Chemotherapy-free Interval Research Articles

Neoadjuvant chemotherapy with six cycles of carboplatin and paclitaxel in advanced ovarian cancer patients not candidates for optimal primary surgery: Safety and effectivenes.

5540 Background: Primary debulking surgery (PDS) has been considered the standard of treatment in advanced ovarian cancer, while neoadjuvant chemotherapy, three cycles followed by interval debulking (ID) surgery, is a valid treatment alternative for patients with non-resectable disease. This study aimed to show the efficacy and safety of six cycles of neoadjuvant chemotherapy (N-CT) followed by cytoreduction, a single institution experience. Methods: Aretrospective analysis was performed of all patients (pts) with advanced ovarian cancer treated with platinum based N-CT, between January/2004 and February/2012. Results: 97 pts underwent N-CT in our institution; 78.1% and 18.8% the patients had extensive stage IIIC or IV disease at diagnosis, respectively. Median age 60 years (36 – 82). Histologic types: serous 84.5%, adenocarcinoma not specified 11.3%, endometrioide 1.0%. A median of six cycles of chemotherapy were performed. Patients did not received chemotherapy after debulking surgery. During the treatment 31.4% had grade 3/4 toxicity, the most commonly observed toxicities were hematologic toxicities and nausea, four (4.1%) patients died during chemotherapy due to disease progression. After N-CT 24.7% achieved clinical complete response, 57.7% partial response and 12.4% disease progression. From this cohort 63.1% underwent a complete resection of all macroscopic and microscopic disease (R0). Median length of hospital stay and postoperative ICU stay was 5 and 0.8 days respectively, surgical complications were not common however five (7.1%) patients needed second surgery due to operatory complications and 19 pts (27.1%) needed blood transfusion after debulking. With a median follow up of 21.8 months (0.5-139.7), median overall survival and chemotherapy-free interval were 57,7 and 9,5 months, respectively. Conclusions: Six cycles of neoadjuvant carboplatin and paclitaxel is safe, effective and does not increase perioperative and postoperative complications for patients with stage IIIC-IV not candidates for optimal/R0 PDS. The overall survival of this cohort is higher than those treated with interval debulking surgery.

Treatment Strategy for Elderly Patients with Metastatic Colorectal Cancer: A Review of the Systemic Chemotherapy Options

Despite many recent advances in the treatment of metastatic colorectal cancer (mCRC) and corresponding improvements in patient survival, most of the pivotal trials have involved fit, young patients. Consequently, it is unclear whether efficacy and safety profiles from these large randomized trials are applicable to patients older than 70 years of age, who account for more than half of those with mCRC. Most of the conclusions regarding chemotherapy for elderly mCRC patients are derived from combined or subgroup analyses from large studies in which elderly patients are typically defined as those more than 65 or 70 years of age. In general, it was concluded that, as with young patients, systemic chemotherapy could be beneficial for these elderly patients also, with tolerable adverse events. Nonetheless, it was subsequently determined that serious adverse events occurred more frequently in elderly patients and that immediate intensive chemotherapy did not always result in better overall survival for this group. In patients scheduled for capecitabine, previous estimation of renal function and careful administration of the drug are necessary; however, contrary to expectations, the quality of life is not better than that achieved with 5-fluorouracil. Another therapeutic option is immediate doublet chemotherapy, but for elderly patients, a stop-and-go strategy or chemotherapy-free intervals should be considered. Targeted agents, including bevacizumab, cetuximab, and panitumumab, have resulted in outcomes no inferior for older than for younger patients, but they require further investigation to optimize their use. The variable findings obtained for elderly patients emphasize the need for a definition of “elderly” that takes into account not only chronological age, but also physiological age, socioeconomic status, and the results of objective tools such as comprehensive geriatric assessment.

Involved-field radiation therapy for locoregionally recurrent ovarian cancer

ObjectiveTo evaluate the effectiveness of definitive involved-field radiation therapy (IFRT) for selected patients with locoregionally-recurrent ovarian cancer. MethodsWe retrospectively reviewed records of 102 epithelial ovarian cancer patients treated with definitive IFRT (≥45Gy). IFRT was directed to localized nodal (49%) and extranodal (51%) recurrences. ResultsThe median time from diagnosis to IFRT was 36months (range, 1–311), and the median follow-up after IFRT was 37months (range, 1–123). Patients received a median of three chemotherapy courses before IFRT (range, 0–9). Five-year overall (OS) and progression-free survival (PFS) rates after IFRT were 40% and 24% respectively; the 5-year in-field disease control rate was 71%.Thirty-five patients (35%) had no evidence of disease at a median of 38months after IFRT (range, 7–122), including 25 continuously without disease for a median of 61months (range, 17–122) and 10 with salvage treatment following disease recurrence, disease-free for a median of 39months after salvage treatment (range, 7–92).Eight clear cell carcinoma patients had higher 5-year OS (88% versus 37%; p=0.05) and PFS (75% versus 20%; p=0.01) rates than other patients. Patients sensitive to initial platinum chemotherapy had a higher 5-year OS rate than platinum-resistant patients (43% versus 27%, p=0.03). Patients who required chemotherapy for recurrence after IFRT often benefitted from longer chemotherapy-free intervals after than before IFRT. ConclusionsDefinitive IFRT can yield excellent local control, protracted disease-free intervals, and even cures in carefully selected patients. RT should be considered a tool in the curative management of locoregionally-recurrent ovarian cancer.

