Ljubisa Acimovic

HYPERFRACTIONATED RADIOTHERAPY ALONE FOR CLINICAL STAGE I NONSMALL CELL LUNG CANCER

PURPOSE Among patients with Stage I nonsmall cell lung cancer (NSCLC), those treated with conventional radiotherapy show poorer prognosis than those treated by surgery. To improve the prognosis of such patients, we have used hyperfractionated radiation therapy. METHODS AND MATERIALS Between 1988 and 1993, 49 patients were treated with hyperfractionated radiotherapy with 1.2 Gy twice daily to a total dose of 69.6 Gy. All patients were technically operable, but 29 had medical problems and 20 refused surgery. The median age and Karnofsky Performance Status was 63 years and 90, respectively. No patient received chemotherapy or immunotherapy. Prophylactic mediastinal irradiation was not given. RESULTS The median survival time was 33 months, and the 5-year survival rate was 30%. The rate at 5 years for freedom from each of relapse, local recurrence, mediastinal lymphnode metastasis, and distant metastasis was 41%, 55%, 89%, and 75%, respectively. Univariate analysis revealed that higher Karnofsky Performance Status score, absence of weight loss before treatment, and T1 stage were associated with better survival, although the T stage became insignificant on multivariate analysis. There were two Grade 3 acute toxicities and three Grade 3 late toxicities, but there was no Grade 4-5 toxicity. CONCLUSION The results of this study compare favorably with those of most previous studies employing conventional fractionation. Further studies on hyperfractionation seem to be warranted for Stage I NSCLC.

Hyperfractionated radiation therapy and concurrent low-dose, daily carboplatin/etoposide with or without weekend carboplatin/etoposide chemotherapy in stage III non–small-cell lung cancer: A randomized trial

Abstract Purpose: To investigate whether the addition of weekend chemotherapy consisting of carboplatin/etoposide to hyperfractionated radiation therapy (Hfx RT) and concurrent daily carboplatin/etoposide offers an advantage over the same Hfx RT/daily carboplatin/etoposide. Methods and Materials: A total of 195 patients (Group I, 98; Group II, 97) were treated with either Hfx RT to a total tumor dose of 69.6 Gy via 1.2 Gy b.i.d. fractionation and daily 50 mg each of carboplatin and etoposide during the RT course (Group I) or the same Hfx RT with daily carboplatin/etoposide consisting of 30 mg each of carboplatin and etoposide and with weekend (Saturdays and Sundays) 100 mg each of carboplatin and etoposide during the RT course (Group II). Results: No difference was found regarding median survival time and 5-year survival rates (20 vs. 22 months and 20% vs. 23%; p = 0.57). Median time to local progression was 20 and 19 months, respectively, while 5-year local progression-free survival rates were 28% and 27%, respectively ( p = 0.66). Also, there was no difference regarding either median time to distant metastasis and 5-year distant metastasis-free survival (21 vs. 25 months and 29% vs. 34%, p = 0.29). There was no difference in the incidence of various nonhematologic toxicities between the two treatment groups, but patients treated with the weekend CHT had significantly more high-grade (≥ 3) hematologic toxicity ( p = 0.0046). Late high-grade toxicity was not different between the two treatment groups. Conclusion: The addition of weekend carboplatin/etoposide did not improve results over those obtained with Hfx RT and concurrent low-dose, daily carboplatin/etoposide, but it led to a higher incidence of acute high-grade hematologic toxicity.

Concurrent Hyperfractionated Radiotherapy and Low-Dose Daily Carboplatin/Paclitaxel in Patients With Early-Stage (I/II) Non–Small-Cell Lung Cancer: Long-Term Results of a Phase II Study

