemorrhage, or proteinuria were clinically manageable.

The most common grade 3 or 4 adverse events in bevacizumab recipients were asthenia, pain, hypertension, diarrhea, and leukopenia. Bevacizumab is associated with an increased risk of gastrointestinal perforations in patients with metastatic colorectal cancer, hemoptysis in patients with advanced NSCLC (particularly those with squamous cell histology), wound healing complications, arterial thromboembolism, sensory neuropathy, and congestive heart failure. Such events have resulted in death, but are relatively uncommon.

Cancer pain management necessitates the use of opioids when pain is moderate or severe. Opioids need to be versatile and effective. Newer formulations may improve patient compliance and may be more conducive to the management of transient flares of pain; they also may be tailored to treat certain special populations and may be particularly effective in certain clinical situations. For example, newer opioids have been developed for transdermal, nasal, and nebulized administration, providing a ‘needle-less’ means of controlling pain in those unable to take oral medications. However, newer opioid formulations are not a substitute for good pain management strategies and will not control pain unless provided in adequate doses and schedules. Newer opioid formulations have niche roles in clinical practice, and pain and palliative specialists need to be aware of new developments in opioids and delivery systems. This state-of-the-art review provides a synopsis of recent advances and evolving technologies.

Background:The combination of intravenous paclitaxel (three-times weekly administration at a dose of 175 mg/m²) and oral capecitabine has been shown to be highly active in the treatment of advanced or metastatic breast cancer. Currently, there is much interest in the use of relatively low dose weekly paclitaxel infusions in this clinical setting.

Aim:To assess the activity and safety of capecitabine plus weekly paclitaxel at a dose of 60 mg/m²in heavily pretreated metastatic breast cancer patients.

Patients and methods:Patients were required to have pretreated metastatic breast cancer with measurable/ evaluable disease and a performance status of 0–2 (Eastern Cooperative Oncology Group score). Capecitabine was administered orally at a dosage of 1000 mg/m²twice daily on days 1–14, followed by a 7-day rest period. Paclitaxel was administered as a 1-hour intravenous infusion on a weekly basis at a dose of 60 mg/m². Twenty-one days of therapy represented one cycle.

Results:The hypothesis of activity of the capecitabine-paclitaxel combination at the level of clinical interest (40% response rate) was accepted when the 15th response was observed and 33 patients were enrolled. The median progression-free survival and median overall survival estimates were 9.2 and 19.6 months, respectively. Therapy was generally well tolerated and manageable on an outpatient basis. The following grade 3/4 adverse events were observed: hand-foot syndrome (21.2%), neutropenia (12.1%), anemia, nausea/vomiting, stomatitis/ mucositis, and nail disorders (all occurred in 9.0%), and vascular/coagulation disorders (<1%).

Conclusions:Oral capecitabine plus weekly paclitaxel at a dose of 60 mg/m²has a favorable activity and tolerability profile and is suitable for the treatment of heavily pretreated advanced breast cancer patients.

Despite an initial response rate of greater than 70% to platinum-based chemotherapy, most patients with advanced epithelial ovarian cancer eventually develop and succumb to recurrent disease. Ovarian cancer patients with platinum-resistant and -refractory disease have the lowest response rates to salvage chemotherapy. Various chemotherapeutic agents, such as paclitaxel, liposomal doxorubicin, topotecan, docetaxel, platinum, etoposide, ifosfamide, gemcitabine, and vinorelbine, are available and result in response rates of 7–40%. Unfortunately, salvage therapy is not curative, and treatment is palliative. Therefore, the therapeutic choice must consider not only the best opportunity for response, but also the tolerability profile, quality-of-life issues, cost of therapy, and patient convenience. Patients should be encouraged to enroll in clinical trials evaluating novel agents and administration schedules.

