Anthracycline Plus Cyclophosphamide Research Articles

Abstract PO4-03-07: The impact of chemotherapy relative dose intensity on pathological complete response in patients with triple negative breast cancer treated with neoadjuvant chemotherapy

Abstract Background: Neoadjuvant chemotherapy (NACT) is the preferred treatment approach for early-stage triple negative breast cancer (TNBC). Achieving pathologic complete response (pCR) after NACT is associated with improved event-free survival and overall survival in patients with TNBC. Major research efforts have been deployed to identify predictive biomarkers for pCR in TNBC. However, the values of chemotherapy (CT) relative dose intensity (RDI) in predicting pCR remain unclear. Methods: A retrospective analysis was conducted among 96 consecutive patients with early stage TNBC who received NACT between February 2018 and January 2023 at the University of Naples Federico II (Naples, Italy). Patients’ demographics, clinical-pathological features, and type of CT schedules were retrieved from electronic medical records. pCR was defined as the absence of residual invasive or in situ carcinoma in primary tumor and/or lymph nodes, upon chemotherapy administration. RDI was calculated as the ratio of delivered to planned CT dose intensity. RDI was defined as low if < 85% or high if ≥85%, respectively. Univariate and multivariate logistic regression were used to evaluate the association between age, tumor stage, RDI, CT regimen dose type, and pCR. Results: All patients were included in the analysis. Median age at diagnosis was 51 years (range 28-75). Sixty-five (68%) and 31 (32%) patients were diagnosed with stage II and stage III TNBC, respectively. Nineteen (19%) patients received a sequential schedule of anthracycline plus cyclophosphamide (AC) and a taxane (T). Sixty-one (64%) patients received AC followed by concurrent carboplatin-paclitaxel (CaP). Sixteen (17%) patients received the anti-PD1 pembrolizumab in addition to ACCaP chemotherapy backbone (ACCaP-Pem). Fifty-four (56%) patients received a dose-dense AC-based CT. A pCR was achieved in 59 (61%) patients. Interestingly, patients who received a dose-dense AC based neoadjuvant CT had higher chance to achieve a pCR compared with those treated with a non dose-dense AC based CT (70% vs 46%, p = 0.03). Overall, 79 (82%) and 17 (18%) patients received a RDI high and RDI low CT, respectively. No difference in terms of age, body mass index, performance status, tumor stage, type of chemotherapy was observed between the two groups (Table 1). At univariate analysis RDI high (OR 5.18, 95%CI: 1.65-16.31, p=0.005) and dose dense AC-based CT (OR 2.42, 95%CI: 0.18-0.97, p=0.04) were significantly associated with pCR. In a multivariate model including RDI, age, tumor stage, and AC regimen dose type, RDI was the only variable independently associated with pCR (OR 4.60, 95% CI: 1.40-15.06, p = 0.01). Conclusion: A chemotherapy RDI≥ 85% independently predicts pCR in early stage TNBC patients treated with standard NACT. In our cohort, one in five patients received a suboptimal chemotherapy dose intensity affecting at least in part tumor response. Studies with larger TNBC patient populations are warranted to confirm the impact of RDI on pCR and long-term outcomes. Table 1 Citation Format: Roberto Buonaiuto, Giuseppe Neola, Aldo Caltavituro, Paola Trasacco, Federica Pia Mangiacotti, Giovanna Pecoraro, Matteo Lambertini, Erica Pietroluongo, Pietro De Placido, Sabino De Placido, Valeria Forestieri, Mario Giuliano, Grazia Arpino, Carmine De Angelis. The impact of chemotherapy relative dose intensity on pathological complete response in patients with triple negative breast cancer treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-03-07.

Antiemetic Efficacy of Adding Olanzapine 5 mg to Aprepitant, Palonosetron and Dexamethasone-Sparing After Day Two for Cancer Patients Receiving Anthracycline and Cyclophosphamide.

