Prognostic factors for longer disease free survival and overall survival after surgical resection of isolated liver metastasis from breast cancer.

PURPOSE: Isolated liver metastases (LMs) from breast cancer (BC) occur in only 1-3% of the cases. Resection of isolated LMs improves survival. We examined the prognostic factors for time to LM development, disease free survival (DFS) and overall survival (OS) after BCLM resection. METHODS: From 2006 to 2009, 32 patients underwent LM resection. All of them had breast cancer surgery for their primary tumor and developed resectable LMs as the first and only site of disease progression. RESULTS: LMs developed after a median of 25 months. With a median follow up of 37 months (range 7-66) after metastases resection, median DFS and OS (with 95% CI) were 22.5 (12-40) and 37 (≥23) months, respectively. Tumor size ≥3 vs <3 cm and adjuvant chemotherapy vs no adjuvant chemotherapy correlated with shorter time to LM development (p<0.01 for both parameters). These parameters and BC negative estrogen (ER)/ progesterone receptors (PR) (ER?/PR? vs other) were related with shorter DFS. Positive (vs negative) axillary lymph nodes and BC negative ER/ PR (ER?/PR? vs other) status correlated with shorter OS (p<0.01 for both parameters). A period to metastases development ≥ 24 months (vs ≤24) and single (vs multiple) metastases were related with longer DFS and OS (p<0.01 for both conditions). CONCLUSION: Despite the relatively small number of patients in this study, we believe that positive ER/PR status for both BC and LMs, negative axillary lymph nodes, time to liver metastases development >24 months and single liver metastases predict longer DFS and OS after LM resection.

Characteristics of local recurrence of lung cancer and possibilities for surgical management.

PURPOSE: To investigate the correlation between stage and histopathological characteristics of patients with lung cancer and local recurrence, as well as the incidence and the characteristics of local recurrence along with the possibility of surgical retreatment. METHODS: Studied were 51 patients with locally relapsing lung cancer, initially treated surgically from 2003 to 2007. The operations performed ranged from conservative wedge resections, standard lobectomies and pneumonectomies to extensive resections of the entire lung and chest wall. All patients underwent regular follow-up including thoracic CT scan every 3 months. RESULTS: All patients were diagnosed with local recurrence after a median of 10 months (range 1-30) after primary surgery with curative intent. There was no statistically significant link between type of surgery and time to local recurrence. Patients with pathological stage I,II, and IIIa had a significantly longer time to local recurrence than those with stage IIIb and IV. Local recurrence sites were the bronchial stump, mediastinal lymph nodes, the remaining lung parenchyma, chest wall and a combination of these. Surgical retreatment was possible in 20 of 51 patients (39.27percnt;). Chest wall was the commonest localization (20 of 51; 39.2%), also the most frequent in the group of surgically retreated patients (13 of 20; 65%). Squamous cell cancer (SCC) was the predominant histological type (38 of 51; 74.5%), followed by adenocarcinoma (9 of 51; 17.7%). CONCLUSION: SCC is the commonest locally relapsing lung cancer. The type of the initial surgical procedure didn't have any impact on the incidence of local recurrence, but the extent and completeness of surgery did. The time to local recurrence heavily depended on the primary tumor pathological stage. Chest wall was the commonest relapse site, and the most suitable for surgical retreatment, which was related to the quality of surgery.

Science ethics education: effects of a short lecture on plagiarism on the knowledge of young medical researchers.

PURPOSE: Plagiarism is the most common form of scientific fraud. It is agreed that the best preventive measure is education of young scientists on basic principles of responsible conduct of research and writing. The purpose of this article was to contribute to the students' knowledge and adoption of the rules of scientific writing. METHODS: A 45 min lecture was delivered to 98 attendees during 3 courses on science ethics. Before and after the course the attendees fulfilled an especially designed questionnaire with 13 questions, specifically related to the definition and various types of plagiarism and self-plagiarism. RESULTS: Although considering themselves as insufficiently educated in science ethics, the majority of the attendees responded correctly to almost all questions even before the course, with percentages of correct responses to the specific question varying from 45.9-85.7%. After completion of the course, these percentages were significantly (p<0.01) higher, ranging from 66.3-98.8%. The percentage of improvement of the knowledge about plagiarism ranged from 9.18- 42.86%. The percentage of impairment ranged from 1.02- 16.33%, the latter being related to the question on correct citing unpublished materials of other people; only for this question the percentage of impairment (16.33%) was greater than the percentage of improvement (11.22%). CONCLUSION: Even a short lecture focused on plagiarism contributed to the students' awareness that there are many forms of plagiarism, and that plagiarism is a serious violation of science ethics. This result confirms the largely accepted opinion that education is the best means in preventing plagiarism.

