The Time-to-progression Research Articles

Comparison of Radiological Tumor Response Based on iRECIST and RECIST 1.1 in Metastatic Clear-Cell Renal Cell Carcinoma Patients Treated with Programmed Cell Death-1 Inhibitor Therapy.

ObjectiveTo evaluate the radiological tumor response patterns and compare the response assessments based on immune-based therapeutics Response Evaluation Criteria in Solid Tumors (iRECIST) and RECIST 1.1 in metastatic clear-cell renal cell carcinoma (mccRCC) patients treated with programmed cell death-1 (PD-1) inhibitors.Materials and MethodsAll mccRCC patients treated with PD-1 inhibitors at Henan Cancer Hospital, China, between January 2018 and April 2019, were retrospectively studied. A total of 30 mccRCC patients (20 males and 10 females; mean age, 55.6 years; age range, 37–79 years) were analyzed. The target lesions were quantified on consecutive CT scans during therapy using iRECIST and RECIST 1.1. The tumor growth rate was calculated before and after therapy initiation. The response patterns were analyzed, and the differences in tumor response assessments of the two criteria were compared. The intra- and inter-observer variabilities of iRECIST and RECIST 1.1 were also analyzed.ResultsThe objective response rate throughout therapy was 50% (95% confidence interval [CI]: 32.1–67.9) based on iRECIST and 30% (95% CI: 13.6–46.4) based on RECIST 1.1. The time-to-progression (TTP) based on iRECIST was longer than that based on RECIST 1.1 (median TTP: not reached vs. 170 days, p = 0.04). iRECIST and RECIST 1.1 were discordant in 8 cases, which were evaluated as immune-unconfirmed PD based on iRECIST and PD based on RECIST 1.1. Six patients (20%, 6/30) had pseudoprogression based on iRECIST, of which four demonstrated early pseudoprogression and two had delayed pseudoprogression. Significant differences in the tumor response assessments based on the two criteria were observed (p < 0.001). No patients demonstrated hyperprogression during the study period.ConclusionOur study confirmed that the iRECIST criteria are more capable of capturing immune-related atypical responses during immunotherapy, whereas conventional RECIST 1.1 may underestimate the benefit of PD-1 inhibitors. Pseudoprogression is not rare in mccRCC patients during PD-1 inhibitor therapy, and it may last for more than the recommended maximum of 8 weeks, indicating a limitation of the current strategy for immune response monitoring.

Randomized, phase II trial of sequential hepatic arterial infusion chemotherapy and sorafenib versus sorafenib alone as initial therapy for advanced hepatocellular carcinoma: SCOOP-2 trial

BackgroundThe efficacy of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) remains unclear. We conducted a multi-center randomized phase II study comparing a sequential HAIC-sorafenib regimen versus sorafenib alone as an initial therapy for HCC.MethodsPatients were randomly assigned (ratio, 1:1) to receive sequential HAIC with cisplatin followed by sorafenib (HAIC group, n = 35) or sorafenib alone (sorafenib group, n = 33) as an initial therapy. The primary endpoint was the one-year survival rate. Secondary endpoint included overall survival (OS), the 2-year survival rate, the time-to-progression (TTP), the objective response rate (ORR), the disease control rate (DCR), and safety.ResultsFor the primary endpoint, the one-year survival rates were 46% in the HAIC group and 58% in the sorafenib group. The median OS period was 10.0 months (95% CI, 7.0–18.8) in the HAIC group and 15.2 months (95% CI, 8.2–19.7) in the sorafenib group (hazard ratio [HR], 1.08; 95% CI, 0.63 to 1.86, P = 0.78). The median TTP, ORR and DCR in the HAIC group were 2.8 months (95% CI, 1.7–5.5), 14.3, and 45.7%, respectively, while those in the sorafenib group were 3.9 months (95% CI, 2.3–6.8), 9.1, and 45.5%, respectively. No unexpected adverse events related to HAIC or sorafenib were observed in either group.ConclusionsSequential HAIC with cisplatin and sorafenib does not improve the survival benefit, compared with sorafenib alone, when used as an initial therapy for advanced HCC. However, this study was underpowered in regard to its primary and secondary endpoints, so the results should be interpreted with caution.Trial registrationUMIN ID 000006147, registration data: August 11, 2011.