Screening, early detection, and effective treatment of patients with prostate cancer have led to a stage shift with an increased proportion of organ-confined and, thus, curable tumors diagnosed. Some studies suggest a decrease in mortality of patients with prostate cancer. At present, 10-year disease-specific survival rates of more than 90% are observed after radical prostatectomy. Nevertheless, there are ongoing controversies over screening and management. Radical prostatectomy, external-beam radiotherapy, interstitial brachytherapy, and ‘watchful waiting’ are widely accepted treatment options. With growing surgical experience, especially in large centres, there is a low perioperative morbidity and mortality associated with radical prostatectomy, even in elderly patients. An experienced surgeon may be able to preserve urinary continence in more than 90% of patients. With the preservation of the neurovascular bundles and modern supportive care, sexual potency and activity may recover in the majority of patients treated in centers of excellence. No other treatment yields better tumor-control rates than radical prostatectomy; however, there has previously been a lack of prospective randomized trials. In cases of high-grade, localized prostate cancers, there are some arguments for the superiority of radical prostatectomy. It remains to be seen whether new, high-dose conformal radiotherapy may compete in this setting.

In elderly patients and those with significant comorbidity, low-volume-low-grade or advanced-disease, conservative management may be considered. Androgen withdrawal may be used as a primary, neoadjuvant, or adjuvant therapy or as treatment at relapse. Data supporting improvement in survival through the use of adjuvant hormonal treatment are derived mainly from studies of external-beam radiotherapy with locally advanced (and most likely micrometastatic) tumors.

The goal of cancer treatment is not just prolonged life but improvement in disease-related symptoms without compromising the patient’s ability to carry out normal activities. Unfortunately, the toxicities associated with common chemotherapeutic treatments frequently cause adverse events that are equal to or worse than disease symptoms. Frequent or prolonged administration of chemotherapeutics and/or complicated measures to limit drug toxicity often disrupt the patient’s normal routine and negatively affect the patient’s quality of life.

Targeted therapies aim to uncouple toxicity from efficacy; however, the efficacy of single-agent therapy has been disappointing, with the exception of imatinib. The novel cytotoxic agent pemetrexed has demonstrated the ability to prolong survival and improve disease-related symptoms and quality of life in malignant pleural mesothelioma without causing the toxicities seen with other cytotoxics of similar potency. Pemetrexed has demonstrated activity as a single agent and in combination with other agents. Because of its broad activity, good tolerability, and convenient administration schedule, pemetrexed has promise in treating patients with a variety of cancers.

Summary

Pegfilgrastim (Neulasta®), the sustained-duration form of filgrastim (recombinant human granulocyte colony-stimulating factor [G-CSF]), is created by the addition of a polyethylene glycol (PEG) moiety to filgrastim. Its approved indication in the US is to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy.

A single subcutaneous injection of pegfilgrastim once per chemotherapy cycle was more effective than placebo as an adjunct to moderately myelosuppressive chemotherapy for breast cancer, no less effective than daily injections of filgrastim as an adjunct to highly myelosuppressive chemotherapy for breast cancer, and as effective as daily filgrastim as an adjunct to chemotherapy for lymphoma (predominantly non-Hodgkin lymphoma [NHL]) and acute myeloid leukemia (AML). Pegfilgrastim has also successfully supported delivery of dose-dense chemotherapy, stem cell mobilization, and stem cell transplantation after high-dose chemotherapy in patients with non-myeloid or myeloid malignancies. By offering a convenient alternative to daily filgrastim, once-per-cycle administration of pegfilgrastim has the potential to simplify the management of chemotherapy-induced neutropenia, further improve patient health-related quality of life, and reduce total treatment costs in breast cancer and NHL, and possibly other cancer settings. Pegfilgrastim should, likewise, permit simplification of G-CSF-based stem cell mobilization and transplantation procedures.

