Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial.

PURPOSE: CDK4/6 inhibitors are used to treat estrogen receptor (ER)-positive metastatic breast cancer (BC) in combination with endocrine therapy. PALLET is a phase II randomized trial that evaluated the effects of combination palbociclib plus letrozole as neoadjuvant therapy. PATIENTS AND METHODS: Postmenopausal women with ER-positive primary BC and tumors greater than or equal to 2.0 cm were randomly assigned 3:2:2:2 to letrozole (2.5 mg/d) for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (C); or palbociclib plus letrozole for 14 weeks. Palbociclib 125 mg/d was administered orally on a 21-days-on, 7-days-off schedule. Core-cut biopsies were taken at baseline and 2 and 14 weeks. Coprimary end points for letrozole versus palbociclib plus letrozole groups (A v B + C + D) were change in Ki-67 (protein encoded by the  MKI67 gene; immunohistochemistry) between baseline and 14 weeks and clinical response (ordinal and ultrasound) after 14 weeks. Complete cell-cycle arrest was defined as Ki-67 less than or equal to 2.7%. Apoptosis was characterized by cleaved poly (ADP-ribose) polymerase. RESULTS: Three hundred seven patients were recruited. Clinical response was not significantly different between palbociclib plus letrozole and letrozole groups ( P = .20; complete response + partial response, 54.3% v 49.5%), and progressive disease was 3.2% versus 5.4%, respectively. Median log-fold change in Ki-67 was greater with palbociclib plus letrozole compared with letrozole (-4.1 v -2.2; P < .001) in the 190 evaluable patients (61.9%), corresponding to a geometric mean change of -97.4% versus -88.5%. More patients on palbociclib plus letrozole achieved complete cell-cycle arrest (90% v 59%; P < .001). Median log-fold change (suppression) of cleaved poly (ADP-ribose) polymerase was greater with palbociclib plus letrozole versus letrozole (-0.80 v -0.42; P < .001). More patients had grade 3 or greater toxicity on palbociclib plus letrozole (49.8% v 17.0%; P < .001) mainly because of asymptomatic neutropenia. CONCLUSION: Adding palbociclib to letrozole significantly enhanced the suppression of malignant cell proliferation (Ki-67) in primary ER-positive BC, but did not increase the clinical response rate over 14 weeks, which was possibly related to a concurrent reduction in apoptosis.

Phase II randomized clinical trial evaluating neoadjuvant chemotherapy regimens with weekly paclitaxel or eribulin followed by doxorubicin and cyclophosphamide in women with locally advanced HER2-negative breast cancer: NSABP Foundation Study FB-9.

Locally advanced breast cancer (LABC) is a good setting in which to monitor response to neoadjuvant chemotherapy, to downsize the tumor (which facilitates breast-conserving surgery), and to test newer agents in untreated patients. Eribulin (E) has shown activity in patients who have undergone previous taxane, anthracycline, and capecitabine treatment. We aimed to evaluate the neoadjuvant use of E followed by doxorubicin and cyclophosphamide (AC) in patients with HER2-negative LABC, using as a control a randomized group of women who received weekly paclitaxel (WP). Fifty women with LABC were accrued January-August 2013. Patients were randomized (1:2) to receive either WP (N = 19) for 12 treatments or E (N = 31) every 3 weeks for 4 cycles followed by AC every 3 weeks for 4 cycles before surgery. 17/19 patients who took WP and 25/30 who took E completed all cycles. Patients were evaluated by clinical examination and breast MRI at baseline and after completion of E or WP. Surgical pCR in breast and lymph nodes was determined by a local pathologist following chemotherapy. Forty-nine patients received ≥1 dose of neoadjuvant chemotherapy and are included in this analysis. Forty-eight underwent surgery; one had disease that was inoperable (on E) and is included as no-pCR patient. 17/19 of these patients who took WP completed 12 doses; 28/30 on E completed 4 cycles. Six discontinued treatment on WP, E, or AC. Both treatments were well tolerated. pCR on WP = 5/19(26 %) and on E = 5/30(17 %). Both regimens were equally well tolerated with no unexpected toxicities. pCR did not suggest higher activity with E than with other standard regimens in these LABC patients.

