Long-term outcomes of dual vs single HER2-directed neoadjuvant therapy in NSABP B-41.

BACKGROUND: The primary aim of this randomized neoadjuvant trial in operable, HER2-positive breast cancer, was to determine the efficacy on pathologic complete response (pCR) of substituting lapatinib (L) for trastuzumab (T) or adding L to T, in combination with weekly paclitaxel (WP) following AC. Results on pCR were previously reported. Here, we report data on planned secondary endpoints, recurrence-free interval (RFI) post-surgery, and overall survival (OS). METHODS: All patients received standard AC q3 weeks × 4 cycles followed by WP (80 mg/m2) on days 1, 8, and 15, q28 days × 4 cycles. Concurrently with WP, patients received either T (4 mg/kg load, then 2 mg/kg) weekly until surgery, L (1250 mg) daily until surgery, or weekly T plus L (750 mg) daily until surgery. Following surgery, all patients received T to complete 52 weeks of HER2-targeted therapy. 522 of 529 randomized patients had follow-up. Median follow-up was 5.1 years. RESULTS: RFI at 4.5 years was 87.2%, 79.4% (p = 0.34; HR = 1.37; 95% CI 0.80, 2.34), and 89.4% (p = 0.37; HR = 0.70; 0.37, 1.32) for arms T, L, and TL, respectively. The corresponding five-year OS was 94.8%, 89.1% (p = 0.34; HR = 1.46; 0.68, 3.11), and 95.8% (p = 0.25; HR = 0.58; 0.22, 1.51), respectively. Patients with pCR had a much better prognosis, especially in the ER-negative cohort: RFI (HR = 0.23, p < 0.001) and OS (HR = 0.28, p < 0.001). CONCLUSIONS: Although pCR, RFI, and OS were numerically better with the dual combination and less with L, the differences were not statistically significant. However, achievement of pCR again correlated with improved outcomes, especially remarkable in the ER-negative subset. CLINICAL TRIALS REGISTRATION: NCT00486668.

Definitive results of a phase III adjuvant trial comparing six cycles of FEC-100 to four cycles of AC in women with operable node-negative breast cancer: the NSABP B-36 trial (NRG Oncology).

PURPOSE: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy. METHOD: NSABP B-36 was a phase III clinical trial originally designed as a 2 × 2 factorial study comparing 6 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC-100) to 4 cycles of conventional doxorubicin and cyclophosphamide (AC) with celecoxib or placebo. Shortly after activation, concerns regarding increased cardiovascular risks among selective COX-2 inhibitors resulted in a decision to remove the celecoxib/placebo from the trial. Women with histologically node-negative invasive breast cancer who had undergone primary surgery with a lumpectomy or total mastectomy were eligible. Primary endpoint was disease-free survival (DFS). RESULTS: Between May 2004 and July 2008, 2722 patients were enrolled. Administration of FEC-100 did not result in improvement in DFS compared to AC (HR 1.09; 95% CI 0.92-1.29, p value = 0.31). The effect of FEC-100 compared to AC on DFS was significantly different for receptor-positive (HR 1.32, 95% CI 1.05-1.66) compared to receptor-negative patients (HR 0.86, 95% CI 0.66-1.11) (treatment-by-receptor status interaction p value = 0.02). There was no statistically significant difference in the effect of treatment on overall survival (OS) with FEC-100 compared to AC (HR 1.06; 95% CI 0.84-1.35, p value = 0.61). Overall, Grade 3 and 4 adverse events were more frequent in the FEC-100 group. CONCLUSION: The results of B-36 do not support use of six-cycle anthracycline-based regimens in node-negative breast cancer. Prolongation of anthracycline-based therapy with FEC-100 does not improve DFS or OS, relative to AC for 4 cycles, and was associated with expected increases in toxicity. A statistically significant interaction between treatment and hormone receptor status favoring AC in hormone-receptor-positive breast cancers is consistent with the hypothesis that optimal duration of chemotherapy may be four cycles in these patients. Late cardiac events and deaths prior to recurrence or second cancer were infrequent on both arms, but slightly higher with FEC-100. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00087178.

Behavioral and health outcomes from the NRG Oncology/NSABP B-36 trial comparing two different adjuvant therapy regimens for early-stage node-negative breast cancer.

