Personalising docetaxel and G-CSF schedules in cancer patients by a clinically validated computational model

Background:

This study was aimed to develop a new method for personalising chemotherapeutic and granulocyte colony-stimulating factor (G-CSF) combined schedules, and use it for suggesting efficacious chemotherapy with reduced neutropenia.

Methods:

Clinical data from 38 docetaxel (Doc)-treated metastatic breast cancer patients were employed for validating a new pharmacokinetic/pharmacodynamics model for Doc, combined with a mathematical model for granulopoiesis. An optimisation procedure was constructed and used for selecting improved treatment schedules.

Results:

The combined model accurately predicted observed nadir timing (r=0.99), grade 3 or 4 neutropenia (86% success) and neutrophil counts over time in individual patients (r=0.63), and showed robustness to CYP3A-induced variability in Doc clearance. For average patients, the predicted optimal support for the standard chemotherapy regimen, Doc 100 μg m⁻² tri-weekly, is G-CSF, 300 μg, Q1D × 3, starting day 7 post-Doc. This regimen largely moderates chemotherapy-induced neutrophil nadir and neutropenia duration. The more intensive Doc dose, 150 mg m⁻², is optimally supported by the slightly less cost-effective G-CSF 300 μg, Q1D × 4, 5 days post-Doc. The latter regimen is optimal for borderline patients (2000 neutrophils per μl) under Doc, 100–150 mg m⁻² tri-weekly.

Conclusions:

The new computational method can serve for tailoring efficacious cytotoxic and supportive treatments, minimising side effects to individual patients. Prospective clinical validation is warranted.     

Factors associated with successful mobilization of progenitor hematopoietic stem cells among patients with lymphoid malignancies

PurposeThis study's main aim was to assess the effect of 2 mobilization regimens (granulocyte colony-stimulating factor [G-CSF] and chemotherapy vs. G-CSF alone) on the yield of CD34⁺ cells in the apheresis components of patients with lymphoid malignancy. We also sought to identify possible predictors of CD34⁺ cell yield in the apheresis components.Patients and MethodsCD34⁺ cells were mobilized and harvested from 89 patients with non-Hodgkin lymphoma (n = 62) or Hodgkin disease (n = 27). Forty-one patients (46.1%) were mobilized with G-CSF, and 48 (53.9%) were mobilized with chemotherapy and G-CSF. Univariate and multivariate analyses were used to examine potential predictors of the CD34⁺ cell yield (collection of > 2.7 > 10⁶ cells/kg), such as the number of peripheral CD34⁺ cells, age, sex, diagnosis, disease stage, weight, bone marrow status at baseline, mononuclear cells, white blood cells, and platelet counts.ResultsThe median patient age was 41 years (range, 12-66 years), and the median patient weight was 72 kg (range, 44-123 kg). Mobilization of peripheral blood progenitor cells (PBPCs) was superior when using chemotherapy and G-CSF versus G-CSF alone (3.6 > 10⁶ cells/kg vs. 2.2 > 10⁶ cells/kg; P = .001). CD34⁺ cell counts and platelet counts in the peripheral blood significantly correlated with CD34⁺ yield (P < .01 and P = .009, respectively). The yield was also significantly affected by weight, diagnosis, mobilization regimen, and baseline bone marrow status (P = .021, P = .05, P = .002, and P = .043, respectively).ConclusionMany factors influence harvesting of PBPCs, including diagnosis, bone marrow status at baseline, patient weight, and the type of mobilization regimen. The number of CD34⁺ cells in the peripheral blood can be used to predict the timing of apheresis and optimize yield.     