PurposeChemotherapy-induced nausea and vomiting (CINV) decrease patient quality of life (QOL). We evaluated the efficacy of adding 5 mg Olz to a three-drug steroid-sparing antiemetic regimen (aprepitant, palonosetron, and dexamethasone-sparing after day two) for breast cancer (BC) patients receiving anthracycline plus cyclophosphamide (AC) chemotherapy.Patients and MethodsWe retrospectively reviewed the records of 177 BC patients with no previous highly emetogenic chemotherapy history receiving AC plus the steroid-sparing three-drug regimen or the steroid-sparing four-drug regimen including Olz 5mg at our hospital between January 2012 and December 2018. The primary endpoint was complete response (CR), defined as no vomiting and no usage of rescue medication during the first AC cycle. We analyzed the odds ratio (OR) of the CR with 95% confidence interval (CI) in the three-drug group against the four-drug group. The OR was adjusted for types of anticancer drugs by the Cochran–Mantel–Haenszel (CMH) test. Secondary endpoints were incidences of nausea, anorexia, fatigue, and somnolence during the first cycle.ResultsCompared to the three-drug group, the four-drug group demonstrated high incidence of no vomiting (71% vs 95%), a similar incidence of no rescue medication usage (50% vs 51%), and a similar CR rate (45% vs 49%). The OR of the CR rate in the three-drug group against the four-drug group after CMH adjustment for drug type was 0.958 (95% CI, 0.46–1.98). Compared to the three-drug group, the four-drug group demonstrated identical incidence of nausea (66%), but lower incidences of anorexia (78% vs 35%) and fatigue (86% vs 73%). The incidence of somnolence in the four-drug group was 49%. We did not have data of somnolence for the three-drug group in the records.ConclusionAdding 5 mg Olz to the steroid-sparing three-drug combination can reduce vomiting, anorexia, and fatigue, although there was no difference in CR rate.

Comparison of Mirtazapine and Olanzapine on Nausea and Vomiting following Anthracycline-cyclophosphamide Chemotherapy Regimen in Patients with Breast Cancer.

We evaluated and compared the efficacy and safety of mirtazapine (MTZ) with olanzapine (OLP) for preventing chemotherapy-induced nausea and vomiting (CINV) following anthracycline plus cyclophosphamide (AC) regimen. Eligible participants were chemotherapy-naive early-stage breast cancer patients who were scheduled to undergo adjuvant AC. The patients were randomized to take oral MTZ or OLP in combination with aprepitant (A), dexamethasone (D), and granisetron (G), (ADG). The endpoints included rates of complete response (CR), complete control (CC), total control (TC), and adverse events during the acute, delayed, and overall phases in the two cycles of chemotherapy. The influence of CINV on the quality of life (QoL) was evaluated on day 6 of chemotherapy. Of 82 patients, 60 were randomized. In the first cycle, CR rates in cycle 1 were 83.3% and 76.6% during the acute period, 80% and 86.6% during the delayed period, and 66.6% and 63.3% during the overall period, for the ADG-M and ADG-O, respectively. High efficacy of both groups was maintained over 2 cycles. More patients in the ADG-M group noted minimal or no impact of CINV on daily life in cycle 2 (89.7% vs. 67.9%; p = 0.044). Incidence of somnolence and fatigue was more frequent with the olanzapine group. In this study, there was no substantial difference between mirtazapine and olanzapine in preventing CINV. Further large randomized trials are essential to demonstrate the anti-emetic effect of mirtazapine in chemotherapy.

One-Day Versus Three-Day Dexamethasone in Combination with Palonosetron for the Prevention of Chemotherapy-Induced Nausea and Vomiting: A Systematic Review and Individual Patient Data-Based Meta-Analysis.

A dexamethasone-sparing regimen consisting of palonosetron plus 1-day dexamethasone for the prevention of chemotherapy-induced nausea and vomiting (CINV) has been studied previously. Here, we evaluate the noninferiority of the dexamethasone-sparing regimen in overall antiemetic control using a meta-analysis based on individual patient data (IPD). We conducted a systematic review for randomized trials reporting CINV outcomes for the comparison of palonosetron plus 1-day dexamethasone (d1 arm) versus the same regimen followed by dexamethasone on days 2-3 after chemotherapy (d3 arm) in chemotherapy-naïve adult patients undergoing either moderately emetogenic chemotherapy (MEC) or anthracycline plus cyclophosphamide (AC)-containing chemotherapy. PubMed and MEDLINE were searched electronically. A manual search was also conducted. The primary endpoint was complete response (CR; no emesis and no rescue medication) in the overall 5-day study period. The noninferiority margin was set at -8.0% (d1 arm-d3 arm). Five studies (n = 1,194) were eligible for analysis and all IPD was collected. In the overall study period, the d1 arm showed noninferiority to the d3 arm for CR as well as complete control (pooled risk difference in CR rate - 1.5%, 95% confidence interval [CI] -7.1 to 4.0%, I2 = 0%; in complete control rate - 2.4%, 95% CI -7.7 to 2.9%, I2 = 0%). There was no significant interaction between dexamethasone regimen and risk factors (type of chemotherapy, sex, age, and alcohol consumption). This IPD meta-analysis indicates that the dexamethasone-sparing regimen is not associated with a significant loss in overall antiemetic control in patients undergoing MEC or AC-containing chemotherapy, irrespective of known risk factors for CINV. Although dexamethasone in combination with other antiemetic agents has been used to prevent chemotherapy-induced nausea and vomiting (CINV), it is of clinical importance to minimize total dose of dexamethasone in patients undergoing multiple cycles of emetogenic chemotherapy. This individual-patient-data meta-analysis from five randomized controlled trials (1,194 patients) demonstrated a noninferiority of the dexamethasone-sparing regimen for complete response and complete control of CINV. The outcomes were comparable across patients with different characteristics. These findings thus help physicians minimize use of the steroid and further reduce the burden of dexamethasone-related side effects in patients undergoing multiple consecutive courses of emetogenic chemotherapy.

