Significant Improvement In Disease-free Survival Research Articles

Outcomes of nasopharyngeal carcinoma screening for high risk family members in Hong Kong

We undertook a large retrospective study to evaluate the impact of screening family members of NPC patients with Epstein Barr Virus (EBV) serology. 1,199 asymptomatic family members of NPC patients were entered into the annual screening program with EBV serology and nasopharyngoscopy between 1994 and 2005. Eighteen participants of our screening program developed NPC; 17 of them were treated in our institute, of whom 16 were detected in screening. The sensitivity and specificity of EBV serology were 83.3 and 87.0%, respectively, and for the program they were 88.9 and 87.0%, respectively. Stage distributions and survival outcomes of the 17 cases were compared with that of 1,185 consecutive symptomatic patients diagnosed in the same period through general referral. It was found that the screening program resulted in early detection of cancer, with 59% presenting at early stage (stage I: 41%, stage II: 18%) compared to 24% (stage I: < 1%, stage II: 23%) of symptomatic cancers (P < 0.001), and a significant improvement in disease-free survival (P = 0.04). The cancer specific survival and overall survival rate at 5-year are also higher (92 vs. 77% and 92 vs. 70%, respectively), though they fail to reach statistical significance. In conclusion, screening asymptomatic family members of NPC patients annually leads to earlier detection of NPC and clinically valuable survival advantage among these family members. A larger sample size is needed to confirm its full potential in survival benefit.

Long-Term Clinical Outcomes Following En Bloc Resections for Sacral Chordomas and Chondrosarcomas

Retrospective study of 20 consecutive patients who underwent en bloc tumor excision of sacral chordomas and chondrosarcomas. To evaluate the functional and oncological outcomes following en bloc tumor excision for sacral chordomas and chondrosarcomas. Chordomas and chondrosarcomas are 2 of the most common malignant primary tumors of the sacrum in adults. To date, few large clinical series with en bloc resection of these tumors exist. An institutional primary spine tumor surgical database was retrospective reviewed. Twenty consecutive patients with sacral chordomas and chondrosarcomas who underwent primary en bloc tumor excisions from 2002 to 2007 were included in the study. Surgical margin, perioperative complications, and postoperative functional status in these patients were analyzed. Disease-free survival following en bloc tumor excision was determined using the Kaplan-Meier method. The study cohort included 8 males and 12 females with an average age of 53.5 years and a man follow-up of 47.8 months. Wide or marginal en bloc resection was achieved in 14 patients. In 6 other patients, tumor was identified at the surgical margins, and they were considered to have contaminated/intralesional resections. The 30-day perioperative morbidities in this series included 1 death from pulmonary embolism and 9 wound complications. Forty percent of the patients had normal bladder and bowel functions after surgery, while 60% of the patients had partial or complete loss of bladder and bowel functions. All but 2 patients in this group remained ambulatory after the surgery. The mean disease-free survival for patients with wide or marginal en bloc tumor excisions was 51 months, but the mean disease-free survival was only 17.5 months for patients who had contaminated/intralesional resections. Wide or marginal en bloc excision of sacral chordoma and chondrosarcoma is associated with significant improvement in disease-free survival with acceptable perioperative morbidity rate.

Randomized Phase III Trial Comparing Biweekly Infusional Fluorouracil/Leucovorin Alone or With Irinotecan in the Adjuvant Treatment of Stage III Colon Cancer: PETACC-3

PURPOSE The primary objective of this randomized, multicenter, phase III trial was to investigate whether the addition of irinotecan to the de Gramont infusional fluorouracil (FU)/leucovorin (LV) adjuvant regimen (LV5FU2) would improve disease-free survival (DFS) in patients with stage III colon cancer. PATIENTS AND METHODS After curatively intentioned surgery, patients with stage II and III colon cancer were randomly allocated surgery to receive LV5FU2 (LV 200 mg/m(2) as a 2-hour infusion, followed by FU; as a 400 mg/m(2) bolus and then a 600 mg/m(2) continuous infusion over 22 hours, days 1 and 2, every 2 weeks for 12 cycles: de Gramont regimen) with or without irinotecan (180 mg/m(2) as a 30- to 90-minute infusion, day 1, every 2 weeks). In total, 260 (7.9%) of 3,278 patients received an alternative high-dose infusional FU/LV regimen (Arbeitsgemeinschaft Internische Onkologie regimen) with or without irinotecan. Results The principal efficacy analysis was based on 2,094 treated patients with stage III disease, randomly allocated in the LV5FU2 strata. After a median follow-up of 66.3 months, the 5-year DFS rate was 56.7% with irinotecan/LV5FU2 and 54.3% with LV5FU2 alone (primary end point: log-rank P = .106). Combining irinotecan with LV5FU2 did not significantly improve overall survival in this patient group compared with LV5FU2 alone (5-year rate 73.6% v 71.3%, respectively; log-rank P = .094). The addition of irinotecan to LV5FU2 was associated with an increased incidence of grade 3 to 4 GI events and neutropenia. CONCLUSION Irinotecan added to LV5FU2 as adjuvant therapy did not confer a statistically significant improvement in DFS or overall survival in patients with stage III colon cancer compared with LV5FU2 alone.