BACKGROUND: The NSABP B-36 compared four cycles of doxorubicin and cyclophosphamide (AC) with six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC-100) in node-negative early-stage breast cancer. A sub-study within B-36, focusing on symptoms, quality of life (QOL), menstrual history (MH), and cardiac function (CF) was conducted. PATIENTS AND METHODS: Patients completed the QOL questionnaire at baseline, during treatment, and every 6 months through 36 months. FACT-B Trial Outcome Index (TOI), symptom severity, and SF-36 Vitality and Physical Functioning (PF) scales scores were compared between the two groups using a mixed model for repeated measures analysis. MH was collected at baseline and subsequently assessed if menstrual bleeding occurred within 12 months prior to randomization. Post-chemotherapy amenorrhea outcome was examined at 18 months and was defined as lack of menses in the preceding year. Logistic regression was used to test for association of amenorrhea and treatment. CF assessment was done at baseline and 12 months. Correlation analysis was used to address associations between changes in baseline and 12-month PF and concurrent CF changes measured by LVEF. RESULTS: FEC-100 patients had statistically significantly lower TOI scores during chemotherapy (P = 0.02) and at 6 months (P < 0.001); lower Vitality score at 6 months (P < 0.01), and lower PF score during the first year than AC patients. There were no statistically significant QOL score differences between the two groups beyond 12 months. No significant differences in symptom severity between the two groups were observed. Rates of amenorrhea were significantly different between FEC-100 and AC (67.4% vs. 59.1%, P < 0.001). There was no association between changes in LVEF and PF (P = 0.38). CONCLUSIONS: Statistically significant QOL differences between the two groups favored AC; however, the magnitude was small and unlikely to be clinically meaningful. There was a clinical and statistically significant difference in risk for amenorrhea, favoring AC. TRIAL REGISTRY: NCT00087178; Date of registration: 07/08/2004.

Plasma Protein Biomarkers in Advanced or Metastatic Colorectal Cancer Patients Receiving Chemotherapy With Bevacizumab or Cetuximab: Results from CALGB 80405 (Alliance).

PURPOSE: CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). Although similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent. PATIENTS AND METHODS: In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405. Prognostic biomarkers were determined using univariate Cox proportional hazards models. Predictive biomarkers were identified using multivariable Cox regression models including interaction between biomarker level and treatment. RESULTS: In the total population, high plasma levels of Ang-2, CD73, HGF, ICAM-1, IL6, OPN, TIMP-1, TSP-2, VCAM-1, and VEGF-R3 were identified as prognostic of worse progression-free survival (PFS) and overall survival (OS). PlGF was identified as predictive of lack of PFS benefit from bevacizumab [bevacizumab HR, 1.51; 95% confidence interval (CI), 1.10-2.06; cetuximab HR, 0.94; 95% CI, 0.71-1.25; Pinteraction = 0.0298] in the combined FOLFIRI/FOLFOX regimens. High levels of VEGF-D were predictive of lack of PFS benefit from bevacizumab in patients receiving FOLFOX regimen only (FOLFOX/bevacizumab HR, 1.70; 95% CI, 1.19-2.42; FOLFOX/cetuximab HR, 0.92; 95% CI, 0.68-1.24; Pinteraction = 0.0097). CONCLUSIONS: In this exploratory, hypothesis-generating analysis, the Angiome identified multiple prognostic biomarkers and two potential predictive biomarkers for patients with mCRC enrolled in CALGB 80405. PlGF and VEGF-D predicted lack of benefit from bevacizumab in a chemo-dependent manner. See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725.

MAF Amplification and Adjuvant Clodronate Outcomes in Early-Stage Breast Cancer in NSABP B-34 and Potential Impact on Clinical Practice.

