FOLFOX4 plus cetuximab administered weekly or every second week in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer: a randomized phase II CECOG study.

BACKGROUND: This randomized phase II study investigated first-line chemotherapy plus cetuximab administered every second week in KRAS wild-type metastatic colorectal cancer. PATIENTS AND METHODS: Patients received FOLFOX4 plus either standard weekly cetuximab (arm 1) or cetuximab (500 mg/m(2)) every second week (arm 2), until disease progression or unacceptable toxicity. Primary end point was the objective response rate (ORR). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety were also investigated. The study was not powered to establish non-inferiority, but aimed at the estimation of treatment differences. RESULTS: Of 152 randomized eligible patients, 75 were treated in arm 1 and 77 in arm 2; ORRs [53% versus 62%, odds ratio 1.40, 95% confidence interval (CI) 0.74-2.66], PFS [median 9.5 versus 9.2 months, hazard ratio (HR) 0.92, 95% CI 0.63-1.34], OS (median 25.8 versus 23.0 months, HR 0.86, 95% CI 0.56-1.30) and DCR (87%) were comparable. HRs adjusted for baseline factors were 1.01 and 0.99 for PFS and OS, respectively. Frequencies of grade 3/4 adverse events in arms 1 versus 2 were similar: most common were neutropenia (28% versus 34%) and rash (15% versus 17%). CONCLUSIONS: Activity and safety of FOLFOX4 plus either cetuximab administered weekly or every second week were similar.

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.

Variant chromosomal arrangement of adult beta-globin genes in rat.

The genomic organization of three haplotypes of beta-globin genes was determined to resolve the question of the number of those genes in rat. Haplotype a, found in inbred strain DA, has three genes or pseudogenes, while haplotypes b, found in AO, Y5 and Wistar strains, and c, found in Wistar strain, have five genes or pseudogenes each. In haplotypes b and c, the first gene is of beta major type and the remaining four are of beta minor type. Partial sequencing of six out of 13 genes shows that duplications of beta minor genes are causing polymorphism in a number of genes. Also, in haplotype b two beta minor genes have a 6.5-kb intron 2, while in haplotype c only one beta minor gene contains such a large intron 2. The three structurally different haplotypes described are not interconvertible by single recombination events. The results indicate that the rat has the highest number of adult beta-globin genes found in mammals so far.

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.

Comparison of the efficacy of two different dosage dacarbazine-based regimens and two regimens without dacarbazine in metastatic melanoma: a single-centre randomized four-arm study.

The aim of this randomized four-arm phase III study was to evaluate whether there is a difference in activity between regimens containing dacarbazine and regimens without dacarbazine in metastatic melanoma, whether there is a dose-effect relationship for dacarbazine, and whether non-dacarbazine-containing aggressive regimens are in any way superior to non-aggressive ones. A total of 219 patients with metastatic cutaneous melanoma were included in this study; 196 of them were evaluable for activity. The patients were randomized into four treatment arms: arm A (standard dose dacarbazine arm), vincristine 1.4 mg/m2 on day 1, carmustine (BCNU) 60 mg/m2 on day 1, and dacarbazine 300 mg/m2 per 24 h on days 2-5; arm B (high-dose dacarbazine arm), vincristine and BCNU as in arm A and dacarbazine 600 mg/m2 per 24 h on days 2-5; arm C ('aggressive' regimen without dacarbazine), vindesine 3 mg/m2 on day 1, bleomycin 7 mg/m2 per 24 h on days 1-4, and cisplatin 30 mg/m2 per 24 h on days 5-8; arm D ('non-aggressive' regimen without dacarbazine), BCNU 100 mg/m2 on day 1 and procarbazine 90 mg/m2 per 24 h on days 1-10. The four arms were well balanced with regard to patient- and disease-related characteristics. On an intend-to-treat basis, the response rate was 11 out of 49 (22%) in arm A, nine out of 47 (19%) in arm B, 16 out of 63 (25%) in arm C and nine out of 60 (15%) in arm D. There was a large overlap between the 95% confidence intervals and no significant differences in the response rates between the four arms. Median survival in the four treatment arms was 4, 5, 6 and 4 months, respectively, again with no significant differences. Median survival for responders (8, 11, 10 and 13 months, respectively) in all four arms was significantly longer than in non-responders (4, 3, 5 and 4 months, respectively). Arms A, B and C were significantly more toxic compared with arm D, which was for all practical purposes devoid of toxicities. The efficacy of all four regimens thus appeared comparable both in terms of response rate and survival. Responders in all four arms achieved a survival benefit. There does not seem to be a dose-effect relationship for dacarbazine in metastatic melanoma. Chemotherapy from arm D, might be well suited for 'fragile' or elderly patients due to the lack of toxicity.

