Superior Disease-free Survival Research Articles

The Outcome of Transplant Strategies for Diffuse Large B Cell Lymphoma in the Last Decade. the EBMT Experience

AbstractAbstract 748 Introduction.The current standard of care for patients who fail first line therapy for diffuse large B cell lymphoma (DLBCL) comprises salvage chemotherapy and an autologous stem cell transplant (SCT). With the development of effective first line immunochemotherapy studies have suggested that the results of salvage autologous SCT have deteriorated and that alternative strategies are required. Myeloablative (MA) allogeneic SCT for DLBCL has been rarely used due largely to the toxicity of the procedure. Consequently reduced intensity conditioning (RIC) regimens prior to allogeneic SCT have been developed. Given these developments we have studied the outcome of both autologous and allogeneic SCT for DLBCL over the last decade. Methods.The EBMT database was searched for patients satisfying the following criteria;- diagnosis DLBCL, diagnosis between 2002 and 2010, age 18–65, first SCT procedure, chemosensitive relapse or primary refractory disease/refractory relapse. Cumulative incidence analysis of non-relapse mortality (NRM) and relapse rate (RR) and Kaplan-Meier estimates of disease free survival (DFS) and overall survival (OS) were calculated. Results.Table IPatient characteristics.Autologous SCTMA AlloSCTRIC AlloSCTNumber342111990Median age (range)48.6 (18-65)40.2 (18-65)48.8 (19-64)Male:female (%)59:4156:4461:39Year of transplant 2002-200640%37%39%Year of Transplant 2007-201160%63%61%Diagnosis to BMT < 1 year (%)1035 (30)55 (46)31 (34)Diagnosis to BMT >1 year (%)2386 (70)64 (54)59 (66)Sensitive Relapse, n (%)2652 (78)54 (45)61 (68)Primary Refractory and resistant relapse, n (%)769 (22)65 (55)29 (32)Performance Status Good12023136Performance Status Poor20087964 Outcomes for patients with chemosensitive relapse.The 1 and 4 year NRM rates were:- 3.2% and 6.4% for autoSCT, 11.7% and 20% for RIC alloSCT and 20% and 23.9% for MA alloSCT respectively (hazard ratio (HR) RIC allo 4.0, HR MA allo 4.5 both p<0.0001). Time from diagnosis to transplant >1 year was the only other factor associated with a higher NRM. The 4 year RR was 49% for autoSCT, 44.5% for RICalloSCT and 39.4% for MA alloSCT (ns). Only female sex was associated with a lower RR (HR 0.81 p=0.004). The 4 year DFS was 45.5%, 37% and 37% for autoSCT, RICalloSCT and MA alloSCT respectively. The DFS was worse for those patients undergoing a MA alloSCT (HR 1.6 p= 0.007). Female patients (HR 0.88 p=0.05) and those transplanted more than 1 year after diagnosis (HR 0.83 p=0.016) experienced a superior DFS. The 4 year OS was 55%, 57% and 42% for autologous SCT, RIC alloSCT and MA alloSCT respectively. The OS was worse for patients undergoing a MA alloSCT (HR 2.2, p=0.0002) and those over the age of 50 at transplant (HR 1.2, p=0.02). Outcomes for patients with chemosensitive relapse transplanted within 1 year of diagnosis.In this subgroup of patients 585, 20 and 17 received an autologous SCT, RICalloSCT and MA alloSCT respectively. The 4 year DFS was 44.6%, 51.7% and 50.4% and the 4 year OS was 54%, 75.8%, and 59.8% for autoSCT, RIC alloSCT and MA alloSCT respectively. The cohorts were too small to permit a multivariate analysis. Outcomes for patients with primary refractory and refractory relapse.The 1 and 4 year NRM rates were:- 6.6% and 7.3% for autoSCT, 15.4% and 15.4% for RIC alloSCT and 19.2% and 19.2% for MA alloSCT respectively. MA alloSCT (HR 2.9, p=0.004) and female sex (HR 1.7, p=0.04) were the only factors associated with a higher NRM. The 4 year RR was 73% for autoSCT, 81.5% for RICalloSCT and 61.3% for MA alloSCT (ns). Only female sex was associated with a lower RR (HR 0.77 p=0.08). The 4 year DFS was 20.7%, 3.9% and 20.7% for autoSCT, RICalloSCT and MA alloSCT respectively. The DFS was significantly better for female patients (HR 0.82 p= 0.04). The 4 year OS was 28%, 8.6% and 17.9% for autologous SCT, RIC alloSCT and MA alloSCT respectively. In multivariate analysis OS was significantly worse for patients undergoing a MA alloSCT (HR 1.5, p=0.02).The year of transplant and the use of immunochemotherapy as first line therapy had no impact on transplant outcomes. Conclusions.Over the last decade patients with chemosensitive relapse can achieve prolonged DFS following an autoSCT at a rate similar to that observed in the pre-Rituximab era. The NRM following an allogeneic SCT continues to be significant without being associated with lower relapse rates although the outcomes following a RICalloSCT are comparable to those following an autoSCT. Disclosures:No relevant conflicts of interest to declare.