A prognostic nomogram to predict overall survival in patients with platinum-sensitive recurrent ovarian cancer

BackgroundPatients with platinum-sensitive recurrent ovarian cancer have variable prognosis and survival. We extend previous work on prediction of progression-free survival by developing a nomogram to predict overall survival (OS) in these patients treated with platinum-based chemotherapy. Patients and methodsThe nomogram was developed using data from the CAELYX in Platinum-Sensitive Ovarian Patients (CALYPSO) trial. Multivariate proportional hazards models were generated based on pre-treatment characteristics to develop a nomogram that classifies patient prognosis based on OS outcome. We also developed two simpler models with fewer variables and conducted model validations in independent datasets from AGO-OVAR Study 2.5 and ICON 4. We compare the performance of the nomogram with the simpler models by examining the differences in the C-statistics and net reclassification index (NRI). ResultsThe nomogram included six significant predictors: interval from last platinum chemotherapy, performance status, size of the largest tumour, CA-125, haemoglobin and the number of organ sites of metastasis (C-statistic 0.67; 95% confidence interval 0.65–0.69). Among the CALPYSO patients, the median OS for good, intermediate and poor prognosis groups was 56.2, 31.0 and 20.8 months, respectively. When CA-125 was not included in the model, the C-statistics were 0.65 (CALYPSO) and 0.64 (AGO-OVAR 2.5). A simpler model (interval from last platinum chemotherapy, performance status and CA-125) produced a significant decrease of the C-statistic (0.63) and NRI (26.4%, P < 0.0001). ConclusionsThis nomogram with six pre-treatment characteristics improves OS prediction in patients with platinum-sensitive ovarian cancer and is superior to models with fewer prognostic factors or platinum chemotherapy free interval alone. With independent validation, this nomogram could potentially be useful for improved stratification of patients in clinical trials and also for counselling patients.

778 INTERMITTENT DOCETAXEL THERAPY FOR CASTRATION RESISTANT PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced (II)1 Apr 2013778 INTERMITTENT DOCETAXEL THERAPY FOR CASTRATION RESISTANT PROSTATE CANCER Haruki Kume, Masayoshi Nagata, Yasuhiko Igawa, Hiroaki Nishimatsu, Yutaka Enomoto, Tohru Nakagawa, Tetsuya Fujimura, Motofumi Suzuki, and Yukio Homma Haruki KumeHaruki Kume Tokyo, Japan More articles by this author , Masayoshi NagataMasayoshi Nagata Tokyo, Japan More articles by this author , Yasuhiko IgawaYasuhiko Igawa Tokyo, Japan More articles by this author , Hiroaki NishimatsuHiroaki Nishimatsu Tokyo, Japan More articles by this author , Yutaka EnomotoYutaka Enomoto Tokyo, Japan More articles by this author , Tohru NakagawaTohru Nakagawa Tokyo, Japan More articles by this author , Tetsuya FujimuraTetsuya Fujimura Tokyo, Japan More articles by this author , Motofumi SuzukiMotofumi Suzuki Tokyo, Japan More articles by this author , and Yukio HommaYukio Homma Tokyo, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.342AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Docetaxel chemotherapy (75 mg/m2, every three weeks, up to 10 cycles) has been one of the standard therapies for castration resistant prostate cancer (CRPC). However, adverse events cannot be underestimated. To reduce them we conducted an intermittent treatment. METHODS CRPC cases were given docetaxel at 75 mg/m2 every three weeks with oral dexamethasone 1.0 mg/day. PSA was monitored every 3 weeks. Chemotherapy was suspended if serum PSA level was reduced by more than 50% and reached a level below 4 ng/mL. Treatment was resumed when serum PSA rose by more than 50% and was over 2 ng/mL. RESULTS Fifty CRPC cases were enrolled to this study. Among them 25 (50%) qualified for intermittent treatment: 10 cases received the second and two cases received the third intermittent therapies. The median first chemotherapy-free interval was 251 days, and second was 140 days. During the chemotherapy-free period appetite loss, fatigue, diarrhea, alopecia, and nail change were fully recovered in 5 of 6 (83.3%), 4 of 8 (50%), 3 of 5 (60%), 13 of 17 (76.5%), and 10 of 14 (41.4%), respectively, while motor neuropathy and sensory neuropathy were fully recovered only in 1of 4 (25%) and 1 of 11 (9.1%). Multivariate analysis demonstrated that lower PSA at the start of docetaxel therapy (<31.03 ng/mL (median), p=0.015, Hazard ratio=6.45) and absence of previous steroid therapy (p=0.041, Hazard ratio=4.77) were significant factors for ensuring intermittent therapy. The overall survival was significantly better in the intermittent cases (Figure, log rank test, p=0.010, Hazard ratio 3.50). CONCLUSIONS This intermittent regimen may result in reduction of adverse events in about half of CRPC patients without impairing oncological outcome during a chemotherapy-free period. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e320-e321 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Haruki Kume Tokyo, Japan More articles by this author Masayoshi Nagata Tokyo, Japan More articles by this author Yasuhiko Igawa Tokyo, Japan More articles by this author Hiroaki Nishimatsu Tokyo, Japan More articles by this author Yutaka Enomoto Tokyo, Japan More articles by this author Tohru Nakagawa Tokyo, Japan More articles by this author Tetsuya Fujimura Tokyo, Japan More articles by this author Motofumi Suzuki Tokyo, Japan More articles by this author Yukio Homma Tokyo, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Design of precise third-line therapy for gastric cancer: target or chemotherpy?