Negative CEA values in metastatic colorectal carcinoma and the likelihood of complete chemotherapy response.

INTRODUCTION: Experimental results reported in the literature have suggested that CEA might inhibit host defense mechanisms and that immunotolerance to CEA could play an important role in the development of metastases in colorectal carcinoma. It might therefore be assumed that negative CEA values during metastatic disease represent a favorable prognostic factor. Surprisingly, there are very few data available about negative CEA. The aim of this study was to determine the significance of negative initial CEA values in patients with metastatic colorectal carcinoma. PATIENTS AND METHODS: Initial CEA values were determined in 114 patients with metastatic colorectal carcinoma. The patients were divided into three groups according to these values: I (n=22) <5 ng/mL; II (n=33) 5-100 ng/mL; III (n=59) >100 ng/mL. RESULTS: Seven/114 complete responses (CR), 22/114 partial responses (PR), 45/114 instances of stable disease (SD) and 38/114 of progressive disease (PD) were registered, while two patients were not evaluable. There were six long-lasting CRs (median 24 months, range 10-37 months) in the CEA-negative patient subset, while in the CEA-positive subset there was only one CR, in a patient with an initial CEA level of 18 ng/mL. The mean initial CEA values in the different response categories were: CR: 4.0 ng/mL; PR: 436 ng/mL; SD: 1442 ng/mL; PD: 6071 ng/mL. The likelihood of response, in particular CR, was highly dependent upon CEA levels (Fisher's exact test, 0.00001). The median survival decreased significantly with increased values of CEA (p=0.006). CONCLUSION: Negative CEA in metastatic disease was the main characteristic of the patient subset capable of attaining CR. When relapsing, all patients but one became CEA positive.

Radio- and chemotherapy variably affect the general immunocompetence of lung cancer patients.

OBJECTIVE: The evaluation of the effects of radiotherapy and chemotherapy on the immune status of lung cancer patients. EXPERIMENTAL DESIGN: Prospective nonrandomized study. SETTING: Hospitalized care. PATIENTS: 121 patients with unresectable non-small-cell lung cancer (Stage IIIb or IV), who were planned for radiotherapy (n = 81) or chemotherapy (n = 40). MEASURES: The relative and absolute numbers of blood T lymphocytes and monocytes, as well as the mitogen-induced proliferative response of the former, and phagocyting capacity of the latter cell subpopulation, were determined in patients before starting any therapy. In radiotherapy (RT)-treated group, the immune parameters were evaluated after 45 Gy and 60 Gy had been given. In chemotherapy (ChT)-treated group, the same parameters were determined three weeks after the 2nd and 4th cycle of ChT. RESULTS: The number and proliferative response of T lymphocytes were significantly (p < 0.001) lower, while the number and phagocyting capacity of monocytes were significantly (p < 0.001) higher in all patients before therapy, in comparison to the controls. After RT, the T cell number and proliferative response were significantly (p < 0.001) decreased, while the number of monocytes and their phagocyting capacity remained unchanged, when compared to the pretreatment values. Unlike RT, chemotherapy did not change any investigated parameter, except for the phagocyting activity of monocytes, which was significantly (p < 0.02) decreased, in comparison to the pretreatment value, after four cycles of ChT only. CONCLUSIONS: Two cancer treatment modalities--radio- and chemotherapy--variably affect the immune status of lung cancer patients. The initial great disturbances of general immunity parameters are further aggravated by radiotherapy. Unlike RT, chemotherapy exerts no suppression at all; on the contrary, it tends to normalize some of the parameters of cellular immunity of lung cancer patients.

