Significance of tumor burden, vascular endothelial growth factor, lactate dehydrogenase and beta-2 microglobulin serum levels in advanced diffuse large B cell lymphoma.

PURPOSE: Lactate dehydrogenase (LDH) and beta-2 microglobulin (B2M) are incorporated in the so-called "serologic staging system", as independent parameters for predicting time to treatment failure (TTF) and overall survival (OS) for aggressive non-Hodgkin's lymphoma (NHL) patients. Elevated values of serum vascular endothelial growth factor (sVEGF) was associated with poor survival in the largest histological subgroup, the diffuse large B cell (DLBCL) and immunoblastic lymphomas. sVEGF has independent influence on survival in multivariate models when tested together with the components of the International Prognostic Index (IPI). The purpose of this study was to define possible correlations between LDH, B2M levels and the novel prognostic parameter sVEGF, with assessed tumor burden, as another parameter of aggressiveness for advanced-stage DLBCLs. METHODS: Serum samples were collected from 29 patients with DLBCL, Ann Arbor clinical stages III and IV, to measure pretreatment serum levels of LDH, B2M and sVEGF. Tumor burden was defined as low and high according to criteria's defined by Jagannath and colleagues. RESULTS: A trend toward significant correlation between high initial levels of sVEGF and high tumor burden was observed (p=0.077). High serum LDH level was strongly associated with high tumor burden (p=0.0091), but B2M correlation with either low or high tumor burden was not confirmed (p=0.249). Complete response (CR) rates (CR vs. non CR) and OS according to tumor burden (low vs. high) showed no statistically significant differences (p=0.245 and p=0.202). CONCLUSION: Our preliminary data confirmed association between serum LDH level and DLBCL burden with a satisfactory sensitivity-specificity relationship. The other two parameters, sVEGF and B2M, failed to demonstrate significant relationship with tumor burden.

Short-term health-related quality of life and symptom control with docetaxel, cisplatin, 5-fluorouracil and cisplatin (TPF), 5-fluorouracil (PF) for induction in unresectable locoregionally advanced head and neck cancer patients (EORTC 24971/TAX 323).

BACKGROUND: The EORTC 24971/TAX 323, a phase III study of 358 patients with unresectable locoregionally advanced squamous cell carcinoma of the head and neck, showed an improved progression-free and overall survival (OS) with less toxicity when docetaxel (T) was added to cisplatin and 5-fluorouracil (PF) for induction and given before radiotherapy (RT). The impact of the addition of docetaxel on patients' health-related quality of life (HRQOL) and symptoms was investigated. METHODS: HRQOL was assessed at baseline, at end of cycle 2, and 4, 6, and 9 months after completion of RT using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) and the EORTC QLQ Head and Neck Cancer-Specific Module (EORTC QLQ-H&N35). The primary HRQOL scale was global HRQOL per protocol. RESULTS: Compliance to HRQOL assessments was 97% at baseline, but dropped to 54% by 6 months. Data were analysed up to 6 months. There was a trend towards improved global HRQOL during the treatment period. At 6 months after the end of RT, global HRQOL was higher in the TPF arm than in the PF arm, but the low compliance does not allow to draw definitive conclusions. Swallowing and coughing problems decreased more in the TPF arm than in the PF arm at the end of cycle 2, but to a limited extent. CONCLUSION: Induction chemotherapy with TPF before RT not only improves survival and reduces toxicity compared with PF but also seems to improve global HRQOL in a more sustainable manner.

Do we know how many cancer patients have a family history of cancer?

PURPOSE: It has been estimated that approximately 5-10% of the general population have a family history that is indicative of hereditary cancer, predominately breast and colorectal. However, it is not precisely known how many patients have positive family history of cancer. The purpose of this study was to determine how many cancer patients have positive family history of cancer. METHODS: Patients were interviewed during the first visit to Daily Chemotherapy Hospital (DCH) of the Institute for Oncology and Radiology of Serbia, Belgrade. Data about patient cancer type and cancer types among family members were recorded in the hospital chart and analyzed. RESULTS: During an 8-month period, 677 newly diagnosed cancer patients with 9 cancer types were referred to DCH for chemotherapy. Positive family history (at least one first degree relative) for any cancer type was recorded in 163 (24.1%) patients and in 47 (6.9%) patients for the same cancer type. The highest percentage of the positive family history for the same type of cancer showed patients with breast cancer (9.9%), followed by colorectal (7.2%) and brain tumors (6.25%). CONCLUSION: The overall incidence of positive family cancer history was 31.0% and was higher than expected. Cancer can be more disturbing for persons who already had experience with this disease in a close family member. Those patients need special attention with more intensive and carefully preplanned psychological support.

Circulating KL-6, a biomarker of lung injury, in obstructive sleep apnoea.