急性白血病患者化疗后CD+34细胞数量变化及其意义

目的 探讨急性白血病(AL)患者化疗后CD+34细胞数量变化对粒细胞集落刺激因子(G-CSF)的应用和判断是否早期缓解的指导意义.方法 50例初发白血病患者化疗后于WBC最低点应用G-CSF,不同时间测定外周血WBC、中性粒细胞数(MNC)、Plt与CD+34细胞数量,并对它们的相关性进行研究.结果 化疗后极期CD+34细胞为(3.05±2.47)个/μl,与化疗前比较明显降低(P＜0.01),在恢复期显著增加,为(113.46±77.16)个/μl(P＜0.01).WBC、MNC、Plt数量变化与CD+34细胞数量呈显著正相关(r分别为0.970、0.837、0.850,P均＜0.01).当极期末WBC/CD+34＞400,能早期判断AL患者是否缓解,CD+34＜5/μl,可应用G-CSF,CD+34＞5/μl,停用G-CSF.结论 白血病患者化疗后监测CD+34细胞数量变化,对早期判断是否缓解和G-CSF的应用具有重要的指导意义.     

Phase II Trial of Neoadjuvant Docetaxel and CG1940/CG8711 Followed by Radical Prostatectomy in Patients With High‐Risk Clinically Localized Prostate Cancer

Background.

Prostate cancer (PC) is the most commonly diagnosed noncutaneous malignancy in American men. PC, which exhibits a slow growth rate and multiple potential target epitopes, is an ideal candidate for immunotherapy. GVAX for prostate cancer is a cellular immunotherapy, composed of PC-3 cells (CG1940) and LNCaP cells (CG8711). Each of the components is a prostate adenocarcinoma cell line that has been genetically modified to secrete granulocyte-macrophage colony-stimulating factor. Hypothesizing that GVAX for prostate cancer could be effective in a neoadjuvant setting in patients with locally advanced disease, we initiated a phase II trial of neoadjuvant docetaxel and GVAX. For the trial, the clinical effects of GVAX were assessed in patients undergoing radical prostatectomy (RP).

Methods.

Patients received docetaxel administered at a dose of 75 mg/m² every 3 weeks for 4 cycles. GVAX was administered 2–3 days after chemotherapy preoperatively for four courses of immunotherapy. The first dose of GVAX was a prime immunotherapy of 5×10⁸ cells. The subsequent boost immunotherapies consisted of 3×10⁸ cells. After RP, patients received an additional six courses of immunotherapy. Pathologic complete response, toxicity, and clinical response were assessed. The primary endpoint of the trial was a pathologic state of pT0, which is defined as no evidence of cancer in the prostate.

Results.

Six patients completed neoadjuvant docetaxel and GVAX therapy. No serious drug-related adverse events were observed. Median change in prostate-specific antigen (PSA) following neoadjuvant therapy was 1.47 ng/ml. One patient did not undergo RP due to the discovery of positive lymph nodes during exploration. Of the five patients completing RP, four had a downstaging of their Gleason score. Undetectable PSA was achieved in three patients at 2 months after RP and in two patients at 3 years after RP.

Conclusions.

Neoadjuvant docetaxel/GVAX is safe and well tolerated in patients with high-risk locally advanced PC. No evidence of increased intraoperative hemorrhage or increased length of hospital stay postoperatively was noted. These results justify further study of neoadjuvant immunotherapy.     

Outcomes of patients with advanced non-small cell lung cancer treated in a phase I clinic

Background.

The outcomes of patients with advanced non-small cell lung cancer (NSCLC) treated in phase I clinical trials have not been systematically analyzed.

Methods.

We reviewed the records of consecutive patients with advanced/metastatic NSCLC who were treated in the Phase I Clinical Trials Program at MD Anderson from August 2004 to May 2009.

Results.