Topoisomerase IIα Amplification and Anthracycline-Based Chemotherapy: The Jury Is Still Out

Topoisomerase IIα Amplification and Anthracycline-Based Chemotherapy: The Jury Is Still Out

Cure rate in early colorectal cancer estimated from disease-free survival curves from phase III comparative clinical trials: Necessity of long follow-up

e15006 Background: The traditional end point for adjuvant clinical trials is overall survival (OS). Short-term disease-free survival (DFS) has been accepted as a surrogate of 5-year OS in colorectal cancer trials. Nevertheless, recent adjuvant trials have not shown a consistent improvement in OS despite a significant improvement in DFS. Two reasons may explain this effect: 1) a delay in relapse produced by treatment, not affecting the cure rate, or 2) more effective treatments in relapsing patients which delay death, hiding a real difference in cure rates. The aim of this project is to study the relationship between DFS and OS in trials of early colorectal cancer. Methods: Phase III comparative trials in colorectal cancer were searched in databases and cancer meetings. Trials were split to build and validate the model. United States 2000 population life table data were obtained from Berkeley Mortality Database. Survival curves were modelled according to a cured fraction following a Weibull distribution and a relapsing fraction following a binomial distribution. DFS was modelled as time to a single event and OS was modelled as time to two events. Cured fraction was estimated and odds ratio (OR) with 95% confidence interval was calculated for experimental arms. Time to achieve a plateau in DFS was estimated as the curve point with a risk of relapse below 1%. Regression analysis between DFS and OS was performed for different intervals of follow up. Results: Thirty six study arms reporting DFS were analyzed to build the model. The model is consistent with an annual event rate of 0.33. DFS curves with this event rate predict a mean cure rate of 0.58 (range: 0.11–0.73). Estimated time to achieve a plateau in DFS is 9.3 years (range: 8.3–11.2 years). Significance of OR is coherent with hazard ratio reported in the studies. Trials finished after 1999 show more OS related to DFS. Regression analysis between DFS and OS show changing parameters at different intervals of follow up and some non-linearities. Trial validation, and analysis with trials reporting relapse free survival will be presented. Conclusions: Follow up of up to 10 years in colon adjuvant trials appears to be appropriate to reliably detect benefit in OS instead of a delay effect on relapse. No significant financial relationships to disclose.

Safety and effectiveness of dose dense neoadjuvant chemotherapy in patients with stage II/III breast cancer

e11566 Background: NSABP B-18 randomized women with operable breast cancer to receive chemotherapy (AC) either pre- or postoperatively; in the study there was no significant difference in disease free survival (DFS) or overall survival (OS) among patients in either group. Pathologic complete response rate (pCR) was directly proportional to DFS and OS. Dose dense adjuvant chemotherapy (ATC) has shown a statistically significant improvement in DFS and OS. Methods: We performed a single institution review of pts enrolled in a neoadjuvant trial and who received dose dense neoadjuvant chemotherapy (doxorubicin 60 mg/m2 IV Q2wks x4, paclitaxel 175 mg/m2 IV Q2wks x4, and cyclophosphamide 600 mg/m2 IV Q2wks x4) to assess response rates, safety, and DFS. Women with newly diagnosed breast cancer, T ≥ 3cm, any N, M0 were enrolled. Results: Since 02/2003, 43 pts were enrolled (mean age 47.6, range 28–64) and received dose dense chemotherapy. 41.4% of the pts were triple negative and 14.6% were Her2+ by FISH or IHC. The median follow-up is 49 months (range 8–69). Two patients dropped out without finishing therapy. Forty one pts completed dose dense chemotherapy and proceeded to surgery. 17 pts (41.4%) achieved a pCR in the breast and of those 14 pts were also negative in the axillary lymph nodes (34.1% pCR in the breast and lymph nodes). 10 of the 17 pts with pCR in the breast (8 out of the 14 pts with pCR in breast and axillary lymph nodes) were triple negative. 18 pts (43.9%) achieved PR, 3 pts (7.31%) had SD and 3 pts (7.31%) had PD. Up to November 2008, 7 pts who did not have a pCR have relapsed (4 triple negative, 1 Her2+, 1 ER/PR positive and 1 ER negative, PR positive) with a relapsed free survival rate of 85%. Hematologic toxicity consisted of grade 3 anemia in 2 patients with no grade 4 anemia, no G4 thrombocytopenia and febrile neutropenia in 2 pts. Non-hematologic grade 3 or 4 toxicity consisted of mediport thrombosis in 2 pts, hyperglycemia in 2 pts, syncope in 1 pt, neuropathy in 1 pt, and varicella zoster in 1 pt. Conclusions: Our results show that dose dense neoadjuvant chemotherapy achieves a pCR (breast + node) in about 1/3 of patients (34%) with tolerable toxicity; although the number of patients is limited, our data suggest that triple negative breast cancer seems to be the most sensitive tumor to this regimen. No significant financial relationships to disclose.