See Article on Page 314-321 It has been accepted since the 1990s that palliative chemotherapy can significantly prolong the survival of patients with advanced gastric carcinoma, compared to supportive care alone [1,2]. However, there is controversy over the benefit of salvage therapy past second-line due to the lack of evidence. Recently, there has been renewed interest in salvage chemotherapy after first- and second-line treatments have failed because of the prolonged survival time and relatively low toxicity of agents. Many clinicians consider second-line chemotherapy after failure of first-line chemotherapy for patients with advanced gastric carcinoma [3]. Phase II trials and retrospective analyses have provided evidence that second-line is effective [4]. Recently, randomized phase III trials have strongly indicated that second line or further chemotherapy is more advantageous than supportive care (Table 1). A German trial found that irinotecan monotherapy improved overall survival compared to best supportive care [5]. A Korean trial found that irinotecan or docetaxel monotherapy prolonged overall survival compared to best supportive care and there was no difference in the treatment effect of docetaxel and irinotecan (p = 0.116) [6]. In the 2013 the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium, it was reported that docetaxel [7] and ramucirumab [8] demonstrated clinical benefit over supportive care in two phase III trials. Both agents significantly prolonged overall survival (Table 1). There is ample evidence to support the use of second line treatment in advanced gastric cancer. However, the issue of which regimen is a standard second-line treatment has not been clarified. Table 1 Randomized phase III trials evaluating the advantage of second-line or further chemotherapy over supportive care Little information concerning the survival advantage of third-line chemotherapy is extant. In a Korean phase III trial, the survival benefit in the chemotherapy arm was preserved in the further chemotherapy group (hazard ratio, 0.812; 95% confidence interval [CI], 0.450 to 1.464) (Table 1). Several retrospective studies presented the natural history of advanced gastric cancer with sequential salvage chemotherapy following first-line treatment [4]. The survival prolongation by second- and third-line salvage chemotherapy indicates its feasibility in selected patients. After failure of first-line chemotherapy based on platinum and fluoropyrimidine, irinotecan, or taxane-based regimens have benefited survival and led to the same clinical outcome as salvage chemotherapy in advanced gastric cancer patients [4,6]. Based on the lack of cross-resistance between irinotecan and taxane, both regimens are plausible salvage treatment options. Additionally, it is necessary to select patients for salvage chemotherapy based on survival predictors including performance status, chemotherapy-free interval, response duration, metastatic pattern, tumor burden, and serum carcinoembryonic antigen level [4,6]. Lee and colleagues [9] evaluated the efficacy and toxicity of docetaxel monotherapy, 75 mg/m2 on day 1 every 3 weeks, in advanced gastric cancer patients who did not respond to oxaliplatin with leucovorin and 5-fluorouracil (m-FOLFOX-4), or to irinotecan with leucovorin and 5-fluorouracil (m-FOLFIRI). This retrospective study included thirty three patients and reported an overall response of 15%, time to progression of 2.1 months (95% CI, 1.63 to 2.58), and an overall survival time of 4.7 months (95% CI, 3.20 to 6.20). The results are comparable to previous reports of the efficacy of third-line treatment. This study provides important evidence that docetaxel is a feasible third-line therapy regimen after m-FOLFIRI and m-FOLFOX-4 regimens. A randomized prospective trial could further support this conclusion. Trastuzumab, a molecular target agent, was approved for HER2 amplified gastric cancer patients, and other anti-HER2 agents-including lapatinib-have been evaluated as first- or second-line treatments. Furthermore, studies have been performed to elucidate biomarkers of chemotherapeutic agents and to investigate molecular biological features, including genetic and epigenetic profiles [10]. On the basis of those outcomes, randomized trials of target agents, and molecular biologic markers would facilitate treatment tailored to the individual patient.