NSAID analgesic ketorolac used perioperatively may suppress early breast cancer relapse: particular relevance to triple negative subgroup

To explain a bimodal relapse hazard among early stage breast cancer patients treated by mastectomy we postulated that relapses within 4 years of surgery resulted from something that happened at about the time of surgery to provoke sudden exits from dormant phases to active growth. Relapses at 10 months appeared to be surgery-induced angiogenesis of dormant avascular micrometastases. Another relapse mode with peak about 30 months corresponded to sudden growth from a single cell. Late relapses were not synchronized to surgery. This hypothesis could explain a wide variety of breast cancer observations. We have been looking for new data that might provide more insight concerning the various relapse modes. Retrospective data reported in June 2010 study of 327 consecutive patients compared various perioperative analgesics and anesthetics in one Belgian hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant therapy. Follow-up was average 27.3 months with range 13-44 months. Updated hazard as of September 2011 for this series is now presented. NSAID ketorolac, a common analgesic used in surgery, is associated with far superior disease-free survival in the first few years after surgery. The expected prominent early relapse events are all but absent. In the 9-18 month period, there is fivefold reduction in relapses. If this observation holds up to further scrutiny, it could mean that the simple use of this safe and effective anti-inflammatory agent at surgery might eliminate most early relapses. Transient systemic inflammation accompanying surgery could be part of the metastatic tumor seeding process and could have been effectively blocked by perioperative anti-inflammatory agents. In addition, antiangiogenic properties of NSAIDs could also play a role. Triple negative breast cancer may be the ideal group with which to test perioperative ketorolac to prevent early relapses.

Adjuvant Therapy for Gastric Cancer: Revisiting the Past to Clarify the Future

The initial publication in 2001 of the Intergroup trial 0116 (INT0116) was a watershed moment in the treatment of gastric and gastroesophageal junction adenocarcinoma, offering the first high-level evidence for improved survival from any adjuvant therapy in gastric cancer. Since that time, however, the evolution of adjuvant therapy for gastric cancer has been far from linear. No adjuvant regimen has definitively supplanted fluorouracil-based chemoradiotherapy, although alternative approaches have proliferated without direct comparison to the approach established by INT-0116. Five years after the initial publication of INT-0116, the British MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy Trial) trial demonstrated the superiority of epirubicin, cisplatin, and fluorouracil (ECF) administered before and after surgical resection when compared with surgery alone. Despite the omission of radiotherapy, perioperative ECF conferred a statistically and clinically significant reduction in death and cancer recurrence, establishing perioperative chemotherapy, without radiation therapy, as an alternative, reasonable standard in the adjuvant treatment of gastric cancer. More recently, clinical trials from Asia demonstrate the efficacy of adjuvant chemotherapy alone after curative resection for gastric cancer. Among 1,059 patients with resected gastric cancer, the Japanese ACTS-GC (Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer) study demonstrated a 33% improvement in overall survival (OS) for patients receiving 1 year of postoperative adjuvant S-1, an oral fluoropyrimidine not commercially available in the United States, when compared with surgery alone. Among 1,035 resected gastric cancer patients in South Korea, Japan, and Taiwan, the CLASSIC (Adjuvant Capecitabine and Oxaliplatin for Gastric Cancer After D2 Gastrectomy) study reported a 44% improvement in diseasefree survival (DFS) for patients randomly assigned to postoperative capecitabine and oxaliplatin (XELOX) when compared with observation. Of note, both ACTS-GC and CLASSIC limited enrollment to patients who had undergone a D2 lymph node dissection, commonplace in Asia, which contrasts to the limited D0 or D1 dissections more widespread in the United States. As such, the generalizability of both the ACTS-GC and CLASSIC trials to patients undergoing a D0 or D1 dissection is less certain. Moreover, the striking epidemiologic and prognostic differences in gastric cancer between Asian and Western populations further confound the application of these well-conducted Asian trials to Western patient populations. With a growing body of evidence supporting adjuvant approaches in resectable gastric cancer, it becomes critical to establish the relative contribution of individual components of adjuvant therapy. Two recently completed trials have directly compared distinct postoperative adjuvant regimens. Among 458 South Korean patients who had undergone a curative gastrectomy with D2 dissection, the ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer) trial compared postoperative capecitabine and cisplatin (XP) to chemoradiotherapy (XP plus radiotherapy with capecitabine). Although the addition of radiotherapy to postoperative chemotherapy did not significantly improve DFS among all enrolled subjects (P .09), patients with node-positive disease (87% of the study population) did experience a superior DFS (P .04). On the other end of the spectrum, the North American Cancer and Leukemia Group B 80101 trial examined whether the benefit of postoperative chemoradiotherapy with fluorouracil and leucovorin (as shown in INT-0116) could be improved by utilizing a more intensive systemic therapy (ECF) with chemoradiotherapy. Interim results, however, find no survival benefit when comparing postoperative ECF chemotherapy before and after chemoradiotherapy to fluorouracil and leucovorin before and after chemoradiotherapy. Into this maelstrom of clinical reports, the INT-0116 investigators offer another critical contribution, featured in this issue of Journal of Clinical Oncology. The investigators report an updated analysis of their findings, now with 10-year median follow-up. Eleven years after the initial publication, is there more that we can learn from INT-0116 today? And, with half a dozen key trials reported since that initial publication, can we improve our understanding of adjuvant therapy in gastric cancer by going back to square one? The report by Smalley et al updates OS and recurrence-free survival (RFS) for the INT-0116 trial. It is reassuring to find that these survival outcomes are largely unchanged, with significant benefits in both OS and RFS. This finding perhaps comes as no surprise, given that the median survival time in both arms had been well surpassed at the time of the original report. Nevertheless, this latest update highlights the durable benefit of postoperative fluorouracil-based chemoradiotherapy in patients with resected gastric and gastroesophageal junction adenocarcinoma. Longer follow-up to confirm the results of a previously reported landmark clinical trial has certain merit in medical science. Beyond supplying confirmatory updated results of the primary treatment hypothesis, completed clinical trials can represent exceptional, well-designed prospective cohorts with detailed clinical data and biospecimens to explore critical questions that arise in the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 19 JULY 1 2012