In obstructive sleep apnoea (OSA), oxidative stress contributes to endothelial dysfunction in the peripheral circulation. In the lung, oxidative stress can lead to alveolar injury. The present authors hypothesised that patients with OSA would have biomarker evidence of increased alveolar wall permeability. Sleep characteristics, brachial artery flow-mediated dilation and plasma KL-6 levels were observed in 11 otherwise healthy patients with OSA and 10 controls. Median (interquartile range) plasma KL-6 levels were higher in patients with OSA compared with controls: 317 (232-506) U.mL(-1) versus 226 (179-257) U.mL(-1), respectively. Higher plasma KL-6 levels were associated with greater time spent asleep with an oxyhaemoglobin saturation <90%, lower nadir saturation, more frequent desaturation of >4% during sleep and lower brachial artery flow-mediated dilation. Adjustment for nadir saturation or flow-mediated dilation attenuated the association between plasma KL-6 levels and OSA. Circulating KL-6 levels are elevated in some patients with obstructive sleep apnoea, possibly reflecting increased alveolar wall permeability.

Expression of HER2/neu, estrogen and progesterone receptors, CA 125 and CA19-9 on cancer cell membrane in patients with serous and mucinous carcinoma of the ovary.

PURPOSE: To examine the expression of the membrane markers of estrogen (ER) and progesterone receptors (PR), CA-125, CA 19-9 and HER2/neu in ovarian cancer tissues. METHODS: Fifty-four samples of ovarian cancer tissues originating from 55 patients were examined by immunohistochemistry. Forty-three had serous papillary ovarian cancer, 9 of which were grade I, 12 grade II and 2 grade III. Twelve patients had a classic mucinous ovarian cancer, 5 of which were grade I, 4 grade II and 0 grade III. RESULTS: Out of 43 patients with serous ovarian cancer, 7 expressed both steroid receptors, 22 had only one (10 ER and 12 PR), while 14 were negative. Only 2/12 patients with classic mucinous ovarian cancer expressed of both receptors. CA-125 was expressed in 37/43 patients with serous ovarian cancer and in 4/12 patients with classic mucinous ovarian cancer. CA 19-9 was expressed in 3/43 patients with serous ovarian cancer, and coexpressed with CA-125 in 2/3 patients. In patients with classic mucinous ovarian cancer, 4/12 had expression of CA 19-9 without coexpression with CA-125. HER2/neu positivity (3+) was proven in only one case with classic mucinous ovarian cancer, and any other expression (1+) in 7 additional patients (1 mucinous and 6 serous ovarian cancers). CONCLUSION: Positive HER2/neu expression in the cells of ovarian cancer is very rare and HER2/neu overexpression is even rarer. Expression of ER and PR does not depend on tumor grade and/or at least not in grade I and II. Positive CA 19-9 expression may be present not only in cases of classic mucinous ovarian cancer but also in typical serous ovarian cancer. However, in the classic mucinous ovarian cancer, CA-125 may be expressed, though in relatively low percentage.

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.

Brain metastases as late breast cancer relapse. Single institution experience and review of the literature.

PURPOSE: Approximately 40% of HER2-positive breast cancer patients will develop brain metastases, usually during the first 2-3 years following initial diagnosis and up to 2 years after overt metastatic spread. However, there are no data about brain metastases development as a late disease relapse. In addition, there are no data whether the high incidence of brain metastases is maintained in patients with HER2 overexpression even in late brain metastases. The aim of this paper was to determine the incidence of brain metastases and the HER2 status in patients who developed late relapse, at least 5 years after the initial diagnosis. PATIENTS AND METHODS: Among 384 consecutive breast cancer patients with late relapse, only 8 developed brain metastases. Archival pathological specimens of the primary tumors of those 8 patients were tested by immunohistochemistry (IHC) for HER2 status. RESULTS: The incidence of late brain metastases was 2% (8/384). None of these patients had HER2 3+ primary breast cancer. CONCLUSION: This study shows that the risk for brain metastases in HER2 3+ breast cancer patients is very low or might be even absent as a late relapse. Absence of late brain metastases in HER2 3+ breast cancer might be attributed to specific biological characteristics of HER2 3+ carcinomas to develop brain metastases mostly in the early course of metastatic disease.

Bimonthly 24 h infusion of high-dose 5-fluorouracil vs EAP regimen in patients with advanced gastric cancer. A randomized phase II study.