Multicenter retrospective analysis of the safety and efficacy of regorafenib after progression on sorafenib in Korean patients with hepatocellular carcinoma.

Background The pivotal RESORCE trial showed that regorafenib was effective as second-line therapy for patients with advanced HCC who progressed on first-line sorafenib. Real-world data are needed to assess clinical outcomes and adverse events in the setting of daily practice. Methods Between April 2017 and August 2017, the Named Patient Program (NPP) was activated to provide controlled, pre-approval access of regorafenib in Korea. This analysis is a multicenter retrospective study of patients who received regorafenib under the NPP. Results A total of 49 patients entered into this NPP, and 40 patients received regorafenib in five Korean institutions. All but one patient received regorafenib as second-line therapy after progression on sorafenib, and 36 (90%) and 34 (85%) patients were classified as Child-Pugh A and BCLC stage C, respectively. The response rate was 10% (n= 4). The median progression-free survival (PFS) was 3.7months (95% CI, 2.5-4.9months), and the median overall survival (OS) was not reached. The 1year OS rate was 54.6%. The time-to-progression (TTP) on prior sorafenib was significantly associated with PFS and OS. The most common grade 3-4 toxicities were hand-foot skin reaction (n= 3, 8%), hypertension (n= 2, 5%), and increased aspartate aminotransferase (n= 2, 5%). Conclusion Regorafenib was well-tolerated and effective in patients with advanced HCC who progressed on first-line sorafenib, with efficacy and safety outcomes consistent with those of the previous RESORCE trial. TTP on first-line sorafenib may predict the efficacy of subsequent regorafenib.

Serum insulin-like growth factor-1 and its binding protein 3 as prognostic factors for the incidence, progression, and outcome of hepatocellular carcinoma: a systematic review and meta-analysis.

PurposePrevious studies have supported an association between serum insulin-like growth factor-1 (IGF1) and IGF-binding protein 3 (IGFBP3) levels and hepatocellular carcinoma (HCC), but the results were inaccurate. It has recently been proposed that IGF1 and IGFBP3 play roles in the time-to-progression (TTP) and overall survival (OS) of HCC patients. Our results revealed that serum IGF1 level is predictive of the progression and survival of HCC patients.ResultsHCC was associated with a significant reduction in serum IGF-1 and IGFBP-3 levels compared to cirrhosis (p = 0.037). Low serum IGF1 levels were predictive of a shorter TTP (OR, 2.74; 95% confidence interval [CI], 1.92–3.90) and poorer OS (odds ratio [OR], 2.20; 95% CI, 1.81–2.68) in HCC patients. The IGF1/IGFBP3 molar ratio was not significantly associated with the risk of HCC (OR, 1.311; 95% CI, 0.761–2.260).Materials and MethodsWe conducted a comprehensive literature search in PubMed, EMBASE, and the Cochrane Library. Twenty studies met the inclusion criteria and were subjected to statistical analysis. The geometric mean and standard deviation (SD) of serum IGF1 and IGFBP3 levels in the healthy, cirrhosis, and HCC groups were calculated. Pooled odds ratios (ORs) were calculated using a fixed-effects model to analyse the association of serum IGF1 level with the progression and survival of HCC patients.ConclusionsSerum IGF1 and IGFBP3 levels were positively associated with the incidence of HCC. Serum IGF1 level is an independent prognostic factor for the progression and survival of HCC patients.

Yttrium-90 radioembolization for hepatocellular carcinoma in hepatitis B: commentary on a 103-patient Asian cohort.