Adjuvant treatment of HER2-positive breast cancer: winning efforts continue to improve HER2-positive patient outcome long-term

Randomized adjuvant trials continue to show significant reductions in distant recurrence and death for early-stage women treated with adjuvant trastuzumab. BCIRG-006 showed superior disease-free and overall survival of two trastuzumab-containing regimens in comparison to a non-trastuzumab-containing regimen. The rates of disease-free and overall survival were not statistically different for the two trastuzumab-containing arms. Ongoing study is needed to identify markers of resistance to trastuzumab and incorporate newer agents in the adjuvant setting in order to further decrease rates of distant recurrence and death from HER2-positive breast cancer.

Infarct-like Necrosis

The response of colorectal adenocarcinoma liver metastases to perioperative chemotherapy can be assessed histologically in partial hepatectomy specimens. Necrosis in this scenario may represent a lack of treatment effect or a therapeutic response to chemotherapy. This study sought to validate the histologic classification of necrosis into 2 types: usual necrosis (UN) representing an absence of treatment effect, and infarct-like necrosis (ILN) representing a therapeutic response to chemotherapy. Tumor regression grade (TRG) is a previously described prognosticating method that estimates tumor replacement by fibrosis. We incorporated ILN into a modified TRG (mTRG) and compared its performance as a prognostic factor against TRG. A retrospective clinical and histologic review was undertaken of all partial hepatectomies performed for colorectal liver metastases at our center between 2004 and 2010. Clinicopathologic features were compared between the 2 types of necrosis, including survival stratified by TRG and mTRG. A total of 109 cases were reviewed, with 46 patients receiving perioperative chemotherapy. ILN was identified in 12 cases, and all of these cases were associated with perioperative chemotherapy. ILN was significantly associated with perioperative treatment with bevacizumab. In patients receiving perioperative chemotherapy, those with ILN had superior disease-free survival compared with those with UN (P=0.047). mTRG1 to 2 scores were associated with significantly better survival compared with mTRG3 to 5 scores. In contrast, use of TRG did not demonstrate a significant difference in disease-free and overall survival. ILN represents a form of treatment effect and should be distinguished from UN. A modified grading system that incorporates ILN may enhance the prognostic utility of TRG.

Long-term outcomes after transplantation of HLA-identical related G-CSF–mobilized peripheral blood mononuclear cells versus bone marrow

AbstractBetween 1996 and 1999, 172 patients (median age, 42 years) with hematologic malignancies were randomly assigned to receive either HLA-identical related bone marrow or G-CSF–mobilized peripheral blood mononuclear cells (G-PBMCs) after myeloablative conditioning. Early results showed that transplantation of G-PBMCs, compared with marrow, was associated with significantly superior 2-year disease-free survival (DFS) and overall survival. Ten-year follow-up showed a sustained DFS benefit associated with G-PBMCs (mortality or relapse hazard ratio, 0.64; 95% confidence interval, 0.4-1.0; P = .03), although the likelihood of overall survival was not significantly different between the 2 groups (mortality hazard ratio, 0.75; 95% confidence interval, 0.5-1.2; P = .20). The 10-year cumulative incidence of chronic GVHD and the duration of systemic immunosuppression were similar in the 2 groups. In summary, transplantation of HLA-identical related G-PBMCs, compared with marrow, was associated with superior short-term and long-term DFS, and there was no evidence that this benefit was outweighed by GVHD-related late mortality.

Definitive Radiation Therapy for Early Glottic Cancer: Experience of Two Fractionation Schedules

ObjectivesThe authors would report the results of definitive radiation therapy (RT) for early glottic cancer by two different radiation dose schedules.MethodsFrom February of 1995 till June of 2008, 157 patients with T1-2N0 glottic cancer were treated with curative RT at Samsung Medical Center. All patients had squamous cell carcinoma, and there were 89 patients (56.7%) with T1a, 36 (22.9%) with T1b, and 32 (20.4%) with T2. Two different radiation dose schedules were used: 70 Gy in 35 fractions to 64 patients (40.8%, group A); and 67.5 Gy in 30 fractions to 93 patients (59.2%, group B). The median treatment durations were 50 days (range, 44 to 59 days) and 44 days (range, 40 to 67 days) in the groups A and B, respectively.ResultsThe median follow-up durations were 85 and 45 months for the groups A and B. No severe late complication of RTOG grade 3 or higher was observed, and there was no difference in acute or chronic complication between the groups. Twenty-four patients experienced treatment failure: local recurrence only in 19 patients; regional recurrence only in one; combined local and regional recurrence in four; and systemic metastasis in none. The overall 5-year disease-free survival and disease-specific survival rates were 84.7% and 94.8%. The disease-free survival rate in the group B was better (78.3% vs. 90.8%, P=0.031). This difference was significant only in T1 stage (83.4% vs. 94.6%, P=0.025), but not in T2 (62.7% vs. 60.6%, P=0.965). Univariate analysis showed that the tumor extent, cord mobility, T-stage, and the dose schedule had significant influence on the disease-free survival, and multivariate analysis showed that only the tumor extent and the dose schedule were associated with the disease-free survival.ConclusionSuperior disease-free survival could be achieved by 2.25 Gy per fraction without increased toxicity over shorter RT duration, when compared with 2.0 Gy per fraction.

