Abstract PURPOSE: Lung cancer retains its status as the most common cancer in the world, with an estimated 1.5 million cases diagnosed in 2007, accounting for about 12% of all cancers. Identifying microscopic lynph-node metastases, could have clinical importance in selecting patients for adjuvant treatment. The purpose of this study wasis to Iidentify and evaluate molecular markers for detection of micrometastases in regional lymph nodes from patients undergoing surgery for non-small cell lung cancer. PATIENTS AND METHODS: Candidate micrometasis markers were selected based on digital transcript profiling in EST and SAGE databases, searching for transcripts with high levels in lung cancers and very low levels in normal lymph nodes. Surfactant protein C (SFTPC) and cytokeratin 19 (CK19) mRNA levels in tumor biopsies and resected regional lymp nodes (N=38) from 24 patients undergoing surgery for non-small cell lung cancer were measured by quantitative RT-PCR. A control material consisting of 22 normal mesenterial lymph nodes from patients undergoing surgery for benign colon disorders was analyzed in parallell. RESULTS: The median relative CK19SFTPC mRNA level in the non-small cell lung tumor biopsies were 446 times higher than the highest level in normal control lymph nodes. SFTPC mRNA was not detectable in the normal lymph nodes, whereas the tumor levels were high (Cq-values ranging from 17-25). Using the highest CK19 mRNA level in the normal lymph nodes as a cut-off, four out of five (80%) lymph nodes from patients with known lymph node metastases (by routine histology) had elevated CK19 levels. Accordingly, 5 (15%) of 33 lymph nodes from patients without known metastases (node-negative) had elevated levels of CK19 mRNA. SFTPC mRNA were detectable in 31 of the 33 lymph nodes from node-negative patients, although the median relative level was 7.1 times higher in the 5 lymph nodes from node-positive patients (P=0.002, Mann-Witney test). Elevated CK19 and SFTPC mRNA levels in regional lymph nodes without known metastases may reflect the presence of micrometastases. CONCLUSION: SFTPC and CK19 mRNA are promising surrogate markers for detection of micrometastases in regional lymph nodes from non-small cell lung cancer patients. However, clinical follow-up in a larger cohort is needed to eludicate the prognostic value of such findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 343. doi:10.1158/1538-7445.AM2011-343
71 Background: The Norwegian Gastrointestinal Cancer Group (NGICG) conducted a phase II randomized study comparing the efficacy and safety of FLOX and FLIRI as first line treatment in metastatic or locally advanced gastric cancer. At progression or unacceptable drug related toxicity, a crossover to the other treatment arm should be done, if second line chemotherapy was indicated. Methods: 66 patients from 6 treatment centers in Norway were randomized to FLOX (oxaliplatin 85 mg/m 2 on day 1, bolus 5-FU 500 mg/m 2 and FA 60 mg/m 2 on day 1 and 2, or FLIRI (irinotecan 180 mg/m 2 on day 1, bolus 5-FU 500 mg/m 2 and FA 60 mg/m 2 on day 1 and 2). Both treatments were repeated every second week. The primary endpoint was response rate (RR) and time to progression (TTP). Secondary endpoints were overall survival (OS) and safety data. Results: At the present time data from 63 patients are available for analysis. First-line treatment: FLOX (n = 32) versus (v.) FLIRI (n = 31): Complete response (CR) n = 0 in both arms, partial response (PR) n = 16 v. 9, stable disease (SD) n = 12 v. 13, progressive disease (PD) n = 3 v. 6, not assessable for evaluation n = 1 v. 3 patients. RR was 50 % in the FLOX arm v. 29 % in the FLIRI arm, p = not significant (n.s), Pearson Chi-Square test. Median TTP was 5 months (95 % CI 2.2-7.8) v. 4 months (95 % CI 2.2-5.8), p = n.s, median OS was 11 months (95 % CI 9.2-12.8 ) v. 10 months (95 % CI 5.7-14.3), p = n.s, Log Rank test. Patient characteristics were well balanced. Febrile neutropenia was present among 10 % of the patients in the FLOX arm versus 7 % in the FLIRI arm. Second line treatment: 30 patients received second line treatment with FLOX or FLIRI. Data regarding RR, TTP, OS and safety will be updated in December 2011. Conclusions: The FLOX and FLIRI regimens are well tolerated among patients with locally advanced and metastatic gastric cancer. As first line treatment the FLOX regime had a higher RR of 50% v. 29% for the FLIRI regime, longer TTP; 5 v. 4 months and longer OS 11 v. 10 months, but the difference did not reach statistical significance.
