Prolonged disease-free survival by maintenance chemotherapy among patients with recurrent platinum-sensitive ovarian cancer

The aim of this prospective, randomized and double-blind study was to assess the effects of a high dose of the analgesic tramadol administered at the conclusion of surgery on extubation time, sedation, and post-anaesthetic shivering. Forty adult patients, ASA physical status I or II, underwent laparoscopic surgery of about 1 h duration and received a standardized anaesthesia that was maintained with isoflurane in O2/N2O. Tramadol 3 mg kg-1 (n = 20) was administered intravenously at the beginning of wound closure, and was compared with saline (n = 20). Post-anaesthetic shivering did not occur in any patient who received tramadol, whereas it occurred in 60% of the control group (P < 0.001). There were no adverse effects on time to extubation and sedation, and discharge-ready time was shorter in the tramadol group (P < 0.05 compared with control). Pain scores in the post-anaesthesia care unit (PACU) were statistically not different between the two groups, but significantly more supplemental medication was administered in the control group to treat shivering and/or pain. In conclusion, administration of a high dose of tramadol at the end of surgery prevents post-anaesthetic shivering without prolongation of extubation time, and shortens the PACU/discharge-ready time.     

Glutathione concentration may be a useful predictor of response to second-line chemotherapy in patients with ovarian cancer

BACKGROUND: No useful predictor of resistance or sensitivity to second-line chemotherapy is known for ovarian cancer. The objective of this prospective study was to determine the utility of tumor glutathione S-transferase-pi (GST-pi) expression or glutathione (GSH) concentration in predicting ovarian cancer patients' responses to second-line chemotherapy. METHODS: Tumor samples were obtained from 26 patients with relapsed epithelial ovarian cancer 3-4 weeks before the initiation of second-line chemotherapy with etoposide (daily on Days 1-5) and cisplatin (on Day 5). The expression of GST-pi in tumor samples was determined by immunohistochemical staining and Western blot analysis. GSH concentration was measured by an enzymatic assay. RESULTS: The response rate was 38.4%. The estimated 3-year survival rate for the responders (66.7%) significantly exceeded that for the nonresponders (9.1%). Expression of GST-pi by immunohistochemical staining was more frequently observed in nonresponders (2 of 10 responders vs. 11 of 16 nonresponders). Western blot analysis detected GST-pi in all cases. There was no significant difference in the relative density values of the GST-pi Western blot analysis between the two groups. The mean value of GSH concentration in nonresponders was significantly higher than in responders (18.4 +/- 9.7 vs. 7.5 +/- 8.2 microg/mg protein). GSH concentration was below the cutoff point (10.3 microg/mg protein) in all responders except one. CONCLUSIONS: Second-line chemotherapy consisting of etoposide and cisplatin is effective in the treatment of relapsed epithelial ovarian cancer. In addition, tumor concentration of GSH may be a useful predictor of the response to this therapy.     

Tumour cell kinetics as prognostic factor in surgically-treated-non-small cell lung cancer

The gene encoding myosin VIIA is responsible for the mouse shaker-1 phenotype, which consists of deafness and balance deficiency related to cochlear and vestibular neuroepithelial defects. In humans, a defective myosin VIIA gene is responsible for Usher syndrome type IB, which associates congenital deafness, vestibular dysfunction and retinitis pigmentosa. In an attempt to progress in the understanding of the function(s) of myosin VIIA, we studied the expression of the myosin VIIA gene during mouse embryonic development. Embryos from day 9 (E9) to E18 were analyzed by in situ hybridization and immunohistofluorescence. The myosin VIIA mRNA and protein were consistently detected in the same embryonic tissues throughout development. Myosin VIIA was first observed in the otic vesicle at E9, and later in a variety of tissues. The olfactory epithelium and the liver express it as early as E10. In the retinal pigment epithelium, choroid plexus, adrenal gland and tongue, expression begins at E12 and in the testis and the adenohypophysis at E13. In the small intestine, kidney and hair follicles of the vibrissae, expression of myosin VIIA starts only at E15. Myosin VIIA expression was observed only in epithelial cell types, most of which possess microvilli or cilia. Interestingly, myosin VIIA expression seems to be concomitant with the appearance of these structures in the epithelial cells, suggesting a role for this myosin in their morphogenesis. The cellular location of myosin VIIA within sensory hair cells and olfactory receptor neurons also argues for a role of this protein in the synaptic vesicle trafficking.     