The evolving role of zoledronic acid in early breast cancer.

Most women with early breast cancer (BC) have an excellent prognosis and will remain disease-free for many years after treatment. However, bone-specific side effects of cancer therapies can have a negative effect on patients' long-term bone health. The accelerated bone loss associated with BC therapies, especially endocrine therapy, can put women at risk for osteoporosis and fractures later in life. Recent treatment guidelines have now begun to address the need for bone-preserving measures to be included in adjuvant therapy regimens. Bisphosphonates have long been used to treat osteoporosis, as well as bone metastases in patients with advanced cancers. Furthermore, in the adjuvant BC setting, the intravenous bisphosphonate zoledronic acid has emerged to play an important role. Several large, randomized phase III trials involving a total of approximately 4,000 premenopausal and postmenopausal women with early BC demonstrated the bone-protective effects of adjuvant zoledronic acid (4 mg every 6 months). Additionally, these same trials also showed significant improvement in disease-free survival for patients receiving adjuvant endocrine therapy plus zoledronic acid that was over and above the benefit achieved with endocrine therapy alone. The results of these zoledronic acid trials will be reviewed herein, and evidence supporting the antitumor effects of adjuvant zoledronic acid will be discussed.

Up-Front Use of Aromatase Inhibitors As Adjuvant Therapy for Breast Cancer: The Emperor Has No Clothes

Up-Front Use of Aromatase Inhibitors As Adjuvant Therapy for Breast Cancer: The Emperor Has No Clothes

Understanding the BIG results: Insights from the BIG 1–98 trial analyses

Third-generation aromatase inhibitors (AIs), including letrozole, are now standard therapy for initial adjuvant endocrine treatment of postmenopausal women with early breast cancer. The International Breast Cancer Study Group's Breast International Group (BIG) 1-98 trial is examining efficacy and safety of letrozole or tamoxifen, whether used upfront or sequentially, for postmenopausal with hormone receptor-positive breast cancer. Women in the BIG 1-98 trial were randomized to either 5 years' monotherapy with tamoxifen or letrozole (trial arms A and B, respectively), or to 5 years' sequential therapy with 2 years of tamoxifen followed by 3 years of letrozole, or 2 years of letrozole followed by 3 years of tamoxifen (arms C and D, respectively). Results of the primary core analysis (PCA) of BIG 1-98, at a median follow-up of 25.8 months, showed a significant improvement in disease-free survival for patients treated with initial adjuvant letrozole relative to those on tamoxifen (P=0.003). Of interest, there was an important reduction in distant metastases, the most common and ultimately fatal type of early recurrence, for patients allocated to initial letrozole compared with initial tamoxifen. Since the PCA, there have been further analyses of BIG 1-98 with variations in the cohorts analyzed and follow-up period. The first and largest central pathology review in an adjuvant AI trial to date was also performed in the BIG 1-98 trial. In light of the impending sequence analysis, expected in late 2008, the goal of this article is to describe and summarize the breadth of information learned to date and highlight the key findings regarding the efficacy and safety of letrozole in the initial adjuvant setting.

