Carcinoma of unknown primary: identification of a treatable subset?

We initiated a phase II study with combination chemotherapy consisting of cisplatin, etoposide and bleomycin in a subset of patients with carcinomas of unknown primary site characterized by the presence of at least one of the following criteria: 1) age below 50 years; 2) clinical evidence of rapid tumour growth; 3) tumour located predominantly in a midline distribution; 4) good response to previous administered radiotherapy. In 34 evaluable patients an objective response rate of 53% (95% confidence limits 35%-70%) was achieved. For patients with poorly differentiated adenocarcinomas the response rate was 35%, and, in most instances, of short duration. A response rate of 79% including complete responses and long-term survivals was achieved in patients with undifferentiated carcinomas. This difference in response rate was statistically significant (p = 0.02). No supplementary prognostic factors predicting response to chemotherapy could be identified. One patient with an initial diagnosis of undifferentiated carcinoma proved to have a malignant lymphoma after additional immunohistochemical investigation. Until a better characterization of this syndrome is possible patients with undifferentiated carcinomas of unknown primary site should be challenged with cisplatin-based chemotherapy.     

E-SHAP: An effective treatment in selected patients with relapsed non-Hodgkin's lymphoma

BACKGROUND:: The optimal treatment of relapsed or refractory non-Hodgkin'slymphoma is unknown. The reported encouraging results of a salvageregimen, E-SHAP (etoposide 40 mg/m²/day x 4, methyl prednisolone500 mg daily x 4, cytosine arabinoside 2 gm/m² one dose andcisplatinum 25 mg/m²/day x 4), at the MD. Anderson Hospitalin Texas, which resulted in a 65% response rate, could not bereproduced in the United Kingdom (0% response). PATIENTS AND METHODS:: Twenty-six patients with relapsed (n = 16) or refractory (n= 10) non-Hodgkin's lymphoma were treated at our Centre by amodified E-SHAP regimen (cytosine arabinoside 1 gm/m² one dose).The treatment was intended as remission induction before BMT(n = 16), as salvage by itself (n = 5) and for palliation ofsymptoms (n = 5). RESULTS:: The overall response rate was 72% (CR = 7 and PR = 11). A comparisonof Kaplan-Meier curves showed a statistically significant improvementin median relapse-free survival in patients who had previouslyachieved CR (p = 0.0012), no bulky disease (P = 0.0006) andno B-symptoms (P = 0.0004). The toxicity was acceptable: 8 instancesof febrile neutropenia, 2 of reversible renal impairment and2 symptomatic electrolyte abnormalities. No fatal toxicitieswere encountered. The median time to treatment failure was 191days and median overall survival was 190 days. CONCLUSIONS:: E-SHAP is an active combination chemotherapy when used as asalvage regimen or for remission induction before bone marrowtransplantation in selected patients with relapsed non-Hodgkin'slymphoma. Patients who previously achieved CR, with low tumourburden and no B-symptoms are the best candidates for this treatment.It has a limited palliative effect. non-Hodgkin's lymphoma, salvage chemotherapy, etoposide, cisplatinum     

Carcinoma of an unknown primary site: a chemotherapy strategy based on histological differentiation--results of a prospective study.

Background:To evaluate the efficacy and toxicity of a chemotherapy strategy based on histological differentiation, for patients with carcinoma of unknown primary site. Patients and methods:Forty-eight patients were prospectively included in the trial. Thirty patients with poorly-differentiated carcinoma or poorly-differentiated adenocarcinoma (group A) received a combination of cisplatin and etoposide. Patients with a responsive or stable disease after two cycles received the same regimen plus bleomycin, ifosfamide and G-CSF. Eighteen patients with well- or moderately-differentiated carcinoma (group B) received cisplatin, continuous infusion 5-fluorouracil (5-FU) and -interferon. Treatment was maintained in case of response or stable disease for up to six cycles. Results:The overall response rate (RR) for the entire group is 43% (95% confidence interval (CI): 35.9%–50.1%): seven CR and five PR in group A (RR = 40%) and six CR and two PR in group B (RR = 44%). Grade 4 leucopenia was observed in 22 (46%) patients and sepsis in 3 (6%). Median survival is 9.4 months (range 5–13.7 months) and 16.1 months (range 11.8–20.3 months), respectively. Conclusions:This chemotherapy strategy is one way to achieve high response rates, particularly for patients with well- or moderately-differentiated adenocarcinoma usually considered poorly chemosensitive.     

Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience.

PURPOSE: We previously reported excellent responses to cisplatin-based chemotherapy in a minority of patients with poorly differentiated carcinoma (PDC) or poorly differentiated adenocarcinoma (PDA) of unknown primary site. We have continued to study and to treat these patients, and now report clinical characteristics, treatment results, and prognostic factors in a large group of patients identified prospectively. PATIENTS AND METHODS: Between February 1978 and December 1989, we treated 220 patients with PDC or PDA of unknown primary site. The median age was 39 years; 48% of patients had predominant tumor location in the mediastinum, retroperitoneum, or peripheral lymph nodes. Specialized pathologic studies resulted in the identification of specific tumor types in only a few cases. All patients received cisplatin-based chemotherapy; between 1978 and 1984, 116 patients received cisplatin, vinblastine, and bleomycin (PVeB) +/- doxorubicin, and 104 patients treated since January 1985 received cisplatin and etoposide +/- bleomycin. RESULTS: One hundred thirty-eight patients (63%) had objective responses to therapy, and 58 (26%) had complete response. Thirty-six patients (16%) are currently disease-free at a median of 61 months following therapy (range, 11 to 142 months). Actuarial 10-year survival is 16%. Favorable prognostic factors identified by Cox regression analysis include: (1) predominant tumor location in the retroperitoneum or peripheral lymph nodes, (2) tumor limited to one or two metastatic sites, (3) no history of cigarette use, and (4) younger age. CONCLUSION: Patients with PDC or PDA of unknown primary site represent another group of patients for whom potentially curative therapy is available. Patients with this syndrome should be distinguished from patients with well-differentiated adenocarcinoma of unknown primary site, and should receive a trial of cisplatin-based chemotherapy.     

A phase II study of cisplatin, etoposide and gemcitabine in an unfavourable group of patients with carcinoma of unknown primary site.

BACKGROUND: The aim of this phase II study was to determine toxicity, response rate, time to progression, and overall survival of cisplatin, etoposide and gemcitabine in patients with carcinoma of unknown primary tumour site. PATIENTS AND METHODS: Thirty patients with no previous chemotherapy and not belonging to a treatable group were treated with cisplatin 70 mg/m(2) on day 1, etoposide 70 mg/m(2) on days 1 and 2, and gemcitabine 700 mg m(2) on days 1 and 8, administered every 3 weeks. Stable or responding patients received a maximum of eight cycles. Twenty patients (67%) had more than three affected sites, and 25 patients (84%) had adenocarcinomas. RESULTS: Overall response rate was 36.6% (11 patients), including four complete responses (13.3%) and seven partial responses (23.3%), with a 95% confidence interval of 19.9-56. Median survival was 7.21 months and eight patients remained alive for >1 year. Myelosuppression was the most important toxicity, with grade 3-4 neutropenia in 18 patients (60%) in 32% of the cycles: eight patients had neutropenic fever and 10 patients had thrombopenia in 11% of cycles. No non-haematological grade 4 toxicity occurred. CONCLUSIONS: Cisplatin, etoposide and gemcitabine is an active combination, inducing objective responses in a subset of heavily advanced disease patients with carcinoma of unknown primary site. The role of adding gemcitabine to cisplatin and etoposide remains to be resolved as to the best schedule to diminish toxicity for the three-drug combination.     