Evaluation of factors predicting recoverability of renal function after pyeloplasty in adults.

AIM: To analyze the status of renal function after pyeloplasty in a large contemporary adult series and to detect which variables predict improvement of renal function. MATERIALS AND METHODS: 85 adult patients were retrospectively identified who had undergone pyeloplasty between January 2002 and May 2011 with available pre- and postoperative diuretic scintigraphy. Preoperative differential renal function (DRF) and single-kidney GFR (SKGFR) were obtained by (99m)Tc-MAG-3 diuretic scintigraphy. Baseline-weighted (bw-) DRF and SKGFR were calculated between baseline conditions and time of last follow-up. Factors that explain the variance of bw-DRF and bw-SKGFR were determined. RESULTS: The mean (SD) preoperative DRF significantly increased from 34% (11.6) to 37.2% (11.8) after pyeloplasty (p < 0.001). Similarly, mean (SD) SKGFR showed a significant improvement from 31.2 (12.9) to 35.9 (15) ml/min (p < 0.001). Patients with a lower baseline DRF (≤40%) showed a significant improvement as opposed to those with a higher baseline DRF (>40%) (p < 0.001 and 0.3, respectively). Baseline DRF and cortical thickness explained the variance in bw-DRF and bw-SKGFR with more contribution of baseline DRF. CONCLUSIONS: Renal function showed improvement after pyeloplasty in adults and preoperative DRF and cortical thickness were the predicting variables.

Changes in differential renal function after pyeloplasty in children.

PURPOSE: Previous series showed controversial differential renal function outcomes after pyeloplasty in children. However, they were limited by study power, methodology and lack of comparable end points. We determined the status of differential renal function after pyeloplasty in children in what is to our knowledge the largest series to date. MATERIALS AND METHODS: After excluding patients with renal anomalies, solitary kidney or bilateral pyeloplasty from analysis, we retrospectively identified 196 younger than 18 years who were treated with pyeloplasty between May 2002 and January 2010 and had preoperative and postoperative renal scintigraphy available. Primary outcome measures were greater than 5% improvement in baseline differential renal function and baseline weighted differential renal function at last followup. Clinical variables predicting outcome measures were determined using univariable and multivariable analyses. RESULTS: During a median followup of 12 months, mean ± SD differential renal function improved from 35.8% ± 10% to 38.7% ± 11% (p <0.001). In the poor and intermediate groups baseline differential renal function improved, while in the good group function was static postoperatively (p <0.001). The linear regression model showed that only baseline differential renal function explained the variance in baseline weighted differential renal function (ß = -0.393, p <0.001). In the Cox proportional hazards model baseline differential renal function (less than 35% HR 3.196, p <0.001 and 35% to 40% HR 2.733, p = 0.002) and cortical thickness (HR 2.114, p = 0.029) were the only predictors of a greater than 5% improvement in postoperative differential renal function. CONCLUSIONS: Renal function improves after pyeloplasty in children. Baseline differential renal function and cortical thickness predict improvement after surgery.

Critical analysis of outcome after open dismembered pyeloplasty in ectopic pelvic kidneys in a pediatric cohort.

OBJECTIVE: To evaluate the functional and morphologic outcome after open pyeloplasty for ureteropelvic junction obstruction (UPJO) in ectopic pelvic kidneys. MATERIALS AND METHODS: A retrospective review of all patients who underwent open pyeloplasty in ectopic pelvic kidneys was conducted. Records were evaluated with respect to age at presentation, preoperative imaging, surgical details, and postoperative course. Patients were followed up regularly for functional and morphologic outcome. Success was defined as symptomatic relief and radiographic improvement of obstruction at the last follow-up. RESULTS: Between 1995 and 2010, 680 patients with primary UPJO underwent open dismembered pyeloplasty at our center. Of these patients, 43 (6.3%) had UPJO in ectopic pelvic kidneys. No perioperative complications were encountered in the study group. Mean follow-up was 42 months (range, 18-90 months), and 5 patients were lost to follow-up. The overall success rate was 82.6%. Postoperative hydronephrosis was improved in 20 (52.6%), stable in 11 (29%), and worsened in 7 (18.4%). Postoperative renal function was improved in 12 (31.6%), stable in 19 (50%), and deteriorated in 7 (18.4%). Redo pyeloplasty was required in 4 patients and secondary nephrectomy in 3. Preoperative differential renal function and surgeon experience were statistically significant predictors of improvement in renal function after pyeloplasty. CONCLUSION: Open pyeloplasty for UPJO in ectopic pelvic kidneys is feasible, but varying degrees of hydronephrosis and radiologic obstruction persist after pyeloplasty that could be attributed to anatomy-related pelvocaliectasis, and so regular follow-up is warranted in this subpopulation.