Incidence of nausea and vomiting in breast cancer patients treated with anthracycline plus cyclophosphamide-based chemotherapy regimens in Italy: NAVY observational study.

Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event with cancer chemotherapy, despite the availability of effective antiemetic agents. This is a prospective observational study of Italian breast cancer patients treated with anthracycline plus cyclophosphamide (AC), assessed CINV incidence, adherence to national antiemetic guidelines (AIOM 2012), and the relationship with CINV outcomes. Patients with breast cancer scheduled to receive their first cycle of an AC-based regimen were enrolled at 12 Italian centers and their clinical data prospectively recorded. CINV incidence was assessed from patient diaries after the first chemotherapy cycle. The relationship between guideline adherence and CINV outcomes was examined using multiple logistic regression. The overall incidence rates of nausea and vomiting among 246 evaluable patients were 63.0 and 25.4%, respectively. Most patients received a 5-HT3-RA agent and dexamethasone for acute phase CINV prophylaxis, whereas a triple combination including aprepitant (NK1-RA), consistent with national guidelines, was used in only 45.5% of cases. In the delayed phase, the guideline adherence was 48.8%, while the overall adherence was 43.5%. After adjusting for confounding factors, adherence to antiemetic prophylaxis guidelines was associated with a significant reduction in the odds of three endpoints, namely any nausea, "significant nausea," and vomiting (OR = 0.49, OR = 0.54, and OR = 0.48, respectively), and a 90% increase in the odds of overall complete protection (OR = 1.90). CINV is still a critical issue in AC-treated patients, despite antiemetic treatment. Non-adherence to antiemetic guidelines may lead to poorer outcomes and indicates the need for strategies to enhance the use of guidelines in clinical practice.

APF530 versus ondansetron, each in a guideline-recommended three-drug regimen, for the prevention of chemotherapy-induced nausea and vomiting due to anthracycline plus cyclophosphamide-based highly emetogenic chemotherapy regimens: a post hoc subgroup analysis of the Phase III randomized MAGIC trial.

BackgroundAPF530, a novel extended-release granisetron injection, was superior to ondansetron in a guideline-recommended three-drug regimen in preventing delayed-phase chemotherapy-induced nausea and vomiting (CINV) among patients receiving highly emetogenic chemotherapy (HEC) in the double-blind Phase III Modified Absorption of Granisetron In the prevention of CINV (MAGIC) trial.Patients and methodsThis MAGIC post hoc analysis evaluated CINV prevention efficacy and safety of APF530 versus ondansetron, each with fosaprepitant and dexamethasone, in patient subgroup receiving an anthracycline plus cyclophosphamide (AC) regimen. Patients were randomized 1:1 to APF530 500 mg subcutaneously (granisetron 10 mg) or ondansetron 0.15 mg/kg intravenously (IV) (≤16 mg); stratification was by planned cisplatin ≥50 mg/m2 (yes/no). Patients were to receive fosaprepitant 150 mg IV and dexamethasone 12 mg IV on day 1, then dexamethasone 8 mg orally once daily on day 2 and twice daily on days 3 and 4. Patients were mostly younger females (APF530 arm, mean age 54.1 years, female, 99.3%; ondansetron arm, 53.8 years, female 98.3%). The primary end point was delayed-phase (>24–120 hours) complete response (CR).ResultsAPF530 versus ondansetron regimens achieved numerically better CINV control in delayed and overall (0–120 hours) phases for CR, complete control, total response, rescue medication use, and proportion with no nausea. APF530 trends are consistent with the overall population, although not statistically superior given the underpowered AC subgroup analysis. The APF530 regimen in this population was generally well tolerated, with safety comparable to that of the overall population.ConclusionAPF530 plus fosaprepitant and dexamethasone effectively prevented CINV among patients receiving AC-based HEC, a large subgroup in whom CINV control has traditionally been challenging.