Eighty-five patients (51 men, 34 women) treated on various phase I protocols were identified. The median age was 62 years (range, 30–85). The median number of previous systemic therapies was two (range, 0–5). A partial response was observed in eight patients (9.5%) and stable disease lasting >4 months was observed in 16 patients (19%). The median overall survival time was 10.6 months and median progression-free survival (PFS) time was 2.8 months, which was 0.6 months shorter than the median PFS of 3.4 months following prior second-line therapy. Factors predicting longer survival in the univariate analysis were an Eastern Cooperative Oncology Group performance status (PS) score of 0–1, no prior smoking, two or fewer organ systems involved, a hemoglobin level ≥12 g/dL, liver metastases, a history of thromboembolism, and a platelets count > 440 × 10⁹/L. In the multivariate analysis, a PS score of 0–1 and history negative for smoking predicted longer survival. Sixty-two (73%) patients had grade ≤2 toxicity, and there were no treatment-related deaths.

Conclusion.

Phase I clinical trials were well tolerated by selected patients with advanced NSCLC treated at M.D. Anderson. Nonsmokers and patients with a good PS survived longer. PFS in our population was shorter in smokers/ex-smokers and patients with a PS score of 2. It is reasonable to refer pretreated patients with a good PS to phase I clinical trials.     

High levels of circulating CD34+ cells at autologous stem cell collection are associated with favourable prognosis in multiple myeloma

Background:

High-dose chemotherapy with autologous stem cell transplantation is a cornerstone in the first-line treatment of multiple myeloma patients. However, only few factors have been identified affecting the outcome in such patients. We hypothesised that varying levels of mobilised CD34+ cells confer prognostic information in myeloma patients undergoing high-dose chemotherapy.

Methods:

We determined circulating CD34+ cells at the day of peripheral stem cell collection in 158 consecutive myeloma patients between January 2001 and August 2010. Patients were stratified into two groups (super vs normal mobilisers) with a cutoff of 100 000 peripheral CD34+ cells per ml.

Results:

We found that patients with more than 100 000 peripheral CD34+ cells per ml had a better overall survival (P=0.005) and a prolonged time to progression (P=0.0398) than patients with CD34+ cell counts below 100 000 CD34+ cells per ml. High levels of CD34+ cells were an independent marker for better overall survival and time to progression in a multivariate analysis that included disease stage, response at transplant, light-chain subtype, age, sex, and height.

Conclusion:

Our results suggest that high levels of mobilised peripheral CD34+ cells are associated with favourable outcome in myeloma patients undergoing autologous transplantation.     

Paclitaxel-ifosfamide-carboplatin combination chemotherapy regimen in advanced uterine and adnexal malignant mixed Mullerian tumours

Background:

Malignant mixed Mullerian tumours (MMMTs) of the uterus and adnexa represent aggressive gynaecologic malignancies with a high rate of loco-regional and distant failure. For that reason, we evaluated the paclitaxel–ifosfamide–carboplatin (TICb) combination in patients with advanced MMMTs.

Methods:

Female patients with advanced MMMTs, WHO-PS 0–2, no prior chemotherapy for systemic disease, unimpaired haemopoietic and organ function were eligible. Chemotherapy was administered at the following doses; paclitaxel: 175 mg m^–2 on day 1, ifosfamide: 2.0g m^–2 day^–1 – days 1 and 2, and carboplatin at a target area under the curve 5 on day 2, with prophylactic G-CSF from day 3.

Results:

Forty patients of a median age 61 (45–72) years, performance status 0–2 with advanced MMMTs of the uterus (n=34), tubes (n=2) or ovary (n=4) have entered and all were evaluable for response and toxicity. Responses were as follows: 27 out of 40 (67.5%) evaluable patients responded, with 11 complete responses and 16 partial responses, while 10 had stable disease, and 3 developed progressive disease. The median response duration was 9 months (range, 4–40 months), median progression-free survival 13 months (range, 3–42 months), while median overall survival 18 months (range, 4–48 months). Grade 3/4 neutropenia was recorded in 22 out of 40 (55%) – with 13 developing grade 4 (⩽7 days) and 7 out of 40 (17.5%) of patients at least one episode of febrile neutropenia.