Science ethics education part II: changes in attitude toward scientific fraud among medical researchers after a short course in science ethics.

PURPOSE: To determine the impact of the short science ethics courses on the knowledge of basic principles of responsible conduct of research (RCR), and on the attitude toward scientific fraud among young biomedical researchers. METHODS: A total of 361 attendees of the course on science ethics answered a specially designed anonymous multiple- choice questionnaire before and after a one-day course in science ethics. The educational course consisted of 10 lectures: 1) Good scientific practice - basic principles; 2) Publication ethics; 3) Scientific fraud - fabrication, falsification, plagiarism; 4) Conflict of interests; 5) Underpublishing; 6) Mentorship; 7) Authorship; 8) Coauthorship; 9) False authorship; 10) Good scientific practice - ethical codex of science. RESULTS: In comparison to their answers before the course, a significantly higher (p<0.001) number of students qualified their knowledge of science ethics as sufficient after the course was completed. That the wrongdoers deserve severe punishment for all types of scientific fraud, including false authorship, thought significantly (p<0.001) more attendees than before the course, while notably fewer attendees (p<0.001) would give or accept undeserved authorship CONCLUSION: Even a short course in science ethics had a great impact on the attendees, enlarging their knowledge of responsible conduct of research and changing their previous, somewhat opportunistic, behavior regarding the reluctance to react publicly and punish the wrongdoers.

Clinical and pathological response to induction chemotherapy used as a prognostic factor in inflammatory breast cancer. Single institution experience.

PURPOSE: To evaluate clinical and pathological characteristics of patients with inflammatory breast carcinoma (IBC). Also, to evaluate the importance of achieved clinical and pathological responses to induction chemotherapy (iCT) and their role in the prognosis of IBC. METHODS: The medical records of 81 female patients with stage IIIB IBC, diagnosed between January 2008 and December 2010 at the Institute for Oncology and Radiology of Serbia (IORS) were evaluated. Almost all of the patients received anthracycline-based iCT. After 3-4 cycles of iCT, the clinical response (defined as complete response/CR, partial response/PR, stable disease/SD and disease progression/ PD) was assessed. Also, pathological response to iCT (defined as pathological complete response/pCR, near complete response/pNCR, partial response/pPR and no change/ pNC) was estimated in patients who had undergone surgery. All first metastatic sites were recorded. RESULTS: Clinical CR/PR was observed in 61.8% of the patients, while the pathological response (pCR, pNCR/near complete response, and pPR) rate in patients who had undergone surgery was 70%. During follow-up 22 (27.2%) patients developed PD (8 responders and 14 non-responders). Most common metastatic sites were the skeleton in non-responders and the liver in responders. Central nervous system (CNS) metastases developed in 24% of non-responders while no responder developed such metastases. Non-responders had shorter OS compared to responders, but without statistical significance. CONCLUSION: Although the number of the patients analysed in this study is relatively small, we believe that response to iCT could be used as a prognostic marker, since patients who initially failed to respond to iCT showed a higher risk for PD with development of distant metastases, primarily in bones and CNS, and shorter survival.

The significance of HER-2 amplification and the size and type of pathological unicentric, initially operable clinical stage I and IIA/IIB breast cancer, in determining the treatment strategy.

PURPOSE: In order to determine the initial treatment strategies for primary operable unicentric breast cancer, the possible relationships of the amplification of human epidermal growth-factor receptor-2 (HER-2), with age, menstrual status, tumor pathological size (pT), histopathological tumor type (HP) and kind of surgical treatment were studied. METHODS: Analysed were 301 patients treated initially by surgery in the period 2006-2009. HP tumor type, pT and HER-2 status (using firstly immunohistochemistry and then chromogenic in situ hybridization/CISH) were determined. The patients were divided into 2 subgroups according to the presence (CISH+)/absence (CISH-) of HER-2 amplification. RESULTS: Data on pT and HER-2 analyses were available for 293/301 (98.3%) patients with ductal (DC) and lobular carcinoma (LC). Amplification of HER-2 was found in 66 (21.9%) patients. No significant difference between the two subgroups regarding age (p=0.08), menstrual status (p>0.05) and kind of operation (p>0.05) was found. HP showed statistically significant difference between DC (55; 83.3%) and LC (11; 16.7%) patients with HER-2 amplification (p<0.01). Further HP analysis of the type of cancer within the pT category as a subgroup showed significantly higher frequency of HER-2 amplification in DC patients for pT1 (p<0.01) and in pT2 + pT3pN0 (p<0.05) compared with patients with LC. CONCLUSION: This study showed a significantly higher incidence of HER-2 amplification in DC tumors, especially in pT1 and pT2, than in LC, which may influence the options in treatment strategies in primary unicentric operable DC type of breast cancer.