Androgen level variations, clinical response to LHRH agonists and changes in the quality of life subscales in metastatic prostate cancer--speculations about possible role of the monoamine system.

The aim of this study was to investigate the effect of goserelin-acetat (Zoladex) on testosterone suppression, to compare achieved suppression with clinical effects in patients with prostate cancer with bone metastases and consequent painful syndrome, to study the behavior of adiol during treatment and to assess life quality with emphases on the physical and psychological domain in relation to clinical and biological treatment effects. Fifteen patients were treated by Zoladex in one dose every 28 days, and followed-up for 12 months. All patients had several metastatic localizations in the bones, initial high prostate specific antigen (PSA), and high acid (AP) and alkaline phosphatase (ALP). PSA, testosterone, adiol (delta-5-androstenediol), luteinizing hormone (LH), foliculostimulating hormone (FSH), ALP and AP were also measured before every cycle. For evaluation of the life quality Rotterdam Symptom Checklist was used. Clinical progression was not registered during follow-up, with drop of PSA, ALP and AP. Testosterone and adiol displayed mainly inverse trends during treatment. The complete testosterone suppression was never achieved. It seems that Zoladex has quite different influence on LH and FSH, as levels of those hormones have shown opposite trend. Some of the observed hormonal effects could be attributed to stimulation of the monoamine system. Suppression of LH level provoked by administration of LHRH agonists increases level of dopamine in hypothalamus which inhibits releasing of its hormones. By inhibition of corticotropic releasing factor and ACTH, and by its influence on adrenal gland, we could explain drop of adiol levels in the first months of administration of LHRH agonists. Testosterone increase and adiol drop in the first months, and adiol increase following testosterone level drop in the fourth to eight month, may be explained by negative feed back mechanism between different androgens which could be stimulated or provoked by LHRH therapy. The question of effects which are results of LHRH agonists modulation of the monoamine system and consequent activation of other central mechanisms of hormonal regulation is still open. Patients' quality of life under therapy was improved for about 30% in psychological and functional domains. There were no significant changes on physical subscale, during treatment. It seems that the obtained positive psychological treatment effect is not only a consequence of pain decrease, but it could be the result of the change in the level of monoamines in CNS under Zoladex.

The role of stable disease in objective response assessment and its impact on survival in advanced colorectal cancer: is "stable disease" a homogenous response category?

Stable disease is a category which is not included in the evaluation of the overall treatment response rate. In many studies with a response rate below 20%, chemotherapy almost doubles the survival of patients. In the most chemotherapy trials with advanced colorectal cancer patients, about 30-50% had stable disease. Despite belonging to the same category of therapy response, some patients with stable disease have achieved symptom improvement, but some have not. The aim of the study was to investigate whether the stabilization of the disease with clinical benefit is associated with benefit in survival. A total of 99 patients with advanced colorectal cancer were treated with carboplatin (80 mg/m2, day 1-7), 5-FU (750 mg/m2, day 1-5), leucovorin (100 mg/m2, day 1-5) every 4 weeks. After 4 courses, in the case of stable disease (SD), the patients were stratified according to clinical benefit achievement in: Group A--patients with clinical benefit who continued with chemotherapy until 8 cycles or until disease progression; group B--patients without clinical benefit in whom chemotherapy was stopped after 4 cycles. Clinical benefit was a composite of assessment of pain, ECOG performance status, weight and temperature. Clinical benefit required a sustained improvement in at least one parameter without worsening in any other. Of 97 evaluable patients 48 achieved stable disease. Of 22 pts. with SD clinical benefit performance status improvement was recorded in 17, pain relief in 14, improvement in body weight in 14 and temperature disappearance in 8 pts. Of 26 pts. with SD without clinical benefit, 7 were asymptomatic from beginning of the chemotherapy. No difference was detected in the survival between responders and SD clinical benefit pts. (p = 0.24), but there was significant difference between responders and SD pts. without clinical benefit (p = 0.0004). SD clinical benefit pts. had significant difference in survival in comparison to pts. with progressive disease (p = 5.1 x 10(-6)). The results of our study indicate that under category "stable disease" there are two different subpopulations of patients with quite different symptom response to chemotherapy, different time to progression and possible different survival.

