Sequential Single-agent Therapy Research Articles

Treating Metastatic Breast Cancer With Systemic Chemotherapies

Treatment selection for metastatic breast cancer (MBC) is guided by multiple factors, most importantly hormone receptor (HR) or HER2 expression, treatment history, and prognostic factors such as short disease-free interval, presence of visceral metastases, performance status, and degree of symptoms. Chemotherapy is indicated as initial therapy for patients with HR-negative disease and following failure of hormonal therapies in HR-positive disease. Patients treated with an anthracycline or a taxane in early-stage settings may no longer be candidates for those drugs in MBC, thus underscoring the need for alternative options. Sequential single-agent therapy or combination therapy are viable strategies. Trials have shown that ixabepilone plus capecitabine significantly improves progression-free survival compared with capecitabine alone in anthracycline- or taxane-pretreated or -resistant patients, and single-agent eribulin improves survival compared with the physician's choice of treatment in patients treated previously with at least two regimens for MBC. Regardless of the regimen, proactive management to detect treatment-related adverse events in a timely manner remains important for ensuring effective delivery of treatment. Many promising investigational agents are in development, including T-DM1 (trastuzumab emtansine) and pertuzumab for HER2-positive disease, as well as PARP-1 (poly[adenosine diphosphate ribose] polymerase-1) inhibitors and cetuximab for triple-negative disease. In addition, new options for the treatment of MBC following failure of an anthracycline and a taxane promise to improve patient outcomes. Nurses should remain vigilant for adverse events and remember that the goal of treatment remains control of the disease and palliation.

Taxane Doublets for Metastatic Breast Cancer: Do We Need Another Cytotoxic Pair or Another Approach?

In the 15 years since taxanes were approved for use in metastatic breast cancer, they have played a prominent role in clinical trials evaluating combination therapy for this disease. A number of randomizedtrialshavebeenconductedaddressingthequestionofsingleagentversuscombinationtherapyortherelatedquestionofsequential versuscombinationtherapy.Someofthesehaveshownthecombination arm to be superior in response rate (RR), progression-free survival (PFS), and even overall survival (OS). Notable examples of successful taxane doublets include the combination of gemcitabine and paclitaxel 1 and the combination of docetaxel and capecitabine, 2 both of which showed improved time to progression (TTP), RR, and OS for the doublet compared with single-agent taxane alone in firstline treatment of metastatic breast cancer. However, later analysis of the docetaxel and capecitabine study showed that in patients who received single-agent docetaxel, poststudy treatment with capecitabine improved survival more than other poststudy treatments. This finding raises the possibility that sequential single-agent therapy may confer the same benefit as combined doublet therapy. 3 Other trials have shown that combination cytotoxic therapy is no better than single-agent or single-agent sequential therapy, 4 and most studies have shown higher toxicity in the combination arms. A recent Cochrane report 5 concluded that combination chemotherapy regimens yielded statistically significant improvements in OS, TTP, and RR yet greater toxicity. However, this report included primarily nontaxane combinations and did not evaluate sequential single agents as a comparison. The National Comprehensive Cancer Network guidelines, version2.2011, 6 statethatthereislittleornocompellingevidencethat combination chemotherapy is superior to sequential single agents. Thus a common consensus opinion is that combination cytotoxic therapy should be used in patients with rapidly progressive disease or in patients with visceral disease and symptoms, where more rapid response is needed. All others should be treated with single agents in sequence. Inthiscontext,Nielsenetal 7 presentinJournalofClinicalOncology a randomized phase III trial conducted by the Danish Breast Cancer Cooperative Group to evaluate the combination of gemcitabine and docetaxel compared with docetaxel alone in the treatment of metastatic breast cancer. This study was conducted between 2001 and2005andincluded337patientswithmetastaticbreastcancerwho

Combination therapy for renal cell carcinoma: review of the clinical evidence

The treatment of metastatic renal cell carcinoma has been revolutionized in recent years with the development of VEGF- and mTOR-targeted therapies. Individually, these agents have shown the ability to improve progression-free or overall survival. While sequential single agent therapy appears to significantly prolong survival, patients still succumb to their disease eventually and further therapeutic advances are clearly needed. A detailed molecular understanding of the limits of the available therapies and the drivers of resistance to each is currently lacking. While those clinical investigations are undertaken, the field has turned its attention to the clinical evaluation of combination regimens containing individual drugs that have demonstrated efficacy in this disease. The largest number of such investigations has combined agents within the VEGF-targeted class with mTOR inhibitors. However, there are reasons to believe that immunotherapy and chemotherapy combinations may also be relevant with this clas...

The future of tyrosine kinase inhibitors: Single agent or combination?

The past 3 years have delivered positive phase 3 trial results for sorafenib, sunitinib, temsirolimus, and bevacizumab in renal cell carcinoma (RCC). The benefit of these therapies has been best defined as either first-line therapy or following cytokine therapy in patients with clear cell RCC. In light of the differences in the molecular targets of each agent, there is reason to believe that sequential single-agent therapy or regimens combining these agents could extend the benefits observed in the reported randomized trials. However, to date, few data have been reported supporting either strategy. A careful consideration of the specific mechanism of action of each agent provides a basis for considering the optimal therapeutic strategies for incorporating each of these agents into the management of metastatic RCC.