PURPOSE Feasibility and activity of concurrent hyperfractionated radiotherapy (Hfx RT) and low-dose, daily carboplatin and paclitaxel were investigated in patients with early-stage (I/II) non-small-cell lung cancer in a phase II study. PATIENTS AND METHODS Fifty-six patients started their treatment on day 1 with 30 mg/m2 of paclitaxel. Hfx RT using 1.3 Gy bid to a total dose of 67.6 Gy and concurrent low-dose daily carboplatin 25 mg/m2 and paclitaxel 10 mg/m2, both given Mondays through Fridays during the RT course, started from the second day. RESULTS There were 29 complete responses (52%) and 15 partial responses (27%), and 12 patients (21%), experienced stable disease. The median survival time was 35 months, and 3- and 5-year survival rates were 50% and 36%, respectively. The median time to local progression has not been achieved, but 3- and 5-year local progression-free survival rates were 56% and 54%, respectively. The median time to distant metastasis has not been achieved, but 3- and 5- year distant metastasis-free survival rates were 61% and 61%, respectively. The median and 5-year cause-specific survivals were 39 months and 43%, respectively. Acute high-grade (> 3) toxicity was hematologic (22%), esophageal (7%), or bronchopulmonary (7%). No grade 5 toxicity was observed. Late high-grade toxicity was rarely observed (total, 10%). CONCLUSION Hfx RT and concurrent low-dose daily carboplatin/paclitaxel was feasible with low toxicity and effective in patients with stage I/II non-small-cell lung cancer. It should continue to be investigated for this disease.

Hyperfractionated radiotherapy for clinical stage II non-small cell lung cancer

BACKGROUND AND PURPOSE Patients with stage II non-small cell lung cancer who are not suitable for or refuse surgery are treated with radiotherapy, but the results reported so far are not satisfactory. To improve the prognosis of such patients, we have used hyperfractionated radiotherapy. In this paper, we retrospectively analyzed results of the treatment. MATERIALS AND METHODS Between 1988 and 1993, 67 patients were treated with hyperfractionated radiotherapy with 1.2 Gy twice daily to a total dose of 69.6 Gy. All patients were technically operable, but 43 had medical problems and 24 refused surgery. The median age and Karnofsky performance status score was 60 and 90 years, respectively. No patient received chemotherapy or immunotherapy. The median follow-up period was 61 months. RESULTS The median survival time and the 5-year survival rate were 27 months and 25% (standard error, SE, 6%), respectively. The 5-year local control rate was 44% (SE,7%). Univariate analysis of prognostic factors revealed that a higher Karnofsky performance status score, weight loss of < or =5% before treatment, and T1 stage were associated with better prognosis, and peripheral location was of borderline significance (P = 0.053). There were two bronchopulmonary and two esophageal acute grade 3 toxicities, and one bronchopulmonary and two esophageal late grade 3 toxicities. No grade 4 or 5 toxicity was observed. CONCLUSION These results are encouraging and further studies on the use of hyperfractionation seem to be warranted for stage II non-small cell lung cancer.

Accelerated Hyperfractionated Radiation Therapy and Concurrent 5-Fluorouracil/Cisplatin Chemotherapy for Locoregional Squamous Cell Carcinoma of the Thoracic Esophagus: A Phase II Study

PURPOSE To improve the poor prognosis of patients with locoregional esophageal squamous cell cancer, we used concurrent accelerated hyperfractionated radiation therapy (ACC HFX RT) and chemotherapy (CHT). MATERIAL AND METHODS Between January 1988 and June 1993, 28 patients were treated with ACC HFX RT with 1.5 Gy twice daily, to a total dose of 54 Gy concurrently with 5-fluorouracil (5-FU) (300 mg/m2, days 1-5) and cisplatin (CDDP) (10 mg/m2, days 1-5), both given during weeks 1 and 4 of the ACC HFX RT course. Following the ACC HFX RT/CHT, two additional courses of 5-FU (500 mg/m2, days 1-5) and CDDP (20 mg/m2, days 1-5) were both given during weeks 7 and 10. The median age and Eastern Cooperative Oncology Group performance status were 62 and 1, respectively. The American Joint Committee on Cancer (AJCC) stage was I in 12 patients, II in 10, and III in 6. RESULTS The median survival time was 26 months, and the 5-year survival rate was 29%. The rates at 5 years for freedom from relapse, locoregional recurrence, and distant metastasis were 29%, 61%, and 45%, respectively. Univariate analysis revealed that performance status, stage, weight loss, tumor length, and tumor location influenced survival, while age and sex did not. The most frequent acute high-grade (3 or 4) toxicities were esophagitis and leukopenia, seen in 50% and 39% of patients, respectively. Late high-grade toxicity was infrequent. There were no treatment-related deaths. CONCLUSION The results of this study compare favorably with those of previous studies, albeit of relatively high incidence of acute high-grade toxicity. Further studies are warranted to compare its efficacy with other approaches.