Colorectal cancer: dilemmas regarding patient selection and toxicity prediction.

Irinotecan (Campto, Rhône-Poulenc Rorer) is probably the most studied drug used as second-line treatment for colorectal cancer. Its main disadvantages are toxicity and cost. Delayed diarrhea and neutropenia are the most common toxic side effects, both of which can usually be predicted, by knowing the criteria for patients who are at increased risk for those side effects. These criteria include poor performance status (>2), bulky disease, previous abdominal-pelvic irradiation, hyperleukocytosis and increased bilirubin >1.5 x normal upper range. There are some other less common toxic effects of irinotecan, such as pneumonitis, cardiac arrhythmia, paralytic ileus, liver dysfunction, tumor lysis syndrome. While these side effects are very rare, physicians should be able to recognize them, because the number of patients being treated with irinotecan is increasing. The authors report four cases of probable irinotecan-related toxicity with fatal outcome in all 4 patients. Two of these 4 patients were not in the known risk categories for irinotecan toxicity. One patient died with signs of hepato-renal syndrome, the other with signs of rapid tumor lysis-like syndrome. Two other patients with bulky disease and performance status 2, had increased urea, creatinine and bilirubin serum levels after irinotecan administration, that could not be explained as manifestation of disease progression only. Data on all uncommon irinotecan toxic effects should be gathered and analyzed so that toxic effects, other than diarrhea and neutropenia, are better defined and predicted.

[A pilot study of high-dose zorubicin in advanced stages of soft tissue sarcoma in adults]. / Etude pilote de la zorubicine à hautes doses dans les stades avancés des sarcomes des tissus mous de l'adulte.

High-dose anthracyclines, doxorubicin 75 mg/m2 and epirubicin 150-180 mg/m2, are the most active drugs in the treatment of advanced soft tissue sarcoma. These dosages are associated with significant hematological toxicity for both drugs and a high risk of cardiotoxicity for doxorubicin. The aim of this pilot study was to investigate the activity of zorubicin in advanced soft tissue sarcoma, with a dosage supposed to be equihematotoxic to epirubicin 180 mg/m2. Twenty of 21 patients who had been included in the study were evaluable for response, 15 males and five females, median age 41 (range 20-67) years. All patients received zorubicin 600 mg/m2 per cycle divided in 3 days, the intercycle interval being 4 weeks. The cardiac function was monitored by determinations of left ventricular ejection fraction before each cycle. Therapeutic response was the following: 2/20 patients (10%) complete response, 6/20 (30%) partial response, 6/20 (30%) stable disease and 6/20 (30%) progressive disease, the overall response rate being 8/20 (40%). Complete responses were observed in a patient with undifferentiated sarcoma of the mediastinum and in a patient with unresectable angiosarcoma of subcutaneous tissues. The major toxicity was hematological, with granulocytopenia grade 4 occurring in 42/66 cycles, and the nadir on day 10 of the treatment cycle. Nine of 66 cycles were complicated by febrile neutropenia and stomatitis of any grade was recorded in only 1/66 cycles. No cumulative cardiotoxicity was observed up to a total cumulative zorubicin dose of 3,000 mg/m2.

Deletion analysis of Duchenne muscular dystrophy using cDNA probes and multiplex PCR.