Abstract P5-11-15: Rolapitant for the prevention of chemotherapy-induced nausea and vomiting in breast cancer patients receiving multiple cycles of emetogenic chemotherapy

Abstract Background: Patients (pts) with breast cancer often receive highly emetogenic chemotherapy, such as anthracycline plus cyclophosphamide (AC). Additionally, young age and female gender are risk factors for chemotherapy-induced nausea and vomiting (CINV) in response to emetogenic chemotherapy. We assessed the ability of the long-acting neurokinin-1 receptor antagonist (RA), rolapitant, in the prevention of CINV over multiple cycles in pts with breast cancer Methods: This is a post hoc analysis of the prevention of CINV in a subset of pts with breast cancer from 3 similarly-designed, randomized, placebo-controlled phase 3 trials in which pts received a single oral dose of 180 mg rolapitant or placebo before chemotherapy. All pts received an oral 5-HT3 RA + dexamethasone (active control). The regimens were cisplatin-based (n=36), AC-based (n=681) or other (n=166; carboplatin, cyclophosphamide, etc). Pts who completed cycle 1 could continue the same antiemetic treatment in multiple cycles. Endpoints for cycle 1 of chemotherapy included complete response (CR; no emesis and no use of rescue medication) and no emesis, and no nausea (maximum visual analogue scale [VAS] <5 mm), in the overall (0–120 h), acute (≤24 h), and delayed (>24–120 h) phases. On days 6-8 of each subsequent chemotherapy cycle, pts self-reported the incidence of emesis or nausea interfering with normal daily life. Results: In cycle 1, CR in both the overall (62.9% rolapitant, 55.1% control; p=0.018) and delayed (66.7% rolapitant, 59.7% control; p=0.032) phases were higher with rolapitant vs control . Rolapitant also improved no emesis rates in the overall (74.4% rolapitant, 62.6% control; p<0.001) and delayed (77.2% rolapitant, 68.5% control; p=0.004) phases. Although less pts were available for follow up over multiple cycles, a numerically greater proportion of rolapitant-treated pts than control pts reported no emesis (cycles 2-6) and no interfering nausea (cycles 2-5) (table). The incidence of treatment-emergent adverse events (TEAEs) was similar for rolapitant (85.2%) and control (83.2%) during cycles 1-6. The most common TEAEs occurred at comparable rates in the rolapitant and control arms: fatigue (28.5% and 29.4%, respectively), alopecia (28.5% and 31.2%, respectively), and constipation (20.0% and 20.9%, respectively). Conclusions: Rolapitant added to 5-HT3 RA and dexamethasone therapy improved CINV control and was safe and well-tolerated in pts with breast cancer receiving multiple cycles of emetogenic chemotherapy, mostly AC and carboplatin, historically a high-risk population for CINV. Pt-Reported Response in Multiple Cycles, % (n/N)* No Emesis No Interfering Nausea CycleRolapitant 180 mgActive Controlp-value *Rolapitant 180 mgActive Controlp-value *288.3 (323/366)80.0 (308/385)0.00271.6 (262/366)68.3 (263/385)0.329390.5 (297/328)80.5 (293/364)<0.00173.8 (242/328)65.9 (240/364)0.025487.5 (266/304)82.4 (277/336)0.07579.3 (241/304)72.0 (242/336)0.033594.9 (111/117)88.2 (127/144)0.05987.2 (102/117)80.6 (116/144)0.152695.3 (102/107)88.9 (120/135)0.07184.1 (90/107)83.0 (112/135)0.811* Unstratified Cochran-Mantel-Haenszel test for between rolapitant and control difference in response rate. Citation Format: Schwartzberg L, Navari R, Arora S, Powers D, Jordan K, Rapoport B. Rolapitant for the prevention of chemotherapy-induced nausea and vomiting in breast cancer patients receiving multiple cycles of emetogenic chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-15.