BACKGROUND: To investigate the activity and toxicity of high dose (HD) infusional 5-FU in comparison to EAP regimen as first-line chemotherapy in patients with advanced gastric cancer. PATIENTS AND METHODS: Histologically confirmed measurable advanced gastric cancer, age < 72 yr, ECOG performance status 0-2, no prior chemo- and radiotherapy, adequate organ functions. TREATMENT: EAP arm: doxorubicin (40 mg/m(2)), etoposide (360 mg/m(2)), and cisplatin (80 mg/m(2)) every 28 d; HD 5-FU arm: 5-FU 2.6 g/m(2) 24 h infusion, biweekly. RESULTS: Sixty patients were randomized. Patient characteristics (arms EAP/HD 5-FU): Median age 57/55 yr, median PS 1/1, LAD (patients) 3/8, M1 (patients) 27/22. Median number of cycles (range): EAP arm 4 (2-8), HD 5-FU arm 2 (1-8). Worst toxicity per cycle (grade 3 and 4 in%): Neutropenia 20/3, thrombocytopenia 9/0, anemia 9/13, diarrhea 3/10, nausea 17/7, vomiting 10/0 for EAP and HD 5-FU arms, respectively. All patients were eligible for response in both arms. Confirmed response rate (95%CI): EAP arm 34% [16-50%]/HD 5-FU arm 10% (0-21%), no change: 46/40%, progression of disease: 20/50, respectively. Overall survival (range): EAP arm A 7 mo [3-27], HD 5-FU arm 6 mo (4-25). CONCLUSIONS: Infusional HD 5-FU showed a low incidence of severe toxicity. But given the low efficacy of 5-FU in the dosage we applied in the study, it cannot be recommended as a single treatment for further studies. Assessment of higher dose intensity and/or dose density of 5-FU, with introduction of other active drugs in combination, could be an option for further studies.

Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial.

PURPOSE: This phase III trial compared the efficacy and safety of doxorubicin and paclitaxel (AT) to 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) as first-line therapy for women with metastatic breast cancer. PATIENTS AND METHODS: A total of 267 women with metastatic breast cancer were randomized to receive either AT (doxorubicin 50 mg/m(2) followed 24 hours later by paclitaxel 220 mg/m(2)) or FAC (5-fluorouracil 500 mg/m(2), doxorubicin 50 mg/m(2), cyclophosphamide 500 mg/m(2)), each administered every 3 weeks for up to eight cycles. Patients had to have measurable disease and an Eastern Cooperative Oncology Group performance status of 0 to 2. Only one prior non-anthracycline, nontaxane-containing adjuvant chemotherapy regimen was allowed. RESULTS: Overall response rates for patients randomized to AT and FAC were 68% and 55%, respectively (P =.032). Median time to progression and overall survival were significantly longer for AT compared with FAC (time to progression 8.3 months v 6.2 months [P =.034]; overall survival 23.3 months v 18.3 months [P =.013]). Therapy was generally well-tolerated (median of eight cycles delivered in each arm). Grade 3 or 4 neutropenia was more common with AT than with FAC (89% v 65%; P <.001); however, the incidence of fever and infection was low. Grade 3 or 4 arthralgia and myalgia, peripheral neuropathy, and diarrhea were more common with AT, whereas nausea and vomiting were more common with FAC. The incidence of cardiotoxicity was low in both arms. CONCLUSION: AT conferred a significant advantage in response rate, time to progression, and overall survival compared with FAC. Treatment was well-tolerated with no unexpected toxicities.

Fluoropyrimidine therapy: hyperbilirubinemia as a consequence of hemolysis.

BACKGROUND: Hemolytic anemia has been noted during treatment with a variety of chemotherapeutic agents. We observed mild compensated hemolytic anemia in a patient receiving capecitabine during a randomized, controlled trial of adjuvant therapy. In order to investigate the hypothesis that hemolysis is the underlying cause of the hyperbilirubinemia sometimes observed during capecitabine treatment, we evaluated factors associated with hemolysis in ten patients. Factors were also analyzed in ten patients receiving 5-fluorourocil/leucovorin (5-FU/LV). METHODS: Twenty chemotherapy-naïve patients undergoing surgery for Dukes' C colon cancer were included in the phase III, 'X-ACT' trial, and randomized to receive 24-week adjuvant treatment with either oral capecitabine (eight cycles of 1,250 mg/m2 twice daily for 14 days, followed by a 7-day rest period) (n=10) or 5-FU/LV administered according to the Mayo Clinic regimen (six cycles of LV 20 mg/m2 followed by 5-FU 425 mg/m2, administered as an i.v. bolus on days 1-5 every 28 days) (n=10). Ten patients randomized in each treatment arm were evaluated. Hemolytic parameters evaluated included bilirubin, lactate dehydrogenase, haptoglobin, and reticulocytes. RESULTS: Seven patients receiving capecitabine and three patients receiving 5-FU/LV experienced grade 1/2 elevations of bilirubin during the 24-week treatment period. In most cases, hyperbilirubinemia was associated with concomitant alterations in other hemolytic parameters. Five episodes of grade 1 compensated hemolytic anemia were reported in four capecitabine-treated patients, all of which were associated with hyperbilirubinemia. CONCLUSION: Adjuvant treatment with capecitabine or 5-FU/LV in a small sample of patients with Dukes' C colon cancer was associated with alterations in hemolytic parameters. These alterations, in particular hyperbilirubinemia, were associated in some patients with low-grade compensated hemolytic anemia. All changes were clinically insignificant, fully reversible, and may represent a fluoropyrimidine class effect. Further studies are indicated to evaluate the incidence and implications of this effect.