The authors studied Duchenne muscular dystrophy (DMD) in 14 Yugoslav families with 16 diseased men. All the sixteen patients showed typical phenotypic features of DMD. The linkage analysis was done with five probes 754, C7, PERT87.15, pERT87.30, and pERTBir. A deletion with pERT87.15 (DX 164) in one family was found. Deletion analysis was mainly performed using cDNA probes and multiplex PCR analysis. Preferential deletions were in the hot spot deletion region covered by cDNA probe 8. Among 14 examined patients with cDNA hybridization deletions were found in 5 cases (5/14). For quick and prenatal analysis the authors used multiplex PCR. With this methods deletions were found in 4 cases (4/15). The percentage of the observed deletions cases was 50% (8/16) in Yugoslav population, which shows good correlation with other European and American populations studied. Prenatal diagnosis was done for two consultants with highly ambiguous carrier risk, and no deletions were found.

Debridement of cartilage lesions before autologous chondrocyte implantation by open or transarthroscopic techniques: a comparative study using post-mortem materials.

We compared the quality of debridement of chondral lesions performed by four arthroscopic (SH, shaver; CU, curette; SHCU, shaver and curette; BP, bipolar electrodes) and one open technique (OPEN, scalpel and curette) which are used prior to autologous chondrocyte implantation (ACI). The ex vivo simulation of all five techniques was carried out on six juvenile equine stifle joints. The OPEN, SH and SHCU techniques were tested on knees harvested from six adult human cadavers. The most vertical walls with the least adjacent damage to cartilage were obtained with the OPEN technique. The CU and SHCU methods gave inferior, but still acceptable results whereas the SH technique alone resulted in a crater-like defect and the BP method undermined the cartilage wall. The subchondral bone was severely violated in all the equine samples which might have been peculiar to this model. The predominant depth of the debridement in the adult human samples was at the level of the calcified cartilage. Some minor penetrations of the subchondral end-plate were induced regardless of the instrumentation used. Our study suggests that not all routine arthroscopic instruments are suitable for the preparation of a defect for ACI. We have shown that the preferred debridement technique is either open or arthroscopically-assisted manual curettage. The use of juvenile equine stifles was not appropriate for the study of the cartilage-subchondral bone interface.

Comparison of four techniques for the fixation of a collagen scaffold in the human cadaveric knee.

OBJECTIVE: Four fixation techniques for a fibrinogen and thrombin coated collagen fleece, used as a scaffold in the cartilage repair, were compared simulating the initial postoperative period in the cadaveric knee joints. METHODS: Full-thickness chondral lesions were made on the medial femoral condyles of seven human cadaveric inferior extremities. Four scaffolds without seeded chondrocytes were implanted into each lesion using four fixation techniques consecutively: self-adhesion without additional material (SA), fibrin sealant (FS), bone sutures (BS), and periosteal cover (PC). After each implantation 150 cycles of continuous passive motion (CPM) were performed. Two cases were additionally exposed to 50 cycles of 10 and 20 kg loading each after the completion of CPM. The scaffolds were evaluated after every 30 cycles, and the fixation strength was tested after the motion was completed. RESULTS: All the SA scaffolds were detached before 60 cycles. The other scaffolds remained stable throughout the testing with only minor disruptions. The endpoint fixation strength was higher for BS and PC than for the FS scaffolds. The FS scaffolds were detached as a result of additional load cycles, while the BS and PC scaffolds showed substantial deformations. CONCLUSION: SA of tested scaffold did not provide sufficient fixation. The FS fixation was easy to perform and assured satisfactory scaffold stability. BS and PC provided excellent scaffold stability, but the techniques were difficult and caused additional injuries. Regardless of the fixation technique used, the tested collagen scaffold may not be exposed to loading in the initial postoperative period.

[Evaluation of quality of life in oncology]. / Procena kvaliteta zivota u onkologiji.

Studies of quality of life are more and more becoming an integral part of cancer care in situations when treatment of cancer patients is burdened with significant toxicity, and results of survival of these patients are unsatisfactory. Modern concept of health-related quality of life measurement means consensus about its two basic features: multidimensionality of concept, and essentially subjective experience in a treated person. As a minimum, domains of physical, psychological and social are assessed, and the patient is considered to be the primary source of information. The most widely used instruments for quality of life assessment are questionnaires, especially developed for cancer patients, with supplemental items for particular diagnosis. These instruments must satisfy the basic psychometric properties-validity and reliability. Quality of life studies are focused mostly on phase III trials, where differences between treatment arms for tumour response and survival are expected to be small. Another approach is developed in parallel which, based upon quality of life measurement, initiates decisions for the treatment of a set of patients up to health policy level. In these "cost-utility" studies, efficacy and cost of the treatment, and improvement of patients' quality of life are independently estimated, and then integrated in medical decision making.

