János Szántó

Docetaxel and Doxorubicin Compared With Doxorubicin and Cyclophosphamide as First-Line Chemotherapy for Metastatic Breast Cancer: Results of a Randomized, Multicenter, Phase III Trial

PURPOSE This randomized, multicenter, phase III study compared doxorubicin and docetaxel (AT) with doxorubicin and cyclophosphamide (AC) as first-line chemotherapy (CT) in metastatic breast cancer (MBC). PATIENTS AND METHODS Patients (n = 429) were randomly assigned to receive doxorubicin 50 mg/m(2) plus docetaxel 75 mg/m(2) (n = 214) or doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) (n = 215) on day 1, every 3 weeks for up to eight cycles. RESULTS Time to progression (TTP; primary end point) and time to treatment failure (TTF) were significantly longer with AT than AC (median TTP, 37.3 v 31.9 weeks; log-rank P =.014; median TTF, 25.6 v 23.7 weeks; log-rank P =.048). The overall response rate (ORR) was significantly greater for patients taking AT (59%, with 10% complete response [CR], 49% partial response [PR]) than for those taking AC (47%, with 7% CR, 39% PR) (P =.009). The ORR was also higher with AT in patients with visceral involvement (58% v 41%; liver, 62% v 42%; lung, 58% v 35%), three or more organs involved (59% v 40%), or prior adjuvant CT (53% v 41%). Overall survival (OS) was comparable in both arms. Grade 3/4 neutropenia was frequent in both groups, although febrile neutropenia and infections were more frequent for patients taking AT (respectively, 33% v 10%, P <.001; 8% v 2%, P =.01). Severe nonhematologic toxicity was infrequent in both groups, including grade 3/4 cardiac events (AT, 3%; AC, 4%). CONCLUSION AT significantly improves TTP and ORR compared with AC in patients with MBC, but there is no difference in OS. AT represents a valid option for the treatment of MBC.

Gemcitabine, Epirubicin, and Paclitaxel Versus Fluorouracil, Epirubicin, and Cyclophosphamide As First-Line Chemotherapy in Metastatic Breast Cancer: A Central European Cooperative Oncology Group International, Multicenter, Prospective, Randomized Phase III Trial

BACKGROUND The objectives of this phase III trial were to compare the time to progressive disease (TtPD), overall response rate (ORR), overall survival, and toxicity of gemcitabine, epirubicin, and paclitaxel (GET) versus fluorouracil (FU), epirubicin, and cyclophosphamide (FEC) as first-line therapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS Female patients aged 18 to 75 years with stage IV and measurable MBC were enrolled and randomly assigned to either gemcitabine (1,000 mg/m(2), days 1 and 4), epirubicin (90 mg/m(2), day 1), and paclitaxel (175 mg/m(2), day 1) or FU (500 mg/m(2), day 1), epirubicin (90 mg/m(2), day 1), and cyclophosphamide (500 mg/m(2), day 1). Both regimens were administered every 21 days for a maximum of eight cycles. RESULTS Between October 1999 and November 2002, 259 patients (GET, n = 124; FEC, n = 135) were enrolled. Baseline characteristics were well balanced across treatment arms. After a median of 20.4 months of follow-up, median TtPD was 9.1 months and 9.0 months in the GET and FEC arms, respectively (P = .557). The ORR was 62.3% in the GET arm (n = 114) and 51.2% in the FEC arm (n = 129; P = .093). Grade 3 and 4 toxicities, including neutropenia, thrombocytopenia, anemia, stomatitis, neurosensory toxicity, and allergy, occurred significantly more often in the GET arm. CONCLUSION No significant differences in terms of TtPD and ORR were observed between the two treatment arms. Treatment-related toxicity was higher in the GET arm.

Pain Killing with Calcitonin Nasal Spray in Patients with Malignant Tumors

The physiological role of calcitonin is the preservation of osseal integrity by reducing the osteoclast activity. On the other hand, this 32 amino acid peptide acts as an analgetic drug in cancer caused by osteolytic metastases. In previous studies using injection form the pain killing activity was observed in 65% of the patients. As medical assistance is required for this treatment form, it was decided to compare the pain reducing activity of nasal spray with the ampule form. It was found that 300 MRC units of nasal spray equalled 100 MRC units injection. The pain killing activity was observed in 53.8% of the patients. The reduction in quantity of other analgetics used daily was 48.5%. The average decrease of the pain duration (in h) was 42.5%. The pain intensity measured by visual analogue scale dropped to 2.13 from 3.00. The results are similar to the analgetic effect observed in the injection form. Taking this into consideration, calcitonin nasal spray is highly recommended instead of ampules.

