A review of the role of surgery for small cell lung cancer and the potential prognostic value of enumeration of circulating tumor cells.

Small cell lung cancer (SCLC) is disseminated in the majority of patients at first presentation and, thus, treated with chemoradiotherapy. Despite initial high response rates, chemoresistance appears rapidly and results in a dismal prognosis. However, patients with limited cancer may exhibit better disease control upon surgical treatment. Correct staging is highly critical in the selection of those patients which are likely to benefit from surgery. Studies of the inclusion of surgery in the multimodal treatment of SCLC vary widely in number of patients, selection, treatment and follow-up. Nevertheless surgical therapy for confined SCLCs achieves favorable long-term survival compared to chemoradiotherapy, depending on a precise assessment of the degree of tumor dissemination. Recently, extremely high counts of circulating tumor cells (CTCs) were reported in patients with SCLC compared to other malignancies. In several studies the number of CTCs was found to constitute a prognostic parameter and a marker of response to therapy. Therefore, the assessment of CTCs as so-called "Liquid Biopsy" seems to constitute a more precise method to detect tumor dissemination earlier when compared to clinical staging. In conclusion, in the era of precision oncology enumeration and identification of CTCs of SCLC patients have the potential to help in the selection of patients most suitable for tumor surgery.

In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines

INTRODUCTION: Chemotherapy for advanced well-differentiated carcinoids is characterised by low response rates and short duration of responses. The present study aimed to assess the in vitro activity of novel platinum-based chemotherapeutic drugs in combination with dichloroacetate (DCA), a sensitiser to apoptosis, against lung carcinoid cell lines. METHODS: Three permanent cell lines (UMC-11, H727 and H835) were exposed to 14 different established cytotoxic drugs and the novel platinum-based compounds as satraplatin, JM118 and picoplatin in combination with DCA, and viability of the cells was measured using a tetrazoliumbased dye assay. RESULTS: With exception of the highly chemoresistant UMC- 11 line, the carcinoid cell lines (H727, H835) were sensitive to the majority of chemotherapeutics in vitro. Among the platinum-based drugs, carboplatin and oxaliplatin showed highest efficacy. H835 cells growing as multicellular spheroids were 2.7-8.7-fold more resistant to picoplatin, satraplatin and its metabolite compared to single cell suspensions. DCA (10 mM) inhibited the growth of UMC- 11 cells by 22% and sensitised these highly resistant cells to carboplatin, satraplatin and JM118 1.4-2.4-fold. CONCLUSION: The highly resistant UMC-11 lung carcinoid cells are sensitive to carboplatin, oxaliplatin and the satraplatin metabolite JM118, but multicellular spheroidal growth, as observed in the H835 cell line and pulmonary tumourlets, seems to increase chemoresistance markedly. The activity of carboplatin and JM118 is significantly and specifically increased in combination with the apoptosis sensitiser DCA that promotes mitochondrial respiration over aerobic glycolysis. In summary, among the novel platinum drugs satraplatin has the potential for treatment of lung carcinoids and DCA potentiates the cytotoxicity of selected platinum drugs (AU)

Achieving full-dose, on-schedule administration of ACE chemotherapy every 14 days for the treatment of patients with extensive small-cell lung cancer.

Extensive small-cell lung cancer (SCLC) is commonly treated with multiple cycles of chemotherapy. Reducing the time interval between cycles of chemotherapy (dose-dense chemotherapy) may improve outcomes in the treatment of extensive SCLC, as it has in other chemosensitive malignancies. To evaluate the feasibility of dose-dense chemotherapy in patients with extensive SCLC, this study evaluates a dose-dense doxorubicin/cyclophosphamide/etoposide (ACE) regimen, supported by the once-per-cycle administration of the hematopoietic growth factor pegfilgrastim. Patients received up to six 14-day cycles of ACE chemotherapy (doxorubicin 40 mg/m,(2) cyclophosphamide 1000 mg/m(2), etoposide 120 mg/m(2) on day 1 IV, plus oral etoposide 240 mg/m(2) daily on days 2-3). On day 4 of each cycle, patients received pegfilgrastim 6 mg by subcutaneous injection. Of 30 patients enrolled, 27 started chemotherapy and received pegfilgrastim. Full-dose, on-schedule chemotherapy was given to all 22 patients starting cycle 2, and in 107 (88%) of 121 cycles. Eighteen of the 27 patients (67%) received full-dose, on-schedule chemotherapy for all 6 cycles. The overall response rate was 17/27 (63%). Nine patients (33%) experienced hematologic toxicities that investigators considered severe or life-threatening. Four patients (15%) had febrile neutropenia. Full-dose, on-schedule dose-dense ACE chemotherapy is feasible with once-per-cycle pegfilgrastim support in extensive SCLC.

