To provide a systematic review of the side effects associated with sorafenib, sunitinib, and temsirolimus and to provide an outline of possible preventive or therapeutic measures.

(1) Many of the significant advances in cancer management in recent years have centered on the development and introduction of molecularly targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors.(2) Despite targeted therapy that has clearly benefited and even cured certain patients (eg, imatinib, trastuzumab), the ultimate goal of curing cancer, and the more immediate goal of replacing non-targeted chemotherapies with less toxic, targeted agents has yet to be achieved for most cancer patients.(3) Based on a systematic review of randomized controlled trials, examples of significant benefits in selected cancers are provided:(a) Non-Hodgkin's lymphoma (NHL) - A large meta-analysis and several individual randomised, controlled trials (RCTs) report that rituximab plus chemotherapy has a major survival advantage over chemotherapy alone in patients with NHL; an overview of six clinical trials supports the survival benefit of rituximab plus chemotherapy.(b) Renal cell carcinoma (RCC) - Temsirolimus or sunitinib has a significant survival benefit relative to interferon-alpha, and sorafenib carries such a benefit in patients resistant to standard therapy.(c) Colorectal cancer (CRC) - An overview of three RCTs in metastatic CRC revealed that bevacizumab plus 5-fluorouracil/leucovorin possesses a significant survival advantage over 5-fluorouracil/leucovorin and irinotecan/5-fluorouracil/leucovorin.(d) Non-small-cell lung cancer (NSCLC) - In refractory NSCLC, erlotinib significantly prolongs survival, particularly in nonsmokers, and gefitinib may have some utility in patients of Asian ethnicity.(e) Head and neck squamous-cell carcinoma (HNSCC) - Cetuximab plus radiotherapy (versus radiotherapy alone) significantly improves locoregional control and survival (hazard ratio [HR] 0.68; p = 0.005) without worsening radiotherapy-related toxicity.

A National Cancer Institute (NCI) clinical announcement recommended i.p. therapy for women with optimally debulked ovarian cancer. Its basis was a summary of eight randomised controlled trials and two systematic reviews, which appear to indicate benefit of i.p. therapy. However, the systematic reviews that inform the recommendations have been inappropriately presented and interpreted. The systematic reviews inappropriately pooled results from 'confounded' trials in which different drugs and different doses of drugs were given in the control and i.p. treatment arms. Therefore, it is not possible to assess which component of treatment is responsible for improving outcome. In addition, none of the trials use a control arm of the internationally accepted standard of care. Using just the unconfounded trials, indirect comparisons show that the magnitude of benefit observed when i.p. regimens are compared with older i.v. regimens [hazard ratio (HR) for overall survival (OS) 0.75; 95% confidence interval (CI) 0.60-0.92, P = 0.006] is smaller than the magnitude of benefit achieved with modern day standard of i.v. treatment compared with the same i.v. regimen used as control in the unconfounded i.p. trials (HR for OS 0.68; 95% CI 0.58-0.80, P < 0.001). A further difficulty is that the reviews cannot recommend an i.p. regimen for standard use. Drug-related toxicity and catheter complications that occur with i.p. therapy are considerable. The NCI recommendations have major implications for the treatment of women with ovarian cancer and for the next generation of clinical trials. We do not believe that the body of evidence currently available supports the recommendation that i.p. therapy should form part of routine care. The choice of treatment of women with newly diagnosed, optimally debulked, ovarian cancer, where therapy has the best chance of influencing OS, is too important to be left with this uncertainty. A clinical trial that investigates a practical and acceptable regimen which gives some or all chemotherapy by the i.p. route and compares this with standard i.v. chemotherapy should be a priority for those who wish to promote its use.