Volumetric Analysis of Remnant Liver Regeneration After Major Hepatectomy in Bevacizumab-Treated Patients

The objective was to determine the liver regeneration capacity and morbidity and mortality rates after major hepatectomy for colorectal metastases in patients having undergone bevacizumab-based chemotherapy (bev+). Between 2006 and 2011, 41 patients underwent major hepatectomy within 3 months of bevacizumab and were matched with 41 patients operated on following systemic chemotherapy without bevacizumab (bev-). The matching criteria were the following: number of courses of chemotherapy, chemotherapy-free interval, age, and type of hepatectomy. After measurements of remnant liver volume (RLV) preoperatively and at 1 month (RLV1M), volumetric gain was calculated as absolute (RLV1M-RLV) or relative regeneration [(RLV1M-RLV/RLV)]. Ninety-day morbidity was rated according to the Clavien-Dindo classification. There were 21 right, 9 extended right, and 11 left hepatectomies in each group. Groups were comparable in terms of matching criteria, body mass index, American Society of Anesthesiologists score, and RLV. No mortalities were observed. There were no intergroup differences in overall morbidity (56% in bev+ vs 34.1%; P = 0.075) or postoperative liver failure. A severe complication occurred in 5 bev+ (4 eviscerations) and 4 bev- (bile leakages) (P = 0.95). The median hospital stay was similar in both groups as were the degrees of absolute and relative liver regeneration (143% in bev+ vs 114%; P = 0.20). Liver regeneration was not influenced by the type of hepatectomy, the number of courses of chemotherapy, or age more than 65 years. In a methodologically robust trial in the largest cohort reported up to date, bevacizumab did not impair liver regeneration after major hepatectomy-even in elderly patients or those with high exposure to chemotherapy.

528PD - The Effect of Chemotherapy Holiday on the Overall Survival of Patients with Advanced Colorectal Cancer: A Meta-Analysis of Randomized Trials

ABSTRACT Background The impact of the duration of chemotherapy on the outcomes of patients with advanced colorectal cancer is controversial. Our objective was to perform a systematic review and meta-analysis of randomized controlled trials (RCT) that compared chemotherapy continuously administered until disease progression versus chemotherapy interruption in patients with metastatic colorectal cancer. Methods We systematically searched for all RCT in which metastatic colorectal cancer patients were randomized to continuous therapy until progression or chemotherapy discontinuation after maximal response or fixed number of cycles. Trials were located through searches of PubMed, Cochrane Library and of ASCO/ESMO abstracts up to February 2012. Two authors independently extracted the data, and consensus was achieved when there was disagreement. Meta-analyses were performed using random-effects model. Hazard ratios (HR) were used for the meta-analysis and were expressed with 95% confidence intervals (CI). Statistical heterogeneity of data was evaluated with the chi-square test, and expressed using the I2 index. Results Our search retrieved 42 RCT, of which five were eligible, with 1815 patients included. The analysis of progression-free survival (PFS) was not possible due to the different definitions of PFS across trials. The median chemotherapy free interval in the discontinuation group was 3.9 months. The pooled analysis of overall survival included 1776 patients (one trial was not included because it did not present extractable data). The metanalysis showed a statistically significant survival benefit with continuously given chemotherapy (HR = 0.90, 95% CI = 0.82 to 0.99; p = 0.03; I2 0%) in comparison to chemotherapy holiday strategy. Quality of life was reported in one trial and no difference was found in it. Conclusions Chemotherapy delivered continuously until tumor progression appears to be associated with a modest but significantly better survival in patients with advanced colorectal cancer over chemotherapy interruption. Continued therapy may be available for selected patients with more aggressive disease. Disclosure All authors have declared no conflicts of interest.

What’s new in metastatic breast cancer?

Overall, breast cancer mortality has declined due to advances in systemic adjuvant treatment in recent years; still, metastatic breast cancer remains an incurable disease. Due to novel treatment options, however, survival was prolonged even in patients with advanced-stage disease. In hormone-receptor positive breast cancer, endocrine therapy is the mainstay of treatment. Currently, different strategies are being evaluated to overcome resistance to anti-hormonal interventions, with the aim to prolong the chemotherapy-free interval. In Her2-positive breast cancer, anti-Her2 targeted therapies such as trastuzumab or lapatinib have improved patients’ outcome. Further substances—antibodies or novel tyrosine-kinase inhibitors—will increase therapeutic options in the future. Limited progress was achieved in the triple-negative sub-type. Bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor, is currently the only biological agent available in this sub-type. In combination with paclitaxel or capecitabine, bevacizumab offers clinically meaningful activity in metastatic breast cancer patients. Other strategies, such as treatment with DNA-damaging agents or the inhibition of DNA-repair mechanisms were not successful so far in a general triple-negative population. This article reviews recent developments and future trends in the field of metastatic breast cancer.

The relationship between microRNA-126 and maintenance therapy with bevacizumab after bevacizumab plus chemotherapy as first-line treatment for patients with metastatic colorectal cancer: Results of the phase III Nordic ACT trial NCT00598156 translational study.

