Gene expression profiling identifies responsive patients with cancer of unknown primary treated with carboplatin, paclitaxel, and everolimus: NCCTG N0871 (alliance).

BACKGROUND: Carboplatin (C) and paclitaxel (P) are standard treatments for carcinoma of unknown primary (CUP). Everolimus, an mTOR inhibitor, exhibits activity in diverse cancer types. We did a phase II trial combining everolimus with CP for CUP. We also evaluated whether a gene expression profiling (GEP) test that predicts tissue of origin (TOO) could identify responsive patients. PATIENTS AND METHODS: A tumor biopsy was required for central confirmation of CUP and GEP. Patients with metastatic, untreated CUP received everolimus (30 mg weekly) with P (200 mg/m(2)) and C (area under the curve 6) every 3 weeks. The primary end point was response rate (RR), with 22% needed for success. The GEP test categorized patients into two groups: those having a TOO where CP is versus is not considered standard therapy. RESULTS: Of 45 assessable patients, the RR was 36% (95% confidence interval 22% to 51%), which met criteria for success. Grade ≥3 toxicities were predominantly hematologic (80%). Adequate tissue for GEP was available in 38 patients and predicted 10 different TOOs. Patients with a TOO where platinum/taxane is a standard (n = 19) tended to have higher RR (53% versus 26%) and significantly longer PFS (6.4 versus 3.5 months) and OS (17.8 versus 8.3 months, P = 0.005), compared with patients (n = 19) with a TOO where platinum/taxane is not standard. CONCLUSIONS: Everolimus combined with CP demonstrated promising antitumor activity and an acceptable side-effect profile. A tumor biomarker identifying TOO may be useful to select CUP patients for specific antitumor regimens. CLINICALTRIALSGOV: NCT00936702.

Alternating dose-dense chemotherapy in patients with high volume disseminated non-seminomatous germ cell tumours.

Only about half of patients with a poor-prognosis non-seminomatous germ-cell tumours can achieve a cure. The aim of this phase II study was to assess the efficacy and toxicity of a dose-dense alternating chemotherapy regimen in this subset of patients. High volume non-seminomatous germ-cell tumours was defined as follows: at least two sites of non pulmonary metastases, an extragonadal primary tumour, a serum human chorionic gonadotropin level higher than 10 000 mIU x ml(-1), or a alpha-foetoprotein level higher than 2000 mIU ml(-1). Patients who fulfilled these criteria were treated with the so-called BOP-CISCA-POMB-ACE regimen (bleomycin, vincristine, and cisplatin; cisplatin, cyclophosphamide, and doxorubicin; cisplatin, vincristine, methotrexate, and bleomycin; etoposide, dactinomycin, and cyclophosphamide) plus granulocyte colony-stimulating factor. A total of 58 patients were enrolled. Patients were retrospectively classified according to the International Germ-Cell Cancer Consensus Group classification; 38 patients (66%) had poor-prognosis disease and 19 patients (33%) had intermediate-prognosis. Patients received a median of 2.5 courses (range 0.25 to five courses) of the BOP-CISCA-POMB-ACE regimen. Forty-two patients (72.4%) had a complete response to therapy. With a median follow-up time of 31 months, the 3-year progression-free survival rate was 71% (95% confidence interval, 60 to 84%) and the 3-year overall survival rate was 73% (95% confidence interval: 62 to 86%). The 3-year PFS rates were 83% (95% confidence interval: 68 to 100%) in the intermediate-prognosis group and 65% (95% confidence interval: 51 to 82%) in the poor-prognosis group. Early side effects included mainly grade 4 haematologic toxicity (neutropaenia in 79% of patients, thrombocytopaenia in 69%, anaemia in 22%), grade 4 stomatitis (19%), and four early deaths (7% of patients), at least partially related to toxicity. The dose-dense BOP-CISCA-POMB-ACE regimen is highly active in patients with non-seminomatous germ-cell tumours classified as intermediate-prognosis or poor-prognosis according to the International Germ-Cell Cancer Consensus Group. Because outcomes with this regimen compare favourably with outcome after standard therapy, dose-dense chemotherapy should be further investigated in this subset of patients.

Management consideration in nonpulmonary visceral metastatic seminoma of testis.

To develop a more appropriate therapeutic strategy for treatment of nonpulmonary visceral metastatic testicular seminoma based on the International Germ Cell Consensus Classification, we reviewed the medical records of patients with nonpulmonary visceral metastatic testicular seminoma who were treated over a 20-year period. Only 15 (2.2%) of the 686 cases of testicular seminoma were nonpulmonary visceral metastatic seminoma. The median age of patients was 38 years (range, 22-53 years). Ten (67%) of the patients had an initial diagnosis of supradiaphragmatic or visceral metastatic disease. In addition to nonpulmonary visceral metastasis, all patients had lymph node metastasis as well, the majority of which involved the retroperitoneal lymph nodes. The median and mean progression-free survival durations after chemotherapy for advanced disease were 19 months and 63.7 months, respectively. Six patients (40%) survived, five relapsed after radiation therapy and four died of chemorefractory disease not dependent on the specific regimen. Although the number of cases reviewed in this study was small, we conclude that the choice of chemotherapeutic regimen among the current treatments for nonpulmonary visceral metastatic seminoma of testis primary does not present a different outcome. Therefore, multimodality therapies using new strategies or new agents are well indicated.

Clinical characteristics of metachronous bilateral testicular tumors in the chemotherapeutic era.