Osseous metastases in breast cancer: radiographic monitoring of therapeutic response.

BACKGROUND: Standard radiographs are primary means of evaluation of therapy-induced changes of the skeletal structure in patients with breast cancer metastatic to the bone, but objective quantitation has been difficult to standardize. MATERIALS AND METHODS: Serial radiographs of therapy-induced changes in the structure of bone metastases secondary to breast cancer were analyzed in 274 patients over a period of 10 years and roentgenologic signs of tumor response evaluated with regard to a defined principal metastasis. RESULTS: Indicators of regression were recalcification/reossification of primary osteolysis (11.6%), the formation of marginal sclerosis around the defect (13.5%) and lack of progression over a period of up to at least 12 months (10.5%). Reduction of sclerosis or structural loosening in primary osteosclerotic metastases (2.5%) may also be evidence of regression. Recurrence or progression of tumor was manifested by new metastases and/or increase in lesion size (56.9%) as well as development of lytic areas in primarily sclerotic or mixed metastases (2.5%). One hundred and one out of 157 patients with initially sclerotic or mixed metastases stayed stable or showed a response which lasted 12 months or longer. The duration of response in osteolytic lesions was less favourable. Irradiation and complex treatment (chemotherapy or hormonal therapy plus irradiation) was most often associated with a favourable objective response, 75%, which in 8 cases reflected nonprogression of disease, recalcification of primary osteolysis in 11 cases, the formation of marginal sclerosis around the defect in 8 lesions and disappearance of metastases in 1 case. CONCLUSION: Standard radiographs are useful in the serial evaluation of the effectiveness of therapy for osseous metastases in that anatomic quantitation of lesions as well as the dynamic evolution of lytic lesions to blastic healing may be observed

Prolonged response to a single androgen suppression phase in a subpopulation of prostate cancer patients.

BACKGROUND: In an intermittent androgen suppression therapy (IAS) trial we observed regular cycles of tumor suppression and regrowth in the majority of patients (17 +/- 2.6 month), with a subpopulation of patients (14 of 72) exhibiting a prolonged response of 28 +/- 7 month (range 18-64+ month) to the first eight-month androgen suppression cycle. PURPOSE: To compare clinical data and laboratory tests (testosterone, prostate-specific antigen, and tissue polypeptide-specific antigen) of matched IAS patients showing either regular treatment cycles (n = 16) or prolonged response (n = 14). RESULTS: Periods of androgen suppression resulted in reversible reduction of serum testosterone (< 1 nmol/l), PSA (< 1 ng/ml) indicating partial growth arrest and apoptotic regression of the tumors. The long-term response subgroup showed significantly lower mean values of tumor gradings, of pretreatment PSA values (11.36 +/- 4.54 vs. 47.5 +/- 12.4 ng/ml PSA), of PSA nadirs during androgen suppression (0.5 vs. 1 ng/ml PSA), and of overall testosterone values (3.9 +/- 1.14 vs. 6.6 +/- 1.18 mmol/l pretreatment) associated with low TPS values. CONCLUSIONS: Patients exhibiting prolonged response to a single cycle of androgen suppression during IAS are characterized by a lower tumor burden, slow growing and less aggressive tumors, lower testosterone serum concentrations and lower absolute PSA nadirs during androgen suppression compared to a matched control group of short-term responders.

Metabolism of camptothecin, a potent topoisomerase I inhibitor, in the isolated perfused rat liver.