P2-01-06: NSAID Analgesic Ketorolac Used Perioperatively May Suppress Early Breast Cancer Relapse: Something for Nothing in Breast Cancer?

Abstract Background: Over a decade ago, we were confronted with data that showed an unexpected bimodal pattern of hazard of relapse among early stage breast cancer patients treated by mastectomy without any adjuvant systemic treatment. This pattern has now been identified in 20 independent databases from US, Europe and Asia. There is an early peak of relapses at 18 months, a nadir at 50 months and a broad second peak extending from 60 months to over 15 years. Fifty to eighty percent of relapses, the proportion increasing with primary tumor size, reside within the first peak. This pattern was not explainable by accepted theories. We proposed based on computer simulations that the broad second peak relapses result from steady stochastic progressions from single dormant malignant cells to avascular micrometastases and then on to growing deposits. To explain the first peak, we had to postulate that something happened at about the time of surgery to provoke sudden exits from dormant phases to active growth and then to detection. There was a particularly sharp early relapse mode within 10 months for premenopausal patients with positive nodes that appeared to be surgery-induced angiogenesis of dormant avascular micrometastases. We have been able to explain a wide variety of breast cancer observations with this hypothesis. These include high effectiveness of adjuvant chemotherapy only for premenopausal node positive women and why early detection works better for women age 50–59 than for women age 40–49. Methods and Materials: Forget et al reported data from a retrospective study of 327 consecutive patients comparing various perioperative analgesics and anesthetics in one Belgian hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant therapy. Follow-up is average 27.3 months with range 13–44 months. Results: NSAID ketorolac, a common analgesic used in surgery, produced far superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse peak is all but absent. These results are superior to any adjuvant therapy we have examined. Discussion: If this observation holds up to further scrutiny, it could mean that the simple use of this safe and effective anti-inflammatory agent at surgery might eliminate early relapses. Concerning a possible mechanism, since ketorolac is the only anti-inflammatory agent among the analgesics studied, our attention is drawn to inflammation. Might this imply that transient systemic inflammation accompanying surgery is part of the metastatic tumor seeding process? Inflammation can be a very rapidly occurring effect since bump and redness following a mosquito bite occur within seconds. It is well established that many cancer patients have circulating cancer cells. Data show a surge in circulating epidermal cells after primary breast cancer surgery but that intriguingly occurs days later. Blood speed in capillaries is 0.03cm/sec which would make leaky capillary venules a very efficient way for circulating cancer cells to enter tissue. From our simulations the few relapses in the ketorolac data look like the leading edge of the late broad peak — viewable for the first time. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-06.

Putting the Cardiovascular Safety of Aromatase Inhibitors in Patients with Early Breast Cancer into Perspective

In the adjuvant setting, the third-generation aromatase inhibitors (AIs) anastrozole, letrozole and exemestane are recommended at some point during treatment, either in the upfront, switch after tamoxifen or extended treatment setting after tamoxifen in postmenopausal patients with hormone receptor-positive early breast cancer. AIs have demonstrated superior disease-free survival and overall benefit-to-risk profiles compared with tamoxifen. Potential adverse events, including cardiovascular (CV) side effects, should be considered in the long-term management of patients undergoing treatment with AIs. AIs reduce estrogen levels by inhibiting the aromatase enzyme, thus reducing the levels of circulating estrogen. This further reduction in estrogen levels may potentially increase the risk of developing CV disease. This systematic review evaluated published clinical data for changes in plasma lipoproteins and ischaemic CV events during adjuvant therapy with AIs in patients with hormone receptor-positive early breast cancer. The electronic databases MEDLINE, EMBASE, Derwent Drug File and BIOSIS were searched to identify English-language articles published from January 1998 to 15 April 2011 that reported data on AIs and plasma lipoproteins and/or ischaemic CV events. Overall, available data did not show any definitive patterns or suggest an unfavourable effect of AIs on plasma lipoproteins from baseline to follow-up assessment in patients with hormone receptor-positive early breast cancer. Changes that occurred in plasma lipoproteins were observed soon after initiation of AI therapy and generally remained stable throughout the studies. Available data do not support a substantial risk of ischaemic CV events associated with adjuvant AI therapy; however, studies with longer follow-up are required to better characterize the CV profile of AIs.