Background: The Adjuvant Zoledronic Acid (ZA) study in early breast cancer (AZURE) showed correlation between a nonamplified MAF gene in the primary tumor and benefit from adjuvant ZA. Adverse ZA outcomes occurred in MAF-amplified patients. NSABP B-34 is a validation study. Methods: A retrospective analysis of MAF gene status in NSABP B-34 was performed. Eligible patients were randomly assigned to standard adjuvant systemic treatment plus 3 years oral clodronate (1600 mg/daily) or placebo. Tumors were tested for MAF gene amplification and analyzed for their relationship to clodronate for disease-free survival (DFS) and overall survival (OS) in MAF nonamplified patients. All statistical tests were 2-sided . Results: MAF status was assessed in 2533 available primary tumor samples from 3311 patients. Of these, 37 withdrew consent; in 77 samples, no tumor was found; 536 assays did not meet quality standards, leaving 1883 (77.8%) evaluable for MAF assay by fluorescence in situ hybridization (947 from placebo and 936 from clodronate arms). At 5 years, in MAF nonamplified patients receiving clodronate, DFS improved by 30% (hazard ratio = 0.70, 95% confidence interval = 0.51 to 0.94; P = .02). OS improved at 5 years (hazard ratio = 0.59, 95% confidence interval = 0.37 to 0.93; P = .02) remaining statistically significant for clodronate throughout study follow-up. Conversely, adjuvant clodronate in women with MAF-amplified tumors was not associated with benefit but rather possible harm in some subgroups. Association between MAF status and menopausal status was not seen. Conclusions: Nonamplified MAF showed statistically significant benefits (DFS and OS) with oral clodronate, supporting validation of the AZURE study.

A randomized trial of nurse-administered behavioral interventions to manage anticipatory nausea and vomiting in chemotherapy.

PURPOSE: Chemotherapy side effects diminish quality of life and can lead to treatment delay. Nausea and vomiting can occur prior to chemotherapy because of classical conditioning. We studied the effects of 20-minute behavioral interventions, administered by oncology nurses, of higher intensity (mindfulness relaxation-MR) or lower intensity (relaxing music-RM), on anticipatory nausea and vomiting (ANV). PATIENTS AND METHODS: Patients undergoing chemotherapy for solid tumors were randomized to MR (N = 160), RM (N = 159), or standard care SC (N = 155). Subjects were mostly female (91.8%) and white (86.1%) with breast cancer (85%). Most patients had early stage disease (Stage I: 26%; II: 52.9%; III: 19%; IV: 0.1%). Anticipatory nausea and vomiting were assessed at the midpoint and end of the chemotherapy course using the Morrow Assessment of Nausea and Emesis (MANE). RESULTS: Compared to SC, there was reduced anticipatory nausea at the midpoint of chemotherapy in those receiving MR (OR 0.44, 95% CI 0.20-0.93) and RM (OR 0.40, 95% CI 0.20-0.93), controlling for age, sex, cancer stage, and emetogenic level of chemotherapy. There was no difference between treatment groups in anticipatory nausea at the end of chemotherapy or in anticipatory vomiting and postchemotherapy nausea and vomiting at either time point. CONCLUSION: A brief nurse-delivered behavioral intervention can reduce midpoint ANV associated with chemotherapy.

Association Between Inflammatory Biomarker C-Reactive Protein and Radiotherapy-Induced Early Adverse Skin Reactions in a Multiracial/Ethnic Breast Cancer Population.

Purpose This study examined an inflammatory biomarker, high-sensitivity C-reactive protein (hsCRP), in radiotherapy (RT)-induced early adverse skin reactions or toxicities in breast cancer. Patients and Methods Between 2011 and 2013, 1,000 patients with breast cancer who underwent RT were evaluated prospectively for skin toxicities through the National Cancer Institute-funded Wake Forest University Community Clinical Oncology Program Research Base. Pre- and post-RT plasma hsCRP levels and Oncology Nursing Society skin toxicity criteria (0 to 6) were used to assess RT-induced skin toxicities. Multivariable logistic regression analyses were applied to ascertain the associations between hsCRP and RT-induced skin toxicities after adjusting for potential confounders. Results The study comprised 623 white, 280 African American, 64 Asian/Pacific Islander, and 33 other race patients; 24% of the patients were Hispanic, and 47% were obese. Approximately 42% and 15% of patients developed RT-induced grade 3+ and 4+ skin toxicities, respectively. The hsCRP levels differed significantly by race and body mass index but not by ethnicity. In multivariable analysis, grade 4+ skin toxicity was significantly associated with obesity (odds ratio [OR], 2.17; 95% CI, 1.41 to 3.34], post-RT hsCRP ≥ 4.11 mg/L (OR, 1.61; 95% CI, 1.07 to 2.44), and both factors combined (OR, 3.65; 95% CI, 2.18 to 6.14). Above-median post-RT hsCRP (OR, 1.93; 95% CI, 1.03 to 3.63), and change in hsCRP (OR, 2.80; 95% CI, 1.42 to 5.54) were significantly associated with grade 4+ skin toxicity in nonobese patients. Conclusion This large prospective study is the first to our knowledge of hsCRP as an inflammatory biomarker in RT-induced skin toxicities in breast cancer. We demonstrate that nonobese patients with elevated RT-related change in hsCRP levels have a significantly increased risk of grade 4+ skin toxicity. The outcomes may help to predict RT responses and guide decision making.