Effect of Molecular Disease Subsets on Disease-Free Survival in Randomized Adjuvant Chemotherapy Trials for Estrogen Receptor–Positive Breast Cancer

The majority of estrogen receptor (ER)-positive cancers are sensitive to endocrine therapy and may not derive much further benefit from chemotherapy, but a subset are potentially chemotherapy sensitive. Molecular diagnostic tests allow the identification of these various subsets with some accuracy. The goal of the current analysis was to examine how the proportion of cases in the various risk (recurrence score [RS]) categories of a commercially available multigene assay influences the power of randomized trials to show benefit from adjuvant chemotherapy. We modeled 10-year disease-free survival (DFS) for hypothetical, two-arm clinical trials that randomly assigned patients with ER-positive breast cancer to endocrine therapy alone or endocrine therapy plus chemotherapy. We varied the proportion of patients in low, intermediate, and high RS categories and used DFS estimates for each risk group based on results from the Southwest Oncology Group 8814 study. The probability of observing significant improvement in DFS as a result of chemotherapy decreases as the proportion of patients in the low RS category increases. For example, if a trial is designed with 80% power and the actual proportion of low RS patients accrued to the study increases from 40% to 60%, the power drops to 63%. Variable accrual of low RS patients into different randomized adjuvant chemotherapy trials may partly explain contradictory results in the literature. Studies can be underpowered to detect improvement with chemotherapy as a result of inclusion of too many patients with low RS. Future adjuvant studies for ER-positive breast cancer will need to consider stratifying patients by molecular subtype.

Aromatase Inhibitors: A New Reality for the Adjuvant Endocrine Treatment of Early-Stage Breast Cancer in Postmenopausal Women

Tamoxifen, a selective estrogen receptor modulator (SERM), has been used for many decades as the "gold standard" adjuvant treatment for patients with hormone-receptor-positive early breast cancer. This drug, when administered for 5 years, reduces the risk for recurrence, contralateral breast cancer (BC) and death. The optimal duration of tamoxifen in the adjuvant setting has not been established yet, but it has been demonstrated that 5 years are better than shorter treatment while it is still unclear if a prolongation of the treatment for more than 5 years is worthwhile. In the last few years, third generation aromatase inhibitors (AIs), either steroidal (exemestane) or non-steroidal (anastrozole, letrozole), have shown to be an effective alternative to tamoxifen in postmenopausal patients with BC regardless of its stage. These agents act by blocking the aromatase enzyme which converts androgens into estrogens. The goal of this article was to review the results of recent randomized trials comparing AIs to tamoxifen in postmenopausal women in the adjuvant setting. Two strategies have been utilized: a direct upfront comparison in which both tamoxifen and AIs were given for 5 years or an early switch in which AIs were administered after 2-3 years of tamoxifen for 3-2 years or vice versa. Both strategies have shown a superiority of AIs over tamoxifen and a different safety profile but, the optimal treatment modality has yet to be defined. Moreover, in an attempt to further reduce patients' risk of recurrence after the administration of tamoxifen for 5 years, three trials have evaluated the role of prolonging the adjuvant treatment with AIs for 5 more years in comparison to placebo (late switch). A significant improvement of disease-free survival and of overall survival in the subgroup of node-positive patients, at least in one trial, has been observed with AIs. Despite these important results several unanswered questions remain and the results of ongoing trials will hopefully clarify some of them.

Multicenter, randomized phase III study of adjuvant chemotherapy for high-risk, node-negative breast cancer comparing tac with fac: 5-year efficacy analysis of the GEICAM 9805 trial

542 Background: Adjuvant docetaxel improves disease-free survival (DFS) and overall survival (OS) in node-positive breast cancer (BC) patients (pts). However, most BC pts at diagnosis are node-negative, and the role of taxanes in such pts is not established. Methods: Pts aged 18–70, with T1-T3, N0, M0 operable BC and at least one high-risk St Gallen 1998 criterion (grade II/III, size >2 cm, age <35 years, hormone-receptor [HR] negative) were eligible. Pts were stratified by institution and menopausal status and randomized to either TAC (docetaxel 75 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m²) or FAC (fluorouracil 500 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m²) every 3 weeks for 6 cycles. Radiotherapy was mandatory after conservative surgery and recommended for pts with tumors > 5 cm. Tamoxifen was given for 5 years to all pts with HR-positive tumors. The primary endpoint was DFS defined as BC recurrence, second primary malignancy including contralateral BC, or death from any cause, whichever occurred first. Primary analysis is planned with 5-yr minimum follow-up (f/u). Results: Between July 1999 and December 2001, 1,059 pts were randomized (TAC 539, FAC 520) with 1,047 (98.9%) evaluable. Median age was 50 (TAC) vs 49 years (FAC), with 55% premenopausal in both arms; other characteristics were balanced between arms. Treatment compliance and toxicity have been reported (Martin et al, Ann Oncol 17: 1205). TAC produced significantly more hematologic toxicity than FAC, although primary prophylaxis with G-CSF reduced the rate of neutropenic fever. No toxic deaths were reported. As of June 7, 2007 (median f/u 6 years), 128 pts experienced a DFS event (TAC: 52 pts, FAC 76 pts) with estimated 5-year DFS of 91% for TAC and 86% for FAC (HR 0.66, 95% CI 0.46–0.94, p=0.0202). With 45 deaths (TAC: 19 pts, FAC: 26 pts), the estimated 5-year OS is 97% for TAC and 95% for FAC (HR 0.72, 95% CI 0.40–1.30, p=0.2677). Conclusions: For pts with high-risk node-negative BC, adjuvant TAC was associated with a significant improvement in DFS compared with FAC, with manageable toxicity. Updated results will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis

Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17

BackgroundMA.17 evaluated letrozole or placebo after 5 years of tamoxifen and showed significant improvement in disease-free survival (DFS) for letrozole [hazard ratio (HR) 0.57, P=0.00008]. The trial was unblinded and placebo patients were offered letrozole. Patients and methodsAn intent-to-treat analysis of all outcomes, before and after unblinding, on the basis of the original randomization was carried out. ResultsIn all, 5187 patients were randomly allocated to the study at baseline and, at unblinding, 1579 (66%) of 2383 placebo patients accepted letrozole. At median follow-up of 64 months (range 16–95), 399 recurrences or contralateral breast cancers (CLBCs) (164 letrozole and 235 placebo) occurred. Four-year DFS was 94.3% (letrozole) and 91.4% (placebo) [HR 0.68, 95% confidence interval (CI) 0.55–0.83, P=0.0001] and showed superiority for letrozole in both node-positive and -negative patients. Corresponding 4-year distant DFS was 96.3% and 94.9% (HR 0.80, 95% CI 0.62–1.03, P=0.082). Four-year overall survival was 95.1% for both groups. The annual rate of CLBC was 0.28% for letrozole and 0.46% for placebo patients (HR 0.61, 95% CI 0.39–0.97, P=0.033). ConclusionsPatients originally randomly assigned to receive letrozole within 3 months of stopping tamoxifen did better than placebo patients in DFS and CLBC, despite 66% of placebo patients taking letrozole after unblinding.

Benefit From Exemestane As Extended Adjuvant Therapy After 5 Years of Adjuvant Tamoxifen: Intention-to-Treat Analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 Trial

Patients with early-stage, hormone receptor-positive breast cancer have considerable residual risk for recurrence after completing 5 years of adjuvant tamoxifen. In May 2001, the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated accrual to a randomized, placebo-controlled, double-blind clinical trial to evaluate the steroidal aromatase inhibitor exemestane as extended adjuvant therapy in this setting. Postmenopausal patients with clinical T(1-3)N(1)M(0) breast cancer who were disease free after 5 years of tamoxifen were randomly assigned to 5 years of exemestane (25 mg/d orally) or 5 years of placebo. Our primary aim was to test whether exemestane prolongs disease-free survival (DFS). In October 2003, results of National Cancer Institute of Canada (NCIC) MA.17 showing benefit from adjuvant letrozole in this setting necessitated termination of accrual to B-33, unblinding, and offering of exemestane to patients in the placebo group. At the time of unblinding, 1,598 patients had been randomly assigned; 72% in the exemestane group continued on exemestane and 44% in the placebo group elected to receive exemestane. With 30 months of median follow-up, original exemestane assignment resulted in a borderline statistically significant improvement in 4-year DFS (91% v 89%; relative risk [RR] = 0.68; P = .07) and in a statistically significant improvement in 4-year relapse-free survival (RFS; 96% v 94%; RR = 0.44; P = .004). Toxicity, assessed up to time of unblinding, was acceptable for the adjuvant setting. Despite premature closure and crossover to exemestane by a substantial proportion of patients, original exemestane assignment resulted in non-statistically significant improvement in DFS and in statistically significant improvement in RFS.

Incorporating Target Immunotherapy into Standard Conditioning Regimen Prior to Autologous Stem Cell Transplantaion (ASCT) Improves the Transplant Outcome for Pateints with Relapsed/Refractroy B Cell Non-Hodgkin Lymphoma (B-NHL).