Abstract PURPOSE: To investigate the prognostic value of Mitotic Activity Index (MAI) in lymph node negative and lymph node positive operable breast cancer patients in an unselected population and to compare it to bone marrow (BM) micrometastatis status. PATIENTS AND METHODS: Analysis of MAI assessed using a strict protocol with proven strong prognostic value (Baak JP et al. in: JCO 2005, Ann Oncol 2008 and Breast Cancer Res Treat 2009) was compared to classic prognosticators and BM micrometastases detected by a real-time RT-PCR multimarker assay including mammaglobin, cytokeratin 19 and TWIST1 mRNA in 179 consecutive early breast cancer patients (median follow-up: 96 months; range: 0 to 126 months). RESULTS: Systemic relapse occurred in 31 patients (17.3%) and 26 (14.5%) of these patients died of breast cancer-related causes. MAI (<10, >=10) was strongly associated with recurrence both in lymph-node (LN)-negative (HR 3.4, Confidence Interval (CI) 1.11-10.66) but less so in LN-positive patients (HR: 2.2, CI 0.87-5.62). BM-status was highly significant in LN-positive patients (HR: 3.7, CI 1.5-9.22) but not in LN-negative patients (HR: 2.4, CI 0.65-8.81). With multivariate Cox regression, BM micrometasis status and MAI were the strongest variables in LN-positive patients for both recurrence-free survival (HR 3.7, CI 1.5 −9.2 and HR 2.2, CI 0.9-5.7 respectively) and breast cancer specific survival (HR 3.3, CI 1.25-8.49 and HR 3.1, CI 1.1-8.9, respectively). In the LN-negative population ER was the strongest prognosticator (HR 0.24, CI 0.08-0.8) for systemic relapse, whereas MAI was the only significant variable in breast cancer specific survival (HR 7.0, CI 1.7-27.9). A multimarker panel including both BM-status and MAI was explored and was found to be the most significant prognostic marker in both LN-positive (HR 4.4, CI 1.3-15.3 / HR 6.0, CI 1.4 to 26.4) and LN-negative (HR 4.1, CI 1.0-16.5 / HR 7.7, CI 1.2-50) for both systemic recurrence free survival and breast cancer specific survival, respectively, in multivariate Cox regression. CONCLUSION: MAI and BM micrometastatic status are independent prognostic factors and supplementary to each other in identifying patient groups with poor prognosis. Patients with high mitotic activity tend to relapse early, whereas BM micrometastatic disease predicts a constant risk over time. The combination of the proliferation marker MAI and assessment of BM micrometastasis is the strongest prognostic marker in both the LN-positive and LN-negative subgroups of 179 early breast cancer patients. This allows better identification of patients at need for more aggressive treatment and warrants validation in a larger trial. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1760.
e13024 Background: Circadian clocks control cellular proliferation and drug metabolism over 24 h. However, circadian chronomodulated chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (chronoFLO4) offered no survival benefit as compared to the non-time stipulated FOLFOX2 in an international randomized trial involving patients (pts) with previously untreated MCC (EORTC05963). We hypothesized that treatment near maximum tolerated dose could disrupt circadian clocks thus impairing the efficacy of chronoFLO4 but not of FOLFOX2. Methods: Pts with available data (N=556) were categorized into three subgroups according to the worst grade of neutropenia experienced during treatment. Distinct multivariate models with time-dependent covariates were constructed for each treatment schedule. Results: Neutropenia incidence (all grades) was 39% on chronoFLO4 and 67% on FOLFOX2 (p<0.0001), and G3-4 was 7% and 25%, respectively (p<0.0001). Neutropenia was more frequent in women than in men (FOLFOX2, p=0.003; chronoFLO4, p=0.04). Median survival was 20.7 months in patients with G3-4 neutropenia as compared to 12.5 months in neutropenia-free patients on FOLFOX2 (p<0.0001). Corresponding figures displayed an opposite trend on chronoFLO4, being 13.7 and 19.4 months respectively (p=0.36). Multivariate analysis confirmed that the occurrence of severe neutropenia independently predicted for a better overall survival on FOLFOX2 (HR=0.56; p=0.015). However, the trend was opposite on chronoFLO4 (HR=1.77; p=0.06) (p for interaction <0.0001). Conclusions: The prediction of a better survival in the neutropenic patients on FOLFOX2 supports the administration of conventional chemotherapy near maximum tolerated dose. The opposite trend shown here for chronoFLO4 supports the novel concept of jointly optimized hematologic tolerability and efficacy through circadian-timed therapy.