Y90 radioembolization [also known as selective internal radiation therapy (SIRT)] is recognized as a safe and effective therapy for hepatocellular carcinoma (HCC), with a particular role for Y90 in patients with large tumors and/ or portal vein thrombosis (PVT). Studies from Europe and the United States, comprised of 776 patients in aggregate, have demonstrated comparable results when taking into account cohort differences in terms of baseline Child–Pugh classification and tumor stage defined by the Barcelona Clinic Liver Cancer system (BCLC) [1–4]. These Western studies included patients predominately with hepatitis C and/or alcohol as the underlying cause of liver disease with limited numbers of patients with hepatitis B virus (HBV) (9–30 %). HBV is the leading cause of HCC worldwide, with over 50 % of all causes of HCC attributable to HBV. While there is convincing data from the REVEAL study that the risk of HCC is impacted by the height of the HBV viral load (VL), there has not been conclusive data that achieving an undetectable HBV VL negates the risk of eventual HCC development. This is hypothesized to be related to the integration of cccDNA into the host DNA with a carcinogenetic capacity via genetic instability. Clinical-pathologic differences have been reported between HBV versus Hepatitis C virus (HCV), the former being more commonly associated with larger tumors, younger age and lower cirrhosis rates [5]. Other single center retrospective reports have sought to determine if a difference exists in outcomes with various therapeutic options. Viral etiology was not found to have an impact on outcome among patients treated with transarterial chemoembolization (TACE) [6]. However, the etiology of disease has been apparent in orthotopic liver transplant (OLT), with a significant decrease in overall survival (OS) in HCV due to recurrent HCV post-transplant [7]. Systemic therapy with sorafenib was associated with shorter median OS among Asian patients relative to a Western cohort; however, there was a similar degree of survival benefit associated with sorafenib relative to placebo (hazard ratios 0.69 and 0.68, respectively) [8, 9]. The experienced team from Singapore has reported a retrospective analysis of 103 Asian patients with nearly half (47.6 %) of the patients with HBV-induced HCC treated with Y90 [10]. The tumor characteristics were comparable to the Western cohorts (Table 1). Safety and tolerability were also similar to other cohorts. While the authors demonstrated a comparable median OS of 14.4 months, the time-to-progression (TTP) of 5.3 months was shorter. Progression (using RECIST 1.1 at 3 months after therapy) was available in only half of the entire cohort (potentially affecting the results and lower response rate). Nonetheless, it is of interest that progression was not seen in the treated lesion(s) and the analysis was limited to the first Y90 administration, demonstrating excellent local tumor control; such a pattern of metastases and the high local control rates have been reported previously [11, 12]. However, 38 % of disease control was due to stable disease which, among TACE cohorts, has been found to predict worse outcomes compared to those with complete/partial response [13]. The use of RECIST 1.1, without taking into account presence of necrosis, makes it impossible to L. Kulik Division of Hepatology, Department of Medicine, Northwestern University, Chicago, IL, USA

Cyclooxygenase-2 inhibitors for non-small-cell lung cancer: A phase II trial and literature review.

Several preclinical and clinical studies have demonstrated that cyclooxygenase-2 (COX-2) inhibitors are efficient for the treatment of non-small-cell lung cancer (NSCLC). However, two recent phase III clinical trials using COX-2 inhibitors in combination with platinum-based chemotherapy failed to demonstrate a survival benefit. Thus, validation and discussion regarding the usefulness of COX-2 inhibitors for patients with NSCLC are required. We conducted a prospective trial using COX-2 inhibitors for the treatment of 50 NSCLC patients accrued between April, 2005 and July, 2006. Patients with untreated advanced NSCLC received oral meloxicam (150 mg daily), carboplatin (area under the curve = 5 mg/ml × min on day 1) and docetaxel (60 mg/m2 on day 1) every 3 weeks. The primary endpoint was response rate. The response and disease control rates were 36.0 and 76.0%, respectively. The time-to-progression (TTP) and overall survival (OS) were 5.7 months [95% confidence interval (CI): 4.6-6.7] and 13.7 months (95% CI: 11.4-15.9), respectively. The 1-year survival ratio was 56.0%. Grade 3 neuropathy was observed in only 1 patient. We performed tumor immunohistochemistry for COX-2 and p27 and investigated the correlation between their expression and clinical outcome. COX-2 expression in the tumor tended to correlate with a higher response rate (50.0% in the high- and 18.2% in the low-COX-2 group; P=0.092). Based on our results and previous reports, various trial designs, such as the prospective use of COX-2 inhibitors only for patients with COX-2-positive NSCLC, including the exploratory analysis of biomarkers associated with the COX-2 pathway, may be worth further consideration.