Background: Refractory or relapse B-NHL has a poor prognosis with conventional chemotherapy. Autologous stem cell transplant (ASCT) preceded by high dose chemotherapy has been the preferred therapeutic choice for such patients. The majority of the treatment failures occur within one to two years post transplant with disease progression after transplant accounted for most of the failures. The incorporation of targeted immunotherapy (rituximab) into the upfront and relapse setting is becoming of the standard of care for patients with B-NHL. The objective of this study is to evaluate the impact of rituximab (R) on disease free survival (DFS) when added to a standard conditioning regimen -- BEAM (carmustine, cytarabine, etoposide, and melphalan) prior to ASCT.Methods: A single institution retrospective analysis of 53 patients (pts), whom were heavily pre-treated, underwent ASCT between 08/98 & 07/06. All pts received rituximab in combination with high dose cytoxan for stem cell mobilization. 37 pts received R-BEAM and 16 received BEAM prior to ASCT. Actuarial rate for DFS was estimated from the day of SCT using the Kaplan-Meier method.Results: The group was predominantly men, 73% and 78%, with a median age of 57 years for both the R-BEAM and BEAM group. With a median follow up of 15.7 months, 13/37 (32%) and 11/16 (64%) pts who received R-BEAM and BEAM respectively developed disease progression after ASCT. The 2-yr actuarial disease-free survivals (figure1) were 60% and 21% for the R-BEAM and BEAM arm respectively (p=0.006).Conclusion: In this study, the outcome of pts who received R-BEAM compares favorably to those who receive BEAM alone with significant improvement in disease-free survival. Thus, incorporating target immunotherapy into standard conditioning regimen may have altered the natural history of the disease for pts undergoing ASCT for relapsed/refractory B-NHL. [Display omitted]

Epigenetic Regulation of CD20 Protein Expression in B-Cell Lymphoma Cells after Rituximab-Containing Chemotherapy.

For the past 10 years, rituximab has been used with some forms of conventional chemotherapy to treat CD20(+) B-cell malignancies as a new molecular targeting drug. Although significant improvements in disease-free survival and cure rate have been obtained, resistance to rituximab has been recognized as a considerable problem. Here we report that CD20(−) tumor transformation is one important mechanism of resistance to rituximab. We also demonstrate a possibility that CD20 protein expression is downregulated by some epigenetic mechanisms, and interestingly, the protein expression can be restored by treatment with certain epigenetic drugs. During the 5 years beginning in 2001, 124 patients with B-cell malignancies were treated with rituximab-containing induction, consolidation, or salvage chemotherapies in our hospital. Relapse or recurrence of disease were confirmed in 36 patients (29.0%), and re-biopsy of tumor tissues was performed in 19 patients. Five cases (DLBCL, 3 cases, and DLBCL transformed from FL, 2 cases) of those 19 patients (26.3%) indicated CD20 protein-negative transformation in flow cytometry (FCM) and/or immunohistochemistry (IH) analyses. We established a CD20(−) lymphoma cell line RRBL1 from a DLBCL patient with CD20(−) transformation from CD20(+) FL after repeated treatment with rituximab, and analyzed molecular mechanisms of the CD20 protein-negative phenotype. CD20 was not expressed by IH, FCM, and immunoblotting analyses, and resistance to rituximab was observed after cell culture with rituximab treatment. Expression of wild-type CD20 mRNA was confirmed by RT-PCR, and no genetic mutation in coding sequence or promoter region was observed. Quantitative RT-PCR showed that the CD20 mRNA expression level was almost 100 times lower than that of CD20(+) B-cell lymphoma cells typically obtained from DLBCL patients. These data suggest that aberrant down regulation of CD20 mRNA may be closely related to the negative CD20 surface antigen expression. Interestingly, CD20 protein re-expression was confirmed by enhancing CD20 mRNA expression using specific epigenetic drugs including histone deacetylase inhibitor Trichostatin A (TSA). In addition, after TSA treatment, sensitivity for rituximab was significantly restored. Chromatin immunoprecipitation assay suggested that recruitment of histone deacetylase complexes to CD20 promoter may be related to the down regulation of CD20 expression. Our data may provide the basis for a new therapeutic strategy, epigenetic therapy combined with molecular targeting therapy using rituximab, for rituximab-resistant CD20(−) transformed B-cell malignancies.