Double-blind, randomized phase 3 trial of low-dose 13-cis retinoic acid in the prevention of second primaries in head and neck cancer: Long-term follow-up of a trial of the Eastern Cooperative Oncology Group-ACRIN Cancer Research Group (C0590).

BACKGROUND: 13-Cis retinoic acid (13-CRA) is a synthetic vitamin A derivative. High-dose 13-CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long-term results from a phase 3 randomized trial that compared treatment with low-dose 13-CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS). METHODS: In total, 176 patients who received treatment for stage I/II SCCHN were randomized to receive either low-dose 13-CRA (weight-based dose of 7.5 mg or 10 mg) or placebo for 2 years. A competing-risk approach and the log-rank test were used to compare the time to SPT and OS, respectively, between groups. RESULTS: 13-CRA neither significantly reduced the cumulative incidence of SPT (P = .61) nor improved the time to SPT (hazard ratio [HR] for 13-CRA/placebo; 0.86; P = .61). Despite limited power, there was a trend toward improved OS for the 13-CRA arm (HR, 0.75; P = .14), particularly among patients whose index tumor was surgically excised (N = 26; HR, 0.50; P = .057) and among women (N = 39; HR, 0.44; P = .065) and never/former smokers (N = 129; HR, 0.61; P = .055), with a median follow-up of 16 years. The main 13-CRA related toxicities were dry skin and cheilitis. CONCLUSIONS: Treatment with low-dose 13-CRA for 2 years did not decrease the incidence of SPT; subset analysis indicates a potential survival advantage among patients who are women and never/former smokers. More targeted interventions based on clinical risk factors and molecular characterization of tumors may yield greater success in future prevention trials. Cancer 2017;123:4653-4662. © 2017 American Cancer Society.

The Effect on Surgical Complications of Bevacizumab Added to Neoadjuvant Chemotherapy for Breast Cancer: NRG Oncology/NSABP Protocol B-40.

BACKGROUND: NRG Oncology/NSABP trial B-40 tested the impact of adding bevacizumab (bev) to neoadjuvant chemotherapy for operable breast cancer. Secondary endpoints included rates of surgical complications after surgery in patients who did or did not receive bev. METHODS: A total of 1206 women with HER2-negative operable breast cancer were randomly assigned to receive one of three different docetaxel-plus-anthracycline-based regimens, without or with bev (15 mg/kg every 3 weeks) for the first 6 of 8 cycles and for 10 doses postoperatively. Surgical complications were assessed from date of surgery through 24 months following study entry. RESULTS: Early surgical complications were significantly more frequent in the bev group (25.4 vs. 18.9%; trend test p = 0.008), but most were grade 1-2. Early noninfectious wound dehiscences were infrequent and not significantly different (5.4 vs. 3.1%; trend test p = 0.15). Long-term noninfectious wound complications were significantly higher for patients receiving bev (11.8 vs. 5.1%; trend test p = 0.0007), but the incidence of grade ≥3 wound dehiscence was low in both groups (<1%). Among 193 patients undergoing expander or implant reconstructions, 19 (19.6%) of 97 in the bev-receiving group versus 10 (10.4%) of 96 in the non-bev group had grade ≥3 complications (Pearson, p = 0.11). CONCLUSIONS: Overall, adding bev increased surgical complications, but most serious complications were not significantly increased. In particular, the need for surgical intervention in patients undergoing breast reconstruction with prosthetic implants was higher with bev but was not statistically significantly different. With precautions, bev can be used safely perioperatively in patients undergoing surgery for breast cancer.

A patient with white blood cell counts more than a million: A diagnostic and therapeutic challenge.