A prospective study of the efficacy of a combination of autologous dendritic cells, cytokine-induced killer cells, and chemotherapy in advanced non-small cell lung cancer patients

Dendritic cells (DC) play a crucial role in the induction of an effective antitumor immune response. Cytokine-induced killer (CIK) cells, a subset of T lymphocytes, have the capacity to eliminate cancer cells. This study was to evaluate the correlation between the frequency of DC/CIK immunotherapies following regular chemotherapy, the time-to-progression (TTP), and overall survival (OS) of advanced non-small lung cancer patients. Sixty patients with IIIB-IV non-small-cell lung carcinoma (NSCLC) were enrolled from August 2007 to December 2009 and were randomized into two groups. All 60 patients received four courses of navelbine-platinum (NP) chemotherapy. In one group, 30 patients were treated with adoptive autologous DC/CIK cell transfusion twice every 30 days. In the other group, the patients received immunotherapies more than twice every 30 days. The adverse effects, TTP, and OS were evaluated between the two groups. Median survival time of all 60 patients was 13.80 months. The 1-, 2-, and 3-year overall survival rates were 60.0, 21.7, and 15.0 %, respectively. The 1-, 2-, and 3-year overall survival rates of patients receiving more than two immunotherapies were 63.3, 30.0, and 23.3 %, and the rates of those receiving two immunotherapies were 56.7, 13.3, and 6.7 %, respectively. The difference between the two groups was statistically significant (P = 0.037). Compared with patients in the fewer immunotherapies group, TTP in the group receiving more immunotherapies significantly prolonged, with the median improving from 6.2 months (95 % CI, 5.35-9.24) to 7.3 months (95 % CI, 5.45-6.95; P = 0.034). The adverse effects of chemoimmunotherapy were tolerable. Advanced NSCLC patients can benefit from the combination of DC/CIK immunotherapies following conventional chemotherapy. More than two immunotherapies improved TTP and OS of those patients in this study.

Comparative analysis of TACE alone or plus RFA in the treatment of 167 cases of intermediate and advanced staged primary hepatocellular carcinoma

To evaluate the clinical efficacy and survival rate of transarterial chemoembolization (TACE) alone or plus radiofrequency ablation (RFA) in patients with intermediate or advanced stage primary hepatocellular carcinoma (HCC). In this retrospective study, 467 cases received RFA or TACE plus RFA. Among them, 167 cases with strict clinical procedure (TACE alone or plus RFA) and complete follow-up data were included. Eighty-seven cases received TACE and 80 cases had TACE plus RFA between January 2000 and December 2006. Hierarchical analyses were performed using log-rank tests and survival curve was estimated by Kaplan-Meier method. A total of 167 patients received TACE alone or plus RFA for a follow-up period of 1 to 89 months. In the TACE alone group, the time-to-progression (TTP) was an average of 3.6 months. The median survival was 13 months, one-year survival rate 52.9%, three-year survival rate 11.5% and five-year survival rate 4.6%. In the TACE plus RFA group, the TTP time was an average of 10.8 months. The median survival time was 30 months, one-year survival rate 85.0%, three-year survival rate 45.0% and five-year survival rate 11.3%. In the TACE alone group, the median survival of intermediate stage HCC was 14 months, one-year survival rate 62.2%, three-year survival rate 13.3% and five-year survival rate 4.4%; In the TACE plus RFA group, the median survival of intermediate stage HCC was 14 months, one-year survival rate 90.1%, three-year survival rate 52.9% and five-year survival rate 13.7%. All differences of two groups has statistical significance (P < 0.05). In intermediate stage HCC, the median survival of TACE alone group was 14 months, one-year survival rate 62.2%, three-year survival rate 13.3%, five-year survival rate 4.4% versus 32 months, 90.1%, 52.9%, 13.7% in the TACE plus RFA group respectively. For the advanced stage HCC, the median survival time was 12 months, one-year survival rate 35%, three-year survival rate 7.1% and five-year survival rate 0 in the TACE alone group versus 28 months, 62.1%, 24.1% and 6.9% in the TACE plus RFA group (P = 0.00). There was significantly statistic difference between both groups in intermediate and advanced staging HCC. Among them, 60/485 (12.4%) patients required a therapy of post-TACE hepatic dysfunctions versus 13/168 (7.7%) in the TACE plus RFA group (P = 0.004, ANOVA method). The regimen of TACE plus RFA has the advantages of tumor control, liver function protection and survival extending in the treatment of HCC than TACE alone in intermediate or advanced stage HCC.