Recurrent and advanced cervical cancers are associated with high mortality and a lack of effective treatment options, especially for women who are poor candidates for surgery or radiation therapy. The broad clinical effectiveness and manageable toxicity of topotecan in other human malignancies as well as promising recent study results suggest that it is highly effective in treating cervical tumors. We therefore conducted a systematic review on the studies using topotecan in cervical cancer. Seven phase I-III clinical trials using topotecan, both as a single agent and in combination with cisplatin or paclitaxel, in patients with recurrent or advanced carcinoma of the cervix were reviewed. Data from two studies in which topotecan was used in combination with radiotherapy for induction therapy were also evaluated. Although single-agent cisplatin-based chemoradiotherapy is the standard of care for high-risk or locally advanced cervical cancer, topotecan, when used concurrently with cisplatin and/or radiation therapy, produces high objective response rates and prolonged survival. Gynecologic Oncology Group (GOG) Protocol 179 for the first time showed significantly improved overall survival and progression-free survival in a combination therapy for advanced cervical cancer compared to cisplatin alone. Recent data suggest that topotecan, when used concurrently with cisplatin, may be the new standard of care for the management of recurrent or advanced cervical cancer. Ongoing phase III studies (GOG-204, AGO-Zervix-1) will compare this combination with other cisplatin-containing and cisplatin-free combinations. Moreover, further evaluation of topotecan appears to be warranted in conjunction with radiotherapy and in the neoadjuvant setting as well as in combination with novel biologic agents.

Oral mucositis (OM) is a serious consequence of some chemotherapy and radiotherapy regimens. A number of reliable instruments are available to assess OM, but none are universally accepted. A unique collaboration of multi-disciplinary experts from Europe was formed to make recommendations on OM assessment, based on a systematic literature review and the experts' experience. The main recommendations are listed. There should be a comprehensive baseline assessment. OM should be frequently assessed using a standardised instrument, or a combination of instruments. Physical, functional and subjective changes should be measured. Subjective measures should be assessed prior to any physical examination. The use of pain scoring, in particular patient self-reporting, should form part of any OM assessment. Any assessment instrument should be validated, easy to use and comfortable for the patient. Training of, and monitoring in, the use of the instrument is vital to successful monitoring of OM.

Treatment of cancer is increasingly more effective but is associated with short and long term side effects. Oral side effects remain a major source of illness despite the use of a variety of agents to prevent them. One of these side effects is oral mucositis (mouth ulcers).

To summarise and critically evaluate the evidence from randomised clinical trials for the effectiveness of individualised herbal medicine in any indication.

This systematic review examines the role of temozolomide in patients with metastatic melanoma. Outcomes of interest include response rate, progression-free survival, overall survival, quality of life, and adverse effects.

To estimate the clinical effectiveness and cost-effectiveness of docetaxel and paclitaxel compared with non-taxane, anthracycline-containing chemotherapy regimens, for the adjuvant treatment of women with early-stage breast cancer.

We undertook a systematic review of the pre-clinical and clinical literature for studies investigating the relationship between platinum and taxane resistance. Medline was searched for (1) cell models of acquired drug resistance reporting platinum and taxane sensitivities and (2) clinical trials of platinum or taxane salvage therapy in ovarian cancer. One hundred and thirty-seven models of acquired drug resistance were identified. 68.1% of cisplatin-resistant cells were sensitive to paclitaxel and 66.7% of paclitaxel-resistant cells were sensitive to cisplatin. A similar inverse pattern was observed for cisplatin vs. docetaxel, carboplatin vs. paclitaxel and carboplatin vs. docetaxel. These associations were independent of cancer type, agents used to develop resistance and reported mechanisms of resistance. Sixty-five eligible clinical trials of paclitaxel-based salvage after platinum therapy were identified. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously recieved paclitaxel had a pooled response rate of 35.3%, n=232, compared to 22% in paclitaxel naïve patients n=1918 (p<0.01, Chi-squared). Suggesting that pre-treatment with paclitaxel may improve the response of salvage paclitaxel therapy. The response rate to paclitaxel/platinum combination regimens in platinum-sensitive ovarian cancer was 79.5%, n=88 compared to 49.4%, n=85 for paclitaxel combined with other agents (p<0.001, Chi-squared), suggesting a positive interaction between taxanes and platinum. Therefore, the inverse relationship between platinum and taxanes resistance seen in cell models is mirrored in the clinical response to these agents in ovarian cancer. An understanding of the cellular and molecular mechanisms responsible would be valuable in predicting response to salvage chemotherapy and may identify new therapeutic targets.