Conclusion:

In this study, it appears that the TICb combination, yielded important activity with manageable toxicity in females with advanced MMMTs warranting further randomised comparison with current standard regimens.     

Levels of circulating CD45(dim)CD34(+)VEGFR2(+) progenitor cells correlate with outcome in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors

Background:

Predicting the efficacy of antiangiogenic therapy would be of clinical value in patients (pts) with metastatic renal cell carcinoma (mRCC). We tested the hypothesis that circulating endothelial cell (CEC), bone marrow-derived CD45^dimCD34⁺VEGFR2⁺ progenitor cell or plasma angiogenic factor levels are associated with clinical outcome in mRCC pts undergoing treatment with tyrosine kinase inhibitors (TKI).

Methods:

Fifty-five mRCC pts were prospectively monitored at baseline (day 1) and day 14 during treatment (46 pts received sunitinib and 9 pts received sorafenib). Circulating endothelial cells (CD45⁻CD31⁺CD146⁺7-amino-actinomycin (7AAD)⁻ cells) were measured in 1 ml whole blood using four-color flow cytometry (FCM). Circulating CD45^dimCD34⁺VEGFR2⁺7AAD⁻ progenitor cells were measured in progenitor-enriched fractions by four-color FCM. Plasma VEGF, sVEGFR2, SDF-1α and sVCAM-1 levels were determined by ELISA. Correlations between baseline CEC, CD45^dimCD34⁺VEGFR2⁺7AAD⁻ progenitor cells, plasma factors, as well as day 1–day 14 changes in CEC, CD45^dimCD34⁺VEGFR2⁺7AAD⁻ progenitor, plasma factor levels, and response to TKI, progression-free survival (PFS) and overall survival (OS) were examined.

Results:

No significant correlation between markers and response to TKI was observed. No association between baseline CEC, plasma VEGF, sVEGFR-2, SDF-1α, sVCAM-1 levels with PFS and OS was observed. However, baseline CD45^dimCD34⁺VEGFR2⁺7AAD⁻ progenitor cell levels were associated with PFS (P=0.01) and OS (P=0.006). Changes in this population and in SDF-1α levels between day 1 and day 14 were associated with PFS (P=0.03, P=0.002). Changes in VEGF and SDF-1α levels were associated with OS (P=0.02, P=0.007).

Conclusion:

Monitoring CD45^dimCD34⁺VEGFR2⁺ progenitor cells, plasma VEGF and SDF-1α levels could be of clinical interest in TKI-treated mRCC pts to predict outcome.     

Successful mobilization of peripheral blood stem cells with the DHAP regimen (dexamethasone, cytarabine, cisplatinum) plus granulocyte colony-stimulating factor in patients with relapsed Hodgkin's disease

High-dose chemotherapy followed by autologous stem cell transplantation can improve the outcome of relapsed and refractory Hodgkin's disease (HD) patients. The objective of the trial was to determine the mobilizing potential of the DHAP salvage regimen (dexamethasone, cytarabine, cisplatin) for the collection of peripheral blood stem cells (PBSC) in patients with relapsed HD. The target yield of harvesting CD34 + cells was ≥ 2 × 10⁶/kg in order to support the subsequent myeloablative chemotherapy. Most of the 105 patients included were intensively pre-treated with different combination chemotherapy regimens prior to mobilization. The use of DHAP followed by granulocyte colony-stimulating factor (G-CSF; 10 μg/kg) resulted in the successful collection of adequate numbers of PBSC in 97.1% of patients (102 of 105) with a median harvest of CD34 + cells of 13 × 10⁶/kg (range 2.6 - 85.1). More than 2.0 × 10⁶ CD34 + cells/kg were achieved in 65 of 103 (63%) patients after 1 apheresis, the maximum number of aphereses for all patients was 3. It was found that the optimal time of PBSC harvest was at days 13 - 16 after initiating the mobilization regimen.