Capecitabine (X) and taxanes in patients (pts) with anthracycline-pretreated metastatic breast cancer (MBC): Sequential vs. combined therapy results from a MOSG randomized phase III trial

570 Introduction: Capecitabine (Xeloda [X]) shows synergy with taxanes and adding X to docetaxel (T) extends overall survival (OS), response rate (RR) and progression free-survival (PFS) beyond T alone. Sequential single-agent therapy could confer convenience benefits and may be more appropriate than combination chemotherapy for some pts. Methods: Pts with anthracycline-pretreated MBC received 3-weekly cycles of 1 of the following regimens: X→taxane (X 1250mg/m2 bid d1–14, followed after progression (PD) by T 100mg/m2 or paclitaxel [P] 175mg/m2 day 1; X+P (X 825mg/m2 bid days 1–14 + P 175mg/m2 day 1) or X+T (X 825mg/m2 bid days 1–14 + T 75mg/m2 day 1). Results: Of the 368 pts enrolled, 91 are either still on therapy or not evaluable. The table shows baseline characteristics, efficacy and safety in evaluable pts. Median follow up is 15.5 months. Median doses for X in each arm (1st cycle vs. 8th cycle, mg/m2 bid): 1218 vs. 1054; 948 vs. 900; 846 vs. 751. Median doses for P and T (1st cycle vs. 8th cycle, mg/m2): 173 vs. 169 and 75 vs. 72, respectively. In the X→taxane arm, 58 pts (64%) received sequential taxane; the remainder did not receive a taxane, either because they were still on X, had CR or had rapid PD. Conclusions: RR is higher with XP and XT, but PFS and OS are similar at a median follow-up of 15.5 months. All regimens were well tolerated with minimal grade 4 AEs. Because there is no clear superiority of sequential vs. combined therapy, pt characteristics are likely to be used to decide which regimen is the most appropriate. [Table: see text] [Table: see text]

Combination versus sequential single-agent therapy for the treatment of metastatic breast cancer

The administration of combination versus single-agent chemotherapy for the treatment of metastatic breast cancer remains an unresolved and controversial issue. Previous randomised trials have shown that, while combinations offer higher objective response rates, they have not always improved time to progression, quality of life or overall survival. Rationally designed combination regimens incorporating new cytotoxic and biological agents have resulted in improved survival rates compared with monotherapy and only modest increases in toxicities. However, trials analysing combination therapies lack formal cross-over arms and do not allow comparison of these regimens with sequentially administered single-agent therapy. This paper presents the latest randomised data and reviews the advantages and disadvantages of these two approaches to the treatment of metastatic breast cancer.

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.

Survival Benefit with Capecitabine/Docetaxel Versus Docetaxel Alone: Analysis of Therapy in a Randomized Phase III Trial

In a large phase III trial of 511 patients with anthracycline-pretreated advanced/metastatic breast cancer, capecitabine/docetaxel combination therapy was shown to have significantly superior efficacy compared with single-agent docetaxel, including superior progression-free and overall survival and objective response rate. An updated survival analysis with ≥ 27 months follow-up shows that patients receiving combination therapy maintained significantly superior survival (hazard ratio [HR], 0.777 [95% CI, 0.645–0.942]; P < 0.01; median survival, 14.5 months vs. 11.5 months) compared with those receiving single-agent docetaxel. Following the failure of docetaxel monotherapy, 35% of patients did not receive additional cytotoxic chemotherapy. Among patients randomized to single-agent docetaxel, only those given poststudy single-agent capecitabine had significantly prolonged survival compared with those given any other poststudy chemotherapy (HR, 0.500; P = 0.0046; median survival, 21.0 months vs. 12.3 months, respectively). By contrast, poststudy vinorelbine-containing chemotherapy did not affect survival following progression on single-agent docetaxel compared with other poststudy chemotherapy regimens (HR, 1.014; P = 0.94; median survival, 13.5 months vs. 12.6 months, respectively). Among patients randomized to combination therapy, discontinuing docetaxel of capecitabine has a similar effect on survival (HR, 0.720; P = 0.20; median survival, 15.8 months vs. 18.3 months, respectively). Median survival was 18.3 months in patients who discontinued docetaxel and continued to receive capecitabine versus 15.8 months in patients who discontinued capecitabine and continued to receive docetaxel, with a trend toward improved survival in patients continuing to receive capecitabine. Although this is a retrospective analysis, these data suggest that the sequential administration of docetaxel followed by capecitabine is associated with prolonged survival in patients who are candidates for sequential single-agent therapy.

New therapeutic strategies for soft tissue sarcomas.