Should clinicians always administer dexamethasone beyond 24 h after chemotherapy to control delayed nausea and vomiting caused by moderately emetogenic regimens? Insight from the re-evaluation of two randomized studies.

PurposeData from two noninferiority trials of a dexamethasone-sparing regimen were assessed for the impact of acute nausea and vomiting on delayed outcome in patients undergoing moderately emetogenic chemotherapy (MEC) or anthracycline plus cyclophosphamide (AC).MethodsChemo-naive patients were randomized to receive palonosetron (0.25 mg IV) plus dexamethasone (8 mg IV) on day 1 of chemotherapy, or the same regimen followed by oral dexamethasone on days 2 and 3 in the MEC (n = 237) and AC (n = 380) cohorts. Patients were divided into two groups according to whether or not they experienced vomiting and/or moderate-to-severe nausea during the acute phase (high- and low-risk groups, respectively). Primary efficacy endpoint was the complete protection (CP) against delayed vomiting and moderate-to-severe nausea. Patient’s satisfaction (0–100 mm visual analog scale) was also analyzed.ResultsAmong the 209 low-risk patients undergoing MEC, delayed CP occurred in 82.9 % of those who received single-dose dexamethasone and 89.8 % of those who received 3-day dexamethasone (P = 0.165). Of the 271 low-risk patients undergoing AC, CP was achieved in 71.7 % of those treated with single-dose dexamethasone and 84.2 % treated with 3-day dexamethasone (P = 0.019). In spite of these observations, the patient satisfaction data was not influenced by dexamethasone regimen. In both cohorts, occurrence of acute vomiting or moderate-to-severe nausea was the key independent-predictor for delayed vomiting or nausea, respectively.ConclusionsThe dexamethasone-sparing regimen provides adequate delayed protection in patients undergoing MEC who are at low risk for delayed symptoms, and can still be discussed for low-risk AC patients as the daily difference in control is modest. Additional dexamethasone doses can be customized on the basis of occurrence or absence of acute symptoms in the first cycle of MEC and even AC.

Palonosetron or granisetron for prevention of CINV in patients with breast cancer receiving dexamethasone and fosaprepitant following anthracycline plus cyclophosphamide (AC) regimen.

9598 Background: Superiority of palonosetron to granisetron is uncertain, for patients with breast cancer receiving both steroid and NK1 inhibitor against CINV caused by AC regimen. Methods: We con...

Palonosetron Plus 1-Day Dexamethasone for the Prevention of Nausea and Vomiting Due to Moderately Emetogenic Chemotherapy: Effect of Established Risk Factors on Treatment Outcome in a Phase III Trial

The non-inferiority of palonosetron plus 1-day versus 3-day dexamethasone in preventing chemotherapy-induced nausea and vomiting (CINV) due to moderately emetogenic chemotherapy (MEC) has been previously demonstrated. The objectives of this prespecified post hoc analysis were to demonstrate the non-inferiority hypothesis in an adjusted model for known risk factors (age, gender, alcohol consumption, and type of MEC [anthracycline plus cyclophosphamide (AC)-based versus other MEC]) for CINV and to explore the impact on antiemetic outcome of these risk factors. Chemonaive patients (n = 324) with solid tumors were randomized to receive palonosetron 0.25 mg IV plus dexamethasone 8 mg IV on day 1 of chemotherapy or the same regimen followed by oral dexamethasone 8 mg on days 2 and 3. The primary end point was complete response (CR, no emesis and no rescue antiemetics) during the 5-day study period. A modified intention-to-treat approach was used for multivariable analysis. Non-inferiority of the 1-day regimen was confirmed even after adjusting for risk factors (risk difference -4.4%, 95% CI -14.1% to 5.4%; P = .381). Only age less than 50 years (P = .044) independently predicted a poor outcome of antiemetic treatment. However, most of the younger patients were women (1-day regimen 81.8%, 3-day regimen 88.4%) who underwent AC-based chemotherapy (1-day regimen 61.1%, 3-day regimen 71.0%). There were no significant between-treatment differences in the CR rate according to risk factors. This analysis confirmed that the 1-day regimen provides a valid treatment option for prevention of CINV in delayed, non-AC-based MEC.