Artificial neural networks for prostate carcinoma risk assessment: An overview

BACKGROUND: The long term survival and toxicity associated with the chemotherapy combination of paclitaxel, carboplatin, and extended-schedule etoposide used for the treatment of patients with metastatic carcinoma of unknown primary site were evaluated. METHODS: Seventy-one patients were treated between March 1995 and November 1996 with paclitaxel, carboplatin, and oral etoposide every 21 days. Stable or responding patients received four to eight courses of therapy. The following histologies were represented: well differentiated adenocarcinoma (34 patients); poorly differentiated adenocarcinoma or poorly differentiated carcinoma (30 patients); poorly differentiated neuroendocrine carcinoma (6 patients); and squamous cell carcinoma (1 patient). RESULTS: Forty-eight percent of assessable patients had major responses to therapy (95% confidence interval, 39%-55%), and 10 patients (15%) had complete responses. There were no response differences among the major histologic types. The median survival for all 71 patients was 11 months, and the 1-year, 2-year, and 3-year survival rates were 48%, 20%, and 14%, respectively. The minimum follow-up period was 34 months (range, 34-50 mos). The regimen was tolerated well with no treatment-related deaths and only 12 hospitalizations for neutropenia and fever. There was no serious long term toxicity. CONCLUSIONS: In this large Phase II trial, the combination of paclitaxel, carboplatin, and oral etoposide produced major responses or stable disease status in nearly 80% of patients who had carcinoma of unknown primary site. The median survival and 1-year, 2-year, and 3-year survival rates were noteworthy. The current study obtained similar or superior results to those seen with chemotherapy for many other groups of patients, such as those who had well defined advanced malignancies, those who were considered to have responsive tumors, and those who had obtained substantial benefits from cytotoxic therapy. Although the regimen reported in the current study can become an attractive option for many patients with carcinoma of unknown primary site, there remains a need for further clinical trials.     

Alternative bimonthly cycles of doxorubicin, cyclophosphamide, and etoposide, cisplatin with hematopoietic growth factor support in patients with carcinoma of unknown primary site

BACKGROUND: Because carcinomas of unknown primary origin are highly malignant tumors with a bad prognosis (median survival, 6-12 months) and no current optimal therapy, the authors designed a prospective dose-dense chemotherapy regimen with the objective of improving the results observed in patients who receive conventional treatment. METHODS: Eighty-two patients received alternative bimonthly cycles of doxorubicin 50 mg/m(2) with cyclophosphamide 1000 mg/m(2) (AC) and etoposide 300 mg/m(2) with cisplatin 100 mg/m(2) (EP). Cycles were given at 2-week intervals with granulocyte-macrophage-stimulating factor support (5 microg/kg per day) from Day 4 to Day 10. Patients without measurable lesions were included, because the major end point was survival. RESULTS: The median number of alternative cycles of AC and EP was 4 cycles (range, 1-12 cycles). An objective response was observed in 24 of 62 patients (39%; 95% confidence interval, 30-48%) with measurable lesions, including 6 patients who achieved a complete response. Among 20 patients with nonmeasurable disease, 9 patients (45%) had no evidence of progressive disease at the end of chemotherapy. The overall median survival of 82 patients was 10 months, with 5 patients surviving clinically disease free at 17 months, 29 months, 45 months, 64 months, and 70 months after the end of treatment. Myelosuppression was the most common toxicity. Two toxic deaths occurred. CONCLUSIONS: Using these doses and schedules, a dose-dense chemotherapy regimen did not appear to improve the outcome of patients with carcinoma of unknown primary site. Alternative studies dealing with news drugs will be required.     

Choroid plexus carcinoma of childhood.

The presentation, growth patterns, and response to therapy of 11 consecutive children with choroid plexus carcinomas were analyzed, and the results were compared with the outcome reported in other series. Patients were a median of 26 months of age at diagnosis. Two patients had thalamic tumors, one had a posterior fossa primary, and the rest had ventricular lesions. Five of 11 (45%) children remain in continuous progression-free remission a median of 48 months from diagnosis. Four of the five in continuous remission had a "gross total" surgical resection, and only one received radiation therapy. Five of six patients with subtotal resections relapsed despite postoperative treatment with radiation therapy (three) and chemotherapy (one). The response to treatment with radiation therapy or chemotherapy at relapse was disappointing, with only one child (treated with etoposide) responding. In combination with other series, 11 of 14 children had prolonged progression-free survival after gross total resection (only two of whom received adjuvant therapy) compared with two of 20 after less than total resections, independent of the type of adjuvant therapy given. Adjuvant therapy for children with choroid plexus carcinomas is of unproven benefit, and this must be considered when analyzing innovative treatment trials for such children, especially for those with totally resected tumors. Patients with partially resected lesions fare poorly with present forms of treatment.     