Pharmacological Properties

Pegfilgrastim is produced by covalently binding a 20 kDa PEG molecule to the N-terminal methionyl residue of filgrastim. Pegfilgrastim and filgrastim share the same mechanism of action (stimulation of granulocytopoiesis) and pharmacodynamic profile (e.g. elevation of absolute neutrophil count [ANC] and reduction in duration of chemotherapy-induced neutropenia); both G-CSFs are administered by the subcutaneous route. However, the greater weight and size of the pegfilgrastim molecule results in reduced renal clearance, an increased terminal elimination half-life, and hence a sustained duration of action relative to filgrastim. In patients with chemotherapy-induced neutropenia after myelosuppressive chemotherapy, plasma concentrations of pegfilgrastim remained elevated throughout the ANC nadir and declined rapidly as ANC recovered. This is consistent with the suggestion that self-regulating, neutrophil-mediated clearance, rather than renal elimination, is the predominant route of elimination of pegfilgrastim.

Therapeutic Efficacy

The efficacy of subcutaneous pegfilgrastim once per cycle in providing neutrophil support after standard regimens of myelosuppressive chemotherapy has been demonstrated in patients, most of whom were previously untreated, with breast cancer or lymphomas (NHL or Hodgkin disease), or AML.

In large, non-inferiority, pivotal, phase III trials in patients with high-risk stage II–IV breast cancer and a phase II trial in patients with lymphoma (predominantly NHL), a fixed (6mg) or body weight-based (100 μg/kg) dose of pegfilgrastim administered once per chemotherapy cycle was no less effective than daily filgrastim 5 μg/ kg (mean/median ≈11 doses per cycle) in reducing chemotherapy-induced neutropenia after highly myelosuppressive chemotherapy. In the studies in patients with breast cancer, which were identical except for the mode of pegfilgrastim dosing, between-group differences in the mean duration of severe neutropenia (ANC <0.5 × 10⁹/L) during the first chemotherapy cycle (primary endpoint) were <1 day, thus satisfying the noninferiority criteria for pegfilgrastim versus filgrastim. A similar outcome was seen in the NHL trial, although this was not formally designed as a noninferiority study.

Notwithstanding the noninferiority design of the studies in patients with breast cancer, a significant reduction in the incidence of febrile neutropenia across all chemotherapy cycles was seen with pegfilgrastim versus filgrastim in the trial of pegfilgrastim 100 μg/kg per cycle (9% vs 18%) as well as in a combined analysis of both trials (11% vs 19%). Additionally, subset analyses in the studies in patients with breast cancer suggested that the effect of pegfilgrastim on the duration of severe neutropenia following one or all (four) cycles of chemotherapy was similar regardless of prior chemotherapy or radiotherapy exposure and, in patients receiving pegfilgrastim 6mg per cycle, irrespective of bodyweight.

Relative to placebo, pegfilgrastim 6mg once per cycle significantly reduced rates of febrile neutropenia (17% vs 1%), hospitalization (14% vs 1%) and intravenous anti-infectives (10% vs 2%) over all cycles in a large, randomized, double-blind, phase III trial in 928 patients with stage I–IV breast cancer who received moderately myelosuppressive chemotherapy.

Pegfilgrastim was also effective in supporting the delivery of dose-dense cytotoxic chemotherapy regimens for previously untreated solid tumors (breast cancer and SCLC) and lymphomas (NHL and Hodgkin disease).

Pegfilgrastim, alone or in combination with myelosuppressive chemotherapy, successfully mobilized CD34+ cells in patients with solid tumors, lymphomas, or multiple myeloma; it also supported stem cell transplantation after high-dose chemotherapy in patients with lymphomas or multiple myeloma.

Pegfilgrastim was, in general, at least as effective as daily filgrastim based on ‘head-to-head’ and/or retrospective comparisons conducted in the settings of AML, dose-dense chemotherapy, and stem cell mobilization.

Tolerability

Pegfilgrastim was generally well tolerated in a total of 465 patients with solid tumors or lymphomas undergoing myelosuppressive chemotherapy in clinical trials; the drug had an adverse event profile (including changes in laboratory values) similar to that of filgrastim.

