Systemic therapy for metastatic colorectal cancer: current options, current evidence.

Combination chemotherapy regimens including irinotecan and oxaliplatin markedly improve response rate and prolong median survival over fluorouracil with leucovorin (FU/LV), and have supplanted FU/LV as the standard systemic approach for metastatic colorectal cancer. The recent availability of five active chemotherapeutic agents has doubled the median overall survival for metastatic colorectal cancer from 10 to 20 months, and though the optimal strategy for incorporation of all drugs is still unclear, current data support the use of chemotherapy doublets in first-line rather than sequential single-agent therapy. Multidrug regimens increase both response rate and the proportion of patients able to undergo potentially curative resection. In addition, as many as 20% to 30% of patients never receive second-line chemotherapy. When used as single agents, bolus and infusional FU/LV and capecitabine are similarly effective but have differing toxicity. Chemotherapy combinations that incorporate infusion of FU are less toxic and more effective than those using bolus FU dosing. Capecitabine is under study as an alternative dosing method for use in combination regimens; however, the optimal dose has not been defined and final safety and efficacy outcomes are being addressed in ongoing phase II and III investigations. Three combinations have shown excellent first-line efficacy in phase III trials--IFL with bevacizumab, FOLFOX, and FOLFIRI--but neither of these combinations is clearly superior. Sound clinical judgment must continue to guide treatment decisions while we await data regarding the optimal combination and sequence of fluorouracil, irinotecan, oxaliplatin, bevacizumab, and cetuximab.

Response and cardiac toxicity of trastuzumab given in conjunction with weekly paclitaxel after doxorubicin/cyclophosphamide.

BACKGROUND: Adjuvant trastuzumab improves relapse-free survival in HER2-overexpressing breast cancer but is associated with cardiac toxicity. This phase II study was undertaken to determine the neoadjuvant clinical and pathologic response rate and the acute and chronic cardiac toxicity of trastuzumab given with weekly paclitaxel after AC (doxorubicin/cyclophosphamide). PATIENTS AND METHODS: Fifty-two women with newly diagnosed, stage II-IV, HER2-overexpressing breast cancer received AC for 4 cycles, followed by weekly TP (paclitaxel/trastuzumab) for 12 weeks, neoadjuvantly or adjuvantly, followed by 40 weeks of adjuvant trastuzumab. RESULTS: Congestive heart failure occurred in 4% of patients (95% confidence interval [CI], 0.5%-13.2%). Asymptomatic left ventricular ejection fraction (LVEF) decreases to < 50% occurred in 21% of patients (95% CI, 11.1%-34.7%); all but 1 recovered by 1.5 years. Median LVEF decreased progressively during therapy from 65% before therapy (95% CI, 63%-66%) to 62% after AC (95% CI, 59%-64%) and 58% after AC-TP (95% CI, 56%-64%; P < 0.01 for each decrease). The decrease in LVEF persisted 1.5 years after study entry at 57% (95% CI, 54%-60%), although all but 1 of the most severe decreases to < 50% recovered to normal. Clinical response rate among 37 patients treated neoadjuvantly was 86%, and the pathologic complete response rate was 19% (95% CI, 8%-35.2%). Because of withdrawals for toxicity, refractory disease, and patient preference, only 35% of patients completed the entire regimen. CONCLUSION: In this study, the AC-TP regimen resulted in a high clinical but moderate pathologic response rate, and although asymptomatic cardiac systolic dysfunction was common, most of the severe decreases recovered over time.

Delivery of a healthy baby after first-trimester maternal exposure to lapatinib.

We report the case of a woman who conceived while being treated on a phase I clinical trial with lapatinib, a dual inhibitor of epidermal growth factor receptor (EGFR) and HER2/neu, for metastatic breast cancer. Despite approximately 11 weeks of exposure to lapatinib in the first and second trimesters, the pregnancy was uncomplicated and resulted in the delivery of a healthy baby. Although concomitant cancer and pregnancy is relatively rare, the increasing use of biologic agents among fertile women, sometimes for as long as a year in the adjuvant setting increases the probability that some women will conceive while taking a growth factor pathway inhibitor. As with systemic chemotherapy given during pregnancy, there exists the potential for teratogenicity or fetal demise from exposure of the developing embryo to inhibitors of EGFR and HER2/neu. Despite the positive outcome of this case, continued caution is warranted with the use of EGFR and HER2/neu inhibitors in pregnancy.

A cautionary tale: fatal outcome of methotrexate therapy given for management of ectopic pregnancy.

BACKGROUND: Medical therapy with methotrexate is a standard practice for the commonly encountered problem of ectopic pregnancy. Methotrexate is excreted predominantly by the kidney and should be used with extreme caution in renal insufficiency. All physicians who administer methotrexate must understand its mechanism of action, distribution, and elimination to minimize potential risks to the patient. CASE: A young, dialysis-dependent woman received a standard dose of methotrexate for an ectopic pregnancy. Prolonged methotrexate exposure resulted. The consequences-pancytopenia, desquamation, acute respiratory distress syndrome, and profound bowel ischemia-ultimately led to her death. CONCLUSION: Methotrexate, even at extremely low doses, can be fatal in patients with renal insufficiency. Alternative means of therapy should be sought for women with ectopic pregnancy and renal failure.

Concomitant pregnancy and breast cancer: options for systemic therapy.

Breast cancers diagnosed during pregnancy and lactation typically have an aggressive phenotype and an advanced stage at presentation. The timing of treatment modalities in pregnant women is complex and requires multidisciplinary input. Alternatives which are relatively safe for both mother and fetus are available, though unforeseen risks may exist. Chemotherapy is not thought to be safe for a fetus during the first trimester; however, in women with high risk cancers, treatment should not be delayed. Thereafter, anthracycline based chemotherapy has a low incidence of fetal complications. Little evidence beyond case reports exists for taxanes or tamoxifen in pregnancy, and less is available regarding the safety of novel molecularly targeted therapeutics such as trastuzumab. The prognosis of breast cancer diagnosed during pregnancy and lactation is poor, largely because of advanced stage and aggressive phenotype; it is unclear whether pregnancy is an independent prognostic marker for poor outcome.