3573 Background: Maintenance therapy during chemotherapy free intervals is a debatable topic in metastatic colorectal cancer (mCRC). In the Nordic ACT trial patients benefitting from induction chemotherapy plus bevacizumab were randomized to bevacizumab with or without erlotinib. MicroRNA-126 (miRNA-126) is believed to influence angiogenesis in several ways, and we investigated the relationship between miRNA-126 and progression free survival (PFS) under maintenance therapy. Methods: The miRNA-126 was analysed by polymerase chain reaction on both genomic DNA (by the pri-miRNA-126 (A24G) single nucleotide polymorphism (SNP)) and paraffin embedded primary tumors, (which were classified as low or high miRNA-126 expressing tumours using the median value as cut-off). Diagnostic biopsies were not processed due to limited tumour tissue. Of the 159 randomized patients blood samples were available from 151 and primary tumours from 91. The PFS (from time of randomization) was compared using the Kaplan-Meier method and the log rank test. The Cox Regression analyses were used to test for independent contributions. Results: The A24G SNP was not related to PFS, but a significant association was seen between genotypes and miRNA-126 expression levels.Furthermore, the PFS was increased in patients with high tumor miRNA-126 expression compared to patients with low expression, hazard ratio (HR) 0.58 (95% confidence interval (CI) 0.38-0.90), p = 0.015. The median PFS was 6.2 months (95% CI 4.3-6.6 months) and 4.0 months (95% CI 2.6-4.5 months), respectively. Results did not differ between treatment arms, but the Cox Regression analysis confirmed an independent prognostic value of the tumor miRNA-126 expression, HR 0.61 (95% CI 0.39-0.95), p = 0.030. Conclusions: The miRNA-126 may be a potential marker for bevacizumab containing maintenance therapy. A similar relationship with PFS has recently been demonstrated in patients with mCRC treated with chemotherapy only. The results call for validation.

Combined analysis of randomized controlled trial (RCT) and patient-preference trial (PPT) evaluating second-line chemotherapy (SLC) in advanced gastric cancer (AGC).

4064 Background: While prolonged overall survival (OS) from SLC compared to best supportive care (BSC) has recently been demonstrated for AGC (Park et al, ASCO 2011), the prognosis of pretreated AGC remains poor. We assessed whether patient preference, willing to participate onto RCT, or other parameters contributed to this OS improvement. Methods: In the phase III trial, pretreated AGC patients (n=372) were first offered RCT. If a patient agreed to participate, randomly assigned 2:1 to SLC or BSC (n=202). If refused RCT, but agreed to receive treatment of their preference, they were offered SLC or BSC (PPT; n=170). OS of RCT participants was compared to that of whole patient population according to prognostic subgroups. In addition, analyses of OS unadjusted for multiple comparisons were conducted across predefined subgroups. Results: Median OS was 6.3 months among 254 patients treated with SLC and 3.3 months among 118 patients treated with BSC (HR, 0.507; 95% CI, 0.405 to 0.637; one-sided p&lt;0.001). Compared to the RCT patients, younger age group, those with an ECOG performance status (PS) of 0, and with one prior chemotherapy were under-represented in the PPT patients. OS was comparable between RCT (5.0 months) and PPT (4.4 months) patients even after controlling for major prognostic factors (log-rank p=0.322). The OS benefit for SLC was preserved when analyzed according to baseline parameters. Parameters that were associated significantly with a prolonged OS included a PS of 0, the chemotherapy-free interval ≥3 months, and one prior chemotherapy. When the analysis was adjusted for these three parameters, patients who received SLC still had improved OS (HR, 0.554; 95% CI, 0.441 to 0.696; p&lt;0.001). Conclusions: The 54% participation rate obtained in the current study represents the best achievable rate for this kind of phase III RCT involving BSC only arm. Even if we consider differences in the baseline characteristics between RCT and PPT patients, it is concluded that the RCT results can be generalized for the patient population and provided additional evidence supporting the use of SLC in patients with pretreated AGC.

A phase II study of maintenance therapy with temsirolimus (TEM) after response to first-line docetaxel (TAX) chemotherapy in castration-resistant prostate cancer (CRPC).