Prolymphocytic leukemias (PLLs) are rare mature lymphoid disorders of B- and T-cell subtypes with distinct features and an aggressive clinical course. PLL represents only 2% of all mature lymphocytic leukemias in adults. T-PLL represents 20% of all PLLs cases. T-cell prolymphocytic leukemia (T-PLL) is more rare and more rapidly progressive and aggressive than B-PLL; it is generally resistant to conventional chemotherapy, and historically the median survival has been about 7 months. Clinicians will often only see a case of T-PLL once every 5 to 10 years, which makes recognition of the disorder difficult. The prognosis is poor and there is no curative therapy. We report a 77-year-old male patient with de novo T-PLL presenting with WBC count of 1,115,000. We will discuss the clinical, morphologic, immunophenotypic and cytogenetic features of this rare entity. A distinctive hematologic aspect of T-PLL is a rapidly rising white blood cell count with a doubling time of weeks to months. The key morphologic feature in the diagnosis of T-PLL is a population of more than 55% prolymphocytes in the peripheral blood. The diagnosis can be made on peripheral blood by flow cytometry where a monoclonal lymphocyte population will show positivity for T-cell markers. T-PLL is characterized by complex chromosomal abnormalities, which suggests that chromosomal aberrations might occur progressively during the course of the disease, thus explaining the aggressive nature of this condition. The main challenge as a clinician treating T-PLL is to deliver long-term disease-free survival. The most important predictor of outcome is response to alemtuzumab therapy (Campath). Knowledge of the disrupted pathways and mechanisms underlying activation and proliferation in T-PLL has raised the possibility of developing future and promising treatment approach that targets these pathways and signals by the use of future molecule inhibitors. T-PLL is a rare disease and careful attention should be given to correctly diagnose this T-cell leukemia. Physicians should be aware of this unusual entity. With the advent of alemtuzumab, although much progress has been made in the treatment of this disease, autologous or allogeneic hematologic stem cell transplant (HSCT) still remains the only hope for cure.

Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial.

BACKGROUND: NSABP B-40 was a 3 × 2 factorial trial testing whether adding capecitabine or gemcitabine to docetaxel followed by doxorubicin plus cyclophosphamide neoadjuvant chemotherapy would improve outcomes in women with operable, HER2-negative breast cancer and whether adding neoadjuvant plus adjuvant bevacizumab to neoadjuvant chemotherapy regimens would also improve outcomes. As reported previously, addition of neoadjuvant bevacizumab increased the proportion of patients achieving a pathological complete response, which was the primary endpoint. We present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints but were collected prospectively. METHODS: In this randomised controlled trial (NSABP B-40), we enrolled women aged 18 years or older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c-3, cN0, cN1, or cN2a, without metastatic disease and diagnosed by core needle biopsy. Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m(2)) with addition of capecitabine (825 mg/m(2) oral twice daily days 1-14, 75 mg/m(2) docetaxel) or with addition of gemcitabine (1000 mg/m(2) days 1 and 8 intravenously, 75 mg/m(2) docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m(2) and 600 mg/m(2) intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses. Randomisation was done (1:1:1:1:1:1) via a biased-coin minimisation procedure to balance the characteristics with respect to clinical nodal status, clinical tumour size, hormone receptor status, and age. Intent-to-treat analyses were done for disease-free survival and overall survival. This study is registered with ClinicalTrials.gov, number NCT00408408. FINDINGS: Between Jan 5, 2007, and June 30, 2010, 1206 patients were enrolled in the study. Follow-up data were collected from Oct 31, 2007 to March 27, 2014, and were available for overall survival in 1186 patients, disease-free survival in 1184, and distant recurrence-free interval in 1181. Neither capecitabine nor gemcitabine increased disease-free survival or overall survival. Median follow-up was 4·7 years (IQR 4·0-5·2). The addition of bevacizumab significantly increased overall survival (hazard ratio 0·65 [95% CI 0·49-0·88]; p=0·004) but did not significantly increase disease-free survival (0·80 [0·63-1·01]; p=0·06). Four deaths occurred on treatment due to vascular disorder (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), sudden death (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), infective endocarditis (docetaxel plus bevacizumab followed by doxorubicin plus cyclophosphamide and bevacizumab group), and visceral arterial ischaemia (docetaxel followed by doxorubicin plus cyclophosphamide group). The most common grade 3-4 adverse events in the bevacizumab group were neutropenia (grade 3, 99 [17%]; grade 4, 37 [6%]), hand-foot syndrome (grade 3, 63 [11%]), and hypertension (grade 3, 60 [10%]; grade 4, two [<1%]) and in the non-bevacizumab group were neutropenia (grade 3, 98 [16%]; grade 4, 36 [6%]), fatigue (grade 3, 53 [9%]), and hand-foot syndrome (grade 3, 43 [7%]). INTERPRETATION: The addition of gemcitabine or capecitabine to neoadjuvant docetaxel plus doxorubicin plus cyclophosphamide does not seem to provide any benefit to patients with operable breast cancer, and should not change clinical practice in the short term. The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent. FUNDING: National Institutes of Health, Genentech, Roche Laboratories, Lilly Research Laboratories, and Precision Therapeutics.