PURPOSE: Camptothecin (CPT) is a potent topoisomerase I inhibitor that has recently been undergoing phase I clinical trials. Though CPT shows high activity against various tumor cells, its biotransformation is still unknown. To investigate the metabolism and biliary excretion of CPT, an isolated perfused rat liver system was used. METHODS: CPT was added to the perfusion medium at a concentration of 20 microM, and bile and perfusate samples were collected for 90 min. CPT (lacton and carboxylate) and three novel metabolites were identified by mass spectroscopy and quantified by reversed-phase high-performance liquid chromatography (HPLC). Kinetic parameters of CPT and its biotransformation products were then estimated in bile and effluent perfusate. RESULTS: Biliary secretion of CPT and its three metabolites reached a peak secretion of 37.6 +/- 16.3, 0.94 +/- 0.29, 0.19 +/- 0.023 and 0.302 +/- 0.076 nmol/g liver/min, respectively, after 20 min. The total amount of CPT and M1-M3 excreted into bile during 90 min of perfusion was 63.5 +/- 15.4%, 1.8 +/- 0.37%, 0.43 +/- 0.06%, and 0.72 +/- 0.15% of CPT cleared from the perfusate during 90 min, respectively. In the perfusate, only one metabolite (M3) could be detected (cumulative release into the perfusion medium: 0.37 +/- 0.026 micromol/liver). Analysis of the biliary metabolites by mass spectroscopy supported the existence of dihydroxy-CPT derivatives (M1 and M2), whereas M3 appears to be a monohydroxy-analog. CONCLUSION: CPT is biotransformed to three novel metabolites, mainly excreted into bile. The possible pharmacological effects of these new metabolites need to be considered.

Resveratrol pretreatment desensitizes AHTO-7 human osteoblasts to growth stimulation in response to carcinoma cell supernatants.

Resveratrol, a natural phytoestrogen, has been reported to promote differentiation of murine MC3T3-E1 osteoblasts and to inhibit proliferation of prostate cancer cell lines. In the present study we tested the effects of resveratrol on the increased proliferation of human AHTO-7 osteoblastic cell line induced by conditioned media (CM) from a panel of carcinoma cell lines. This compound was found to modulate AHTO-7 proliferation in a tamoxifen-sensitive mechanism at lower concentrations, but failed to induce the osteoblast differentiation marker alkaline phosphatase (ALP) in contrast to vitamin D3. The proliferative response of AHTO-7 cells to conditioned media from carcinoma cell lines was diminished (30-71.4% inhibition) upon pretreatment with 0.5 microM resveratrol. Highest inhibition was demonstrated for pancreas (BxPC3, Panc-1), breast (ZR75-1) and renal (ACHN) carcinoma cell line supernatants whereas the effect on colon carcinoma (SW620, Colo320DM) cell CM and prostate cancer (PC3, DU145 and LNCaP) CM was less pronounced. Direct addition of resveratrol affected only supernatants of cell lines (<25% inhibition) exhibiting growth stimulatory activity for normal WI-38 lung fibroblasts. Resveratrol inhibited proliferation of DU145 and LNCaP cells in concentrations exceeding 5 microM, altered cell cycle distribution of all prostate cancer cell lines in concentrations as low as 0.5 microM, but did not inhibit the production of osteoblastic factors by these lines. In conclusion, resveratrol failed to induce ALP activity as marker of osteoblast differentiation in human osteoblastic AHTO-7 cells, however, inhibited their response to osteoblastic carcinoma-derived growth factors in concentrations significantly lower than those to reduce growth of cancer cells, thus effectively modulating tumor - osteoblast interaction.

Measurements of free and total PSA, tissue polypeptide-specific antigen (TPS), and CYFRA 21-1 in prostate cancer patients under intermittent androgen suppression therapy.

BACKGROUND: The present study evaluated monthly measurements of free and total prostate-specific antigen (PSA), and the tumor proliferation markers tissue polypeptide-specific antigen (TPS) and cytokeratin fragment 21-1 (CYFRA 21-1) in patients with advanced prostate cancer receiving intermittent androgen suppression therapy (IAS). METHODS: Thirty-four men received alternating cycles of 8 month androgen suppression and treatment cessation (mean duration, 10.3 months) until PSA increased to >20 microg/l. Measurements of testosterone, percentage of free PSA, TPS, and CYFRA 21-1 were performed using ELISA and RIA assays. RESULTS: Periods of androgen suppression resulted in reversible reductions of testosterone (from 6 +/- 0.8 to <0.58 ng/ml), PSA (from 31.2 +/- 4.5 to <1.7 microg/l), and prostatic volume (mean reduction, 22.2 +/- 4.6%), indicating apoptotic regression of the tumors. Upon treatment cessation, testosterone increased to 6.1 +/- 0.56 ng/ml within 2 months, followed by an increase of PSA to 5.8 +/- 0.8 microg/l. The mean percentage of free PSA (15.1 +/- 2.6%) exhibited no significant change during the whole IAS cycle. TPS showed a decrease of 50% after 3 months, and CYFRA 21-1 a 25% decrease after 7 months of androgen suppression treatment. During treatment cessation, TPS exceeded the normal cutoff value of 90 U/l late in tumor regrowth (9-11 months), whereas CYFRA 21-1 remained below the normal cutoff value of 3.3 ng/ml. CONCLUSIONS: PSA is the best and most sensitive marker of prostate cancer regression and regrowth during IAS cycles of the markers tested in this study. Free PSA constitutes approximately 15% of total PSA (range, 5-32%), and its percentage showed no significant change during IAS cycles. The TPS and CYFRA 21-1 proliferation marker changes in IAS seem to be related mainly to effects on normal androgen-dependent tissues.