Is there a correlation between molecular markers and response to neoadjuvant chemoradiotherapy in locally advanced squamous cell esophageal cancer?

PURPOSE: To evaluate the expression of epidermal growth factor receptor (EGFR), p53, p21 and thymidylate synthase (TS) in a pretherapy biopsy specimen of locally advanced squamous cell esophageal cancer and correlate these markers with response to neoadjuvant chemoradiotherapy. METHODS: Sixty-two patients with histopathologically proven locally advanced (T3 or greater) squamous cell esophageal cancer were enrolled. The expression of EGRF, p53, p21 and TS markers was assessed with immunohistochemistry. Semiquantitative assessment of expression of these markers was performed based on the percent of the stained cells. Radiotherapy (45-50.4 Gy) was delivered concomitantly with 5-fluorouracil (5-FU)/leucovorin (LV)/cisplatin (CIS) chemotherapy. Five to 6 weeks after chemoradiation, response to treatment was assessed. Medically fit and operable patients were operated. The resected material underwent histopathological evaluation of tumor expansion, histological classification after initial multimodality treatment (yp TNM), residual status and tumor regression grade (TRG). RESULTS: Out of 62 patients enrolled, 41 (66%) were evaluated for molecular markers. Clinical response rate was 43.9%. Out of 41 patients, 12 (29%) underwent surgery. TRG 1 was noted in 58% of the patients. In a pretherapy tumor specimen, positive expression was noted in 80, 90, 80 and 71% for EGFR, p53, p21 and TS, respectively. We noted no statistically significant difference neither between tumor marker expression and clinical response to chemoradiation, nor between tumor marker expression and TRG. CONCLUSION: We registered no difference in response to treatment between EGFR, TS, p21 and p53 positive and negative staining.

Expression of ERCC1 protein in biopsy specimen predicts survival in advanced ovarian cancer patients treated with platinum-based chemotherapy.

PURPOSE: The purpose of this study was to investigate whether the expression of excision repair cross complementing 1 (ERCC1) protein I in tumor tissue was associated with resistance to standard carboplatin and paclitaxel (PC) combination chemotherapy in patients newly diagnosed with advanced epithelial ovarian carcinoma (EOC). METHODS: Fresh frozen tumor tissue was obtained from EOC patients. The protein expression levels of ERCC1 in tumor tissue were determined by Western blot analysis in 55 samples with advanced and metastatic EOC with different histologic subtypes; then these patients were treated with PC. RESULTS: The results showed that the clinical objective responses were significantly different in different categories of ERCC1 protein expression levels in patients with EOC. Time to progression (TTP) and overall survival (OS) in EOC patients previously treated with platinum-based chemotherapy were significantly longer in those with low expression compared with patients showing high expression of ERCC1 protein. CONCLUSION: Our results revealed that ERCC1 protein expression could potentially be used to customize chemotherapy by defining subsets of patients who would benefit the least from platinum-based chemotherapy.

Science ethics education part I. Perception and attitude toward scientific fraud among medical researchers.

PURPOSE: To assess the knowledge of basic principles of responsible conduct of research and attitude toward the violations of good scientific practice among graduate biomedical students. METHODS: A total of 361 subjects entered the study. The study group consisted mainly of graduate students of Medicine (85%), and other biomedical sciences (15%). Most participants were on PhD training or on postdoctoral training. A specially designed anonymous voluntary multiple-choice questionnaire was distributed to them. The questionnaire consisted of 43 questions divided in 7 parts, each aimed to assess the participants' previous knowledge and attitudes toward ethical principles of science and the main types of scientific fraud, falsification, fabrication of data, plagiarism, and false authorship. RESULTS: Although they considered themselves as insufficiently educated on science ethics, almost all participants recognized all types of scientific fraud, qualified these issues as highly unethical, and expressed strong negative attitude toward them. Despite that, only about half of the participants thought that superiors-violators of high ethical standards of science deserve severe punishment, and even fewer declared that they would whistle blow. These percentages were much greater in cases when the students had personally been plagiarized. CONCLUSION: Our participants recognized all types of scientific fraud as violation of ethical standards of science, expressed strong negative attitude against fraud, and believed that they would never commit fraud, thus indicating their own high moral sense. However, the unwillingness to whistle blow and to punish adequately the violators might be characterized as opportunistic behavior.

Do the time to chemotherapy response and the dose intensity have an impact on patient outcome in advanced non-small cell lung cancer?