Stem Cell Transplantation Can Provide Durable Disease Control in Blastic Plasmacytoid Dendritic Cell Neoplasia (BPDC): A Retrospective Study From the European Group for Blood and Marrow Transplantation (EBMT)

Abstract 3077Blastic plasmacytoid dendritic cell neoplasm (BPDC), formerly known as blastic NK cell lymphoma, is a rare hematopoietic malignancy preferentially involving the skin, bone marrow and lymph nodes. The overall prognosis of BPDC is dismal. Most patients show an initial response to acute leukemia-like chemotherapy, but relapses with subsequent drug resistance occur in virtually all patients resulting in a median overall survival of only 9–13 months. However, anecdotal long-term remissions have been reported in young patients who received early myeloablative allogeneic stem cell transplantation (alloSCT). We therefore performed a retrospective analysis of patients identified in the EBMT registry in order to evaluate the outcome of autologous stem cell transplantation (autoSCT) or alloSCT for BPDC. Eligible were all patients who had been registered with a diagnosis of BPDC or Blastic NK cell lymphoma and had received autologous stem cell transplantation (autoSCT) or alloSCT in 2000–2009. Centres were contacted to provide a written histopathology and immunophenotyping report and information about treatment and follow-up details. Patients who did not have a diagnostic score ≥ 2 as proposed by Garnache-Ottou et al. (BJH 2009) were excluded. RESULTS:Overall, 139 patients could be identified in the database who fulfilled the inclusion criteria (alloSCT 100, autoSCT 39). Of 74 patients for whom the requested additional information could be obtained, central review confirmed the diagnosis of BPDC in 39 patients (34 alloSCT, 5 autoSCT). The 34 patients who had undergone alloSCT had a median age of 41 years (range: 10–70 years), were transplanted from a related (n=11) or unrelated donor (n=23); received peripheral blood stem cells (n=9), bone marrow stem cells (n=19) or cord blood (n=6); and had been treated with a reduced intensity conditioning regimen (RIC, n=9) or myeloablative conditioning (MAC, n=25). Nineteen of 34 patients were transplanted in CR1. After a median follow up time of 28 months (range: 4–77+ months), 11 patients relapsed (median time to relapse: 8 months, range: 2–27 months) of whom 8 died due to disease progression. 9 patients died in the absence of relapse. No relapse occurred later than 27 months after transplant. Median disease free survival (DFS) was 15 months (range: 4–77+ months) and median overall survival (OS) was 22 months (range: 8–77+ months; Figure 1a). However, long-term remissions of up to 77 months after alloSCT could be observed. Patients allografted in CR1 tended to have a superior DFS (p=0.119) and OS (p=0.057; Figure 1b). MAC was associated with a better OS (p=0.001) which was attributable to the significantly higher non-relapse mortality (NRM) rate of patients after RIC (p=0.014), who had been significantly older (age RIC: 56 years, age MAC: 36 years, p=0.0014). The relapse rate was not different in patients after RIC and MAC, respectively. However, there was no survivor after RIC. Median age in the autoSCT group was 47 years (range: 14–62 years). Three of 5 patients were transplanted in CR1 of whom 1 patient relapsed after 8 months, 1 patient experienced treatment related mortality and 1 patient remained in CR for 28 months. The 2 remaining patients had more advanced disease at autoSCT and relapsed 4 and 8 months thereafter. [Display omitted] CONCLUSION:AlloSCT is effective in BPDC and might provide curative potential in this otherwise incurable disease, especially when performed in CR1. However, it remains to be shown by prospective studies if the potential benefit of alloSCT in BPDC is largely due to conditioning intensity, or if there is a relevant contribution of graft-versus-leukemia activity. Disclosures:Tilly:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses; Genentech: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Janssen Cilag: Speakers Bureau.

PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin–cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer—outcome on prognosis

BackgroundThe objective of this study was to compare the effect of dose-intensified neoadjuvant chemotherapy with that of standard epirubicin plus cyclophosphamide followed by paclitaxel in combination with or without darbepoetin on survival in primary breast cancer. Patients and methodsA total of 733 patients received either four cycles of neoadjuvant epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks followed by four cycles of paclitaxel 175 mg/m2 every 3 weeks (EC→T), or three cycles of epirubicin 150 mg/m2 every 2 weeks followed by three cycles of paclitaxel 225 mg/m2 every 2 weeks followed by three cycles of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (Edd→Tdd→CMF). The patients were randomly assigned to receive darbepoetin or none. The primary objective was to demonstrate a superior disease-free survival (DFS) of Edd→Tdd→CMF compared with EC→T. ResultsEstimated 3-year DFS was 75.8% with EC→T versus 78.8% with Edd→Tdd→CMF [hazard ratio (HR) 1.14; P = 0.37] and overall survival (OS) 88.4% versus 91.5% (HR 1.26; P = 0.237). Three-year DFS was 74.3% with darbepoetin versus 80.0% without (HR 1.31; P = 0.061) and OS 88.0% versus 91.8% (HR 1.33; P = 0.139). Patients with a pathologically documented complete response [pathological complete response (pCR)] had a significantly better DFS compared with those without achieving a pCR (estimated 3-year DFS: 89.2% versus 74.9%; HR 2.27; P = 0.001). ConclusionNeoadjuvant dose-intensified chemotherapy compared with standard chemotherapy did not improve DFS, whereas the addition of darbepoetin might have detrimental effects on DFS.