The impact of extracellular matrix on the chemoresistance of solid tumors--experimental and clinical results of hyaluronidase as additive to cytostatic chemotherapy.

Chemoresistance is of outstanding importance for the limited results of chemotherapy in solid tumors. Chemoresistance of multicellular tumor tissues is more pronounced than that of single cells in vivo and in vitro. The enzyme hyaluronidase is able to loosen the cell-cell contact and the interstitial connective tissue and as such, in a number of preclinical and clinical trials, was shown to enhance the efficacy of cytostatic agents. Although proven to be very effective as additive to local chemotherapy, the systemic efficacy is not documented as well. We present a randomized trial done in high-grade astrocytomas with combined chemotherapy and radiation therapy with and without hyaluronidase. After very promising pilot results with systemic hyaluronidase in various tumor entities and also astrocytomas, this randomized study failed to show synergy to chemotherapy and radiation therapy in high-grade astrocytomas concerning survival. The promising preclinical data and the rather well documented activity in therapeutic use as additive to local chemotherapy seem to be an adequate motive to further elucidate the complex manner in which hyaluronidase is active in the interstitial tumor matrix and to obtain more information concerning the optimal route of application, the optimal dosage and the spectrum of tumor entities where it is synergistic with cytostatic chemotherapy and perhaps even radiation therapy.

P-glycoprotein-mediated multidrug resistance is modulated by pretreatment with chemosensitizers in HCT-8 carcinoma cells in vitro.

The effects of pretreatment with the multidrug resistance (MDR) modulators verapamil (VPM), tamoxifen (TMX), cyclosporin A (CsA), and SDZ PSC833 (PSC) on drug sensitivity of the P-glycoprotein (Pgp) expressing human ileocecal carcinoma cell line HCT-8 is described. Following pretreatment of 2, 16 and 48 h with the individual modulators, rhodamine 123 efflux (RHO), transepithelial vinblastine transport (VIN) across treated HCT-8 monolayers, and chemosensitivity to doxorubicin (DOX) were determined and compared to Pgp protein expression and phosphorylation. After 2 h, VPM, TMX, CsA and PSC inhibited RHO efflux and VIN transport and increased the chemosensitivity of HCT-8 to DOX significantly. Prolonged exposure failed to further increase inhibition of Pgp-mediated transport, but in contrast maximized phosphorylation of Pgp (16 h) and Pgp protein expression (48 h), respectively.

Phase II trial of gemcitabine in advanced non-small-cell lung cancer.

Gemcitabine has shown activity in different solid tumors. In the present study we have evaluated its efficacy in 32 patients with advanced non-small-cell lung cancer in a phase II trial. Gemcitabine (1250 mg/m2) was given intravenously as a 30-minute infusion on days 1, 8 and 15. Cycles were repeated every 4 weeks. Twenty-nine patients were evaluable for response and all patients for toxicity. Partial remissions and stable disease were seen in 4 (14%) and 13 (45%) patients, respectively. Improvement of symptoms occurred in 54% of the patients. Side effects were mild and included predominantly leukopenia and thrombocytopenia. In conclusion, gemcitabine is active and well tolerated in patients with advanced non-small-cell lung cancer.

Surgery for cure followed by chemotherapy in small cell carcinoma of the lung. For the ISC-Lung Cancer Study Group.