Effect of age on treatment outcome to palonosetron (PALO) plus 1-day dexamethasone (DEX) for the prevention of nausea and vomiting in women receiving anthracycline plus cyclophosphamide (AC)-based chemotherapy: A meta-analysis of two phase III trials.

e19536 Background: Women receiving AC-based chemotherapy represent a situation with a particularly high risk of developing chemotherapy-induced nausea and vomiting (CINV). Age younger than 50 years has also been identified as a risk factor for developing CINV. Combined data from two phase III trials evaluating a DEX-sparing regimen against CINV due to moderately emetogenic chemotherapy were assessed for potential effect of age on treatment outcome. Methods: A total of 405 chemo-naïve women with breast cancer who underwent AC-based chemotherapy were randomized to receive a single IV dose of PALO 0.25 mg plus DEX 8 mg IV on day 1 of chemotherapy (1-day regimen; n=200) or the same regimen followed by DEX 8 mg orally on days 2 and 3 (3-day regimen; n=205). The primary endpoint was complete response (CR; no emesis, and no rescue anti-emetics) in the 5-day study period. The effect of the 1-day regimen and age (<50 and ≥50 years) was investigated by a modified intention-to-treat approach. Meta-analysis of individual patient data was performed using the CR in the overall study period as dependent variable. A generalized mixed linear model with study and treatment group as dummy fixed effect was used for the analysis. Results: Patients under the age of 50 years comprised 43.5% and 49.3% of the 1-day and 3-day regimen groups, respectively. Among women receiving the 1-day regimen, 55.2% of younger patients achieved overall CR compared with 54% of older patients. In the 3-day regimen group, 51.5% of younger patients achieved overall CR compared with 58.7% of older patients. In the adjusted analysis, younger age was not associated with CR to anti-emetic treatment (risk difference, -3.1%; 95% CI, -13 to 6.7%; P=0.533). Conclusions: These findings provide evidence that younger age does not predict for worse outcome in terms of overall CR to anti-emetic coverage with PALO plus single-dose DEX in women receiving AC-based chemotherapy.

Differential time course of action of 5-HT3 and NK1 receptor antagonists when used with highly and moderately emetogenic chemotherapy (HEC and MEC)

Cisplatin-based highly emetogenic chemotherapy (HEC) displays a biphasic pattern of emesis with both an early and delayed period. In contrast, moderately emetogenic chemotherapy (MEC) has a monophasic pattern. The objective of this analysis was to further investigate the impact of the NK1-receptor antagonist aprepitant on these patterns. Three phase III HEC (patients scheduled to receive cisplatin-based chemotherapy) and one phase III MEC (breast cancer patients scheduled to receive anthracycline plus cyclophosphamide (AC)) trials of aprepitant were included. In all studies, patients were randomized in a 1:1 ratio to an aprepitant regimen (aprepitant plus ondansetron plus dexamethasone) or the standard regimen (ondansetron plus dexamethasone). The exact dosing regimen for ondansetron and dexamethasone was different in each study. In a post hoc analysis, multivariate logistic regression models were used to assess the impact on first emesis at different time intervals after chemotherapy. One thousand five hundred twenty-seven patients and 856 patients were randomized and assessed for efficacy in the HEC and MEC trials, respectively. For HEC, aprepitant reduced the risk of first emesis by 38-77% vs. standard regimen, beginning 15-18 h after cisplatin and extending to 60 h. For MEC, aprepitant reduced the risk of first emesis by 38-61% vs. active control, beginning 3 h after AC and for up to 12 h. Time of onset and duration of enhanced control of emesis with the addition of aprepitant differed between HEC and MEC. This suggests that the pattern of NK1-sensitive mechanisms may vary for different chemotherapy regimens.

Palonosetron in combination with 1-day versus 3-day dexamethasone for prevention of nausea and vomiting following moderately emetogenic chemotherapy: a randomized, multicenter, phase III trial