These results demonstrate that the salvage chemotherapy regimen, such as DHAP combined with G-CSF, can be successfully used to mobilize PBSC in HD patients.     

Estrogen Receptor Expression and Docetaxel Efficacy in Patients with Metastatic Breast Cancer: A Pooled Analysis of Four Randomized Trials

Background.

Differences in the efficacy of various chemotherapies in patients with estrogen receptor (ER)⁺ metastatic breast cancer are not well understood. In the present study, we assessed the efficacy of docetaxel in patients with metastatic breast cancer according to ER expression.

Methods.

The efficacy of docetaxel in terms of the response rate and progression-free survival (PFS) time was analyzed according to ER expression in four randomized trials comparing a docetaxel-based regimen with a nontaxane regimen that included a total of 1,631 patients. The odds ratio for tumor response was estimated with logistic regression and a hazard ratio (HR) for PFS was estimated with Cox proportional hazards models.

Findings.

ER expression was assessable in 1,037 patients included in these trials (64%). ER was expressed in 601 tumors (58%). Docetaxel was associated with a similarly higher response rate in both patients with ER⁺ (odds ratio, 2.90; 95% confidence interval [CI], 1.72–4.87) and patients with ER⁻ (odds ratio, 2.55; 95% CI, 1.44–4.51) disease. The lower hazard for disease progression with docetaxel was also similar in ER⁺ (HR, 0.82; 95% CI, 0.67–1.00) and ER⁻ (HR, 0.86; 95% CI, 0.70–1.07) cancers. The effect of docetaxel was not different in ER⁺ and ER⁻ disease, in terms of both the response rate and PFS time (interaction test, p = .77 and p = .93).

Interpretation.

Docetaxel produces a higher response rate and lower risk for disease progression to a statistically similar extent in both patients with ER⁺ and patients with ER⁻ metastatic breast cancer.     

The insulin-like growth factor-I receptor inhibitor figitumumab (CP-751,871) in combination with docetaxel in patients with advanced solid tumours: results of a phase Ib dose-escalation, open-label study

Background:

This phase Ib trial assessed safety, tolerability, and maximum tolerated dose (MTD) of figitumumab (CP-751,871), a fully human monoclonal antibody targeting the insulin-like growth factor type 1 receptor (IGF-IR), in combination with docetaxel.

Methods:

Patients with advanced solid tumours were treated with escalating dose levels of figitumumab plus 75 mg m^–2 docetaxel every 21 days. Safety, efficacy, pharmacokinetics (PKs), and biomarker responses were evaluated.

Results:

In 46 patients, no dose-limiting toxicities were attributable to the treatment combination. Grade 3 and 4 toxicities included neutropaenia (n=28), febrile neutropaenia (n=11), fatigue (n=10), leukopaenia (n=7), diarrhoea (n=5), hyperglycaemia, lymphopaenia, cellulitis, DVT, and pain (all n=1). The MTD was not reached. Four partial responses were observed; 12 patients had disease stabilisation of ⩾6 months. Pharmacokinetic and biomarker analyses showed a dose-dependent increase in plasma exposure, and complete sIGF-IR downregulation at doses of ⩾3 mg kg^–1. Pharmacokinetics of docetaxel in combination was similar to when given alone. Out of 18 castration-resistant prostate cancer patients, 10 (56%) had ⩾5 circulating tumour cells (CTCs) per 7.5 ml of blood at baseline: 6 out of 10 (60%) had a decline from ⩾5 to <5 CTCs and 9 out of 10 (90%) had a ⩾30% decline in CTCs after therapy.

Conclusions:

Figitumumab and docetaxel in combination are well tolerated. Further evaluation is warranted.     

Combined effect of low-penetrant SNPs on breast cancer risk

Background:

Although many low-penetrant genetic risk factors for breast cancer have been discovered, knowledge about the effect of multiple risk alleles is limited, especially in women <50 years. We therefore investigated the association between multiple risk alleles and breast cancer risk as well as individual effects according to age-approximated pre- and post-menopausal status.