HER‐2 overexpression/amplification in Barrett’s oesophagus predicts early transition from dysplasia to adenocarcinoma: a clinico‐pathologic study

Barrett’s oesophagus (BO) is the primary precursor lesion for oesophageal adenocarcinoma (ADC). The natural history of metaplasia-dysplasia-carcinoma sequence remains largely unknown. HER2/neu oncogene results overexpressed/amplified in preneoplastic lesions and in ADC of the oesophagus and it has been associated with poor prognosis. Our aim was to evaluate the role of HER2 overexpression/amplification in predicting the conversion from precursor lesions to ADC. We retrospectively evaluated by univariate analysis of single variables clinical records and histological specimens of 21 patients with a confirmed diagnosis of BO and/or oesophageal dysplasia. Clinical variables included age, gender, alcohol and smoking intake, presence of symptoms (pyrosis, disphagia) and endoscopic features (length). HER2 status was studied by immunohistochemistry and fluorescence in situ hybridization (FISH) on paraffin-embedded tissue. The end-points were the occurrence of progression and the time-to-progression (TTP) from the initial histologic lesion to the worst pathological pattern. Median age at diagnosis was 63 years (range 37–84). BO median length was 4.5 cm. Progression occurred in 11 of 21 patients and median TTP was 24 months. HER2 was overexpressed/amplified in 8 of 21 (38%) patients. HER2 overexpression/ amplification and the presence of dysplasia were statistically associated with progression (P= 0.038). This study provides evidence for a possible role of HER2 in the transition from dysplasia to ADC of the oesophagus. This fact could help in identifying patients at high risk of malignant transformation.

The Impact of Cytogenetics on the Outcomes of Treatment with Lenalidomide Plus Dexamethasone in Relapsed or Refractory Multiple Myeloma.

Background: Lenalidomide improves survival for patients with relapsed or refractory multiple myeloma (MM). However, the benefit of this treatment in patients with highrisk cytogenetic abnormalities is not well studied. We have previously reported in an initial sub-analysis of a large, open-label study (MM016 study) the effects of the most common unfavorable cytogenetic abnormalities on outcomes in MM patients treated with lenalidomide plus dexamethasone. Since then we have performed an update of this sub-analysis within a larger cohort of patients and a longer median follow-up time of 19.6 months.Methods: The MM016 is a multicenter single arm open label expanded access program for Lenalidomide in relapsed and refractory MM. Patients received dexamethasone orally (40mg, days 1–4; 9–12 and 17–20 for 4 cycles, then days 1–4 beginning with cycle 5) and Lenalidomide 25mg orally on days 1–21 of a 28 days cycle. Using fluorescence in situ hybridization, we examined the influence of three most common and recurrent cytogenetic abnormalities [del(13q), t(4;14), and del(17p13)] in 130 patients with FISH results available for the three genomic aberrations. Blade criteria were used to define RR. TTP and OS were defined according to the international uniform response criteria.Results: The median age was 61 yrs (31–84), 55.4% had ISS stage II or III, median beta2-microglobulin was 3.125 mg/L (1.1–16.75), median number of prior treatments was 2 (1–6) with 53.8% previously treated with thalidomide, 45.9% with bortezomib and 73.3% with SCT. Del(13q), t(4;14) and del(17p13) were detected in 54 (41.5%), 28(21.5%) and 12 (9.2%) of patients, respectively. The overall response RR (CR+PR) to len-dex was 83.1% (13.1% CR and nCR) and 76.4% for the del13q, 78.6% for t(4;14) and 58.3% for del17p patients. In univariate analysis the time-to-progression (TTP) hazard ratio (HR) for del(13q) and for t(4;14) were 1.563 (P = .0479) and 1.680 (P = .0470) respectively. However in multivariate analysis, neither the presence of either del(13q) nor t(4;14) did adversely affect TTP. Similarly neither of these genomic aberrations did affect overall survival (OS) hazard ratio with HR= 1.472 (P= .1507) for del(13q) and HR=1.091 (P = .788) for t(4;14). TTP (HR 2.626, P = .0032) and OS (HR 3.213, P =0.0016) were significantly worse with del(17p13) in univariate and multivariate analysis. Among the other variables studied prior thalidomide exposure did result in a shorter TTP (HR= 2.330; P = .0004) but not OS (HR= 1.690; P = .0612).Conclusion: Lenalidomide plus dexamethasone can overcome the negative prognostic effect of high-risk cytogenetic abnormalities conferred by the presence of del(13q) and t(4;14), and represents a good treatment option for relapsed or refractory MM patients with these adverse cytogenetic profiles. (Clinicaltrials.gov number, NCT00179647.)