PurposeA phase III trial assessed the efficacy of palonosetron plus dexamethasone given once in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) following a broad range of moderately emetogenic chemotherapy (MEC) regimens.MethodsThis multicentre, randomized, open-label, non-inferiority trial evaluated two different treatment groups. One group received palonosetron (0.25 mg intravenously) and dexamethasone (8 mg intravenously) before chemotherapy, while the other was administered the same regimen on day 1 followed by dexamethasone 8 mg orally on days 2 and 3. The primary endpoint was complete response (CR; defined as no emetic episodes and no rescue medication) during the overall phase (days 1–5 after chemotherapy initiation). The non-inferiority margin was predefined as a 15% difference between groups in the primary endpoint.ResultsOf 332 chemotherapy-naïve patients included in the intention-to-treat analysis, 65.1% were female, and 35.2% received anthracycline plus cyclophosphamide (AC)-based regimens. Overall CR rates were 67.5% for those administered dexamethasone only on day 1 (n = 166), and 71.1% for those also administered dexamethasone on days 2 and 3 (n = 166; difference −3.6% (95% confidence interval, −13.5 to 6.3)). CR rates were not significantly different between groups during the acute (0–24 h post-chemotherapy; 88.6% versus 84.3%; P = 0.262) and delayed phases (days 2–5; 68.7% versus 77.7%; P = 0.116).ConclusionsPalonosetron plus single-dose dexamethasone administered before common MEC regimens provide protection against acute and delayed CINV which is non-inferior to that of palonosetron plus dexamethasone for 3 days. However, the major benefit of the single-day regimen occurs in patients receiving non-AC MEC regimens.

Trastuzumab Plus Chemotherapy: Convincing Survival Benefit or Not?

Trastuzumab has altered the lives of many women with Her-2/neu–amplified metastatic breast cancer (MBC). Within our clinical practice, we have several women who continue receiving trastuzumab 5 to 9 years after the initiation of therapy. Long survival durations in MBC are not uncommon for patients with hormonally sensitive tumors, but for Her-2/neu–amplified tumors the prognosis was dismal before the use of this agent. Improvements in survival from first relapse with MBC have occurred during the last decades secondary to the development of new hormonal and cytotoxic agents. Despite these gradual improvements in survival from first relapse, there are few trials demonstrating convincing benefits in overall survival for a novel regimen compared with a more standard comparator. The article by Marty et al in this issue of the Journal of Clinical Oncology confirms an overall survival benefit produced by a trastuzumab plus chemotherapy combination over chemotherapy alone. The survival benefit for a combination of trastuzumab plus chemotherapy was originally described by Slamon et al in one of the pivotal clinical trials of trastuzumab. In the trial by Marty et al, weekly trastuzumab plus docetaxel 100 mg/m every 3 weeks proved superior to the same dose of single-agent docetaxel in all end points including response rate, response duration, time to progression, treatment failure, and most importantly, overall survival (31.2 v 22.7 months; P .0062). In the pivotal trial, there was also a statistically significant survival benefit when patients treated with chemotherapy plus trastuzumab (n 235) were compared with those treated with chemotherapy alone (n 234; 25.1 v 20.3 months; P .046). In that trial, women with no prior anthracycline adjuvant therapy received an anthracycline plus cyclophosphamide (AC) alone or in combination with trastuzumab. Women with prior anthracycline adjuvant therapy were randomly assigned to paclitaxel 175 mg/m every 3 weeks alone or with trastuzumab. The overall survival advantage for AC trastuzumab over AC alone was 26.8% v 21.4% (P .16). An unexpected high cardiotoxicity rate led to the recommendation to avoid concomitant anthracycline use with trastuzumab outside of clinical trials. These recommendations are being challenged by provocative trials, such as the neoadjuvant trial by Buzdar, in which paclitaxel followed by an epirubicin-containing regimen was administered with concurrent trastuzumab, resulting in a 65% pathologic complete response rate with no cardiotoxicity. Other trials are re-exploring anthracyclines plus trastuzumab, also with encouraging efficacy results and a relative lack of cardiotoxicity. Examples include the liposomal doxorubicins and epirubicin. However, such combinations should still be limited to clinical trials. Although the anthracycline plus trastuzumab clinical trials cited above are of interest for future development, data by Marty et al are more relevant to current practice, given that taxane plus trastuzumab combinations are commonly used worldwide for the treatment of MBC. This practice is based on the results from the paclitaxel plus trastuzumab subset of the pivotal trial, which reported an overall survival benefit compared with paclitaxel alone (22.1 v 18.4 months), although this result was not statistically significant (P .17). We believe that paclitaxel administered on a 3-week schedule is unlikely to be the most effective combination for Her-2/neu–amplified MBC for three reasons. First, efficacy seems less for administration of paclitaxel on a 3-week schedule than on a weekly schedule. Second, a recent phase III trial of paclitaxel compared with docetaxel every 3 weeks showed superiority for docetaxel in all end points, including overall survival (15.4 v 12.7 months; P .03). Third, the trial by Marty et al showed a statistically significant survival benefit, whereas the pivotal trial using paclitaxel plus trastuzumab did not. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 19 JULY 1 2005