Amsacrine and cisplatin in poor prognosis patients with metastatic transitional cell carcinoma of the urothelium: a phase-II study.

OBJECTIVES: Amsacrine, as a single agent, was reported to be effective in patients with metastatic transitional cell carcinoma of the urinary bladder. Amsacrine is also associated with a lower toxicity than cyclophosphamide, doxorubicin and cisplatin therapy and has similar activity. But amsacrine has been forgotten in clinical studies of transitional cell carcinoma of the urinary bladder. The aim of present study was to investigate the toxicity and efficacy of amsacrine and cisplatin in chemotherapy-naive patients with metastatic transitional cell carcinoma of the urinary bladder. METHODS: We have treated 54 patients (41 males/13 females) with a median age of 62 (38-72) years. Performance status was 0/2, I/27 II/17 and III/8. The treatment included: amsacrine 85 mg/ m(2), days 1-2, and cisplatin 30 mg/m(2), days 2-5. Cycles were repeated every 4 weeks. We applied 169 cycles (median 3/patient). Of 54 patients, 39 had previous surgery and 12 had previous radiotherapy. Histological tumor grade was I/7, II/27 and III/20. RESULTS: 51 patients were evaluable for response (3 patients refused further treatment during the first cycle): 2 complete remission (4%); 15 partial remission (29%); 23 stable disease (45%), and 11 progressive disease (22%). The response rate was 33% (95% CI 21-46). On an intent-to-treat basis the response was 32% (95% CI 19-44). Durations of complete and partial responses were 14 (range 12-16) and 6.5 (range 3-11) months, respectively. Median survival was 9 (range 3-21) months. All patients were evaluable for toxicity. Grades III-IV toxicity was as follows: anemia 11%; neutropenia 37%, and thrombocytopenia 20%. None of the patients was excluded from the study because of toxicity. CONCLUSION: The combination of amsacrine and cisplatin is a regimen with mild and manageable toxicity. The present regimen seems to be active. Randomized study of the present regimen versus another low-toxicity regimens are necessary, especially for poor prognosis patients including those with a low performance status.

[Chemotherapy of colorectal carcinoma]. / Hemoterapija karcinoma kolorectuma.