e15152 Background: TAX is the standard first-line chemotherapy for CRPC. However, a number of questions remain regarding the optimal use of TAX following maximal response. Aside from intermittent TAX, maintenance therapy with well-tolerated agents such as the mTOR inhibitor TEM could be one strategy to prolong treatment response and the chemotherapy-free interval, without significantly compromising quality of life. In fact, the mTOR pathway is involved in many aspects of CRPC, and mTOR inhibitors have demonstrated significant anti-CRPC activity in preclinical testing. Methods: CRPC pts eligible for this single-arm, multicenter phase II trial must have received between 6 to 8 cycles of first-line TAX (75 mg/m2 q3wks) with documented treatment response by PSA (>50% decline from baseline) or RECIST criteria. 30 pts will be enrolled and administered weekly TEM (25 mg iv x 4/cycle). The primary endpoint is time to treatment failure (TTF, by RECIST or symptomatic progression). Secondary endpoints include safety (NCI-CTCAE v3.0), quality of life (FACT-P, PPI), changes in PSA doubling time and time to PSA progression, objective tumor response rate (RECIST), and overall survival. We will also study correlative endpoints using plasma and peripheral blood mononuclear cells (i.e., markers of mTOR inhibition, of antiangiogenic TEM effects and of intratumoral hypoxia/acidosis, the latter as potential predictive markers). Results: 10 pts have been enrolled to date: mean age 68 (range 52 - 80), prior definitive local therapy (7) - radiation (6), prostatectomy (1), mean PSA at entry 99.28 (2.3 - 380.7), ECOG 0 (4) or 1 (6), prior cycles of TAX 6 (6) or 8 (4), sites of metastasis - bone (8), lymph nodes (4), visceral (3). 6 pts have been discontinued due to treatment failure after a mean of 5.3±1.9 cycles (range 3-8) - RECIST (1), symptomatic (2), combined (3). 4 pts are on cycle 1-2-8-9, respectively. TEM has been generally well tolerated without unexpected side-effects, but may have contributed to worsening lymphedema in 1 pt. Conclusions: TEM maintenance therapy in CRPC pts that have responded to first-line TAX is well tolerated and appears to result in meaningful TTF.

Second-line chemotherapy in patients with primary unknown cancer

There are few existing reports on the efficacy of second-line chemotherapy in patients with cancer of unknown primary site (CUP). The aim of this study was to identify characteristics of CUP patients linked to a positive response to chemotherapy. We retrospectively studied the clinical outcomes of second-line chemotherapy in patients with CUP who had previously been treated with platinum-based first-line chemotherapy. A total of 27 patients received second-line chemotherapy. Of these patients, 5 (19%) showed an objective response to second-line chemotherapy; 4 of these patients had shown a favorable response to first-line chemotherapy and had a chemotherapy-free interval (CFI) of more than 4.5months. Among the 8 patients in whom the CFI was more than 4.5months, 4 (50%) showed an objective response to platinum-based second-line chemotherapy, whereas among the 16 patients with a CFI of less than 4.5months, only 1 (6%) showed a response to any chemotherapeutic regimen. The response to second-line chemotherapy in CUP patients who had received platinum-based first-line treatment seemed to be associated with the response to first-line chemotherapy and the CFI. Although it remains unclear whether second-line chemotherapy might contribute to a survival benefit in patients with CUP, patients who show a favorable response to first-line chemotherapy and also a relatively prolonged CFI appear to be likely to benefit from second-line chemotherapy.

Phase II study of maintenance therapy with temsirolimus (TEM) after response to first-line docetaxel (TAX) chemotherapy in castration-resistant prostate cancer (CRPC).

160 Background: TAX is the standard first-line chemotherapy for CRPC. However, a number of questions remain regarding the optimal use of TAX following maximal response. Aside from intermittent TAX, maintenance therapy with well-tolerated agents such as the mTOR inhibitor TEM could be one strategy to prolong treatment response and the chemotherapy-free interval, without significantly compromising quality of life. In fact, the mTOR pathway is involved in many aspects of CRPC, and mTOR inhibitors have demonstrated significant anti-CRPC activity in preclinical testing. Methods: CRPC pts eligible for this single-arm, multicenter phase II trial must have received between 6 to 8 cycles of first-line TAX (75 mg/m2 q3wks) with documented treatment response by PSA (&gt;50% decline from baseline) or RECIST criteria. 30 pts will be enrolled and administered weekly TEM (25 mg iv × 4/cycle). The primary endpoint is time to treatment failure (TTF, by RECIST or symptomatic progression). Secondary endpoints include safety (NCI-CTCAE v3.0), quality of life (FACT-P, PPI), changes in PSA doubling time and time to PSA progression, objective tumor response rate (RECIST), and overall survival. We will also study correlative endpoints using plasma and peripheral blood mononuclear cells (i.e., markers of mTOR inhibition, of antiangiogenic TEM effects and of intratumoral hypoxia/acidosis, the latter as potential predictive markers). Results: 10 pts have been enrolled to date: mean age 68 (range 52-80), prior definitive local therapy (7)—radiation (6), prostatectomy (1), mean PSA at entry 99.28 (2.3- 380.7), ECOG 0 (4) or 1 (6), prior cycles of TAX 6 (6) or 8 (4), sites of metastasis—bone (8), lymph nodes (4), visceral (3). 6 pts have been discontinued due to treatment failure after a mean of 5.3±1.9 cycles (range 3-8) - RECIST (1), symptomatic (2), combined (3). 4 pts are on cycle 1-2-8-9, respectively. TEM has been generally well tolerated without unexpected side-effects, but may have contributed to worsening lymphedema in 1 pt. Conclusions: TEM maintenance therapy in CRPC pts that have responded to first-line TAX is well tolerated and appears to result in meaningful TTF. No significant financial relationships to disclose.