Initial Results of PX-171-004, An Open-Label, Single-Arm, Phase II Study of Carfilzomib (CFZ) in Patients with Relapsed Myeloma (MM)

Background: (CFZ) is a novel proteasome inhibitor of the epoxyketone class that exhibits a high level of selectivity for the proteasome and has been shown in a phase 1 study to result in greater than 80% proteasome inhibition on a QDx2 consecutive day schedule. We piloted this agent in MM patients with relapsed disease after one to three prior therapies.Methods: PX-171-004 is an open-label, multicenter study. Pts are stratified into bortezomib (BTZ) naïve, BTZ responsive (> 6 month response) or BTZ non-responsive(< 6 months response) cohorts. Pts received CFZ 20 mg/m2 IV Days 1, 2, 8, 9, 15 and 16 every 28 days, for up to 12 cycles. Dexamethasone 4 mg po was administered prior to each dose in cycle 1. Responses were evaluated by the International Uniform Response Criteria for Multiple Myeloma.Results: 31 patients were enrolled, including 45% BTZ naïve, 45% BTZ responsive, and 10% BTZ non-responsive. 29 pts initiated therapy, completed at least one cycle of CFZ, had measurable M-protein and were evaluable for response. The mean number of prior therapies (excluding transplant) was 2.4;65% received prior thalidomide(THAL), 36% prior lenalidomide (LEN) and 87% prior stem cell transplant (SCT).To date, pts received a median of 4 cycles (range 1–8) of CFZ. 19 pts started at least 4 cycles, and 17 remain on therapy. In the evaluable BTZ naïve population (n=13), the overall response rate (ORR) was 54%, including 1 complete response (CR), 2 very good partial responses (VGPR), and 4 partial responses (PR). There were 4 additional pts with stable disease (SD). In 1 pt with insufficient data to evaluate response, due to tumor lysis syndrome (TLS) onset after 2 CFZ doses, an M-protein drop was noted that suggested a PR. Time to response was rapid, frequently occurring in the 1st cycle. There have been no progressions in this subset. With a median follow-up of 109 days, the time-to-progression(TTP) has not yet been reached, and all responders remain in remission. In 16 evaluable BTZ prior treated pts, 3 pts (19%) achieved PR, 1 (6%) pt achieved a minimal response (MR, as defined by EBMT criteria), and 9 pts had SD. The median TTP is 169 days for this subset. CFZ was generally well tolerated. The most common non-hematologic adverse events (AEs) were fatigue (61%), nausea (58%), vomiting (36%), and insomnia (32%). Worsening of hematologic parameters: neutropenia (32%), anemia (29%), and thrombocytopenia (23%) were primarily Grade 1/2; Grade 3/4 occurred in 10% or less of pts. Reports of peripheral neuropathy (PN) were uncommon. Increased creatinine, both drug and non-drug related, was seen in 5 pts (16%), but treatment was discontinued in only 1 pt due to a renal adverse event. Possible tumor lysis was reported in 2 BTZ naïve patients and resulted in early drug discontinuation in 1 pt, as described above; the 2nd event was fatal.Conclusions: The preliminary results of this trial indicate that CFZ has substantial activity as a single agent in relapsed MM patients, with an ORR of >50% in BTZ naïve patients, indicating better activity in this pt population. CFZ was generally well tolerated, and toxicities were manageable. TLS, which was observed in 2 pts, may be a reflection of the robust drug activity of CFZ. As observed in prior studies with CFZ, reports of PN were uncommon. These observations support further evaluation of CFZ as a promising new agent in MM. Enrollment in this study is ongoing, and additional studies of CFZ in combination with other chemotherapy agents in MM pts are underway.