Malignancies associated with systemic sclerosis.

The outcome of systemic sclerosis (SSc) has become more favorable during the past years. Respiratory failure or renal crisis became less frequent, therefore more attention should be paid to long-term comorbidities, such as malignancies secondary to scleroderma. The incidence of malignant lymphoproliferative diseases, as well as that of solid tumors are higher in a number of rheumatic diseases including SSc. Some cytotoxic agents, primarily cyclophosphamide used in the treatment of SSc, as well as exposure to chemicals or smoking may further increase cancer risk. We also present malignancies in 218 scleroderma patients undergoing follow-up in our department were assessed for secondary malignancies. Although the number of SSc patients with tumor is relatively small, we compared our cohort to the Health for All Hungarian database and calculated standard incidence ratios (SIR). We identified 11 cases of malignancy in 10 SSc patients (4.6%). One patient had two types of tumor: breast cancer before the onset of SSc and later malignant lymphoma. Half of SSc patients with cancer belonged to the diffuse cutaneous (dcSSc) subtype. The mean age at onset of SSc was 54.6 years, while that at the diagnosis of malignancy was 61.5 years. The mean disease duration of scleroderma at the time of cancer diagnosis was 6.6 years. Five patients died, 4 due to the underlying malignancy. Among the five surviving patients, the mean survival time was 4.9 years. Altogether 3 patients had non-Hodgkins lymphoma, 2 had bronchial cancer, 2 had breast cancer, one had leiomyosarcoma of the leg, one had esophageal cancer, one had cervix cancer and one had skin cancer. In comparison to the Health for All database, the overall SIR of all malignancies in SSc was 1.07 (CI: 0.82-1.38) varying between 5.8 and 52.4 in different tumor types. Only one cancer patient received cyclophosphamide therapy. In conclusion, secondary tumors including lung, skin and breast cancer, as well as lymphomas are more common in SSc than in the general population. The adequate treatment and follow-up of scleroderma patients may help us to lower the risk of malignancies secondary to SSc.

Maintenance treatment with medroxyprogesterone acetate in patients with advanced breast cancer responding to chemotherapy: results of a randomized trial

The purpose of this randomized phase III trial was to study whether medroxyprogesterone acetate (MPA) maintenance treatment prolongs the time to progression in advanced breast cancer patients responding to an induction chemotherapy. Patients with progressive advanced breast cancer previously untreated with anthracylines and progestins were given epirubicin (30 mg/m2) and ifosfamide (2 g/m2) on days 1 and 8 at 3‐weekly intervals. Patients without disease progression after 6 cycles of chemotherapy were randomly assigned to receive, until progression, either no treatment or MPA at a daily total dose of 500 mg. Ninety patients were randomized: 46 to the MPA arm and 44 to the observation arm. Median time to progression was longer in the MPA arm: 4.9 months versus 3.7 months in the intent‐to‐treat analysis (p=0.02), and 4.9 months versus 3.0 months in the secondary efficacy analysis (p=0.012). Seven patients were removed from MPA due to side effects. The changes in patient‐rated quality of life scores were similar in both groups. The median length of survival from randomization was 17.4 months for patients receiving MPA and 18.3 months for patients randomized to observation (p=0.39). In conclusion, in patients with advanced breast cancer achieving remission or non‐progression with 6 cycles of epirubicin and ifosfamide chemotherapy, MPA maintenance treatment led to a significant, though modest, prolongation of the time to progression without affecting overall survival of the study patients.