PURPOSE: To better define the importance of early response rate (RR) as well as dose intensity (DI) in advanced non small cell lung cancer (NSCLC) patients treated with platinum-based combination chemotherapy. PATIENTS AND METHODS: Analysed were stage IIIB and IV NSCLC patients included in 4 prospective clinical trials. All of them were treated with cisplatin 120 mg/m2 (the majority of patients) or carboplatin 500 mg/m2, and since 2000 with AUC 5 (the minority of patients) with second-generation platinum-based regimens. Responding patients (complete response/CR and partial response/PR) were divided into 4 different categories, depending on the time when response was first registered. DI and total dose (TD) of cisplatin was calculated for 93 patients with response or stable disease (SD). RESULTS: Among 362 patients analysed, 117 (32%) were responders. Although "early" responders (54 patients after the 2nd cycle, median survival 10 months; 42 patients after the 3rd cycle, median survival 11 months) lived shorter than "late" responders (11 patients after the 4th cycle median survival 12 months; 10 patients after the 5th cycle, median survival 19 months), these differences were not statistically significant, neither in terms of overall survival (OS) nor in time to progression (TTP). DI in patients with CR+PR+SD was 30 mg/m2/week (median). TD of cisplatin in CR+PR patients was 577 mg, whereas it was 475 mg in patients with SD (p=0.004). These differences followed significant differences in the number of the cycles received and median survival between CR+PR vs. SD patients. CONCLUSION: Early response was not associated with better survival, DI in SD patients did not differ from responding patients, but responding patients received more cisplatin and lived longer.

Radiotherapy-induced changes of peripheral blood lymphocyte subpopulations in cervical cancer patients: relationship to clinical response.

PURPOSE: To determine the absolute number and percentage of peripheral blood lymphocyte subpopulations positive (+) cells CD8(+), CD8(+)NKG2D(+), CD8(+), Granzyme B(+) (GrB), CD16(+), CD16(+)NKG2D(+), CD56(+) and CD56(+)NKG2D(+) in cervical cancer patients before and after radiotherapy (RT), and to analyze whether their changes are related to the clinical response. MATERIALS AND METHODS: Stage IIB - IVA cervical cancer patients received external irradiation and concomitant intracavitary brachytherapy. Blood samples for immunophenotypic analysis by flow cytometry were collected from each patient one day before starting RT and one day after completing RT. Fifteen healthy volunteers served as controls. Surface marker expression and granzyme B positivity were quantified on FACSCalibur flow cytometer. RESULTS: Unlike their absolute numbers, the percentages of all analyzed lymphocyte subsets of all patients, including those with complete response (CR), were significantly increased (p <0.05) after RT. Only in patients with progressive disease (PD), CD8(+), CD8(+)NKG2D(+), CD16(+) and CD56(+)NKG2D(+) lymphocytes were not significantly increased. In healthy volunteers, the percentage of CD8(+)GrB(+) lymphocytes was lower than in patients after RT, while the percentages of CD56(+) and CD56(+)NKG2D(+) cells were higher than in patients before RT (p <0.05). CONCLUSION: Our data indicate that RT, besides its direct cytoreductive effect on tumor cells, may contribute to better immunological control of cervical cancer.

Postmastectomy radiotherapy in intermediate risk stage I-II breast cancer patients.

PURPOSE: To evaluate the correlation of postmastectomy radiotherapy (PMRT) with local relapse rate, disease-free survival (DFS) and overall survival (OS) in a group of breast cancer (BC) patients at intermediate risk for locoregional relapse (stage I-II with either 1-3 positive axillary nodes, or node-negative grade III BC) treated with radical mastectomy. PATIENTS AND METHODS: We evaluated 482 stage I-II BC patients, with either node-negative grade 3 tumors or with 1-3 positive nodes irrespective of tumor grade, treated with radical mastectomy at our Institute from 1986 to 1994. After mastectomy they received either adjuvant CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy (N=172), or adjuvant endocrine therapy (N=310). Postoperative radiotherapy (RT group) to the regional lymph nodes with tumor dose (TD) 48 Gy in 22 fractions was delivered to 199 patients. RESULTS: After a median follow-up of 79.5 months, no difference in relapse rate between the two groups was seen (30.6% in the RT group vs. 36.7% in the no RT group; x(2), p=0.1). Local recurrence rate occurring alone or with distant metastases was 4.52% in the RT group vs. 7.77% in the no RT group (x(2), p=0.1). However, local recurrence rate alone was significantly higher in the RT group compared to the no RT group (2.01 vs. 6.01%, x(2), p=0.041). In premenopausal patients local relapses occurred in 3.2% of patients with postoperative RT and in 8.2% in patients without RT (Fisher's exact test, p=0.48). Non significant difference was registered in postmenopausal patients with (4.76%) or without RT (6.58%). Ten-year DFS and OS were 53.5% and 68.7% in the RT group vs. 52.9% and 75.2% in the no RT group (non significant difference). CONCLUSION: Our results did not show that PMRT significantly influences the incidence of disease relapse, DFS and OS in stage I-II BC patients with intermediate risk for disease relapse. However, it seems that PMRT might influence the occurrence of locoregional recurrence in these patients.