A formal assessment of the drug-drug interaction potential of any investigational drug product often requires multiple metabolic and pharmacokinetic evaluations. In contrast to a small-molecule drug, investigating the drug-drug interaction potential of a monoclonal antibody is inherently complicated. High molecular weight monoclonal antibodies are often genetically engineered to demonstrate strong specificity for a particular human antigen target. Consequently, monoclonal antibodies usually have few clinically relevant animal models--other than nonhuman primates--in which to conduct appropriate nonclinical studies. Likewise, clinical drug-drug interaction studies of monoclonal antibodies with long elimination half-lives pose definite operational challenges as conventional crossover studies with adequate washout periods are difficult to conduct. Furthermore, the current regulatory guidance on the design and conduct of in vitro and in vivo drug-drug interaction studies applies more readily to small-molecule drugs than protein-based biologics. Nevertheless, a certain amount of clinically useful information has begun to emerge from the published literature on drug-drug interaction potentials of therapeutic monoclonal antibodies. This article provides a systematic review of the current literature and offers some practical considerations for the design and conduct of pharmacokinetic drug-drug interaction assessments involving novel monoclonal antibodies. Ideally, these evaluations should be performed throughout all stages of drug development. In particular, pharmacokinetic interaction studies with any marketed drugs that are likely to be coadministered with the monoclonal antibody will yield the most clinically useful information for practitioners and patients alike.

To systematically review the research evidence on the effectiveness of hypnosis for cancer chemotherapy-induced nausea and vomiting (CINV). A comprehensive search of major biomedical databases including MEDLINE, EMBASE, ClNAHL, PsycINFO and the Cochrane Library was conducted. Specialist complementary and alternative medicine databases were searched and efforts were made to identify unpublished and ongoing research. Citations were included from the databases' inception to March 2005. Randomized controlled trials (RCTs) were appraised and meta-analysis undertaken. Clinical commentaries were obtained. Six RCTs evaluating the effectiveness of hypnosis in CINV were found. In five of these studies the participants were children. Studies report positive results including statistically significant reductions in anticipatory and CINV. Meta-analysis revealed a large effect size of hypnotic treatment when compared with treatment as usual, and the effect was at least as large as that of cognitive-behavioural therapy. Meta-analysis has demonstrated that hypnosis could be a clinically valuable intervention for anticipatory and CINV in children with cancer. Further research into the effectiveness, acceptance and feasibility of hypnosis in CINV, particularly in adults, is suggested. Future studies should assess suggestibility and provide full details of the hypnotic intervention.

To evaluate the effectiveness of cardiac markers to quantify anthracycline-induced cardiotoxicity in children with cancer.

To evaluate the technologies used to reduce anthracycline-induced cardiotoxicity in children. Also to evaluate cardiac markers to quantify cardiotoxicity, and identify cost-effectiveness studies and future research priorities.

The aim of this study was to assess the efficacy of currently available topical drugs for vernal keratoconjunctivitis (VKC) through a meta-analysis of randomised clinical trials (RCTs).

Despite evidence in the literature suggesting that a strong correlation exists between the pharmacokinetic parameters and pharmacodynamic effect of anticancer agents, many of these agents are still dosed by body surface area. Therapeutic drug monitoring with the aim of pharmacokinetic-guided dosing would not only maintain target concentrations associated with efficacy but may potentially minimise the likelihood of dose-related systemic toxicities. The pharmacokinetic parameter that displays the best correlation with the pharmacodynamics of anticancer drugs is the area under the plasma concentration-time curve (AUC). However, accurate determination of the AUC requires numerous blood samples over an extended interval, which is not feasible in clinical practice. Therefore, limited sampling strategies (LSSs) have been proposed as a means to accurately and precisely estimate pharmacokinetic parameters with a minimal number of blood samples. LSSs have been developed for many drugs, particularly ciclosporin and other immunosuppressants, as well as for certain anticancer drugs. This systematic review evaluates LSSs developed for the platinum compounds and categorises 18 pertinent citations according to criteria adapted from the US Preventive Services Task Force. Thirteen citations (four level I, six level II-1, three level II-2) pertained to LSSs for carboplatin, four citations (one level II-1, one level II-2, two level III) to cisplatin LSSs, and one citation (level II-2) to nedaplatin. Based on the current evidence, it appears that LSSs may be useful for pharmacokinetic-guided dosage adjustments of carboplatin in both adults and children with cancer. Although some validation studies suggest that LSSs can be extended to different cancer populations or different chemotherapy regimens, other studies dispute this finding. Although the use of LSSs to predict the pharmacokinetic parameters of cisplatin and nedaplatin appear promising, the quality of evidence from published studies does not support routine implementation at this time.LSSs represent one approach in which clinicians can make specific dosage adjustments for individual patients to optimise outcomes. However, the limitations of these strategies must also be taken into consideration. There is also a need for prospective studies to demonstrate that application of LSSs for platinum agents ultimately improves patient response and decreases systemic toxicities.