Pain Killing with Calcitonin in Patients with Malignant Tumours

The most essential role of Miacalcic (Calcitonin Sandoz), a 32-amino-acids peptide, is the preservation of osseal integrity. Based on this physiological fact it is assumed that this hormone may have a bone-regenerating effect in bone metastasis formation and sometimes in other malignancies. Though no considerable calcium incorporation could be revealed in our 58 patient treated with Miacalcic, a marked relief of pain was observed in 65.5% of the patients. For objectivation of the subjective pain sensation, the decrease in the quantity of other analgetics used daily, duration of pain and changes of its intensity were studied. These figures were 35.4% on the average, from 12.5-6 h and 23.6%, respectively. The pain-killing character of Miacalcic cannot be explained, but the following assumptions are made: (1) it partially inhibits the synthesis of algogenous peptides; (2) with its possibly cytostatic effect it inhibits the cell proliferation in loco and normalizes the internal pressure of the destroyed region, and (3) by conversion into beta-endorphin it exerts its effect centrally. Compared to the pain-killing effect, the simultaneous improvement of the quality of life seems to be even more essential. It has been proved earlier that a hormone physiologically present, when applied in a high dose, has an analgetic effect, i.e. by utilizing the endogenous substance of the organism, relief of pain can be achieved. We should like to point out that Miacalcic is the only analgetic agent capable of ensuring relief of pain with a simultaneous improvement of the quality of life. Accordingly, the application of Miacalcic in patients suffering from malignant tumours is highly recommended.

The efficacy of a combination of etoposide, ifosfamide, and cisplatin in the treatment of patients with soft tissue sarcoma

Successful chemotherapy for patients with soft tissue sarcoma (STS) has been limited by a lack of active drugs. The most effective single agents are doxorubicin, dacarbazine, and, more recently, ifosfamide. Previously the most widely used combination has been CYVADIC (cyclophosphamide, vincristine, doxorubicin, and dacarbazine). In one randomized trial, ifosfamide was superior to cyclophosphamide; two nonrandomized studies also reported favorable results. Etoposide monotherapy was successful in 8%; the effectiveness of cisplatin was 5–23%. In view of these findings, the authors treated STS patients with an etoposide, cisplatin, and ifosfamide (VIP) combination.

Analysis of EGFR Gene Amplification, Protein Over-expression and Tyrosine Kinase Domain Mutation in Recurrent Glioblastoma

Gefitinib and erlotinib are both selective EGFR tyrosine kinase inhibitors (EGFR-TKIs) that have produced responses in a small subgroup of lung cancer patients. The strongest evidence for a role of EGFR in the biology of glioblastoma stems from clinical trials in which 15–20% of recurrent glioblastoma patients experienced significant tumour regression in response to these small-molecule EGFR kinase inhibitors. We examined the protein-kinase domain of the EGFR gene, EGFR protein expression and EGFR gene amplification in 20 cases of recurrent GBMs. EGFR protein over-expression was found in 65% of cases. EGFR protein over-expression was associated with EGFR gene amplification in 35% of cases, and with high polysomy in 15% of cases. No mutations were found in the TK domain of the EGFR gene. Our results confirm that mutations in the kinase domain are absent in recurrent GBM, and this might be a preponderant factor in the lack of major clinical responses of TKIs in GBM, recent studies have suggested that responsiveness to EGFR kinase inhibitors was strongly associated with coexpression of EGFRvIII and PTEN. Further prospective validation of EGFRvIII and PTEN as predictors of the clinical response to EGFR kinase inhibitors in recurrent GBM is strongly anticipated.

Increased production of the soluble tumor-associated antigens CA19-9, CA125, and CA15-3 in rheumatoid arthritis: Potential adhesion molecules in synovial inflammation?