The influence of steroid receptors status on disease outcome in early breast cancer patients treated with adjuvant cyclophosphamide, methotrexate and fluorouracil chemotherapy.

PURPOSE: To assess the influence of steroid receptors (SR) status on disease outcome of early breast cancer patients treated with adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy. PATIENTS AND METHODS: Sixty-six node-negative patients with grade 3 invasive breast carcinoma and 95 patients with 1-3 involved axillary lymph nodes regardless of tumor grade received adjuvant CMF chemotherapy. The endpoints of this analysis were disease-free survival (DFS) and overall survival (OS). Statistical analysis included log rank test and Cox regression models. RESULTS: The median follow-up period was 81 months (range 6-208). Patients with progesterone receptor (PR) - negative tumors had better DFS compared to women with PR-positive tumors (log rank test, p=0.033). Estrogen receptor (ER) - negative and PR-negative patients in the node-negative subgroup had better DFS than ER-positive and PR-positive patients (for ER: log rank test, p=0.009, and for PR: log rank test, p=0.004). However, positive lymph nodes were the only significant predictor of disease progression among patients receiving CMF therapy (Likelihood Ratio test, p <0.001). Women under 40 bearing SR-positive breast cancer had a trend toward worse DFS (log rank test, p=0.054) compared to older SR-positive premenopausal women. CONCLUSION: We can not unequivocally reveal the influence of SR status on disease outcome in early breast cancer patients treated with adjuvant CMF, although SR-positive patients in the node-negative group were shown to have worse DFS in comparison to SR-negative ones. However, nodal status remained the only independent predictor of disease progression in these patients.

Primarily tamoxifen-unresponsive, steroid receptor-positive breast cancer may respond to an aromatase inhibition: a pilot study.

PURPOSE: Breast carcinomas becoming tamoxifen-resistant after objective clinical response to antiestrogen therapy may remain responsive to other endocrine agents due to different mechanisms of action. The aim of our study was to analyze whether primarily tamoxifen-unresponsive/steroid receptor (SR) - positive breast carcinomas can respond to an aromatase inhibition. PATIENTS AND METHODS: Thirteen postmenopausal, SR-positive, metastatic breast cancer (MBC) patients were included: they had previously failed to respond to tamoxifen, either as primary systemic therapy for advanced disease, or as adjuvant treatment (5 and 8 patients, respectively). Patients were treated with 2.5 mg letrozole daily, from 2-25 months, mostly until disease progression. RESULTS: Partial response (PR) was obtained in one third of the patients (4/13); additionally, 3 patients showed disease stabilization (SD) longer than 6 months. The observed response duration lasted from 7 to 36+ months (median 9). Overall survival from the beginning of letrozole treatment was better in letrozole responders compared with nonresponders. It appeared as if there were two different subgroups of patients: one completely endocrine-unresponsive, and the other unresponsive to tamoxifen but responsive to letrozole (supposed to be primarily tamoxifen-resistant, but otherwise endocrine-responsive). HER-2 overexpression (immunohistochemically determined as 2+ and 3+) was found in 3 patients, which could not account for the different endocrine responsiveness. CONCLUSION: Our study confirmed that some SR-positive breast carcinomas, primarily tamoxifen-unresponsive, may respond to letrozole, thus being endocrine-responsive, while others did not respond, probably due to complete endocrine unresponsiveness. It is not likely that HER-2 was the biomarker that made the difference between these two subgroups.

Use of high-dose cytarabine to enhance cisplatin cytotoxicity-effects on the response and overall survival rates of advanced head and neck cancer patients.