Methods:

Ten previously described breast cancer-associated single-nucleotide polymorphisms (SNPs) were analysed in a joint European biobank-based study comprising 3584 breast cancer cases and 5063 cancer-free controls. Genotyping was performed using MALDI-TOF mass spectrometry, and odds ratios were estimated using logistic regression.

Results:

Significant associations with breast cancer were confirmed for 7 of the 10 SNPs. Analysis of the joint effect of the original 10 as well as the statistically significant 7 SNPs (rs2981582, rs3803662, rs889312, rs13387042, rs13281615, rs3817198 and rs981782) found a highly significant trend for increasing breast cancer risk with increasing number of risk alleles (P-trend 5.6 × 10⁻²⁰ and 1.5 × 10⁻²⁵, respectively). Odds ratio for breast cancer of 1.84 (95% confidence interval (CI): 1.59–2.14; 10 SNPs) and 2.12 (95% CI: 1.80–2.50; 7 SNPs) was seen for the maximum vs the minimum number of risk alleles. Additionally, one of the examined SNPs (rs981782 in HCN1) had a protective effect that was significantly stronger in premenopausal women (P-value: 7.9 × 10⁻⁴).

Conclusion:

The strongly increasing risk seen when combining many low-penetrant risk alleles supports the polygenic inheritance model of breast cancer.     

外周血CD_(34)~+细胞检测对外周血干细胞采集结果及时机选择的意义

 目的　研究外周血CD+34 细胞数对采集结果的意义,并探索可用于临床指导外周干细胞采集时机选择的参考阈值。方法　2007年1月至2009年12月共57例次自体造血干细胞移植动员采集患者,以环磷酰胺（CTX）化疗+粒细胞集落刺激因子（G-CSF）（5～10 μg／kg）动员,COBE分离仪（Spectra Version 6）行外周血造血干细胞采集,应用流式细胞术监测外周血中CD+34 细胞绝对计数。结果　采集产品单个核细胞（MNC）中位数4.6×108／kg（0.3×108／kg～10.5×108／kg）,CD+34 细胞中位数2.4×106／kg（0.16×106／kg～34.9×106／kg）,外周血CD+34 细胞数是产品MNC和CD+34 细胞总量唯一相关指标,外周血白细胞（WBC）与采集产品MNC和CD+34 细胞数无关。进一步分析提示外周血CD+34 计数≥15／μl,单次采集效率提高,CD+34 细胞采集量达1×106／kg和2×106／kg比例为81 %和60 %,采集产品MNC和CD+34 总数明显提高。提示外周血CD+34 细胞数15／μl可作为启动采集。ROC分析发现外周血CD+34 细胞 25（26.5～28.6）／μl,单次采集足量CD+34 细胞概率最大。结论　外周血CD+34 细胞计数是外周血自体干细胞采集重要的相关指标,CD+34 细胞 15／μl可作为采集时机选择的阈值。     

Endo180 modulation by bisphosphonates and diagnostic accuracy in metastatic breast cancer

Background:

Endo180 (CD280; MRC2; uPARAP)-dependent collagen remodelling is dysregulated in primary tumours and bone metastasis. Here, we confirm the release and diagnostic accuracy of soluble Endo180 for diagnosing metastasis in breast cancer (BCa).

Methods:

Endo180 was quantified in BCa cell conditioned medium and plasma from BCa patients stratified according to disease status and bisphosphonate treatment (n=88). All P-values are from two-sided tests.