Taxanes for the adjuvant treatment of early breast cancer: systematic review and economic evaluation

To estimate the clinical effectiveness and cost-effectiveness of docetaxel and paclitaxel compared with non-taxane, anthracycline-containing chemotherapy regimens, for the adjuvant treatment of women with early-stage breast cancer. Major electronic databases were searched between October 2005 and February 2006. A systematic review of the literature on adjuvant taxane versus anthracycline non-taxane chemotherapy for women with early breast cancer was undertaken. A mathematical model was developed to synthesise the available data on costs, disease-free survival and health-related quality of life (HRQoL) of patients receiving taxane-containing chemotherapy versus non-taxane-containing chemotherapy. Eight of the 11 selected trials (six docetaxel and five paclitaxel) reported a significant improvement in disease-free survival (DFS) or time to recurrence (TTR) for taxanes over comparator regimens. Docetaxel was associated with more adverse events than paclitaxel, most notably febrile neutropenia. Taxanes produced cardiotoxicity, although this was not reported to be greater than for anthracycline comparator arms in all trials. Treatment-related deaths were uncommon. Where reported, all chemotherapy regimens caused HRQoL to deteriorate during treatment. Following treatment, there were no clinically significant differences between taxane and comparator treatment groups. There were few data available comparing licensed regimens of taxanes with chemotherapy regimens commonly used in the UK. The three trials selected as the basis for the economic analysis were those that used the taxanes in accordance with current UK marketing authorisation and had also reported in full. The estimated incremental cost-effectiveness ratio for docetaxel compared to FAC6, based on the BCIRG 001 study, is 12,000 pounds (7000-39,000 pounds) and for paclitaxel compared with Adriamycin/cyclophosphamide, based on the NSABP B28 and CALGB 9344 studies, is 43,000 pounds (16,000 pounds-dominated) and 39,000 pounds (12,000 pounds-dominated), respectively. However, the comparators used in these trials restrict the generalisability of the results, as they do not conform to current standard care in the UK, typically FEC6 and E4-CMF4. An exploratory indirect comparison shows that the benefits of taxane containing regimens compared to regimens in current use in the UK is subject to large uncertainty due to the lack of direct trial comparisons between these interventions. Assumptions regarding the benefits in the taxane arm after the trial follow-up period and the annual rate of recurrence in this period have the most significant influence on the ICER. There is a large degree of heterogeneity in the evidence base for the effectiveness of taxane- compared with non-taxane-containing regimens in terms of the interventions, comparators and populations. Eight of the 11 trials providing effectiveness data reported a significant improvement in DFS or TTR for taxanes over comparator regimens. The remaining three trials found no significant differences between the groups in DFS/TTR. The cost-effectiveness results suggest that the cost per quality-adjusted life-year for taxane- compared with non-taxane-containing chemotherapy varies between 12,000 pounds and 43,000 pounds, depending on the taxane under consideration and the specific trial used as the basis of the analysis. However, the comparators used in these trials do not conform to current standard care in the UK. More research is needed, comparing taxanes used in line with their current UK marketing authorisation and with anthracycline-containing regimens commonly used in the UK. The on-going TACT trial is expected to provide useful data. There are currently few data on the effectiveness of taxanes for the over-70s. Further research is required into the long-term outcomes of taxane therapy, such as whether there are any long-term adverse events that significantly impact on overall survival or quality of life and whether the increases in DFS will translate into increases in overall survival.

Positron Emission Tomographic Scanning Predicts Survival After Induction Chemotherapy for Esophageal Carcinoma

The ability to accurately predict clinical and pathological response and survival in patients undergoing preoperative chemotherapy may have a significant impact on treatment strategy for esophageal carcinoma. This study assessed the predictive accuracy of clinical response (CR) and positron emission tomography (PET) scanning in determining pathological downstaging and disease free survival (DFS) after chemotherapy. This is a retrospective review of patients who underwent chemotherapy prior to complete surgical resection for esophageal carcinoma between 1999 and 2005. Clinical response was correlated with pathological downstaging and survival. For PET scanning, the percent reduction in maxSUV after induction therapy was determined and we identified the optimal threshold of percent reduction in maxSUV for predicting clinical response and pathological downstaging. Sixty-two patients (52 men, median age 62.3) were evaluated. Thirty-nine patients (62.9%) had either a partial (n = 32) or complete clinical response (n = 7) to induction therapy. The sensitivity, specificity, positive, and negative predictive value of an objective clinical response in predicting downstaging in T and (or) N were 85.7%, 55.9%, 61.5%, and 82.6%, respectively. There was no difference in DFS between responders and nonresponders. The PET sensitivity, specificity, positive, and negative predictive values for predicting pathologic downstaging were 77.8%, 52.9%, 56.8%, and 75%, respectively. Thirty-seven patients (59.7%) had a 50% or greater reduction in the maxSUV of their primary tumor and had a significant improvement in DFS compared with patients with a less than 50% reduction in maxSUV (median DFS time: 35.5 months vs 17.9 months, respectively, p = 0.03). Significantly, 11 patients had a 100% reduction in maxSUV despite the presence of residual tumor. Complete response and PET appear equivalent in predicting pathological downstaging. However, a 50% reduction in the maxSUV after induction therapy is more significantly associated with improved DFS than CR or pathological downstaging. Additionally, a complete absence of PET signal cannot be equated with a complete pathological response.