The benefit of adjuvant therapy in colorectal cancer (CRC) has been provided in clinical studies that have demonstrated reduction of up to 30% in a 5-year overall mortality in patients (pts.) with TNM stage III (Dukes' stage C) carcinoma. Patients with metastatic CRC are usually in a relatively good condition despite their advanced disease. Therefore, some clinicians wished to withheld the toxicity of chemotherapy until the disease became symptomatic. Others, however, felt it appropriate to treat patients early in the course of the disease. Four clinical trials may be cited addressing this clinical uncertainty (Table 1). Patients receiving chemotherapy had a significantly longer median survival in comparison with only best supportive care. The delay of the carrying out of systemic chemotherapy in patients with metastatic disease decreases the symptom free interval (2 vs. 10 months, p < 0.001), time to disease progression (3 vs. 8 months, p < 0.001) and median survival (14 versus 9 months, p < 0.02) compared to an early start of therapy [7C. Patients with metastatic colorectal cancer benefit from early chemotherapy in terms of survival and quality of life. It is clear that survival is determined by prognostic factors, mainly the performance status, which is a highly significant predictor of therapeutic response and overall survival in advanced colorectal cancer patients. Some authors suggests that the response is a potent and independent prognostic factor of survival, and that response can be used as surrogate marker of survival. Stable disease is a category in therapy response evaluation which is not included in the overall response rate. In many studies with a response rate below 20%, chemotherapy almost doubles the survival of patients. In most chemotherapy trials in advanced colorectal cancer patients, about 30-50% had stable disease. One of the possible reasons may be that in colorectal cancer stabilization of disease is a clinically relevant effect of chemotherapy. If we accept that disease stabilization is a clinically relevant effect of chemotherapy, should we continue with chemotherapy after 3 or 4 courses, and for how long, or should we stop treatment according to rules for stable disease, i.e. following 4 courses? The results of on study, which we performed in 99 patients with advanced colorectal cancer, indicate that under category of "stable disease" there are two different subpopulations of patients with quite different symptom responses as an effect of chemotherapy, different time to progression and possible different survival (Graph 1 and Graph 2). It seems that stable disease patients with clinical benefit could be a target group for policy "to treat until disease progression". The tumour response is likely to be positively correlated with improvement in quality of life when a patient is a symptomatic from cancer before the treatment. Stable disease patients without symptom improvement have no benefit from further chemotherapy and in these patients treatment should be stopped. Such selection would spare from toxicity stable disease patients without clinical benefit. We have no data whether different number of chemotherapy cycles in the groups of patients with and without clinical benefit could lead to a bias in survival estimation. Patients who achieved also a stable disease, but who were asymptomatic from the beginning of chemotherapy, and who are still asymptomatic after 4 chemotherapy courses, make a group for which is hard to make decision either to continue or to stop chemotherapy. We have treated and followed-up these stable disease patients as patients without clinical benefit. We have no answer if they could reach better time to progression and/or survival if they had been treated for more than 4 courses. Careful studies in the evaluation of the quality of life in connection with treatment effects for all stable disease subpopulations of patients are warranted. (ABSTRACT TRUNCATED)

[Chronotherapy with high dose carboplatin, 5-fluorouracil and leucovorin in advanced colorectal carcinoma]. / Hronoterapija velikim dozama karboplatina, pet-fluororacila i leukovorina u napredovalom carcinomu kolorektuma.

INTRODUCTION: Fluorouracil (5-FU) has remained the mainstay of treatment of advanced colorectal cancer disease for nearly 40 years, and despite the implementation of various strategies to increase response rates no substantial improvement in survival has been achieved. 5-FU efficacy has been enhanced by modulating its cytotoxicity with leucovorin (LV) or by administering it as a continuous intravenous infusion. These regimens resulted in a few-fold improvement of tumour response rate in patients with metastatic disease compared with standard 5-FU treatment. The figures are still low (25%), and survival is affected only modestly [1, 2]. Cisplatin and carboplatin are also able to modulate 5-FU cytotoxicity in experimental systems [3]. Recent results of experimental studies suggested that high doses of carboplatin were necessary to achieve biochemical modulation of 5-FU cytotoxicity in vivo [6]. The use of chronobiologically determined drug over a 24-hour period may allow an increase in antitumour effect and a decrease in side effects. Experiments in animals revealed large changes in the toxic effects of 5-FU and platinum analogues, depending on the circadian rhythm of drug administration [9, 10]. The aim of the study was to investigate the toxicity and efficacy of combination of high dose carboplatin, fluorouracil and leucovorin in patients with advanced colorectal adenocarcinoma. Carboplatin and 5-FU were administered in circadian-dependent rhythm regimen in a 4-h infusion. PATIENTS AND METHODS: An open, prospective study was carried out in 99 patients enrolled in the study. The following treatment schedule was used: carboplatin 150 mg, a 4-hour-infusion, start at 8 a.m., day 1-7; 5-FU 750 mg/m2, a 4-hour-infusion, start at 6 p.m., day 1-5; leucovorin 100 mg/m2, bolus i.v. at 8 p.m., day 1-5. The cycles were repeated every 28 days. Dose modifications were not planned. Treatment response and toxicity were evaluated according to WHO criteria [11]. Time to progression was calculated from the beginning of chemotherapy. Survival was calculated from start of chemotherapy using the Kaplan-Meier method [12]. RESULTS: We treated 99 patients (27 colon and 72 rectal cancers) with metastatic diseases. There were 52 males and 47 females, average age 58 years (range 34-72). There were 82 patients (pts) with previous surgical treatment, 30 pts. with previous radiotherapy and 19 pts. with previous adjuvant chemotherapy. Performance status was 0 for 9 pts., 1 for 53 pts., 2 for 33 pts. and 3 for 4 pts. We carried out 469 cycles (mean 4/pts.). Ninety seven pts. were evaluated. The response rate was 28% (95% CI: 19.9-37.9) with 4/97CR, 23/97PR, 48/975D and 22/97PD. Mean time to progression was 5.5 months (range 2-18). The mean survival time was 7 months (range 4-27). The mean survival time was 11 months for responders and 6 months for non-responders. WHO grades 3 and 4 leukopenia were observed in 19 pts (19.2%). WHO grades 3 and 4 thrombocytopenia occurred in 21 (21.2%) pts. The main nonhaematologic toxicity were diarrhea, nausea/vomiting and mucositis. No grades 4 of nonhaematological toxicity were seen, except diarrhea grade 4 was observed in one patient. There was no life-threatening toxicity. DISCUSSION: Carboplatin is able to modulate 5-FU cytotoxicities [3]. A high dose of carboplatin is necessary to achieve biochemical modulation of 5-FU cytotoxicities in vivo [6]. The studies of colon tumour cell lines demonstrated sensitivities to carboplatin when used at clinically achievable dose level [4]. Clinical studies of carboplatin, as a single agent or in combination, in the treatment of colorectal cancer, reported controversial results [19, 20]. Animal studies indicated large and predictable changes in the toxic effects of carboplatin and 5-FU, depending on the circadian rhythm of drug administration. Mechanisms included 24 h changes in the activities of several enzymes involved in 5-FU and carboplatin catabolism or in the anabolism of its cyt