Results:

Endo180 is released by ectodomain shedding from the surface of MCF-7 and MDA-MB-231 BCa cell lines. Plasma Endo180 was significantly higher in recurrent/metastatic (1.71±0.87; n=59) vs early/localised (0.92±0.37; n=29) BCa (P<0.0001). True/false-positive rates for metastasis classification were: 85%/50% for the reference standard, CA 15-3 antigen (28 U ml⁻¹); ⩽97%/⩾36% for Endo180; and ⩽97%/⩾32% for CA 15-3 antigen+Endo180. Bisphosphonate treatment was associated with reduced Endo180 levels in BCa patients with bone metastasis (P=0.011; n=42). True/false-positive rates in bisphosphonate-naive patients (n=57) were: 68%/45% for CA 15-3 antigen; ⩽95%/⩾20% for Endo180; and ⩽92%/⩾21% for CA 15-3 antigen+Endo180.

Conclusion:

Endo180 is a potential marker modulated by bisphosphonates in metastatic BCa.     

Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor

Background:

Tumoural interstitial hypertension, possibly modulated by platelet-derived and vascular endothelial growth factor receptors (PDGFR and VEGFR), may mediate resistance to chemotherapy.

Methods:

Forty-eight patients with advanced solid tumours received oral PDGFR inhibitor CP-868,596 (60–100 mg twice daily (BID)) and docetaxel (75–100 mg m^–2), or CP-868,596 (60 mg BID), docetaxel (75 mg m^–2), and VEGFR inhibitor axitinib (5 mg BID).

Results:

The CP-868,596/docetaxel was escalated as above. The CP-868,596/docetaxel/axitinib was not dose escalated because of increased incidence of mucositis-like adverse events (AEs) with concurrent neutropenia relative to that expected for docetaxel. All tested regimens were tolerable, including 100 mg BID CP-868,596 (recommended phase II dose) plus 100 mg m^–2 docetaxel (maximum approved dose). Most treatment-emergent AEs were mild–moderate and reversible, commonly including nausea, diarrhoea, vomiting, constipation, fatigue, and anaemia (CP-868,596/docetaxel), and hypertension, lethargy, diarrhoea, and fatigue (CP-868,596/docetaxel/axitnib). Pharmacokinetics were unaffected by co-administration. Twenty-one patients achieved stable disease, including all seven evaluable on CP-868,596/docetaxel/axitinib. All nine CP-868,596/docetaxel/axitinib patients received therapy for a median of six (range, 3–16) cycles.

Conclusions:

The CP-868,596/docetaxel was well tolerated, but increased efficacy was not observed. Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs.     

Plerixafor is superior to conventional chemotherapy for first-line stem cell mobilisation,and is effective even in heavily pretreated patients

This study (PHANTASTIC) compares first-line plerixafor with granulocyte colony-stimulating factor (G-CSF) in 98 myeloma and lymphoma patients with 151 historic controls mobilised by conventional chemotherapy+G-CSF. Eleven patients developed mild transient symptoms possibly related to plerixafor. No serious adverse events were seen. Seventy (71%) plerixafor-mobilised patients achieved both ⩾4 × 10⁶ CD34⁺ cells/kg in ⩽2 aphereses and no neutropenia (<1.0 × 10⁹/l). This is significantly >48 (32%) of 151 historical chemotherapy+G-CSF-mobilised control patients achieving this end point (P<0.001). Ninety-six (98%) plerixafor-mobilised patients achieved ⩾2 × 10⁶ CD34⁺ cells/kg within one harvest round compared with 114 (75%) of controls (P=0.001). Engraftment times and 12-month outcome were comparable in both groups. Prior treatment was summarised by two scoring systems. Controls mobilising either >2.0 or >4.0 × 10⁶ CD34⁺ cells/kg have significantly lower scores than mobilisation failures (P=0.002), but this relationship was not seen for plerixafor-mobilised patients. Plerixafor is a more effective and less toxic mobilising agent than conventional chemotherapy (especially in heavily pretreated patients), with comparable subsequent outcome, and merits consideration as the first-line standard of care for stem cell mobilisation.     