Time-to-progression in breast cancer: A stratification model for clinical trials

The development of new anti-tumour drugs without clear cytoreductive activity has necessitated changes in the design of clinical trials. Defining the “time” parameter has become the essential objective of the majority of these trials. However, in breast cancer, this parameter is highly variable and, as such, difficult to quantify. We developed a useful tool that takes into account the inter-relatedness of all the variables known to have the capacity to predict the time-to-progression (TTP) in advanced breast cancer. From the Álamo database (GEICAM), we selected 1798 patients diagnosed as having metastatic breast cancer. Univariate analysis was performed using the method of Kaplan–Meier. Multivariate analysis was with the Cox regression method. The variables that were shown to have independent predictive value for the TTP were: non-visceral metastatic disease, single metastases, hormonal receptor positive N/ T ratio<2 and disease-free interval (DFI) ⩾24 months. Taking into account the variables that had reached an independent predictive value, we constructed a model of scoring in which the patients were grouped according to the TTP. Using our new scoring model, it is possible to group patients with metastatic breast cancer according to the predicted TTP. This can be a useful tool at the time of selecting and stratifying patients on entry into new randomised clinical trials.

5-Fluorouracil, Leucovorin and Oxaliplatin plus Bevacizumab in the First-Line Treatment of Metastatic Colorectal Cancer: A Single-Institute Study

Background: The addition of bevacizumab to 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) improved the time-to-progression (TTP) and overall survival (OS) in comparison to FOLFOX in the second-line treatment of metastatic colorectal cancer (MCRC). However, limited survival data are available to support FOLFOX plus bevacizumab in a first-line setting. We conducted a retrospective study of first-line FOLFOX plus bevacizumab to better characterize the safety and efficacy of this regimen in the first-line treatment of MCRC. Methods: Records of patients treated with first-line FOLFOX plus bevacizumab between January 2003 and March 2006 were reviewed. Grade 3 and 4 toxicity as well as efficacy data were collected. TTP and OS analyses were done using the Kaplan-Meier method. Results: 51 patients were treated with FOLFOX plus bevacizumab. Oxaliplatin treatment was interrupted prior to progression in 67% of patients. Grade 3 neuropathy, neutropenia and diarrhea occurred in 16, 8, and 8% of patients, respectively. The overall response rate, median TTP and median OS were 41%, 9.9 months and 23.2 months, respectively. Conclusions: First-line FOLFOX plus bevacizumab is associated with favorable TTP and OS. The definitive role of bevacizumab in the first-line setting in combination with FOLFOX chemotherapy should be explored further in randomized clinical trials.

Rituximab Therapy for Patients With Newly Diagnosed, Advanced-Stage, Follicular Grade I Non-Hodgkin's Lymphoma: A Phase II Trial in the North Central Cancer Treatment Group

Patients with newly diagnosed, advanced-stage, follicular grade 1 non-Hodgkin's lymphoma (NHL) are often asymptomatic and can be observed without immediate chemotherapy. The goals of this study were to assess the overall response rate (ORR) to rituximab in this patient population and to determine the time-to-progression (TTP) and time-to-subsequent-chemotherapy (TTSC). Eligible patients had untreated follicular grade 1 NHL, and measurable stage III/IV disease. Patients received rituximab 375 mg/m(2) intravenous weekly x 4 doses and were then followed for response and progression; no maintenance therapy was provided. Thirty-seven patients were accrued; one patient was ineligible. The median age was 59 years (range, 29 to 83 years). Six patients (18%) had elevated lactate dehydrogenase levels. The ORR was 72%, with 36% complete remissions. Fourteen (39%) of 36 patients remain in unmaintained remission, two died without disease progression, and three died with disease progression. Twenty (56%) of 36 patients have disease progression. The median TTP was 2.2 years (95% CI, 1.3 to not yet reached). Eighteen patients have subsequently been treated with chemotherapy, with a median TTSC of 2.3 years (95% CI, 1.6 to not yet reached). Patients with a high lactate dehydrogenase level had a lower ORR of 33% and a short TTP of only 6 months. Rituximab can be safely administered to patients with advanced-stage follicular grade 1 NHL with efficacy and minimal toxicity. This therapy is highly active and offers an acceptable alternative to observation in this patient population. Patients with high LDH should not be considered for rituximab monotherapy.