Medullary bone pain was the most common treatment-related adverse event with pegfilgrastim, occuring in approximately one-quarter of patients who received the drug in clinical trials. The incidence, severity, and duration of bone pain with a single injection of pegfilgrastim 6mg or 100 μg/kg per cycle was not significantly different from that with daily doses of filgrastim 5 μg/kg in the two pivotal phase III trials in patients with breast cancer. However, if bone pain occurred, the onset was earlier after the initial and final cycles of chemotherapy in the fixed-dose trial of pegfilgrastim 6mg once per cycle. Bone pain was generally of mild-to-moderate intensity and usually resolved with non-narcotic analgesics.

In the large, non-inferiority, phase III studies in patients with breast cancer, transient elevations in plasma levels of lactate dehydrogenase, alkaline phosphatase, and uric acid with pegfilgrastim were not clinically significant, and no neutralizing antibodies against the drug were detected.

Pharmacoeconomic Considerations

Preliminary reports of economic modelling studies based on outcomes in the two pivotal phase III trials in patients with breast cancer suggested that once-per-cycle pegfilgrastim 6mg or 100 μg/kg may reduce total chemotherapy-induced neutropenia management costs over all four cycles relative to daily filgrastim 5 μg/kg.

According to other preliminary reports, universal (i.e. non-targeted) primary prophylaxis with pegfilgrastim is predicted to be cost saving compared with no G-CSF treatment when the risk of developing febrile neutropenia in the first chemotherapy cycle is >23% in patients receiving cyclophosphamide, doxorubicin, vincristine, and prednisolone for NHL and >16% in patients receiving docetaxel, with or without doxorubicin, for breast cancer.

Stereotactic radiosurgery has emerged as an accepted treatment for many types of intracranial tumors. Based on the understanding of the limitations of prior radiosurgical systems, image-guided robotic radiosurgery was developed to overcome many of these restrictions. The CyberKnife® is a commercially available frameless image-guided radiosurgical system that provides state-of-the-art radiosurgery for intracranial tumors, and has also revolutionized the use of radiosurgery to treat tumors in other parts of the body. This review focuses on the current use of the CyberKnife® to treat cranial and spinal tumors.

Brain metastases have long been treated with other radiosurgical systems, but the CyberKnife® allows patients with brain metastases to be treated multiple times as successive tumors are discovered, without the repetitive placement of a stereotactic head frame. Benign tumors such as acoustic neuromas, pituitary tumors, and meningiomas are also easily treated with the CyberKnife®, with radiographic tumor-control rates of >90% for pituitary tumors and 95% for acoustic neuromas and meningiomas. A subset of meningiomas and pituitary tumors surround the optic nerves and are considered to be perioptic tumors. Historically, these tumors have not been treatable with radiosurgery because of the risk of visual loss. The frameless nature of the CyberKnife® allows the radiosurgery treatment to be delivered in separate stages (typically 24 hours apart); this has been shown to significantly reduce the risk of visual loss, and thus allows effective radiosurgery treatment to be delivered. Staged radiosurgery treatment has also been used at our institution to treat acoustic neuromas, with the understanding that several stages of radiation delivery may be associated with a higher level of hearing preservation than a single-staged radiosurgery treatment. Malignant gliomas and nasopharyngeal carcinoma tumors have historically been treated with conventional radiotherapy techniques. However, we have learnt that supplementing these radiotherapy treatments with a CyberKnife® stereotactic boost after radiotherapy can improve response rates to treatment.

Spinal radiosurgery is a novel development; prior frame-based radiosurgery devices did not allow treatment of lesions outside the brain and neck. We have observed high rates of tumor control when treating benign spinal tumors with the CyberKnife®, and have noted excellent pain relief and tumor-control rates in patients with spinal metastases. Future CyberKnife® stereotactic applications will focus on the continual expansion of this technology to treat tumors outside the CNS, including cancers of the lung, pancreas, liver, and prostate.