A Randomized Trial Comparing Postoperative Adjuvant Chemotherapy with Cisplatin and 5-Fluorouracil Versus Preoperative Chemotherapy for Localized Advanced Squamous Cell Carcinoma of the Thoracic Esophagus (JCOG9907)

Patients with esophageal carcinoma receiving postoperative chemotherapy showed superior disease-free survival than those receiving surgery alone in a Japan Clinical Oncology Group trial (JCOG9204). The purpose of this study was to evaluate optimal perioperative timing-that is, before or after surgery-for providing chemotherapy in patients with locally advanced esophageal squamous cell carcinoma. Eligible patients with clinical stage II or III, excluding T4, squamous cell carcinoma were randomized to undergo surgery followed (group 1) or preceded (group 2) by chemotherapy consisting of two courses of cisplatin plus 5-fluorouracil. The primary end point was progression-free survival. We randomized 330 patients, with 166 assigned to group 1 and 164 to group 2, between May 2000 and May 2006. The planned interim analysis was conducted after completion of patient accrual. Progression-free survival did not reach the stopping boundary, but overall survival in group 2 was superior to that of group 1 (P=0.01). Therefore, the Data and Safety Monitoring Committee recommended early publication. Updated analyses showed the 5-year overall survival to be 43% in group 1 and 55% in group 2 (hazard ratio 0.73, 95% confidence interval 0.54-0.99, P=0.04), where the median follow-up of censored patients was 61.6months. Concerning operative morbidity, renal dysfunction after surgery in group 2 was slightly higher than in group 1. Preoperative chemotherapy with cisplatin plus 5-fluorouracil can be regarded as standard treatment for patients with stage II/III squamous cell carcinoma.

Adjuvant Radiotherapy for Pediatric and Young Adult Nonrhabdomyosarcoma Soft-Tissue Sarcoma

To evaluate the prognostic factors, outcomes, and complications in patients aged ≤30 years with resectable nonrhabdomyosarcoma soft-tissue sarcoma treated at the University of Florida with radiotherapy (RT) during a 34-year period. A total of 95 pediatric or young adult patients with nonrhabdomyosarcoma soft-tissue sarcoma were treated with curative intent with surgery and RT at the University of Florida between 1973 and 2007. The most common histologic tumor subtypes were synovial sarcoma in 22 patients, malignant fibrous histiocytoma in 19, and malignant peripheral nerve sheath tumor in 11 patients. The mean age at RT was 22 years (range, 6-30). Of the 95 patients, 73 had high-grade tumors; 45 had undergone preoperative RT and 50 postoperative RT. The prognostic factors for survival, local recurrence, and distant recurrence were analyzed. The median follow-up was 7.2 years (range, 0.4-30.5). The actuarial 5-year local control rate was 88%. A microscopically negative margin was associated with superior local control. Although 83% of local recurrence cases initially developed in the absence of metastases, all patients with local failure ultimately died of their disease. The actuarial estimate of 5-year overall survival and disease-free survival was 65% and 63%, respectively. Of all the deaths, 92% were disease related. An early American Joint Committee on Cancer stage, tumor<8 cm, and the absence of neurovascular invasion were associated with superior disease-free survival. The National Cancer Institute Common Toxicity Criteria, version 3, Grade 3-4 treatment complication rate was 9%. No secondary malignancies were observed. In the present large single-institution study, we found positive margins and locally advanced features to be poor prognostic factors for both local progression and survival. The results from the present study have helped to characterize the therapeutic ratio of RT in pediatric and young adult sarcoma patients and have provided a basis for identifying high-risk patients for whom treatment intensification might be justified.

Clinical and pathological response rates of docetaxel-based neoadjuvant chemotherapy in locally advanced breast cancer and comparison with anthracycline-based chemotherapies: Eight-year experience from single centre

The administration of neoadjuvant chemotherapy (NACT) prior to local therapy is advantageous for women with locally advanced breast cancer (LABC), since it can render inoperable tumors resectable and can increase rates of breast conservative surgeries. We retrospectively analyzed LABC patients who received NACT from January 2000 to December 2007. Out of 3000 case records screened, 570 (19%) were LABC and 110/570 (19%) treatment-naïve patients started on NACT were analyzed. Ninety-one (37 docetaxel [D], 54 anthracycline [A]) patients were eligible for response and survival analysis. Pathological complete remission (pCR) was defined as no evidence of malignancy in both breast and axilla. Median age of the whole cohort was 45 years (range 25-68 years). Premenopausal were 42% and estrogen receptor + 49.5%. Most (90%) were T4 tumors and 70% were Stage IIIB. Median numbers of preoperative cycles were six and three in the D and A group respectively. Overall clinical response rates for breast primary were 74.3% and 53.7% (CR 28.6% vs. 16.7%, P=0.58) while for axilla ORR were 75.7% vs. 54.8% (51.4% vs. 40.4% CR, P=0.77) respectively for D and A. Corresponding pCR rates were 19% vs. 13% respectively. There was no significant difference in disease-free (three-year 56.84% vs. 61.16%, P=0.80) and overall survival (three-year 70% vs. 78.5%, P=0.86) between the two groups. Although pCR rates were higher with docetaxel-based NACT, it did not translate into superior disease-free survival / overall survival compared to anthracycline-based chemotherapies.