Relationship of variations in tumor cell kinetics induced by primary chemotherapy to tumor regression and prognosis in locally advanced breast cancer

We have studied binding of isradipine to A7r5 vascular smooth muscle cells as a function of membrane potential and cell proliferation. Consistent with a voltage-modulated receptor model, two classes of binding sites were detected in confluent cultures: high-affinity sites under depolarizing (50 mM K+) conditions (Kd = 45 +/- 3 pM), and lower affinity sites under resting (5 mM K+) conditions (Kd = 181 +/- 20 pM). However, proliferating cells also displayed the high-affinity state at rest (Kd = 29 +/- 9 pM) in addition to a low-affinity site (Kd = 869 +/- 383 pM). Analysis of dissociation rates also revealed two receptor classes during proliferation. Proliferating cells showed a single class of high-affinity sites (Kd = 39 +/- 6 pM) when depolarized, similar to confluent cells. Receptor density in confluent monolayers increased from 15 +/- 3 fmol/10(6) cells at 5 days to 72 +/- 6 fmol/10(6) cells after 10 days. These results suggest (i) that some L-type Ca2+ channels are spontaneously active in proliferating vascular smooth muscle cells, but require depolarization to activate in a confluent monolayer, and (ii) that the density of dihydropyridine receptors increases after a monolayer becomes confluent.     

Local host response in osteosarcoma after chemotherapy referred to radiographs, CT, tumour necrosis and patient survival

PURPOSE: The necrotic effect of chemotherapy on primary osteosarcoma has been shown to be predictive of the final outcome. Little attention has been paid to the local response of the host (LHR), which reflects the tumour-host relationship. DESIGN: A four-step grading system was developed based on distinct histological patterns of the LHR around the lesion. These responses were correlated with the chemotherapy-induced necrosis or chemosensitivity and analysed in an attempt to ascertain their influence on the patient prognosis. The ability of conventional radiographs and computed tomography to measure LHR was studied. METHODS: The grading system was applied to macroslides of specimens obtained from 72 patients with stage II B primary osteosarcoma in various limbs after wide resection and complete courses of pre- and postoperative chemotherapy who were treated between 1985 and 1991 with a median follow-up of 5 years and 9 months. The histological specimens were blindly reviewed by two pathologists and two experienced musculoskeletal oncologists to assign a grade of response. The results were correlated with tumour necrosis, patient survival and response features on conventional radiographs and CT images. RESULTS: Significant correlation was found between LHR and tumour necrosis or chemosensitivity (r=0.55) and between LHR and CT response (r=0.56). There was no correlation between LHR and the findings on conventional radiographs. A grade 4 LHR was predictive of long-term survival. CONCLUSIONS: The LHR to preoperative chemotherapy has a prognostic influence on patient survival and can be predicted by CT.     

Consolidation/maintenance chemotherapy for ovarian cancer

A recently reported randomized trial has demonstrated that administration of single-agent paclitaxel to women with advanced ovarian cancer who attain a clinically defined complete response to platinum/paclitaxel-based chemotherapy can substantially improve progression-free survival. Whether this strategy will improve overall survival in this clinical setting remains uncertain.     

Interstitial methotrexate kinetics in primary breast cancer lesions

The transfer of cytotoxic agents across the tumor endothelium into the interstitial tumor space is considered a critical step in clinical resistance of solid tumors to antineoplastic chemotherapy. However, experimental data on drug transfer from the blood into the interstitium of solid tumors are scarce. Therefore, in this study, we used an innovative technique, in vivo microdialysis, for measuring interstitial tumor pharmacokinetics and plasma-to-tumor transfer rates of methotrexate (MTX) in breast cancer patients. Microdialysis probes were inserted into the primary tumor and the periumbilical s.c. adipose layer of nine previously chemotherapy-naive breast cancer patients to monitor interstitial concentrations following i.v. administration of MTX (40 mg/m2) during a three-drug treatment regimen. Mean interstitial MTX load in breast tumors, expressed as area under curve (AUC), was 60 +/- 20% (mean +/- SE; coefficient of variation = 100%) of mean plasma MTX load. There was no correlation between plasma AUC and the AUC in the interstitial space of tumor tissue (P = 0.93). Not one of the parameters plasma, interstitial tumor load, and transfer rate of MTX to the interstitial space was associated with favorable clinical response. In conclusion, plasma levels of MTX are not predictive of intratumor levels. There is a high interindividual variability in transendothelial MTX transfer. Under the present conditions, access of MTX to the interstitial space is not a rate-limiting step for clinical response to chemotherapy.     