4531 Background: From 2000-2007, 1,380 Norwegian and Swedish patients (pts) with seminomatous germ cell testicular cancer (SGCT) were followed prospectively according to a nationwide community-based treatment protocol, SWENOTECA V. The main objectives were to register all pts within the multicenter setting of the SWENOTECA in order to maintain and possibly improve the good results in the treatment of SGCT. Methods: Staging procedures, treatment and follow-up were standardized according to the protocol. Based upon physician and patient's preference treatment of clinical stage (CS) I pts were between surveillance (n=508) and 25.2 Gy radiotherapy (n=478) given to a para-aortic and ipsilateral iliac field. As data on adjuvant chemotherapy emerged, pts were also offered one course of adjuvant carboplatin (AUC7) (n=185). In clinical stage IIA, recommended treatment was radiotherapy to a total dose of 27.0 Gy. For clinical stages IIB-IV, cisplatinbased chemotherapy in the form of EP × 4 was recommended. However, in highly advanced seminoma initial BEP chemotherapy was recommended. Results: Of all pts 86% were in CS I, 10.7% in CS II, 1.8% in CS III and 1.4% in CS IV. Median follow-up was 4.7 years, IQR 3.2-6.4. OS survival was 97.6% (26 deaths). CSS was 99.6% (6 deaths) with only one death in primary CS I. In CS I surveillance yielded a relapse rate of 15.3%, adjuvant radiotherapy 0.9% and adjuvant Carboplatin 4.2%. In clinical stage IIA, 10.9% (3/29) relapsed after radiotherapy. In comparison no (0/67) CS IIB pts relapsed after chemotherapy. There were no deaths in CS IIA-B. Conclusions: Anationwide community-based treatment protocol for SGCT is feasible with excellent results. Surveillance is a good option for CS I pts. Despite a low relapse rate, adjuvant radiotherapy has now been abandoned in SWENOTECA as a recommended treatment option due to concerns of induction of secondary cancers. Adjuvant carboplatin (AUC7) in CS I will reduce the rate of relapse by about 70% compared to surveillance. The high rate of relapse in CS IIA pts treated with radiotherapy is of concern, especially when compared to the low number of relapses in CS IIB pts treated with chemotherapy (p=0.011). No significant financial relationships to disclose.
The use of 5-Fluorouracil and Leucovorin is recommended as palliative chemotherapy in metastatic colorectal cancer in patients under 75 years of age with symptomatic disease or objective progression of disease. However, the oncology units do not have the capacity to cope with this large group of patients and this presents a problem. The chemotherapy regime described is simple to use and can be administered by a general practitioner in cooperation with an oncology unit. Courses were held to inform general practitioners, surgeons and internists about the treatment. After an initial evaluation of the patient by an oncologist, treatment was given by the general practitioner according to written instructions. The treatment was evaluated jointly by the oncologist and the general practitioner. It is essential that the general practitioner should have easy access to advice from the oncology unit. It should be considered advantageous to the patient that the medical treatment be given as close to home as possible. This model for treatment will become increasingly important as more antitumour drugs, which can be administered by the general practitioner, become available.
A portable, battery-driven, programmable drug infusion system which administers up to four different drugs through a single i.v. line is described ("IntelliJect I.V. Drug Delivery System"). The IntelliJect System can be used for a wide range of simple and complex regimens, including cytostatic therapy, antibiotic therapy, antiemetic therapy or pain control. If the actual drugs are not compatible, one channel can be programmed for flushing with sodium chloride. The system assures infusion of the right drug at the right time, while allowing delivery of preferred regimens in all settings--hospital, outpatient and home. A central venous access is necessary when used in an outpatient setting. The system needs minimal nurse or patient manipulation. Chemical stability and questions concerning microbiological contamination must be clarified, because drugs will be in the pump from several hours to several days. Applications of the system for cancer treatment are described, and documentation of patient preference of such a system is demonstrated. "IntelliJect I.V. Drug Delivery System" has the potential of optimizing cancer therapy, with regard to both quality of life and scheduling of cytotoxic drugs which can reduce toxicity and thereby possibly allow dose escalation.