We wanted to present the results of our experience with bilateral testis tumor and to suggest the effects of chemotherapy in suppressing the development of second primary testicular tumors. Between 1978 and 1997, 2,345 patients were treated for testicular tumor at The University of Texas M. D. Anderson Cancer Center. Of these, 2,107 had germ cell cancers. There were 22 (0.94%) cases of bilateral testicular tumor in the overall patient population and 21 (1.0%) cases among patients with germ cell cancer. We reviewed the medical records to determine the incidence of the histological subtype, the incidence of metachronous versus synchronous formation of contralateral tumors, and tumor stage in this patient population. We also examined the effect of chemotherapy in treating the first tumor and preventing the occurrence of a second tumor. Finally, we compared the effect of ultrasonography, serum tumor marker elevation, and physical examination in detecting second tumors. Only one contralateral germ cell tumor developed synchronously; all others developed metachronously. Fifty percent of first tumors were seminomas, compared to 55% of second tumors. The histologic concordance rate for first and second tumors was 35%. Tumor stage was higher among first tumors than second tumors. The majority of second tumors in patients who received chemotherapy for first malignancies tended to be metachronous seminomas. Ultrasonography detected 6 of 21 (28.6%) contralateral tumors before they were evident by physical examination or serum tumor marker elevation. Seminomas were more prevalent among patients with bilateral germ cell disease than patients with unilateral disease. Chemotherapy, when used as treatment for first tumors, may have some effect in preventing the development of nonseminomatous germ cell tumors in the contralateral testicle. Close follow-up of the contralateral testis with ultrasonography is essential for early detection of second tumors. The outcome for patients with bilateral testicular germ cell cancer is excellent, secondary to early detection.

Germ cell tumors: staging, prognosis, and outcome.

Germ cell tumors (GCT) remain the model for solid tumor therapy. Until 1997, GCT staging was based on individual institution systems, which limited comparison of data and collaboration between GCT groups. GCT staging is based on four basic criteria: disease site of origin, histology, secretion of serum tumor markers (STM), and bulk of disease. Within most staging systems developed by investigators, clinical stage I disease is confined to the testis based on radiographic imaging and STM or pathological stage I based on lack of histological disease at retroperitoneal lymphadenectomy. Stages II and III are considered to be disease outside the testis categorized by lymphatic spread to the retroperitoneal lymph nodes or hematological spread to lungs and visceral organs, respectively. The major staging systems previously used include the Indiana University Staging System; Modified Samuels' Classification (M.D. Anderson Cancer Center); Memorial Sloan Kettering Cancer Center Mathematical Model; and the Tumor, Nodal, Metastases (TNM) Staging System (American Joint Committee on Cancer). The most recent evolution in staging systems is the 1997 International Germ Cell Consensus Classification, which is based on prognosis and outcomes. This system allows for comparison of data and collaboration between Germ Cell Tumor Groups.

Mechanism of platelet activating factor-induced vascular leakage in the rat trachea.

Platelet activating factor (PAF) is a phospholipid mediator of inflammation and vascular leakage that may be important in the etiology of asthma. We and others have demonstrated that PAF causes vascular leakage in the rat trachea. In the present study, we attempted to determine how PAF mediates this effect. Vascular leakage was quantitated by measuring the amount of intravascular Evans blue dye extravasated into tracheal tissue. Intravenously administered PAF increased vascular leakage, although Lyso-PAF and Enantio-PAF had no effect. PAF-induced vascular leakage was inhibited in a dose-dependent fashion by the PAF receptor blocker WEB 2086. However, PAF-induced vascular leakage was not inhibited by blockade of cyclooxygenase/lipoxygenase, calmodulin, calcium channels, protein kinase C, histamine receptors, or by destruction of peptidergic sensory nerves. We conclude that PAF causes vascular leakage in the rat trachea by a stereospecific receptor-mediated mechanism that does not depend on arachidonic acid metabolites, calcium, protein kinase C, histamine, or peptidergic sensory nerves.

Effects of platelet-activating factor on vascular permeability and granulocyte recruitment in the rat trachea.

Platelet-activating factor (PAF) is a phospholipid mediator known to produce several features of airway inflammation. We examined the effects of intravenous PAF on vascular permeability and granulocyte recruitment in the rat trachea. To assess vascular permeability, anesthetized rats were given injections of Evans blue dye (30 mg/kg, iv) and PAF (1-10 micrograms/kg, iv), and then their tracheas were removed and assayed spectrophotometrically for dye content. We found that a PAF dosage of 6 micrograms/kg increased the tracheal dye content 7-fold compared to controls. The amount of extravasated dye in the tracheas was significantly increased 1 min after PAF injection, was maximal at 5 min, and had returned to control levels by 10 min. To assess granulocyte recruitment, anesthetized rats were given an injection of PAF (6 micrograms/kg, iv), and then their tracheas were removed and stained to reveal myeloperoxidase-containing neutrophils and eosinophils. We found that the number of neutrophils in the tracheal mucosa was increased 7-fold from controls 5 min after PAF injection, but was not significantly increased 6 h later. The number of eosinophils in the tracheal mucosa was not significantly increased from controls at any time after PAF injection. We conclude that intravenous PAF causes a rapid but transient increase in vascular permeability in the rat trachea, and that intravenous PAF also causes a rapid but transient recruitment of neutrophils into the tracheal mucosa without a similar effect on eosinophils.