Elevated serum level of IL-23 correlates with expression of VEGF in human colorectal carcinoma.

BACKGROUND AND AIMS Interleukin-23 (IL-23) has a role in inflammatory bowel diseases (IBD) as a condition of higher risk of colorectal carcinogenesis. Vascular endothelial growth factor (VEGF) is overexpressed in IBD and colorectal carcinoma. Therefore, we aimed at uncovering the relationship between serum level of IL-23 and expression of VEGF in colorectal cancer (CRC) patients and to establish the relationship between VEGF and p53 and serum levels of IL-23, as well as its possible role in carcinogenesis of colorectal carcinomas. METHODS Levels of IL-23 from serum samples of patients with colorectal carcinoma (n = 40) and healthy control samples (n = 37) were examined for IL-23-Ab using an ELISA assay. We also determined the expression of VEGF and p53 by immunohistochemistry in 59 cases of CRC. RESULTS We found significantly higher serum levels of IL-23 in patients with CRC compared to control subjects (IL-23; mean 189.46 pg/mL vs. mean 34.77 pg/mL, p = 0.033). We also detected higher serum levels of IL-23 in patients with overexpressed VEGF (p = 0.028). Our results also showed that concomitant expression of VEGF and increased serum levels of IL-23 are in positive correlation with histological grade 2 (p <0.05). CONCLUSIONS Our data indicate that serum IL-23 levels are significantly elevated in CRC vs. control patients and are strongly associated with overexpression of VEGF, thus they may play an important role in carcinogenesis of CRC.

Prolonged administration of oral etoposide alone or with intravenous carboplatin in Stage IV non-small cell lung cancer: a randomized trial

BACKGROUND To investigate whether the addition of intravenous carboplatin (CBDCA) to prolonged oral administration of etoposide improves treatment results over that obtained with the same etoposide given alone in patients with Stage IV non small-cell lung cancer (NSCLC). MATERIAL AND METHODS Patients, 120 were randomized to receive either 400 mg/m2 of CBDCA, day 1 and 50 mg/m2 of etoposide, days 1-21 (Group I) or the same etoposide alone (Group II). Cycles were repeated every 4 weeks for up to 6 cycles or until tumor progression was noted. RESULTS Patients, 117 were fully evaluable for this report. Patients in Group I achieved better response rate than those in Group II (31 versus 20%, P = 0.19). They also had longer median survival time and higher 1- and 2-year survival rates than those in Group II (9 versus 5 months, respectively; 38 and 12% versus 24 and 5%, respectively; P = 0.015). There were no treatment-related deaths. Leukopenia (P = 0.047) and thrombocytopenia (P = 0.000) were more frequent in Group I, but only 15 (26%) patients in Group and 7 (12%) patients in Group II experienced high-grade (> or = 3) hematological toxicity. Apart from alopecia (P = 0.000), other non-hematological toxicity was not different between the two treatment Groups. CONCLUSION Results of this study showed improvement in survival for the two-drug regimen. Together with mild to moderate toxicity and low cost, they may warrant further studies comparing it with other approaches in patients with Stage IV NSCLC.

