Differences in efficacy and safety between capecitabine and infusional 5-fluorouracil when combined with irinotecan for the treatment of metastatic colorectal cancer.

BACKGROUND: Capecitabine is an oral fluoropyrimidine that is shown to have similar efficacy to 5-fluorouracil (5-FU) when used both alone and in combination with oxaliplatin in the treatment of colorectal cancer (CRC). Capecitabine and irinotecan combinations (XELIRI) have been developed for the treatment of this disease but randomized comparisons with standard infusional 5-FU and irinotecan (FOLFIRI) showed conflicting results. PATIENTS AND METHODS: We searched the literature for randomized controlled trials comparing XELIRI to FOLFIRI for the treatment of metastatic colorectal cancer. Odds ratios with 95% confidence intervals were used to analyze dichotomous variables. Hazard ratios for progression and death were combined with an inverse variance method based on logarithmic conversion. The fixed-effect model and Mantel-Haenszel method were used. Heterogeneity was investigated with the Q-test and I2. Sensitivity analyses were performed. RESULTS: Only 3 studies were identified, involving a total of 450 patients. XELIRI was associated with significantly shorter progression-free survival (PFS) and increased grade 3/4 gastrointestinal toxicities such as nausea, vomiting, and diarrhea. Severe neutropenia, however, was significantly more frequent with FOLFIRI. No differences in responses and febrile neutropenia events were observed. CONCLUSION: Our analysis suggest that the 2 regimens are not equivalent. XELIRI remains an option for the first-line treatment of metastatic CRC but FOLFIRI should be preferred as it confers more benefits in terms of PFS and induces fewer GI toxicities.

Adjuvant chemotherapy--the dark side of clinical trials. Have we learnt more?

Large adjuvant trials, over many years, have randomised thousands of women with early breast cancer to different regimens. They have been instrumental in defining our current approach in the adjuvant setting. However in clinical practice with each patient, we still have the difficulty of targeting their specific therapy, as results relating to the average trial population are often not transferable to the individual. This review of adjuvant chemotherapy trials focuses on the heterogeneity of disease, treatment, mechanisms of chemotherapy action and risk. These issues are of key importance in our interpretation and application of results from adjuvant trials. A critical issue in adjuvant chemotherapy is identification of patients at high risk of recurrence who have chemosensitive tumours. Risk of relapse does not always correlate with chemosensitivity, and cytotoxic therapy in patients with chemorefractory disease may be ineffective and associated only with toxicity. Rather than general sensitivity to cytotoxics, we need predictive biomarkers to guide which specific therapy will be effective in a particular patient. Assessment of specific biomarkers as predictive tools may individualise care and see chemotherapy implementation as targeted agents, with tumour heterogeneity reflected in heterogeneity of intervention. Already with trastuzumab, we have a subgroup predicted by Her-2 gene amplification. Anthracyclines and taxanes, whilst widely used, do not yet have prospectively proven biomarkers to predict response. Potential biomarkers for anthracyclines include topoisomerase II alpha and markers of DNA repair dysfunction, whilst for taxanes, microtubule-associated proteins may play a role. The basal phenotype may be predictive of benefit from DNA damaging agents.

Taxanes in the elderly: can we gain as much and be less toxic?

Taxanes are very effective agents in several types of cancer. However, their activity is counterbalanced by side effects that could represent a limitation of their use in older cancer patients. This review aims at evaluating whether or not there are data supporting a tailored use of standard taxanes i.e. docetaxel and paclitaxel in elderly patients with the aim to increase their therapeutic index. In addition, recent data on the role of nanoparticle albumine-bound paclitaxel in breast cancer are discussed in this paper.

Topoisomerase II alpha as a marker predicting anthracyclines' activity in early breast cancer patients: ready for the primetime?

PURPOSE: This manuscript reviews and discusses results from randomised clinical studies evaluating topoisomerase II alpha (topo II) as a marker predicting anthracyclines' activity in early breast cancer patients. METHODS: A Medline search has led to the identification of six phase III clinical trials, in which topo II has been retrospectively evaluated as a marker predicting anthracyclines' activity in the adjuvant setting. RESULTS: Rates of topo II gene aberrations, in particular gene deletion, seem to vary substantially between the studies. No extensive correlation has been found between topo II gene status and protein levels. Five of the six trials suggest that topo II gene amplification is associated with increased tumour sensitivity to anthracyclines. Two of the three studies evaluating topo II gene deletions suggest that topo II deleted tumours might also derive an increased benefit from anthracyclines. CONCLUSION: Current data suggest that topo II might become a predictive tool to identify patients candidate to receive anthracyclines in the adjuvant setting. Ongoing studies will likely address some pending issues which, at present, prevent the use of this marker in daily practice.

Clinical decision making in breast cancer: TAM and aromatase inhibitors for older patients -- a jungle?

Aromatase inhibitors and inactivators (AIs) have been/are being widely investigated as an alternative to tamoxifen in the treatment of postmenopausal breast cancer patients. In this paper we have reviewed data from phase III studies to define the role of AIs versus tamoxifen as first-line therapy in patients with metastatic breast cancer, as primary therapy for not operable or early breast cancers not suitable for conservative surgery and as adjuvant treatment for women with early breast cancer. An effort has been performed to evaluate whether specific recommendations were needed for older postmenopausal patients. AIs play a key role in the treatment of advanced breast cancer and represent the agent of choice in patients who are candidates to neoadjuvant hormone-therapy. Longer follow-up of already published trials and additional data coming from ongoing studies will better define when and how to use AIs in the adjuvant setting.

Using specific cytotoxics with a targeted mind.

It is largely known that clinical activity of a given cytotoxic agent may vary between different patients. This suggests that breast cancer sub-types can be identified within the endocrine-resistant cohort, each of them with a specific degree of sensitivity to different cytotoxic drugs. Pre-clinical and early clinical data suggest that in the future some molecular markers might have practical value in predicting cytotoxics activity in the clinical setting. The most relevant evidence is summarized below according to the type of cytotoxic agent: (a) Anthracyclines Topoisomerase II alpha (topo II) gene aberrations (amplification or deletion) and/or topo II protein overexpression seem to predict response to topo II inhibitors such as anthracyclines. Of note, HER-2 amplified tumors have a concomitant topo II gene aberration in approximately 50% of cases. Moreover, the majority of hyper-proliferating tumors carry topo II protein overexpression. Early clinical data suggest the existence of a direct correlation between anthracyclines activity and the presence of topo II gene aberration or topo II protein overexpression. (b) Taxanes Microtubule-associated parameters (MTAP) such as the TAU protein, HER-2 gene amplification, and p-53 gene mutations, have been suggested as potential predictive markers for taxanes. Although early clinical data support pre-clinical experiments, the lack of large prospectively designed clinical studies makes it difficult to draw conclusions on the predictive value of these molecular markers. (c) DNA-damaging agents The BRCA 1 protein seems to play a major role in activating DNA repair mechanisms. Loss-of-function BRCA 1 mutations might lead to a substantial deficit in DNA repair mechanisms. This could ultimately translate into increased tumor sensitivity to DNA-damaging agents such as alkylating compounds and platinum-derivates. Pre-clinical and early clinical data seem to suggest that some BRCA 1 gene mutations might render the tumor more sensitive to DNA-damaging agents and clinical studies have recently been activated to investigate properly this hypothesis. A new generation of ongoing clinical studies and a "focused" use of the gene micro-array technology will hopefully clarify the complex interaction existing between molecular targets and cytotoxic drug activity. This "targeted" approach to chemotherapy might ultimately lead to a more effective strategy in breast cancer medical treatment.