The antiangiogenic agent ZD4190 prevents tumour outgrowth in a model of minimal residual carcinoma in deep tissues

Background:

Tumour cells may persist at the operative site after seemingly adequate surgery. Radiotherapy is often given in an attempt to prevent repopulation, but this modality cannot be relied upon to prevent locoregional recurrence. An alternative strategy is to take advantage of the requirement of tumour cells to develop an independent blood supply and block this process to prevent recurrence.

Methods:

In this study, we evaluate the effect of the angiogenesis inhibitor, ZD4190, using a rodent model of residual carcinoma in deep tissues, mimicking the clinical scenario where low numbers of malignant cells persist at the operative site.

Results:

The tumour burden that could be eliminated was dependent on the site where the cells were implanted. Immediate treatment with ZD4190 prevented outgrowth of up to 2.5 × 10⁵ cells in the rectus muscle and 1 × 10⁵ in the gastrocnemius, whereas control animals developed large tumours. When more than 2.5 × 10⁶ cells were implanted into the rectus or 1 × 10⁶ into the gastrocnemius and treatment was maintained for 3 weeks, the carcinomas that developed in ZD4190-treated animals showed a reduced microvessel density and increased necrosis when compared with the vehicle-treated controls, but an infiltrative growth pattern was common.

Conclusion:

These findings suggest that antiangiogenic agents have a role to play in preventing outgrowth of residual carcinoma and are likely to be most effective when the tumour burden is minimal.     

Granulocyte-colony stimulating factor decreases the extent of ovarian damage caused by cisplatin in an experimental rat model

Objective

To investigate whether granulocyte-colony stimulating factor (G-CSF) can decrease the extent of ovarian follicle loss caused by cisplatin treatment.

Methods

Twenty-one adult female Sprague-Dawley rats were used. Fourteen rats were administered 2 mg/kg/day cisplatin by intraperitoneal injection twice per week for five weeks (total of 20 mg/kg). Half of the rats (n=7) were treated with 1 mL/kg/day physiological saline, and the other half (n=7) were treated with 100 µg/kg/day G-CSF. The remaining rats (n=7, control group) received no therapy. The animals were then euthanized, and both ovaries were obtained from all animals, fixed in 10% formalin, and stored at 4℃ for paraffin sectioning. Blood samples were collected by cardiac puncture and stored at -30℃ for hormone assays.

Results

All follicle counts (primordial, primary, secondary, and tertiary) and serum anti-Müllerian hormone levels were significantly increased in the cisplatin+G-CSF group compared to the cisplatin+physiological saline group.

Conclusion

G-CSF was beneficial in decreasing the severity of follicle loss in an experimental rat model of cisplatin chemotherapy.     

Effect of Talactoferrin Alfa on the Immune System in Adults With Non‐Small Cell Lung Cancer

Background.

Talactoferrin alfa (talactoferrin), an agent with immune-stimulating properties, has demonstrated safety and preliminary efficacy in clinical trials.

Methods.

Ten patients (five males and five females) with stage IV non-small cell lung cancer (NSCLC) in a single-arm pilot study received orally administered talactoferrin (1.5 g, b.i.d.) for up to 24 weeks. Radiographic and immunologic studies were performed at baseline and at weeks 6 and 12. Circulating immune cells (natural killer cells [NKCs], CD4⁺, CD8⁺, and regulatory T cells) and systemic cytokine levels were measured to assess immune response.

Results.

Patients enrolled in the study had received a median of four prior chemotherapy regimens, and all patients were symptomatic. Talactoferrin was well tolerated, with no grade 3 or 4 toxicities. Median time to progression (TTP) and overall survival were 6 weeks and 14.5 weeks, respectively. The four patients with ≥9 weeks TTP had evidence of immunologic activity (three with increased NKC activity).

Conclusions.

The median of four previous chemotherapy regimens, with elevated levels of interleukin (IL) 6 and tumor necrosis factor-alfa in most patients, suggests these patients were poor candidates for immunotherapy.