First-line chemotherapy for advanced ovarian cancer: paclitaxel, cisplatin and the evidence

As of June 1998, four randomized trials have been completed comparing the combination of paclitaxel and cisplatin with a cisplatin-based control arm. The results of three of these trials are available; one has been published as a full paper, the other two in abstract form only. Two of the reported trials (GOG-111 and the Intergroup trial) provide clear evidence that cisplatin combined with paclitaxel is a more effective regimen than one using the same dose of cisplatin combined with cyclophosphamide. The results of the third reported trial (GOG-132) are rather different, suggesting that a higher dose of single-agent cisplatin may be as effective as the paclitaxel/cisplatin combination tested in the other two trials. A number of explanations for these unexpected results have been proposed: false-positive results in GOG-111 and the Intergroup trial; false-negative results in GOG-132; high crossover in GOG-132 (including crossover before progression); the cyclophosphamide in the control arm of GOG-111 and the Intergroup trial had a negative impact on outcome in the control group in these trials; the higher dose of cisplatin when used as a single agent in GOG-132 had a positive impact on outcome for the control group in this trial. These explanations are discussed in detail, and their implications explored.     

Breast cancer and prognostic factors. Tumour size, degree of differentiation, proliferation kinetics and expression of steroid hormone receptors

In a group of 161 patients with operable cancer of the breast, tumour size, axillary node status and histopathological grading were correlated. Furthermore, steroid hormone receptor status was assessed both biochemically and immunohistochemically. The rate of Ki67-positive cells, the ploidy status and the S-phase fraction of the carcinoma, as assessed by means of flow-cytometry, were measured and correlated with tumour size and conventional histopathological grading. As expected, a significant correlation between tumour size and the frequency of axillary lymph node metastases was found (p < 0.00001). There was however, also a significant increase of undifferentiated cancers with increasing tumour size (p < 0.001). There was no correlation between steroid hormone receptor expression and grading but a slight decrease of immunohistochemically oestrogen receptor positive cancers with increasing tumour size (p < 0.02). On the other hand, there was a marked increase of both Ki67-score (p < 0.003) and S-phase fraction (p < 0.001) with increasing tumour size. Neither of the first two parameters correlated significantly with grading. The frequency of aneuploid tumours was dependent on tumour size (p < 0.05) as well as grading (p < 0.01). The findings point towards a change of biological properties of the cancer during the course of growth, such as histopathological dedifferentiation and increased proliferation fraction and frequency of aneuploid tumours. The expression of steroid hormone receptors however is virtually unchanged.     

Risk of leukemia after platinum-based chemotherapy for ovarian cancer

BACKGROUND: Platinum-based chemotherapy is the cornerstone of modern treatment for ovarian, testicular, and other cancers, but few investigations have quantified the late sequelae of such treatment. METHODS: We conducted a case-control study of secondary leukemia in a population-based cohort of 28,971 women in North America and Europe who had received a diagnosis of invasive ovarian cancer between 1980 and 1993. Leukemia developed after the administration of platinum-based therapy in 96 women. These women were matched to 272 control patients. The type, cumulative dose, and duration of chemotherapy and the dose of radiation delivered to active bone marrow were compared in the two groups. RESULTS: Among the women who received platinum-based combination chemotherapy for ovarian cancer, the relative risk of leukemia was 4.0 (95 percent confidence interval, 1.4 to 11.4). The relative risks for treatment with carboplatin and for treatment with cisplatin were 6.5 (95 percent confidence interval, 1.2 to 36.6) and 3.3 (95 percent confidence interval, 1.1 to 9.4), respectively. We found evidence of a dose-response relation, with relative risks reaching 7.6 at doses of 1000 mg or more of platinum (P for trend <0.001). Radiotherapy without chemotherapy (median dose, 18.4 Gy) did not increase the risk of leukemia. CONCLUSIONS: Platinum-based treatment of ovarian cancer increases the risk of secondary leukemia. Nevertheless, the substantial benefit that platinum-based treatment offers patients with advanced disease outweighs the relatively small excess risk of leukemia.     