Absence of thoracic radiation myelitis after hyperfractionated radiation therapy with and without concurrent chemotherapy for Stage III nonsmall-cell lung cancer

PURPOSE To investigate whether thoracic spinal cord dose of 50.4 Gy given via 1.2 Gy b.i.d. fractionation carries a risk of developing radiation myelitis during studies using hyperfractionated radiation therapy (HFX RT) with and without concurrent chemotherapy (CHT). METHODS AND MATERIALS Of 300 patients with Stage III nonsmall-cell lung cancer (NSCLC) who were treated on two consecutive Phase III studies, 158 patients received 50.4 Gy to a portion of their spinal cord and survived > 1 year after the beginning of the therapy. RESULTS None of these 158 patients developed thoracic radiation myelitis. Therefore, influence of potentially contributing factors on the occurrence of radiation myelitis, such as interfraction interval, or those unproven yet, such as cord length or administration of concurrent CHT, was not possible to investigate. CONCLUSION Given the continuing interest in HFX RT and encouraging results obtained in studies in lung cancer, further investigation is needed to get more informations about risks of developing thoracic radiation myelitis with this cord dose.

Influence of interfraction interval on the efficacy and toxicity of hyperfractionated radiotherapy in combination with concurrent daily chemotherapy in Stage III non–small-cell lung cancer

PURPOSE To investigate the influence of the interfraction interval (IFI) on treatment outcome and toxicity in hyperfractionated (HF) radiotherapy (RT) for Stage III non-small-cell lung cancer. METHODS AND MATERIALS Data for 301 patients treated with 1.2 Gy b.i.d. to a total of 69.6 Gy and concurrent chemotherapy in our 3 prospective studies were analyzed. The chemotherapy regimen was either (1) 50 mg each of carboplatin and etoposide (CE) given on RT days (163 patients) or (2) 30 mg of CE on RT days and 100 mg of CE on Saturdays and Sundays during the RT course (138 patients). An IFI of 4.5-5 h or 5.5-6 h had been nonrandomly assigned for each patient, and this interval was kept throughout the treatment. RESULTS No difference was observed in treatment outcome due to the chemotherapy protocol, and the 2 groups were combined. Patients treated with the shorter IFI had a better local control rate (38% at 5 years) and survival rate (30% at 5 years) than those treated with the longer interval (23% and 14%, respectively; p < 0.001). However, female patients and those with a high Karnofsky performance status score (KPS), weight loss of < or =5% in the previous 6 months, or Stage IIIA disease had been more often treated with the shorter IFI, and these characteristics were associated with better treatment outcome. In multivariate analysis, only gender, KPS, and weight change proved to be significant prognostic factors influencing both local control and survival, and the effect of IFI was not significant. The incidence of Grade 4 acute esophagitis tended to be higher in the shorter interval group (p = 0.072), but there were no differences in the incidence of late or other acute RT-related toxicities between the 2 groups. CONCLUSIONS The possible influence of the IFI on local control and survival could not be verified using multivariate analysis. To better understand the influence of the IFI, randomized studies with more patients and wider ranges of intervals (e.g., 5 h vs. 8 h) seem to be necessary.

Phagocytic activity of monocytes in patients with breast cancer at different clinical stages

The investigation was designed to evaluate numerical and functional properties of peripheral blood monocytes (PBMo) in patients with breast cancer at different clinical stages. Monocyte phagocytosis test was performed in 19 patients with benign breast tumor, 29 patients with breast cancer and 10 healthy subjects. Cancer patients were divided into three groups on the basis of the clinical stage of disease: groupA, patients with localized disease; groupB, patients with regional lymph node metastasis; and groupC, patients with distant metastasis. Patients with advanced disease (groupC) showed an increase in neutrophils, but no differences in the total count of leukocytes and absolute number of lymphocytes as compared with healthy individuals, patients with benign breast tumor or patients with lower stage. However, the mean number of monocytes decreased in patients with benign disease and further decreased in cancer patients, reaching the significantly lowest value in patients with distant metastasis. Phagocytic activity of PBMo was found to be significantly lower in patients with benign tumor, and it became further reduced in the cancer group, related to the clinical stage. Thus, we noted a sixfold decrease in the capacity of phagocytosis, fourfold decrease in percentage of phagocytosis and twofold decrease in phagocytic index in patients with advanced stage (groupC). The alterations in number and function of PBMo in patients with benign and malignant breast tumor were observed in close association with clinical stage of disease, and thus they could be considered as indicators of tumor progression. However, further studies are required to determine whether monocyte dysfunction could provide additional prognostic information in the case of breast cancer diagnosis and therapy.