Patients receiving cancer treatments commonly experience haematological adverse effects (AEs) related to chemotherapy or molecularly targeted therapies, which may be associated with high healthcare costs. The objective of this review was to summarise the published literature on the economic burden of neutropenia, thrombocytopenia and anaemia as AEs of cancer treatment.

The purpose of this study was to provide a systematic review on prevention and treatment of uterine bleeding in the setting of hematologic malignancy. We performed MEDLINE, PubMed, EMBASE and Cochrane searches with the terms uterine bleeding, uterine hemorrhage, hematologic malignancy. All identified literature sources were included in the review. The identified literature is largely comprised of case series and pilot studies. No evidence-based protocols for gynecologists and hematologists are available. The majority of the identified literature centers on menstrual suppression with GnRH agonists in hematologic malignancy, although no randomized trials could be identified. Review of the identified literature suggests that medical prevention with GnRH agonist therapy is highly effective for prevention of uterine bleeding in hematologic malignancy. With respect to treatment of acute uterine bleeding in the setting of hematologic malignancy, medical therapy can be used and is successful in the majority of patients, according to the identified studies. Surgical treatment should be used expeditiously if medical treatment options fail to control acute bleeding. Empiric prevention and treatment algorithms for the discussed clinical settings are proposed. More research is necessary on the topic, with the goal to develop evidence-based guidelines for gynecology and hematology-oncology care providers. Close cooperation between the specialties may improve morbidity and mortality associated with uterine bleeding in hematological malignancy in the future.

Short term side-effects of chemotherapy include fatigue, nausea, vomiting, mucositis and myelosuppression or neutropenia. These occur during the course of treatment and generally resolve within months of completion of chemotherapy. A variety of Chinese medicinal herbs have been used for managing these side effects.

The introduction of monoclonal antibodies (MoAbs) into the treatment of cancer has led to improvements in patient survival. However, to the authors' knowledge, little attention has been paid to the infectious complications associated with their use. The authors performed a systematic review of the literature to identify randomized controlled trials (RCTs) that included in their outcomes a comparison of the infectious complications of a MoAb plus chemotherapy or radiotherapy versus the therapy regimen given without the addition of a MoAb. Twenty RCTs with relevant data regarding the use of MoAbs in patients with hematologic malignancies (10 RCTs) and solid tumors (10 RCTs) were retrieved. Six RCTs compared rituximab in conjunction with the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus CHOP alone for the treatment of B-cell non-Hodgkin lymphoma (NHL). No significant increase in the incidence of infections was observed with the addition of rituximab to chemotherapy (based on data from 5 RCTs). However, in patients who were seropositive for the human immunodeficiency virus (HIV), a 12% increase in infection-related deaths and a rate of higher opportunistic infections was associated with the rituximab-containing regimen (data taken from 1 RCT). Five RCTs either compared trastuzumab plus chemotherapy versus chemotherapy alone or trastuzumab monotherapy versus observation in patients with breast cancer. The addition of trastuzumab to the various chemotherapy regimens was found to cause a slight increase in the frequency of high-grade infections while bevacizumab caused a negligible increase in Grade III/IV infections compared with the same regimens given of chemotherapy alone. Based on a single trial, a higher comparable increase in the rate of high-grade infections was noted with the use of cetuximab in addition to chemotherapy compared with chemotherapy alone. MoAbs added to chemotherapy appear to have infectious complications that are comparable to the chemotherapy-alone regimen when administered for the treatment of NHL, with the exception of HIV-seropositive patients. Trastuzumab, which is reported to have a clear benefit in the prognosis of breast cancer patients, was found to cause a small increase in Grade III/IV infectious complications; however, there was no apparent difference in the rate of infection-related death.