Gemcitabine-Containing Chemotherapy in the Treatment of Patients with Advanced Soft Tissue Sarcoma

Background: To assess the role of gemcitabine (G) or gemcitabine-containing regimens (GCR) in advanced soft tissue sarcoma (STS), we analyzed the response rate and the time-to-progression (TTP) in advanced STS patients (pts) following G/GCR treatment. Patients and Methods: From 8/98 to 12/01, 38 pts were treated with G alone (N = 9), or GCR including docetaxel (N=14); cisplatin (N = 13); or vinorelbine or paclitaxel (N = 2). Histologies included advanced STS in 32 pts and gastrointestinal stromal tumors (GIST) in 6 pts. Thirty-three pts including 27 STS pts had been pre-treated with a median of two prior regimens. Therapy consisted of a median of 3 cycles (range: 1 - 13) of G/GCR at a median G dose/application of 909 mg/m2 infused over 30 min. Results: Among the 32 non-GIST pts, there were 5 partial (15.6 %) and 2 minor (6 %) responses, with a median response duration of 17.8 + (range, 15.5 + - 63 +) weeks. In the group of 27 pre-treated STS pts, 3 partial (11 %) and 2 minor (7 %) responses were observed. With a median follow-up of 26 weeks, the median time-to-progression (TTP) was 18.4 weeks. Progression-free rates at 8, 12, and 24 weeks among pre-treated STS pts. were 73 %, 68 %, and 35 %, respectively. Conclusion: The response and PF rates observed in this analysis are comparable to those previously described for second-line anthracyclines and DTIC. Given the limited number of active cytostatic drugs for STS pts, these data suggest further evaluation of G or G-containing regimens in advanced STS.

Predicting Response of Ovarian Cancer to Paclitaxel Treatment Based on Trend Analysis of Serum CA125

Recent randomized studies have reported significantly improved quality of life and survival in cancer patients who underwent tumor marker-directed treatment compared with patients treated according to Union Internationale Contre le Cancer (UICC) criteria [see Ref. (1) and references therein]. According to these studies, systematic analysis of tumor markers may document whether therapy is effective and should be continued in spite of its ultimate adverse toxic effects or whether it should be terminated because of ineffectiveness. The advantages of biochemical assessment are objectivity and reproducibility as well as the fact that tumor marker assays are subjected to longitudinal external and internal quality control. We aimed to determine whether changes in serum concentrations of the tumor marker CA125 evaluated by a newly developed algorithm predict response to chemotherapy in paclitaxel-treated ovarian cancer patients. Ovarian cancer patients with advanced disease (stage III at the time of diagnosis; n = 101; median age, 56 years; age range, 33–69 years) were enrolled in a prospective study monitoring changes in serum CA125 and the effect of therapy. Patients were treated with paclitaxel (Taxol; Bristol-Myers-Squibb) as part of a first-line combination chemotherapy. They received a median of six courses (range, three to nine) of chemotherapy. During a total of 689 chemotherapy cycles, serum CA125 concentrations were evaluated (AxSYM; Abbott Laboratories) and externally controlled through the CAPTMX tumor marker survey. Serum samples were obtained before starting therapy (specimen c ) and before each chemotherapy cycle (specimens c 1– c n). The univariate Cox regression model and the stepwise Cox regression model were used for selecting the optimal variables that most accurately predicted disease-free interval. The statistical package SAS, release 8.22 (SAS, Inc.), was used. The time-to-progression (TTP) in different patient groups was compared using Wilcoxon and log-rank tests. CA125 concentrations between groups of responders and nonresponders to …