A Hispanic female patient with heartburn: A rare presentation of Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant, acquired clonal hematopoietic stem cell disease that can present with bone marrow failure, hemolytic anemia, smooth muscle dystonias, and thrombosis. We present a case of a 32 year-old-female, G2P2A0 with no past medical history of any systemic illnesses who refers approximately 2 months of progressively worsening constant heartburn with associated abdominal discomfort. CBC showed leukopenia (WBC 2.9 x 103 /µL) with neutropenia (segmented neutrophils 48%), macrocytic anemia (Hgb 6.1 g/dL, hematocrit 20%, MCV,113 fL) and thrombocytopenia (platelet count 59 x 109/L). Abdomino-pelvic CT scan revealed a superior mesenterc vein thrombosis, which was treated initially with low-molecular-weight heparih for full anticoagulation. Peripheral blood flow cytometry assays revealed diminished expression of CD55 and CD59 on the erythrocytes, granulocytes and monocytes.' Paroxysmal nocturnal hemoglobinuria is a rare, clonal, hematopoietic stem-cell disorder whose manifestations are almost entirely explained by complement-mediated intravascular hemolysis. The natural history of PNH is highly variable, ranging from indolent to life-threatening. The median survival is 10 to 15 years, but with a wide range. Thrombosis is the leading cause of death, but others may die of complications of bone marrow failure, renal failure, myelodysplastic syndrome, and leukemia. Anticoagulation is only partially effective in preventing thrombosis in PNH; thus, thrombosis is an absolute indication for initiating treatment with Eculizumab. Nevertheless, bone marrow transplantation (BMT) is still the only curative therapy for PNH but is associated with significant morbidity and mortality.

Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial.

BACKGROUND: Bisphosphonates are thought to act through the osteoclast by changing bone microenvironment. Previous findings of adjuvant clodronate trials in different populations with operable breast cancer have been mixed. The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-34 aims to ascertain whether oral clodronate can improve outcomes in women with primary breast cancer. METHODS: NSABP B-34 is a multicentre, randomised, double-blind, placebo-controlled study in 3323 women with stage 1-3 breast cancer. After surgery to remove the tumour, patients were stratified by age, axillary nodes, and oestrogen and progesterone receptor status and randomly assigned in a 1:1 ratio to either oral clodronate 1600 mg daily for 3 years (n=1662) or placebo (1661). The primary endpoint was disease-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00009945. FINDINGS: Median follow-up was 90·7 months (IQR 82·7-100·0) and 3311 patients had data for this period. Disease-free survival did not differ between groups (286 events in the clodronate group vs 312 in the placebo group; hazard ratio 0·91, 95% CI 0·78-1·07; p=0·27). Moreover, no differences were recorded for overall survival (0·84, 0·67-1·05; p=0·13), recurrence-free interval (0·83, 0·67-1·04; p=0·10), or bone metastasis-free interval (0·77, 0·55-1·07; p=0·12). Non-bone metastasis-free interval was slightly increased with clodronate (0·74, 0·55-1·00; p=0·047). Analyses in women age 50 years or older on study entry showed benefits of clodronate for recurrence-free interval (0·75, 0·57-0·99; p=0·045), bone metastasis-free interval (0·62, 0·40-0·95; p=0·027), and non-bone metastasis-free interval (0·63, 0·43-0·91; p=0·014), but not for overall survival (0·80, 0·61-1·04, p=0·094). Adherence to treatment at 3 years was 56% for the clodronate group and 60% for the placebo group. Grade 3 or higher liver dysfunction was noted in 23 of 1612 patients in the clodronate group and 12 of 1623 patients in the placebo group; grade 3-4 diarrhoea was noted in 28 patients in the clodronate group and in ten in the placebo group. There was one possible case of osteonecrosis of the jaw in the clodronate group. INTERPRETATION: Findings of NSABP B-34 suggest that bisphosphonates might have anticancer benefits for older postmenopausal women. A meta-analysis of adjuvant bisphosphonate trials is suggested before recommendations for use in non-osteoporotic postmenopausal women with primary breast cancer are made. FUNDING: National Cancer Institute, Bayer Oy (formerly Schering Oy).