Randomized comparison of progenitor-cell mobilization using chemotherapy, stem-cell factor, and filgrastim or chemotherapy plus filgrastim alone in patients with ovarian cancer

PURPOSE: This was the first randomized study to investigate the efficacy of peripheral-blood progenitor cell (PBPC) mobilization using stem-cell factor (SCF) in combination with filgrastim (G-CSF) following chemotherapy compared with filgrastim alone following chemotherapy. PATIENTS AND METHODS: Forty-eight patients with ovarian cancer were treated with cyclophosphamide and randomized to receive filgrastim 5 microg/kg alone or filgrastim 5 microg/kg plus SCF. The dose of SCF was cohort-dependent (5, 10, 15, and 20 microg/kg), with 12 patients in each cohort, nine of whom received SCF plus filgrastim and the remaining three patients who received filgrastim alone. On recovery from the WBC nadir, patients underwent a single apheresis. RESULTS: SCF in combination with filgrastim following chemotherapy enhanced the mobilization of progenitor cells compared with that produced by filgrastim alone following chemotherapy. This enhancement was dose-dependent for colony-forming unit-granulocyte-macrophage (CFU-GM), burst-forming unit-erythrocyte (BFU-E), and CD34+ cells in both the peripheral blood and apheresis product. In the apheresis product, threefold to fivefold increases in median CD34+ and progenitor cell yields were obtained in patients treated with SCF 20 microg/kg plus filgrastim compared with yields obtained in patients treated with filgrastim alone. Peripheral blood values of CFU-GM, BFU-E, and CD34+ cells per milliliter remained above defined threshold levels longer with higher doses of SCF. The higher doses of SCF offer a greater window of opportunity in which to perform the apheresis to achieve high yields. CONCLUSION: SCF (15 or 20 microg/kg) in combination with filgrastim following chemotherapy is an effective way of increasing progenitor cell yields compared with filgrastim alone following chemotherapy.     

Immunohistochemically detected p53 and P-glycoprotein predict the response to chemotherapy in lung cancer

While resistance to chemotherapy is a major problem in lung cancer treatment, there is no useful predictor of treatment response. We thus designed this study to determine the utility of p53 and P-glycoprotein expression in predicting the response to chemotherapy in patients with primary lung cancer, retrospectively. We evaluated transbronchial biopsy (TBB) specimens from 60 patients with lung cancer, who were previously untreated. Formalin-fixed, paraffin-embedded TBB specimens were immunostained using anti-p53 antibody (DO-1) and anti-P-glycoprotein antibody (JSB-1). The positivity of p53 was 63%, and that of P-glycoprotein was 17%. No correlation was observed between p53 and P-glycoprotein immunostaining. Positivity of p53 correlated significantly (P = 0.004) with a lack of response to chemotherapy in non-small cell lung cancer (NSCLC), but not in small cell lung cancer (SCLC). In contrast, positivity of P-glycoprotein was correlated with chemotherapy resistance in SCLC (P = 0.003), but not in NSCLC. Multiple logistic regression analysis revealed that positive immunostaining for p53 was a significant risk factor for chemotherapy resistance in NSCLC. These results suggest that immunostaining of p53 and P-glycoprotein for TBB specimens may help to predict response to chemotherapy in NSCLC and SCLC, although the results should be confirmed in a larger, more homogeneous series.     

Single agent vs combination chemotherapy in the treatment of ovarian cancer

One hundred and eight patients with Stage III or IV epithelial ovarian cancers were randomly allocated to treatment with either melphalan or the combination of Actinomycin-D, 5-fluorouracil, and cyclophosphamide (ACFUCY). Those patients receiving the ACFUCY combination had a higher objective response rate and a statistically significantly lower progression rate. The ACFUCY combination gave a higher incidence of severe toxicity.     

Long-term survival data and prognostic factors of a complete response to chemotherapy in patients with head and neck cancer treated with platinum-based induction chemotherapy: a Hellenic Co-operative oncology Group study

Sudden infant death syndrome (SIDS) is the most common cause of postneonatal infant death in developed countries. The causes of SIDS remain unknown. The principal hypothesis appears abnormality of cardiorespiratory control, sleep-wake regulation. Also in our personal date the autopsy have not been of sufficient specificity and sensitivity to explain the disease.     