A phase II neoadjuvant trial of sequential nanoparticle albumin-bound paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide in locally advanced breast cancer.

BACKGROUND: Neoadjuvant chemotherapy has become standard treatment for women with locally advanced breast cancer (LABC). Various regimens have explored the addition of newer agents to determine safety and efficacy. The aim of this phase II study was to incorporate albumin-bound paclitaxel with sequential anthracycline-based therapy. PATIENTS AND METHODS: Sixty-six women with LABC but without prior treatment and regardless of hormone receptor or HER2 status were enrolled. All patients were to receive albumin-bound paclitaxel weekly for 12 weeks followed by 5-fluorouracil/ epirubicin/cyclophosphamide (FEC) every 3 weeks for 4 cycles. Trastuzumab was allowed in HER2-positive (HER2+) patients. Primary endpoint was pathologic complete response (pCR; CR) in breast. Secondary endpoints included pCR in breast and nodes, clinical CR, 2-year progression-free survival, and overall survival. RESULTS: Sixty-five patients received at least 1 dose of chemotherapy and were included in this analysis. Sixty-three patients completed 4 cycles of albumin-bound paclitaxel. Sixty-two patients received at least 1 dose of FEC, and 58 completed 4 cycles. Seventeen of 19 HER2+ women received trastuzumab. The pCR in breast was 29% (19 of 65). For the HER2+ subset, the pCR was 58% (11 of 19). Both albumin-bound paclitaxel and FEC were well tolerated. The most significant toxicities were grade 2/3 neuropathy (16%) with albumin-bound paclitaxel and grade 3/4 febrile neutropenia (7%) with FEC. CONCLUSION: Albumin-bound paclitaxel given over 12 weeks is well tolerated. Albumin-bound paclitaxel should be further evaluated in a randomized setting in both adjuvant and neoadjuvant trials.

Gemcitabine/epirubicin/paclitaxel as neoadjuvant chemotherapy in locally advanced breast cancer: a phase II trial of the NSABP Foundation Research Group.

BACKGROUND: This phase II protocol of neoadjuvant chemotherapy with gemcitabine/epirubicin/paclitaxel (GET) was designed to determine the pathologic complete response (pCR) rate in the breast, clinical response rate, disease-free survival, and overall survival at 2 years as well as toxicity in patients with locally advanced breast cancer. This trial also evaluated the feasibility of tissue collection for gene-expression profiling. PATIENTS AND METHODS: Seventy-six women with stage IIB, IIIA, and IIIB breast cancer were entered into this trial. Patients received a maximum of 6 cycles of neoadjuvant GET chemotherapy every 21 days (gemcitabine 1000 mg/m2 intravenously [i.v.] on days 1 and 4, epirubicin 90 mg/m2 i.v. bolus on day 1, and paclitaxel 175 mg/m2 i.v. on day 1). After chemotherapy, patients underwent surgery and were assessed for pathologic response. RESULTS: The pCR rate among the 74 patients evaluable for efficacy was 23% (95% CI, 14%-34.2%). Adverse events among the 76 patients evaluable for toxicity included anemia requiring transfusion (14.5%), infection with grade 3/4 neutropenia (10.5%), febrile neutropenia (7.9%), and platelet transfusion (6.6%). Infectious complications occurred in 24 patients (31.6%), of whom 18.4% were in the setting of neutropenia. High-quality RNA and successful probe synthesis were obtained from all pretreatment core biopsy specimens that contained tumor cells (n=66; 88%). CONCLUSION: Neoadjuvant GET chemotherapy is an active regimen but with substantial toxicity. Tissue collection for gene-expression profiling is feasible in a multi-institutional setting.