UNLABELLED: It has been reported that cytarabine, acting by at least two different mechanisms, enhances the cytotoxic effect of cisplatin in in vitro systems. The aim of this open, prospective, randomised study was to estimate the eventual benefits from the inclusion of high-dose cytarabine in the cisplatin-5-fluorouracil (5-FU) regimen as first-line treatment of patients with advanced head and neck cancer. The study recruited successive patients with unresectable grade I/II head and neck cancer who were not suitable for irradiation treatment (T any N3 or T4 N2C), metastatic or previously irradiated. All patients gave their informed consent. A joint ear, nose and throat (ENT) oncological committee performed the selection. A total of 170 patients were included in the study. Patients randomised to arm A were given 1000 mg/m(2) cytarabine on day 1 preceding for 6 h cisplatin infusion, 30 mg/m(2)/24 h cisplatin intravenous (i.v.) bolus days 1-4 and 1000 mg/m(2)/24 h 5-FU in a 4-h infusion on days 1-4. Patients in arm B were given cisplatin and 5-FU in the same dosage and schedule as in arm A. Additional irradiation+/-surgery was performed if and when feasible. Patients in both arms were well balanced with regard to clinical variables. The following results were obtained: Arm A: 84 patients were included, 74 were evaluable for activity; RESPONSE: complete response (CR) 8 (11%), partial response (PR) 40 (54%), stable disease (SD) 11 (15%), progressive disease (PD) 15 (20%). The overall response rate (RR) based on the evaluable patients was 48/74 (65%, 95% confidence interval (CI) 54-75%); The RR based on an intent-to-treat analysis was 57%, 95% CI 47-67%; Median survival was 13 months; There were 50 episodes of granulocytopenia grade IV and 15 of febrile neutropenia per 316 cycles. Arm B: 86 patients were included, 80 were evaluable for activity; RESPONSE: CR 7 (9%), PR 29 (36%), SD 10 (12.5%), PD 34 (42.5%); The overall RR based on the evaluable patients was 36/80 (45%, 95% CI 35-56%); The RR based on an intent-to-treat analysis was 42%, 95% CI 32-52%; Median survival was 8 months; There were 14 episodes of granulocytopenia grade IV and 7 febrile neutropenias per 324 cycles. The RR was significantly higher in arm A (P=0.013), power (one-sided) 80%. The proportion of patients from the appropriate subset who achieved a clinical response making additional treatment feasible was higher in arm A (P=0.00015), as well as the proportion of patients with a performance status 2+3 achieving a response (P<0.0001). Using the Log-rank test, patients from arm A achieved a significantly longer survival (P=0.009), with the probability of survival at 12 months of 0.58 for patients in arm A and 0.28 for patients in arm B. Grade IV granulocytopenia and thrombocytopenia were more frequent in arm A. Due to its haematological side-effects, cytarabine might not be the ideal drug to modulate the cytotoxicity of cisplatin. However, other modulators of its activity could be of interest for further studies in head and neck cancer patients.

Survival advantage for carboplatin substituting cisplatin in combination with vindesine and mitomycin C for stage IIIB and IV squamous-cell bronchogenic carcinoma: a randomized phase III study.

This communication represents the definitive report of a randomized phase III study comparing cisplatin and carboplatin, in combination with vindesine and mitomycin C in stage IIIB and IV squamous-cell bronchogenic carcinoma. A total of 221 patients entered the study and were randomized into two arms. Of these, 114 patients (109 evaluable for activity) were randomized to arm A, receiving cisplatin 120 mg/m(2), mitomycin C 8 mg/m(2) and vindesine 3 mg/m(2) per cycle; 107 patients (101 evaluable for activity) were randomized to arm B receiving carboplatin 500 mg/m(2) with the same doses of mitomycin C and vindesine per cycle. Patients with progressive disease (PD) were excluded from the study after the 2nd cycle, and those with stable disease (SD), partial response (PR) and complete response (CR) received six cycles of chemotherapy (or less in case of early progression). Patients were stratified according to the clinical stage (IIIB vs. IV), performance status (0+1 vs. 2+3) and tumor histological grade (I+II vs. III). In the cisplatin arm two patients (1.9%) achieved a CR, 38 (34.9%) a PR, 45 (41.2%) a SD and 24 (22.0%) had PD; the overall response rate was 40/109 (36.8%). In the carboplatin arm five patients (5.0%) achieved a CR, 31 (30.7%) a PR, 40 (39.6%) a SD, and 25 (24.7%) had PD; the overall response rate was 36/101 (35.7%). No statistically significant difference in response rate was present between the two arms, and the response rate was not influenced by performance status, histological grade or clinical stage. The Kaplan-Meyers curves displayed a significant advantage both for time to progression (P=0.005) and overall survival (P=0.008) for patients in the carboplatin arm. The advantage for patients receiving carboplatin instead of cisplatin appeared evident in univariate setting for patients with a good performance status and clinical stage IV, and occurred irrespectively of tumor histological grade; response duration and survival of responders was identical in the two arms. Patients achieving a stable disease survived longer in the carboplatin than in the cisplatin arm (P=0.012). Thus, substitution of cisplatin by carboplatin in the combination chemotherapy regimen, although more hematologically toxic (but less emetogenic) resulted in a similar response rate, but a significantly longer time to progression and overall survival.

[Role of radiotherapy in combined therapy of soft tissue sarcoma in children and adolescents]. / Uloga radioterapije u kombinovanom lecenju sarkoma meki tkiva kod dece i omladine.