Abstract:  Some tumor‐associated antigens (TAAs) are expressed on inflammatory cells. We previously detected carcinoembryonic antigen (CEA; CD66) in the rheumatoid (RA) synovium. The production of CEA, CA19‐9, CA125, and CA15.3, may be increased in patients with RA, scleroderma, lupus, and Sjögrens syndrome (SS). Some of these TAAs contain sialylated carbohydrate motifs and they are involved in tumor‐associated cell adhesion and metastasis. We assessed levels of TAAs in the sera of RA patients and healthy subjects. Serum TAA levels were correlated with disease markers including serum rheumatoid factor (RF), C‐reactive protein (CRP), and anti‐CCP antibody levels, DAS28, age disease duration. TAAs including CEA, CA15‐3, CA72‐4, CA125, and CA19‐9, and neuron‐specific enolase (NSE) were assessed by immunoassay in the sera of 75 patients with RA and 50 age‐ and sex‐matched healthy controls. Normal upper limits for these TAAs were 3.4 μg/L, 25 kU/L, 6.9 kU/L, 35 kU/L, 34 kU/L, and 16.3 μg/L, respectively. There were significantly more RA patients showing abnormally high levels of CA125 (10.8% versus 7.1%), CA19‐9 (8.1% versus 0%), and CA15‐3 (17.6% versus 14.3%) in comparison to controls (P < 0.05). The mean absolute serum levels of CA125 (23.9 ± 1.8 versus 16.8 ± 2.2 kU/L) and CA19‐9 (14.2 ± 1.2 versus 10.5 ± 1.6 kU/L) were also significantly higher in RA compared to controls (P < 0.05). Among RA patients, serum CEA showed significant correlation with RF (r= 0.270; P < 0.05). None of the assessed TAAs showed any correlation with CRP, anti‐CCP, DAS28, age or disease duration. The concentration of some TAAs may be elevated in the sera of patients with established RA in comparison to healthy subjects. CEA, CA19‐9, CA125, and CA15‐3 contain carbohydrate motifs and thus they may be involved in synovitis‐associated adhesive events. Furthermore, some TAAs, such as CEA, may also correlate with prognostic factors, such as serum RF levels.

Tumor-associated antigens in systemic sclerosis and systemic lupus erythematosus: Associations with organ manifestations, immunolaboratory markers and disease activity indices

BACKGROUND Some tumor-associated antigens (TAAs) are expressed on inflammatory cells. We previously detected increased production of CA15-3, CA19-9 and CA125 in rheumatoid arthritis (RA). The production of some TAAs may also be increased in patients with systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and other connective tissue diseases. Some of these TAAs contain sialylated carbohydrate motifs and they are involved in tumor-associated cell adhesion and metastasis. OBJECTIVES We assessed levels of TAAs in the sera of SSc, SLE patients, patients with infectious diseases and healthy subjects. Serum TAA levels were correlated with each other, as well as with disease activity markers and organ involvement. METHODS TAAs including CEA, CA15-3, CA72-4, CA125 and CA19-9 were assessed by immunoassay in the sera of 92 patients with SSc, 40 patients with SLE, 50 age- and sex-matched healthy controls, as well as with 40 patients with current bacterial or viral infections. Normal upper limits for these TAAs were 3.4 mg/l, 25 kU/l, 6.9 kU/l, 35 kU/l and 34 kU/l, respectively. RESULTS There were significantly more SSc patients showing abnormally high levels of CA19-9 (8.8% vs 2.0%), CA125 (11.0% vs 6.0%) and CA15-3 (28.4% vs 14.0%) in comparison to controls (p < 0.05). In SLE, significantly more patients had elevated levels of CEA (32.5% vs 20.0%), CA19-9 (7.5% vs 2.0%), CA125 (15.0% vs 6.0%) and CA72-4 (15.0% vs 8.0%) than did controls (p < 0.05). The mean absolute serum levels of CEA (6.6+/-1.7 vs 1.8+/-1.4 mg/l) and CA15-3 (22.9 +/- 1.8 vs 18.6 +/- 2.2 kU/l) were also significantly higher in SSc compared to controls (p < 0.05). We found numerous correlations between the serum levels of different TAAs within the SSc and SLE population. Among SSc patients, serum CEA (R = 0.290; p = 0.005), CA15-3 (R = 0.260; p = 0.020) and CA19-9 (R = 0.257; p = 0.013) correlated with renal involvement. Serum CA15-3 also correlated with joint involvement (R = 0.329; p = 0.003), ANA positivity (R = 0.288; p = 0.010) and CRP levels (R = 0.407; p < 0.001). Within the SLE population, serum CA72-4 correlated with central nervous involvement (R = 0.624; p = 0.004) and CA125 correlated with the SLEDAI composite activity index (R = 0.666; p = 0.002). Patients with infections exerted serum TAA patterns similar to healthy controls. CONCLUSION The concentration of some TAAs may be elevated in the sera of patients with SSc or SLE in comparison to healthy subjects. Pathogenically, most of these TAAs contain carbohydrate motifs and thus they may be involved in inflammation-associated adhesive events. Furthermore, the production of some TAAs may correlate with organ involvement or disease activity in scleroderma or lupus.