Intermittent Docetaxel Chemotherapy in Patients With Castrate-resistant Prostate Cancer

To determine whether intermittent docetaxel might control disease while limiting the toxicity and improving the quality-of-life parameters in patients with advanced, castrate-resistant prostate cancer. Intermittent docetaxel represents an appealing therapeutic approach. We reviewed the records of 35 patients with chemotherapy-naive castrate-resistant prostate cancer who had received docetaxel 45 mg/m(2) every 2 weeks, with oral prednisone 5 mg twice daily. Treatment was held when the patients had reached a >50% prostate-specific antigen reduction from baseline that was confirmed by a second measurement 4 weeks later, in the absence of disease progression. Docetaxel was resumed at a >25% prostate-specific antigen increase from the nadir level, also confirmed by a second measurement 4 weeks later, or in cases of documented disease progression. Of the 35 patients, 18 (51.42%) had entered the first chemotherapy-free interval (CFI) after a median of 6 infusions (range 2-12), 6 patients had entered a second CFI after a median of 4 months (range 2-12), and 1 patient, a third CFI at the last follow-up point. The median interval "off chemotherapy" was 4.5 months (range 1-16) for the first CFI. Two patients discontinued docetaxel because of Grade 4 nonhematologic toxicity. The median interval to treatment failure was 8.1 months (95% confidence interval 5.1-12.2) for the entire cohort and 12.2 months (95% confidence interval 8.3-25+) for the patients who had entered the first CFI. The results of our study have shown that intermittent docetaxel is a clinically active and likely more tolerable and less costly therapeutic strategy for patients with castrate-resistant prostate cancer than continuous administration. Additional validation of this approach is warranted.

Reply to T. Maughan et al

We thank Maughan et al for their interest and commentary on the OPTIMOX2 (Optimized Leucovorin-Fluorouracil-Oxaliplatin) study, which should be considered along with the editorial by Hochster. Some remarks have already been discussed. Maintenance therapy and chemotherapy-free interval were stopped at progression in most patients. They were stopped in six patients (3%) before (but not until) the tumor reached the baseline measure in case of previous response, or in case of tumor-related symptoms. The COIN (COntinuous chemotherapy versus INtermittent chemotherapy) trial showed that continuous therapy was associated with a trend toward better survival compared with chemotherapy discontinuation, as in the OPTIMOX2 study. The hazard ratio for overall survival in the OPTIMOX2 study was 1.14, with a 95% CI of 0.8259 to 1.574, compared with the hazard ratio of 1.084 in the COIN trial, with a 80% CI of 1.008 to 1.165. We used duration of disease control (DDC) because it has been proven that progression-free survival (PFS) is not a suitably reliable end point to predict overall survival (OS) when patients can receive more than one course of treatment. It has been proposed that DDC can capture the treatment effect in strategic trials. It is defined as the sum of PFS of the first treatment phase and the PFS of the following treatment phases when progression is not observed at their first evaluation. We showed in a pooled analysis that there was a strong association between DDC and OS (r 0.93; P .001), but there was no statistically significant correlation between PFS and OS (r 0.45; P .49). There is no difficulty in using DDC if data postprogression are available. On the basis of the OPTIMOX study, we decided not to plan chemotherapy discontinuation at baseline, but only in selected patients after at least 6 months induction chemotherapy. A normal carcinoembryonic antigen level at 3 months from baseline was found to be a predictive factor for a prolonged chemotherapy-free interval and favorable prognostic factor for overall survival. We agree that additional large data sets will give us new information about patient eligibility for chemotherapy discontinuation. Benoist Chibaudel, Frederique Maindrault-Goebel, Christophe Tournigand, and Aimery de Gramont Hopital Saint-Antoine, Assistance Publique des Hopitaux de Paris, Paris, France

Reply to T. Maughan et al

COIN (COntinuous chemotherapy versus INtermitent chemotherapy) trial investigators Maughan et al question the conclusions of the editorial on the OPTIMOX2 (Optimized Leucovorin-Fluorouracil-Oxaliplatin) trial that chemotherapy-free intervals should not be a routine standard of care. This follows as a result of the COIN trial, recently presented in abstract form at the European Society for Medical Oncology meeting in September. As these data have not been published, and there is still much to be known about this study, it is difficult to incorporate their results into a consideration of chemotherapy scheduling for advanced colorectal cancer. As noted in the letter, 1,630 patients were randomly assigned to fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CapeOX) continuously versus intermittent therapy consisting of 12 weeks of treatment followed by observation until the first signs of progression. The results presented and quoted in the letter show a hazard ratio of 1.08 favoring the continuous treatment, which does not fit their (admittedly strict) definition of noninferiority. Even in the COIN trial, 12-week induction therapy was inferior to continuous treatment. However, we should also note that the median overall survival for both arms was quite short at 15 months and did not reach the survivals reported in recent colorectal trials conducted in the United States and Europe. A general practice in the United Kingdom is to stop all chemotherapy at the time neurotoxicity is reached with FOLFOX or CapeOX regimens. COIN may therefore come down to a comparison of 12 weeks of FOLFOX versus a somewhat longer treatment of 20 to 24 weeks. Data on median number of doses given in both arms were not presented, but the investigators reveal that only a disconcerting 38% (309 of 815 patients) in arm C actually received additional therapy or an actual intermittent approach. Furthermore, for those in arm B, even with KRAS wild-type tumors, the addition of cetuximab did not improve PFS or OS, as compared with a number of other positive first-line trials adding anti-epidermal growth factor receptor antibodies to combination chemotherapy. Failure to optimize use of oxaliplatin, as done in the CONcePT (Combined Oxaliplatin Neurotoxicity Prevention Trial) study, would tend to dilute the added effect of any biologic. In short, COIN may be statistically valid, but clinically the results may be of limited applicability to US and European treatment paradigms. The COIN investigators have, in fact, echoed my editorial comments that better biomarkers or predictive tests are needed to prospectively identify those patients that we see in the clinic who have highly responsive tumors and a long, more indolent course. Such patients, as a matter of course, are treated intermittently, but until appropriate biomarkers are available, clinical observation still governs our management, and we should not routinely adopt chemotherapyfree intervals for all patients.