Endocrine therapy and chemotherapy play important roles in the management of postmenopausal women with metastatic breast cancer. This paper specifically reviews the indications and options for first-line treatment of metastatic breast cancer and recent advances are highlighted, with particular attention to randomized, controlled, phase III clinical trials.

Until recently, tamoxifen was standard first-line endocrine treatment for patients with metastatic breast cancer. Now, potent third generation aromatase inhibitors, such as letrozole and anastrozole, have shown superiority to tamoxifen as first-line endocrine treatment and provide an alternative for postmenopausal women.

The most active chemotherapy agents for patients with advanced breast cancer have, until recently, been the anthracyclines, doxorubicin and epirubicin. However, their increasing use in the adjuvant setting has resulted in a need for novel active non-cross-resistant cytotoxic drugs for metastatic breast cancer. Real progress has been made with the introduction of the taxanes, paclitaxel and docetaxel. Other developments include the use of single agent cytotoxics such as vinorelbine, the oral fluoropyrimidine capecitabine and gemcitabine, all of which have some activity following either taxanes or anthracyclines, along with a low toxicity profile. Bisphosphonates are bone-specific palliative treatments that have been instituted on the basis of their impact on symptoms and skeletal related morbidity.

Finally, the era of biological therapy in the clinic for patients with breast cancer has been heralded with the development and introduction of trastuzumab, a humanized monoclonal antibody which targets the cell surface growth factor receptor HER2/neu. Importantly, each of these new treatment options has provided an incremental improvement in efficacy over previous standard first-line therapies.

The design of chemotherapy schedules for treatment of malignancies is based on the selection of optimal drug doses with tolerable adverse effects. Interindividual variation in absorption, distribution, metabolism and excretion may exist for a given dose, which depend on both physiological and pathological factors. These factors will be of importance for the outcome of treatment in terms of efficacy as well as toxicity. As chemotherapy usually consists of a combination of drugs, pharmacological interactions may be expected. This also holds for other drug classes, such as analgesics, antidepressants, antibiotics, that are frequently coadministered to patients receiving chemotherapy. The study of pharmacokinetics can give insight in to the extent of interindividual variability based on genetic and patient factors, as well as in the occurrence of drug interactions.

Many anticancer agents need specific enzymes for their metabolism. Polymorphisms in gene expression resulting in differences in enzyme activity have been described, such as thiopurine methyltransferase for metabolism of 6-mere ap top urine, dihydropyrimidine dehydrogenase for fluorouracil and uridine diphosphate (UDP) glucuronosyl transferase 1A1 for SN-38 (the active metabolite of irinotecan). Cytochrome P450 isoenzymes form a very important drug-metabolizing family and CYP3A4 is responsible for the metabolism of several classes of drugs. This isoenzyme system can easily be induced or inhibited by other drugs. Interactions combining drugs requiring both CYP3A4 for metabolism and P1 70-glycoprotein (Pgp) for transport may result in enhanced adverse effects in patients. A well-known example is the interference of taxanes with the pharmacokinetics of anthracyclines.

Patient factors, other than variable expression of drug-metabolizing enzymes, that may account for altered pharmacokinetic properties are: age, obesity, hypoalbuminemia, impaired renal or liver function. A combination of these factors may occur, especially in patients with advanced cancer.

The presence of a drug interaction may be advantageous in some instances. For example, the limited oral bioavailability of paclitaxel may be improved by inhibition of Pgp-mediated drug efflux from the intestine. The same holds true for blocking the breast cancer resistance protein transporter in the intestine to enhance oral absorption of topotecan.

It is only through prospective, preclinical and early clinical evaluation of both pharmacokinetics and pharmacodynamics, i.e. the effects of the drug on the body, that the pharmacological behavior of a particular drug can be identified. Changes in drug dose, sequence, or infusion duration, increase of the time-interval between drugs, etc., can be measures required to provide an optimal therapeutic index of combination chemotherapy for the patient with cancer.