Over last decades with modern approach to combined treatment of soft tissue sarcoma in children and adolescents, with effective systemic chemotherapy and adequate local control most frequently with conservative surgery and radiotherapy, or radiotherapy alone, results of treatment from 20% of a three-year overall survival to 75% were improved significantly. Nevertheless, combined treatment involves risk of acute radiation reactions and late side effects, so there is a need for precise radiotherapy planning with optimal schedule of fractionating, adequate radiation volume and optimal tumour dose. The purpose of our study was to evaluate the results of combined treatment of soft tissue sarcoma, role of radiotherapy in local control use of the optimal tumour dose and assessment of acute radiation reactions in an examined group of patients. A retrospective clinical study involved 47 patients treated with radiotherapy at the Institute of Oncology and Radiology of Serbia over the period from 1990 to 1997. The most frequent tumour sites were the head and neck and the extremities. According to the IRS classification most patients were in CS III (21 patients). Forty patients had histological type--Rhabdomyosarcoma (Table 1). All patients were treated with chemotherapy, and local therapy were surgery and radiotherapy or radiotherapy alone. Thirty one patients were operated on. All 47 patients were treated with radiotherapy; in 37 patients as primary treatment and in 10 patients as therapy for local relapse. Radiotherapy was planned according to tumour size, tumour site, age of the patient and type of surgery. Tumour dose from 45 Gy to 60 Gy was given in cases with a residual tumour. Lower tumour doses were used in cases of postoperative microscopic disease, in certain cases of local relapse treatment or when the size of residual tumour and patient's age allowed no delivery of higher tumour doses. Standard fractionating regimen was given to all patients, with daily fractions from 150 cGy to 214 cGy, five times per week. The majority of patients (24) were treated on Linear Accelerator machine with X photons of 10 MeV energy and with X photons of 6 MeV energy (13 patients) (Table 2). Statistical data processing was made by the following methods: Kaplan-Meier for survival rate and Long-rang and Wilcox test for assessment of the statistical significance in survival difference. In our group of patients treated over the period from 1990 to 1997 a three-year overall survival was 59.15%, and disease free survival was 46.68% (Figure 1). There were 21 patients (44.7%) without signs of the disease, 12 patients had a local disease (25.5%), 9 patients had both local and metastatic disease (19.1%) and 5 patients had only metastatic disease (10.50%). In the group of 47 patients who received radiotherapy, 24 patients received a tumour dose from 45 Gy to 60 Gy and 23 patients a tumour dose from 32 Gy to 45 Gy. The group of patients treated without tumour dose more than 45 Gy had a significantly better overall survival rate (p = 0.002) (Figure 2). Although the obtained results are in agreement with data from literature, a critical analysis is necessary. Namely, in addition to the group irradiated with a tumour dose from 32 Gy to 45 Gy, because of the postoperative microscopic disease, certain number of patients was irradiated with a "lower" dose because of an objective impossibility to administer a "higher" dose or this dose was planned for palliative reasons. The tumour dose of 45 Gy was delivered to 6 of 10 patients treated for local relapse. The tumour dose of 45 Gy was also used in four patients in CS IV, in two subjects for local control and in two as a palliative treatment. Seven patients in CS III received a tumour dose of 45 Gy, because the age of children, tumour site and tumour size permitted no higher tumour doses. That is when planning an adequate local therapy one must have in mind the initial tumour size, type of administered systematic chemo

Expression of epidermal growth factor receptor in breast cancer, from early stages to advanced disease.

Epidermal growth factor receptor was determined in 106 newly diagnosed breast cancer patients, using the biochemical method. The group consisted of 58 patients in stage I-II, and 48 patients in stage III-IV. Although a significant inverse correlation was found between EGF-R status, and ER or PR status, quantitative content of EGF-R did not correlate either with quantitative ER, or PR levels. The ER/PR content was similar in all clinical stages, suggesting their stability during the clinical course of the disease. EGF-R content was significantly higher in stage IV, compared to stage I, while intermediate clinical stages and all substages did not differ according to the EGF-R content. EGF-R was confirmed as a weak prognostic factor within clinical stages. However, in a whole group, the overall survival was significantly better in patients whose tumors EGF-R content was lower than 26 fmol/mg, compared to those with higher ERF-R content. EGF-R content was highly predictive for the response to systemic endocrine treatment, in metastatic breast cancer patients. In locally advanced breast cancer a trend towards higher levels of EGF-R was found in inflammatory breast cancers, compared to non-inflammatory ones. Slightly higher levels were found in responders to local non-endocrine primary treatments (radiotherapy with or without chemotherapy), compared to non-responders, suggesting the possible predictive role of EGF-R for the response to such treatments. Our results emphasized the usefulness of quantitative receptor determination suggesting the relative stability of EGF-R content during the clinical course of breast cancer, its independence from ER, its significant predictive and weak prognostic values, and a possible correlation with the aggressiveness of the disease, and response to non-endocrine treatments.