The treatment of patients with metastatic soft tissue sarcomas (STS) is complex. There are limited agents available and many are associated with significant toxicity. When evaluating a patient with metastatic disease, physicians should ask themselves whether there is a role for surgery to render the patient free of disease. Combination chemotherapy in patients who have not received chemotherapy in the adjuvant setting is one option, particularly in a young patient with a good performance status. Sequential single-agent therapy for patients who are more elderly or debilitated by their disease may be more appropriate. Gemcitabine appears to be an agent with activity, particularly in patients with leiomyosarcomas. The data regarding prolonged gemcitabine infusions suggest improved activity that was predicted based on prolonged intracellular gemcitabine levels. Because of these data, the prolonged infusion schedule should be used. In addition, because of the paucity of effective agents, consideration of clinical trial participation for patients with newly diagnosed metastatic disease is appropriate, particularly in chemotherapy-insensitive histologies. The role of the newer agents (eg, ecteinascidin-743, epothilones, and mammalian target of rapamycin) is undefined. Ecteinascidin-743 has been the most extensively tested agent, and its ability to slow growth kinetics of a tumor and stabilize it clinically is intriguing. Data regarding the response to BMS-247550 will be published shortly and will help define the further role of epothilones in this disease. There is a preclinical rationale that makes the mammalian target of rapamycin inhibitors attractive for the treatment of muscle-derived neoplasms. In addition, there are cell-line data suggesting activity in rhabdomyosarcoma. These agents are being tested in adult STS and will likely be tested in pediatric histologies when there are more safety data available in that population. SU11248 will continue to be tested in patients refractory to imatinib mesylate and may well prove to be another active agent for patients with gastrointestinal stromal tumors. As depicted by the analysis of gemcitabine efficacy, agents with activity in a subgroup of STS may be overlooked by the "come one come all" approach to clinical trials in STS. Identifying key targets in specific STS will be helpful in the testing of newer molecularly targeted agents. Biologic differences will support histology-specific trials to better understand the activity of an agent in a specific disease site or specifically target a biologic pathway with relevance to the malignant potential of the disease. For future clinical trials in STS to achieve the goal of histology-specific trials, cooperative group and multi-institutional trials will be required to obtain the appropriate patients with these rare histologies. It will also be increasingly important to be committed to obtaining tumor tissue in these patients to validate hypotheses regarding tumor biology and the effectiveness of therapeutic agents.

Doxorubicin and taxane combination regimens for metastatic breast cancer: Focus on cardiac effects

Investigation of the combination of the taxanes with doxorubicin in the treatment of breast cancer has logically progressed, with the ultimate goal of identifying a safe and effective regimen for use in the adjuvant setting. Initial phase II findings of the concurrent doxorubicin/paclitaxel combination resulted in substantial response rates, but at a high cost. A much higher percentage of patients than expected developed anthracycline-induced cardiomyopathy. Subsequent phase II and phase III trials have determined administration schedules of doxorubicin/paclitaxel that reduce the risk for cardiotoxicity. However, the overall response rate is only modestly improved over sequential single-agent therapy or standard doxorubicin-containing combination therapy. The lack of cardiotoxicity with docetaxel, its high antitumor activity, and its linear pharmacokinetics have made it an attractive taxane for combination with doxorubicin. In addition, it is easily administered in the outpatient setting. Phase I/II trials of the combination of doxorubicin/docetaxel resulted in high response rates with a lack of adverse modification of anthracycline-induced cardiomyopathy. These findings have been confirmed in a large phase III randomized trial where overall response rates and time to disease progression were significantly improved, but the incidence of cardiomyopathy was not different for the doxorubicin/docetaxel versus doxorubicin/cyclophosphamide (AC) regimen. Ongoing studies are underway to assess the role of the doxorubicin/ docetaxel combination in the adjuvant setting as primary chemotherapy in the neoadjuvant setting. It is here that the most benefit on survival of breast cancer patients is likely to be shown. At the same time, it is in the adjuvant setting where the absence of potentially late cardiac and other toxicities must be assured.

Combination versus sequential single‐agent chemotherapy in the treatment of patients with advanced non‐small cell lung cancer

We have carried out a randomized phase III study in 105 patients with advanced non-small cell lung cancer, comparing a four-drug cisplatin-mitomycin-based combination chemotherapy regimen to sequential single-agent therapy. The combination chemotherapy regimen consisted of mitomycin C (10 mg/m2), vinblastine (5 mg/m2), methotrexate (40 mg/m2), and cisplatin (40 mg/m2) given every 28 days. Sequential single-agent chemotherapy consisted of mitomycin C (10 mg/m2) monthly until progression followed by vinblastine (5 mg/m2) every 2 weeks until progression followed by methotrexate (40 mg/m2) weekly until relapse. Patients failing either regimen were followed with supportive care. The objective response rate for the sequential single-agent therapy was 19% versus 25% for the combination chemotherapy group (P greater than .5). The median survival for the single-agent group was 166 days and 191 days for the combination chemotherapy group. Overall survival was not statistically different between the two groups (P greater than .5). Leucopenia, anemia, and prolonged anorexia with nausea and vomiting were more common in the combination chemotherapy group compared to the single-agent group. This study failed to demonstrate a sufficient therapeutic benefit in the face of the added toxicity for the combination chemotherapy regimen compared to sequential single-agent therapy.