A phase II study of maintenance therapy with temsirolimus (TEM) after response to first-line docetaxel (TAX) chemotherapy in castration-resistant prostate cancer (CRPC).

TPS246 Background: TAX chemotherapy is the standard of care for first-line cytotoxic therapy of CRPC. However, a number of questions remain regarding the optimal use of TAX following maximal response. Aside from intermittent TAX chemotherapy, maintenance therapy with well- tolerated cytotoxic or cytostatic agents could be one strategy used to prolong the treatment response and chemotherapy-free interval without significantly compromising quality of life. The mammalian target of rapamycin (mTOR) serine/threonine protein kinase is involved in many aspects of CRPC, and mTOR inhibitors have demonstrated significant anti-prostate cancer activity in preclinical testing. Methods: This nonrandomized, open-label, multicenter phase II trial studies maintenance therapy with the mTOR inhibitor temsirolimus (TEM) in patients that have responded to TAX chemotherapy. Eligible CRPC patients must have received between 6 to 8 cycles of first-line TAX chemotherapy (75 mg/m2 q3weeks plus prednisone 5 mg po bid) with documented treatment response by PSA (>50% decline from baseline) or RECIST criteria. They will be administered weekly TEM (25 mg iv) until treatment failure, i.e., objective (RECIST) or symptomatic disease progression. Assuming an increase in time to treatment failure (the primary endpoint of this trial) from 3 to 6 months by using TEM, a type I error rate of 0.05, a power of 80% and a 15% drop-off rate, 30 patients will be enrolled. Secondary clinical endpoints include safety (NCI-CTCAE v3.0) and quality of life (FACT-P and PPI) assessments, changes in PSA doubling time and time to PSA progression, objective tumor response rate (RECIST) and overall survival. Correlative studies on serum/plasma and peripheral blood mononuclear cell lysates will assess surrogate markers of mTOR inhibition (e.g., phospho-p70S6 kinase), cellular and molecular markers of the postulated antiangiogenic effects of TEM (e.g., circulating endothelial (progenitor) cells, vascular endothelial cell growth factor), and markers of intratumoral hypoxia/pH (e.g., osteopontin, carbonic anhydrase IX, as potential predictive markers of treatment benefit). No significant financial relationships to disclose.

Chemotherapy-Free Intervals in Patients With Metastatic Colorectal Cancer: A Tale of Two Cities?

Chemotherapy-Free Intervals in Patients With Metastatic Colorectal Cancer: A Tale of Two Cities?

Alemtuzumab maintenance may safely prolong chemotherapy-free intervals in chronic lymphocytic leukemia

This prospective, single-arm study utilized alemtuzumab as a single agent in a novel maintenance schedule in previously treated chronic lymphocytic leukemia patients with the goal of delaying progression of disease and requirement for chemotherapy. In previously treated CLL patients who had achieved stable disease or better, the following schedule of subcutaneous alemtuzumab was administered: a dose escalation in the first week (3, 10 and 30 mg), followed by 7 weeks of 30 mg alemtuzumab once weekly, 16 weeks of 30 mg once every 2 weeks, followed by once every 3 weeks for 24 weeks. Thus, the entire duration of the planned treatment was 48 weeks. A total of 12 patients were enrolled 11 of which had at least one marker of poor prognosis (unmutated, Zap 70+, CD38+, del11q and del17p). The median chemotherapy-free interval was 13 months, and the median time to disease progression was 10 months. Three patients achieved a CR, one achieved nPR, one had a PR, five failed and two had shown a beneficial response but because of recurrent ITP had to stop alemtuzumab. In six of the 10 patients with previously relapsed disease, the chemotherapy-free interval was longer than their prior chemotherapy-free period. One patient had a reactivation of CMV antigenemia, and another had a bacterial pneumonia. There were no grade 3 or 4 toxicities. Alemtuzumab used in a maintenance schedule is a potentially safe and useful tool in delaying disease progression and chemotherapy-free intervals in previously treated CLL patients.