Epirubicin 150 mg/m2-cisplatin versus epirubicin 180 mg/m2-cisplatin for advanced soft tissue sarcoma.

We have previously reported the superiority of the epirubicin 180 mg/m2-cisplatin combination over single drug epirubicin 180 mg/m2 for advanced soft tissue sarcoma both in terms of response (54% vs. 29%, p = 0.025) and survival (p = 0.001). The aim of the present study was to establish whether decreasing the dosage of epirubicin to 150 mg/m2 would result in the same activity but with less hematological toxicity. One hundred fifty-nine patients with advanced soft tissue sarcoma were randomized for either epirubicin 150 mg/m2-cisplatin 120 mg/m2 (group A) or epirubicin 180 mg/m2-cisplatin 120 mg/m2 (group B). The results were as follows: group A: 79 patients were evaluated. Overall response rate was 24/79 (30%) (95% CI 21-41%). Median survival was 11 months and probability of survival at 1 year was 0.46. Grade IV granulocytopenia was present in 111/274 cycles and febrile neutropenia in 22/274. Group B: 73 patients were evaluated. The overall response rate was 39/73 (53%), (95% CI 42-64%). Median survival was 14 months and probability of survival at 1 year was 0.58. Grade IV granulocytopenia was present in 136/295 cycles and febrile neutropenia in 30/295. The differences were as follows: for overall response rate p = 0.004; power (for p = 0.05) 85%; for survival p = 0.09; for grade IV granulocytopenia p = 0.3; and for febrile neutropenia p = 0.61. A survival advantage (p = 0.043) was evident for patients randomized to group B and with performance status 0 or 1 compared with similar patients from group A. A plateau-like formation on the probability level of 0.26 on the survival curve started from month 26 onwards. In conclusion, both regimens share the same toxicity but epirubicin 180 mg/m2-cisplatin seems more active in soft tissue sarcoma, possibly indicating a breakthrough for activity between an epirubicin dosage of 150 mg/m2 and 180 mg/m2 in combination with cisplatin. The superiority of the epirubicin 180 mg/m2-cisplatin regimen appears evident both in terms of response and survival.

Comparison of two non-anthracycline-containing regimens for elderly patients with diffuse large-cell non Hodgkin's lymphoma--possible pitfalls in results reporting and interpretation.

Age over 65 years is a risk factor per se for doxorubicin administration, and coexisting diseases pose additional problems. There is still controversy whether chemotherapy regimens for elderly patients with aggressive NHL should be full-dose doxorubicin containing or whether development of non-anthracycline containing regimens is warranted. In this prospective study, 47 patients aged over 65 years with diffuse large cell NHL clinical Stage I/IE bulky-IV and no other initial exclusion criteria were randomized to receive either BCNU 120 mg/m2 d. l, VP 16 60 mg/in2 d.2-4, procarbazine 85 mg/m2 d. 2-8 (arm A, 27 patients) or mitoxantrone 6 mg/m2 d. l. with VP16 and procarbazine in the same dosage and schedule (Arm B, 20 patients). Partial responders received additional irradiation treatment if feasible. Arms were well balanced according to age, sex, clinical stage and performance status. Ten patients from arm A and 13 from arm B had PS 2 or 3; 14 patients from arm A and 8 from arm B had clinically significant antecedent and/or concomitant disease (SACD: cardiac, vascular, cerebrovascular, neurological, renal or other). On the intent-to-treat basis, the results were the following. ARM A: median number of cycles 3 (range 1--6); early death 3 patients; 16/27 responses (59%), 7 complete (30%). ARM B: median number of cycles 3 (range 1-6); early death 4 patients; 12/20 responses (60%), 3 complete (15%). There was no difference either in response rate or survival between the two arms, and pooled results from the two arms displayed a plateau on the survival curve from the 20-th month onwards on the probability level of 0.40. Clinical stage of NHL, bulky disease, age and sex did not influence survival. Initial performance status did influence survival at the significance level of p = 0.045. Although presence of SACD did not influence initial performance status, it had a strong negative impact on survival p = 0.0004). The results point to the existence of two prognostic categories of elderly patients with large cell NHL, one with a poor survival, the other achieving a significant response rate and relapse free survival. Comorbidity (SACD) apparently accounts for the poor survival in a subpopulation of elderly patients. Clinical trials with elderly patients with NHL with PS 0 or 1 and no serious coexisting disease as inclusion criteria, analyzed on an evaluable patients basis, target only to a prognostically better subpopulation among these patients.