Randomized trial of postoperative adjuvant therapy in stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: A final report

4050 Background: We conducted a prospective randomized trial to define the optimal sequence of chemotherapy and radiotherapy of postoperative adjuvant treatment in stage II and III rectal cancer. Methods: Three hundred eight patients were enrolled onto the study. We randomly assigned 155 to arm I (early radiotherapy group) and 153 to arm II (late radiotherapy group). Treatment included eight cycles of chemotherapy at 4-week intervals and pelvic radiotherapy of 45 Gy in 25 fractions. Radiotherapy started on day 1 of the first chemotherapy cycle in arm I and on day 1 of the third chemotherapy cycle in arm II. The chemotherapy regimen consisted of fluorouracil 375 mg/m2/d and leucovorin 20 mg/m2/d. Chemotherapy was administered for 3 days per cycle in two cycles during the period of radiotherapy and for 5 days per cycle in the remaining six cycles. (J Clin Oncol 2002 20:1751- 8) Results: Twenty patients in arm I and 14 in arm II were not eligible. We included 274 patients in the analysis. With a median follow-up of 94 months for surviving patients, there was a trend for improved disease-free survival(DFS) in arm I compared with arm II, although it was not reached statistical significance (72% v. 63% at 7 years; P =.157). Especially, in patients who received abdominoperineal resection (APR), DFS was prolonged in arm I compared with arm II (66% v. 41% at 7 years; P=.033) Thirty six recurrences (26.7%) occurred in arm I and 49 (35.3%) in arm II (P =.151). Overall survival was not significantly different between arms I and II (71% v. 68% at 7 years; P =.855). Conclusions: With a long-term follow-up, this study failed to show a significant survival advantage for early radiotherapy with concurrent chemotherapy after resection of stage II and III rectal cancer. In patients with APR, significant improvement in DFS for arm I was observed. No significant financial relationships to disclose.

Phase III randomized trial of postoperative radiotherapy (RT) with or without carboplatin (Cb) in patients (pts) with head and neck squamous cell carcinoma (HNSCC)

6078 Background: Postoperative RT plus cisplatin is a standard treatment in high-risk resected HNSCC. However, the role of Cb in the same setting has not been established. Methods: Eligible were pts with macroscopically resected stage III/IV HNSCC with high-risk pathologic features (=3 nodes, extracapsular extension, perineural or angiolymphatic invasion, or involved margins), ECOG performance status 0–2, and adequate laboratory parameters. Pts were randomized to receive RT 59.4 Gy (1.8 Gy/day) versus the same RT plus Cb 100 mg/m2 intravenously once weekly during RT. The primary endpoint was the 2-year disease-free survival (DFS); with a projected sample size 100 patients/arm, the power was 0.81 with alpha 0.1 to detect a 15% improvement (50% to 65%). Results: From 4/94 to 4/02, 76 pts were randomized, of whom 72 pts were eligible and analyzable (36/arm). The study was prematurely closed due to slow accrual. Median age 54 years (24–83); male/female: 60 pts/12 pts; primary sites: oral cavity (n=26), oropharynx (n=23), hypopharynx (n=8), larynx (n=15); stage III/IV: 6 pts/66 pts; ECOG performance status 0/1/2: 40 pts/30 pts/2 pts. Median follow-up was 5.3 years. The 2-, 3- and 5-year DFS with RT/Cb vs. RT was 70%, 60%, and 46% vs. 55% (p=0.21), 51% (p=0.48), and 43% (p=0.79) and the 2-, 3- and 5-year overall survival (OS) was 74%, 71%, and 47% vs. 51% (p=0.04), 51% (p=0.07) and 40% (p=0.59). There were no statistically significant differences in median DFS or OS. In the subset of pts with primary sites other than the oropharynx (n=49), RT/Cb resulted in better OS vs. RT (p=0.05, Wilcoxon; p=0.27, log-rank). RT/Cb was associated with infrequent grade III/IV toxicities, including leukopenia (RT/Cb 8% vs. RT 0%), stomatitis (11% vs. 3%), and dermatitis (6% vs. 3%). Gastrostomy tube was placed in 15 pts (RT/Cb 8 vs. RT 7). Conclusions: Our data do not show a statistically significant improvement in DFS with RT/Cb vs. RT but this may reflect insufficient sample size. The potential benefit of RT/Cb for a subset of pts merits further study. No significant financial relationships to disclose.