Origin of rat beta-globin haplotypes containing three and five genes.

We have reported in rat three adult beta-gene haplotypes containing either five or three genes. Detailed sequence analysis reveals that the leftmost gene is the major gene and that at the opposite end downstream lies the minor gene. All of the genes lying between them are minor-major hybrids indicating their origin by unequal crossing-over. In two haplotypes beta-globin genes were found with an L1(1) element inserted directly into IVS2. The described results allow the formulation of a pathway of mutational events leading from the ancient two-beta-gene rodent ancestor through a three-gene haplotype to five-gene haplotypes, one of which is postulated to have arisen in common laboratory strains since their capture in the wild.

Tumor 'flare' hypercalcemia--an additional indication for bisphosphonates?

The most serious, potentially life-threatening manifestation of 'flare' is hypercalcemia, registered in 4-5% of breast cancer patients with bone metastases, usually during the first few weeks of tamoxifen treatment. There are no specific treatment recommendations for flare hypercalcemia, except tamoxifen withdrawal. There are no reports on the use of bisphosphonates in the treatment of flare hypercalcemia. Among 87 hypercalcemic patients with metastatic breast cancer observed during a 7-year period, 10 patients had tamoxifen-induced hypercalcemia. Diagnosis of flare hypercalcemia was based on the normal pretreatment values of serum calcium and the development of hypercalcemia within a maximum of 6 weeks of hormonal drug initiation. The median time from hormonal drug initiation to flare hypercalcemia was 14 days, the median duration 8.5 days, and the median calcium level was 3.09 mmol/l (range 2.79-4.46 mmol/l). All patients were treated with hydration, and 7 patients with calcium levels above 3.0 mmol/l were also treated with disodium pamidronate in various single doses (30-90 mg/24 h). Normocalcemia was achieved in all patients, and tamoxifen was continued without relapse of hypercalcemia. Median survival was 177 days (range 12-570 days). It seems that the use of bisphosphonates in the treatment of flare hypercalcemia could allow safe readministration of tamoxifen and prevent premature and unjustified tamoxifen discontinuation. Flare hypercalcemia might represent one more indication for the use of bisphosphonates.