The Lung Cancer Study Group of the International Society of Chemotherapy (ISC-LCSG) organized multinational, cooperative, prospective and randomized trials for the cure of patients with small cell lung cancer at early stages (T1,2N0M0). Surgery for cure was used first, followed by postoperative chemotherapy, and thereafter by prophylactic cranial irradiation. Eight cycles of standard chemotherapy (CAV-cyclophosphamide-doxorubicin-vincristine) or 6 intermittent cycles of alternating chemotherapy, using 3 different drug combinations, were administered 1-2 weeks postoperatively for 6 months after randomization. A total of 183 evaluable patients received surgery for cure at 23 cooperating hospitals. The preliminary evaluation of ISC-studies I and II per May 1993 resulted in the 30-month total survival of 63% from 68 patients after complete resection at TN0M0R0-stages and 37% from 27 patients after such resections at TN2M0R0-stages. Their incidence of local recurrence as first relapse was quite similar (11/47:8/39). The related 4-year recurrence-free survival (57%, 37%), indicating a plateau-like curve of long-term survivors. These promising results have to be confirmed by larger studies. We conclude that the indication for surgery as the first treatment step for SCLC should be the same as for the other non-small subtypes of lung cancers.

The use of epidemiology for screening and early detection of cancer: examples from Austria.

Reduction of mortality rates and the costs of screening programs have sometimes been discussed on basis of certain therapeutic nihilism especially concerning the treatment of some cancer localizations. Interest of an epidemiological institute should, however, concern specific regions with high cancer risk and in these areas, well defined by epidemiological investigations, screening projects should be performed. A screening program initiated in Oberpullendorf, a district in the federal country of Burgenland in Austria resulted in a rate of 53% Dukes A colorectal cancer stages (0% Dukes D) compared to 27% Dukes A stage (19% Dukes D) without screening. As regards the lung cancer screening programs, these are controversial, due to high costs and no evident influence on mortality rates. The mortality rate for Vienna is about 20% above the Austrian average. In women the discrepancy between the capital and the federal countries is especially high, as in Vienna 44% more women die on lung cancer as compared to the Austrian average. Some promising results in the treatment of lung cancer, especially in small cell carcinoma and combined treatment by chemo- and radiotherapy might justify a screening program for lung cancer. The highest increase of mortality in lung cancer is found in patients at the age of 75 and older. Those patients, however, suffer from other diseases too, therefore "screening programs for polymorbidity" should be discussed.

Multimodality treatment for small cell bronchial carcinoma. Preliminary results of a prospective, multicenter trial. The ISC-Lung Cancer Study Group.

Preliminary results of the 1984 ISC (International Society of Chemotherapy) lung cancer studies I and II as of June 1990 are based on 146 patients with small cell bronchial carcinoma from 23 departments of thoracic surgery. All patients received surgery for cure in cTNM stages I and II followed by randomization for two different types of chemotherapy. For disease-free patients after completion of postoperative chemotherapy, prophylactic cranial irradiation (PCI) was administered. For the two different chemotherapeutic regimens, no statistically significant differences in survival (SVR) could be observed. Each patient was classified by the pTNM system. There were 63 patients with stage I, 44 patients with stage II and 38 patients with stage III disease. Four years after surgery, 63 patients with N0 disease had a SVR of 50%, 51 patients with N1 disease 31%, and 32 patients with N2 disease, 23%. No prolongation of brain-metastasis-free time for 62 patients receiving PCI was shown. It is concluded that initial surgical resection for small cell lung cancer in stages I and II followed by intensive chemotherapy is an appropriate therapeutic approach.

Tumor markers for the diagnosis, prognosis, treatment and follow-up of gynaecological tumors.

It would be of benefit for the clinical relevance of tumor marker determination to be demonstrated, as a lot of markers are now in clinical use. Increased levels of carcinoembryonic antigen correlate with the stage of breast carcinoma. CA 15-3 should also be measured during follow-up of patients with this disease. The latest findings suggest a higher sensitivity and specificity of CA 15-3 than of CEA. The prognostic value and the usefulness of CEA measurement in screening seem to be poor. The measurement of CA 125 seems to be a reliable method for monitoring the presence and clinical behavior of ovarian cancer. It is suggested that invasive diagnostic procedures are not required in patients with normal marker levels. The management of chorion carcinoma can be determined as an ideal model in the range of marker application. Only in this disease does the marker HCG reach almost 100% sensitivity and specificity. The definition of response to chemotherapy and the appearance of relapse can be based on HCG measurement.