Bevacizumab added to neoadjuvant chemotherapy for breast cancer.

BACKGROUND: Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response. METHODS: We randomly assigned 1206 patients to receive neoadjuvant therapy consisting of docetaxel (100 mg per square meter of body-surface area on day 1), docetaxel (75 mg per square meter on day 1) plus capecitabine (825 mg per square meter twice a day on days 1 to 14), or docetaxel (75 mg per square meter on day 1) plus gemcitabine (1000 mg per square meter on days 1 and 8) for four cycles, with all regimens followed by treatment with doxorubicin-cyclophosphamide for four cycles. Patients were also randomly assigned to receive or not to receive bevacizumab (15 mg per kilogram of body weight) for the first six cycles of chemotherapy. RESULTS: The addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs. 32.7%; P=0.69). Both capecitabine and gemcitabine were associated with increased toxic effects--specifically, the hand-foot syndrome, mucositis, and neutropenia. The addition of bevacizumab significantly increased the rate of pathological complete response (28.2% without bevacizumab vs. 34.5% with bevacizumab, P=0.02). The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor-positive and hormone-receptor-negative subgroups. The addition of bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand-foot syndrome, and mucositis. CONCLUSIONS: The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response, which was the primary end point of this study. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00408408.).

Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03.

PURPOSE: Although chemoradiotherapy plus resection is considered standard treatment for operable rectal carcinoma, the optimal time to administer this therapy is not clear. The NSABP R-03 (National Surgical Adjuvant Breast and Bowel Project R-03) trial compared neoadjuvant versus adjuvant chemoradiotherapy in the treatment of locally advanced rectal carcinoma. PATIENTS AND METHODS: Patients with clinical T3 or T4 or node-positive rectal cancer were randomly assigned to preoperative or postoperative chemoradiotherapy. Chemotherapy consisted of fluorouracil and leucovorin with 45 Gy in 25 fractions with a 5.40-Gy boost within the original margins of treatment. In the preoperative group, surgery was performed within 8 weeks after completion of radiotherapy. In the postoperative group, chemotherapy began after recovery from surgery but no later than 4 weeks after surgery. The primary end points were disease-free survival (DFS) and overall survival (OS). RESULTS: From August 1993 to June 1999, 267 patients were randomly assigned to NSABP R-03. The intended sample size was 900 patients. Excluding 11 ineligible and two eligible patients without follow-up data, the analysis used data on 123 patients randomly assigned to preoperative and 131 to postoperative chemoradiotherapy. Surviving patients were observed for a median of 8.4 years. The 5-year DFS for preoperative patients was 64.7% v 53.4% for postoperative patients (P = .011). The 5-year OS for preoperative patients was 74.5% v 65.6% for postoperative patients (P = .065). A complete pathologic response was achieved in 15% of preoperative patients. No preoperative patient with a complete pathologic response has had a recurrence. CONCLUSION: Preoperative chemoradiotherapy, compared with postoperative chemoradiotherapy, significantly improved DFS and showed a trend toward improved OS.

Evaluation of breast cancer care under Puerto Rico's Health Care Reform.

Puerto Rico has implemented Health Care Reform legislation that shifted medically indigent and underserved persons from direct care by public sector institutions to managed care arrangements through the private sector. Our aim is to assess how previously underserved women with breast cancer have fared during the first three years of the Reform. Medical claims data were obtained on breast cancer cases in San Juan who were either enrolled in the capitated Reform plan or in a commercial policy offered by the same insurer. A set of indicators reflecting initial therapy, use of key services, and cumulative utilization rates of various medical procedures were constructed. Statistical tests were conducted to assess whether these indicators differed between Reform- and commercially-insured patients. Failure to reject null hypotheses of indicator differences were then used to judge Reform progress. We found some differences, but they were neither pervasive nor unidirectional. On balance, we conclude that previously underserved women are being treated for breast cancer roughly on par with other patients. This conclusion, however, is preliminary and subject to important qualifications.