A Pilot Study of the Combination of Nilotinib and Hyper-CVAD for Philadelphia Chromosome Positive Acute Lymphocytic Leukemia and Lymphoid Blast Crisis Chronic Myelogenous Leukemia

AbstractAbstract 2144 Background:Nilotinib is a second generation bcr-abl tyrosine kinase inhibitor (TKI) that has at least 30 times the potency of Imatinib (IM). Nilotinib has been approved by the FDA for the treatment of adults with chronic myeloid leukemia (CML) in chronic phase (CP) in the frontline, and for CP or accelerated phase (AP) who are either resistant or intolerant to prior therapies, including IM. Philadelphia chromosome positive (Ph+) acute lymphocytic leukemia (ALL) and lymphoid blast crisis of CML (Ly-BC) is aggressive and rapidly fatal. Complete remissions rates are low and have short durability. Relapse is inevitable unless patients (pts) receive an allogeneic stem cell transplant (SCT). The use of TKIs against Ph+ ALL or Ly-BC has shown limited durability of response as single agents. The transient nature of response to TKI is because only some of the blasts are still sensitive to bcr-abl inhibition, while the rest of the clones are not and require the addition of chemotherapy. Hyper-CVAD combined with the first generation TKI, IM is one such chemotherapy regimen that has been used in the management of adults with Ph+ ALL or Ly-BC (Thomas D, et al. Blood, 2004). Despite achieving >90% complete remission (CR) during induction phase, some pts have resistant disease or relapse shortly after attaining remission. We hypothesized that combining nilotinib with hyper-CVAD would achieve greater rates of sustained CR which ultimately translate into lower relapse rates, superior disease free survival, long term survival, and potential cure post SCT. The goal of our pilot case series was to study the feasibility of combining the more potent TKI, nilotinib to hyper-CVAD in pts with Ph+ ALL or Ly-BC, so as to improve the efficacy. Methods:Our case series involves 5 pts at our institution diagnosed with either Ph+ ALL or Ly-BC treated with a combination of hyper-CVAD and nilotinib given orally 400mg twice daily (initiated the day after completion of chemotherapy until the start of next cycle). After completion of eight cycles of chemotherapy, pts received either SCT or maintenance POMP in combination with nilotinib. Supportive care included prophylactic antibiotics, granulocyte colony stimulating factor, and transfusions as needed. None of them had central nervous system (CNS) involvement, but received intrathecal prophylaxis. Clinical characteristics at baseline, safety assessments, and efficacy evaluations including morphologic, cytogenetic, and molecular responses were analyzed. Results:All 5 pts (p190 Ph+ ALL-4, p210 Ly-BC-1; all males; Hispanic-2, Caucasian-3) received the combination for a median of 5 months. The median age was 29 (range 22–72) and the median follow-up period was 14 months. The Ly-BC pt was treated upfront with IM during CP and achieved major molecular remission (MMR) for 39 months, however due to noncompliance, relapsed with progression. All 5 patients achieved complete remission (CR), 60% after the first course. All of them achieved complete cytogenetic remission (CCyR) while 4 achieved MMR. Of the 2 Ph+ ALL pts who completed eight cycles, 1 received SCT and is in MMR for 20 months, while the other pt remains in MMR on POMP-nilotinib maintenance for over 19 months. Another pt is in MMR for 5 months. Two patients relapsed and died: the Ly-BC pt who achieved CR (without MMR) for 3 weeks and another pt that was in CCyR and MMR for 11 months. Most common adverse events included pancytopenia, fever, and infections (with no treatment related life threatening events). Conclusions:Our pilot study is the first to demonstrate the feasibility of combining nilotinib with hyper-CVAD. The results thus far are encouraging and will be expanded into a larger investigator initiated phase II study that can potentially prevent the emergence of resistant clones and improve survival in patients with Ph+ ALL or Ly-BC.Table 1ParameterHyper-CVAD + NilotinibNo. treated5Performance, ECOGn (%)04 (80%)1 to 21 (20%)WBC count at diagnosisn (%)30 or higher2 (40%)Platelet count at diagnosisn (%)Lower than 503 (60%)Responsen (%)CR5 (100%)Resistant0 (0%)Death2 (40%)Courses to CRn (%)13 (60%)21 (20%)More than 21 (20%)Adverse Events (Grade)n (%)Pancytopenia (4)5 (100%)FUO (2)2 (40%)Bacteremia (3)2 (40%)PNA (3)1 (20%)Cellulitis (2)1 (20%)Transaminitis (2)2 (40%) Disclosures:Off Label Use: Pilot study of Nilotinib and hyper-CVAD in Ph+ ALL.

Carbonic anhydrase XII expression is associated with histologic grade of cervical cancer and superior radiotherapy outcome

BackgroundTo investigate whether expression of carbonic anhydrase XII (CA12) is associated with histologic grade of the tumors and radiotherapy outcomes of the patients with invasive cervical cancer.MethodsCA12 expression was examined by immunohistochemical stains in cervical cancer tissues from 183 radiotherapy patients. Histological grading was classified as well (WD), moderately (MD) or poorly differentiated (PD). Oligonucleotide microarray experiment was performed using seven cervical cancer samples to examine differentially expressed genes between WD and PD cervical cancers. The association between CA12 and histological grade was analyzed by chi-square test. CA12 and histological grades were analyzed individually and as combined CA12 and histologic grade categories for effects on survival outcome.ResultsImmunohistochemical expression of CA12 was highly associated with the histologic grade of cervical cancer. Lack of CA12 expression was associated with PD histology, with an odds ratio of 3.9 (P = 0.01). Microarray analysis showed a fourfold reduction in CA12 gene expression in PD tumors. CA12 expression was marginally associated with superior disease-free survival. Application of the new combined categories resulted in further discrimination of the prognosis of patients with moderate and poorly differentiated tumor grade.ConclusionsOur study indicates that CA12 may be used as a novel prognostic marker in combination with histologic grade of the tumors.

Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia

AbstractKiller-cell immunoglobulin-like receptor (KIR) genes form a diverse, immunogenetic system. Group A and B KIR haplotypes have distinctive centromeric (Cen) and telomeric (Tel) gene-content motifs. Aiming to develop a donor selection strategy to improve transplant outcome, we compared the contribution of these motifs to the clinical benefit conferred by B haplotype donors. We KIR genotyped donors from 1409 unrelated transplants for acute myelogenous leukemia (AML; n = 1086) and acute lymphoblastic leukemia (ALL; n = 323). Donor KIR genotype influenced transplantation outcome for AML but not ALL. Compared with A haplotype motifs, centromeric and telomeric B motifs both contributed to relapse protection and improved survival, but Cen-B homozygosity had the strongest independent effect. With Cen-B/B homozygous donors the cumulative incidence of relapse was 15.4% compared with 36.5% for Cen-A/A donors (relative risk of relapse 0.34; 95% confidence interval 0.2-0.57; P < .001). Overall, significantly reduced relapse was achieved with donors having 2 or more B gene-content motifs (relative risk 0.64; 95% confidence interval 0.48-0.86; P = .003) for both HLA-matched and mismatched transplants. KIR genotyping of several best HLA-matched potential unrelated donors should substantially increase the frequency of transplants by using grafts with favorable KIR gene content. Adopting this practice could result in superior disease-free survival for patients with AML.

Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: pathologic response correlates with five-year overall survival

We have previously demonstrated high pathologic response rates after neoadjuvant concurrent chemoradiation in patients with locally advanced breast cancer (LABC). We now report disease-free survival (DFS) and overall survival (OS) in the context of pathologic response. 105 LABC patients (White 46%, Non-White 54%) were treated with paclitaxel (30 mg/m² intravenously twice a week) for 10-12 weeks. Daily radiotherapy was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2-7 of paclitaxel treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction. Pathological complete response (pCR) was defined as the absence of invasive cancer in breast and lymph nodes and pathological partial response (pPR) as the persistence of <10 microscopic foci of invasive carcinoma in breast or lymph nodes. Pathologic response (pCR and pPR) after neoadjuvant chemoradiation was achieved in 36/105 patients (34%) and was associated with significantly better DFS and OS. Pathological responders had a lower risk of recurrence or death (HR = 0.35, P = 0.01) and a longer OS (HR = 4.27, P = 0.01) compared with non-responders. Median DFS and OS were 57 and 84 months for non-responders, respectively, and have not yet been reached for responders. Importantly, pathologic response was achieved in 54% of patients with HR negative tumors (26/48). In conclusion, pathologic response to concurrent paclitaxel-radiation translated into superior DFS and OS. Half of the patients with HR negative tumors achieved a pathologic response.

Allogeneic hematopoietic cell transplantation outcomes for children with B-precursor acute lymphoblastic leukemia and early or late BM relapse

Large registry studies have shown superior disease-free survival (DFS) with matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT) over chemotherapy alone for patients with B-precursor acute lymphoblastic leukemia (ALL) and a late BM relapse. As most of these patients will not have an MSD, the decision to pursue an unrelated allo-HCT in second remission (CR2) or await a future relapse and perform HCT in third remission (CR3) continues to be debated. Between 1990 and 2006, 41 children with relapsed B-precursor ALL received a myeloablative allo-HCT at the University of Minnesota. Graft sources consisted of matched related donor (n=11), matched unrelated donor (n=9), and unrelated umbilical cord blood (n=21). Before allo-HCT, 15 patients had an early relapse (<36 months from diagnosis) and 26 had an initial late relapse (36 months from diagnosis). In all, 30 patients (73%) were in CR2 and 11 were in CR3 (27%) at time of allo-HCT. Five year OS/DFS were similar for patients with an early or late marrow relapse, but there was inferior DFS among late-relapse patients transplanted in CR3 compared with CR2 (30% vs 75%, P=0.04). These results suggest that allo-HCT should be pursued in children after a first marrow relapse, rather than waiting for subsequent recurrence.

Molecular predictors of efficacy of adjuvant weekly paclitaxel in early breast cancer

Treatment with fluororacil, epirubicin, and cyclophosphamide followed by weekly paclitaxel (FEC-P) yielded superior disease-free survival than FEC in the adjuvant breast cancer trial GEICAM 9906. We evaluate molecular subtypes predictive of prognosis and paclitaxel response in this trial. Two molecular subtype classifications based on conventional immunohistochemical and fluorescent in situ hybridization determinations were used: #1: Four groups segregated according to the combination of hormone receptor (HR) and HER2 status; #2: Intrinsic subtype classification (Triple Negative (TN), HER2, Luminal B and Luminal A). Both subtype classifications yielded prognostic and predictive information. HR +/HER2- patients (and Luminal A patients) had a significantly better outcome than the other subgroups of patients. The superiority of FEC-P over FEC was clearly more marked in HR-/HER2- patients (TN patients), particularly in the subset with basal phenotype (TN and either EGFR+ or cytokeratins 5/6+). The Luminal A subtype also achieved a significant benefit with FEC-P. The molecular-defined subgroup of TN was clearly predictive of better response to treatment with FEC-P. Luminal A patients had the best prognosis and also have a better outcome with weekly paclitaxel.