Response to chemotherapy in cerebral primary lymphoma

INTRODUCTION: Primary central nervous system lymphomas (PCNSL) are infrequent, rapidly growing and generally limited to the central nervous system (CNS). In recent years there has been a threefold increase in cases occurring in immunocompetent individuals. Conventional treatment with corticosteroids and radiotherapy is effective, but over 80% relapse in less than a year. Chemotherapy has significantly improved the results of treatment. CLINICAL CASE: We present a case of PCNSL in an immunocompetent patient which was resistant to radiotherapy (RT). There was progression of the lymphoma three months after irradiation, and later multicentric progression one month after radiosurgery. The patient had complete radiological remission after systemic chemotherapy. The clinical improvement was obvious, since before chemotherapy was started the patient was in coma and had episodes of apnea. The therapeutic response obtained was consolidated by intensive chemotherapy and hemopoietic support. The condition is still in remission three years after completion of this treatment. CONCLUSIONS: There are no publications about the results of combined radiotherapy and chemotherapy in series of patients with PCNSL, since there are relatively few patients and many methods of treatment are tried.     

CA 19-9 in evaluating the response to chemotherapy in advanced pancreatic cancer

BACKGROUND/AIMS: The determination of serum carbohydrate antigen 19-9 (CA 19-9) level is useful in managing pancreatic cancer. However, the usefulness of this marker in evaluating the response to chemotherapy has not been fully established. MATERIALS AND METHODS: Serial changes of serum CA 19-9 levels were studied during chemotherapy in 66 pancreatic cancer patients who showed CA 19-9 level of 100 U/ml or greater before treatment. We investigated the relationship between patient survival and reduction in serum CA 19-9 level after treatment. RESULTS: When a responder was defined as a patient whose serum CA 19-9 level was reduced by more than 50% of the pre-treatment level within 2 months after treatment, CA 19-9 response was observed in 9 (13%) of the 66 patients. Median survival times of CA 19-9 responders and non-responders were 141 and 88 days, respectively. Based on Cox regression analysis, the relative risk of cancer death in CA 19-9 responders for non-responders was 0.47 (95% confidence interval, 0.21 to 1.05). CONCLUSIONS: CA 19-9 reduction may be useful for assessing the efficacy of chemotherapy for advanced pancreatic cancer.     

Adjuvant chemotherapy in colorectal cancer with high-dose leucovorin and fluorouracil: impact on disease-free survival and overall survival

PURPOSE: The rationale for using adjuvant chemotherapy in colorectal cancer is to achieve better disease control and thus reduce the high rates of tumor recurrence and mortality in patients who undergo curative surgery. The current literature, including relevant abstracts, on clinical trials of fluorouracil (5-FU) in combination with high-dose leucovorin as adjuvant chemotherapy for colorectal cancer is reviewed. The intent is not to present new data, but to present the reader with a broad perspective and larger patient experience on which to base well-reasoned treatment decisions. DESIGN: Published clinical trials and abstracts presented at the 1996 American Society of Clinical Oncology (ASCO) meeting that assessed 5-FU in combination with high-dose leucovorin as adjuvant chemotherapy for colorectal cancer were surveyed. End points of interest were disease-free survival (DFS), overall survival, and toxicity. RESULTS: In randomized trials that used high-dose leucovorin at doses that ranged from daily-times-five 200 mg/m2 to weekly 500 mg/m2 in combination with 5-FU, significant improvements in both DFS and overall survival were observed over surgery alone (control). In patients treated with high-dose leucovorin/5-FU, DFS rates ranged from 71% to 77% compared with control (58% to 64%). A similar trend was seen in overall survival, with a range of 75% to 84% compared with control (63% to 77%). Toxicities observed for high-dose leucovorin administered on a weekly or daily-times-five schedule were diarrhea, stomatitis, myelosuppression, and nausea. CONCLUSION: Overall, the results of these randomized trials support the use of high-dose leucovorin/5-FU as adjuvant therapy for colorectal cancer. Longer follow-up studies are needed to compare the benefits of these different regimens in terms of survival and to characterize adverse effects, especially those that may not be immediately evident. Adjuvant therapy with high-dose leucovorin/5-FU is an effective regimen that is well tolerated by many patients with colorectal cancer.