E-SHAP: Inadequate treatment for poor-prognosis recurrent lymphoma

Background: The treatment of refractory and recurrent lymphomasremains problematic, with the majority of patients showing noresponse to ‘salvage’ therapies. One regimen whichhas been suggested as showing particular efficacy is etoposide(40 mg/m² daily x 4), cytosine arabinoside (2.0 g/m² one dose),cisplatin (25 mg/m²/day infused over 4 days) and methylprednisolone(500 mg daily x 4) (E-SHAP). This study attempted to reproducethe encouraging results seen with this regimen in North America. Patients and methods: Twenty-eight patients with recurrent orrefractory lymphoma were treated with E-SHAP given 3 to 4 weekly.Thirteen patients were treated at first recurrence and twenty-twohad previously received etoposide. Results: No objective responses were seen although five patientshad a transient reduction in tumour before regrowth despitecontinued treatment. Sixteen patients received further chemotherapyafter failure of E-SHAP of whom four had responses. The principaltoxicity was myelosuppression with over half the patients requiringhospital admission for neutropenia-associated fever. Mediantime to treatment failure was 2.5 months and median survival7 months from the start of E-SHAP. Conclusions: These results are in marked contrast to those reportedfrom North America, possibly due to differing patient selection.E-SHAP shows strictly limited efficacy but marked toxicity inthe treatment of recurrent or refractory lymphomas with poorprognostic features. non-Hodgkin's lymphoma, salvage chemotherapy, etoposide, platinum     

Relapse-free and overall survival in patients with pathologic stage II nonseminomatous germ cell cancer treated with etoposide and cisplatin adjuvant chemotherapy.

PURPOSE: To assess the long-term relapse-free survival and overall survival of patients with stage II nonseminomatous germ cell tumor (NSGCT) who received two cycles of adjuvant etoposide and cisplatin (EP) after primary retroperitoneal lymph node dissection. PATIENTS AND METHODS: Eighty-seven patients with completely resected pathologic stage II NSGCT were treated with adjuvant EP chemotherapy. Adjuvant EP consisted of two cycles of etoposide (100 mg/m(2)) plus cisplatin (20 mg/m(2)) per day, administered days 1 to 5 at a 21-day interval. RESULTS: Ten patients (11%) had pN1 disease, 73 (84%) had pN2 disease, and four (5%) had pN3 disease. Eighty-six patients received two cycles of EP, and one patient received an additional two cycles of EP after a transient marker increase after his first cycle. Eighty-seven patients are alive, and 86 patients (99%) remain relapse-free at a median follow-up of 8 years (range, 0.9 to 13.5 years). CONCLUSION: Two cycles of adjuvant EP is highly effective in preventing relapse in patients with pathologic stage II pN1 and pN2 NSGCT. An alternative treatment strategy is surveillance with full-course chemotherapy at relapse. Because there is a higher risk of relapse for patients with pN2 disease, these patients are offered adjuvant chemotherapy.     

Peritoneal carcinomatosis from an unknown primary site. Management of 15 patients

AIMS AND BACKGROUND: Peritoneal carcinomatosis from an unknown primary site is a rare and ill-defined entity. This work attempts to identify clinical and pathological features of patients with this disease and report the results of an aggressive combined treatment modality. METHODS: Retrospective analysis was performed of medical records of 15 patients with peritoneal carcinomatosis with no primary site identified at a single institution between 1989 and 2000. A primary gastrointestinal cancer was ruled out after a thorough endoscopic and radiologic work-up and complete exploratory surgery. RESULTS: Four women and 11 men were identified; the average age was 49 years. All patients had cytoreductive surgery with peritonectomies; 4 patients underwent a second-look operation. Perioperative intraperitoneal chemotherapy was given to 10 of the 15 patients, and 9 patients received post-cytoreduction chemotherapy given intraperitoneally (1), systemically (7) or both intraperitoneally and systemically (1). Overall median survival from diagnosis was 19.0 months; 1 patient is alive with disease at 21 months; and 3 patients are disease-free at 17, 38, and 60 months from diagnosis. Significant positive predictive factors for survival were a small volume of ascites (P = 0.02), a large number of peritonectomies performed (P = 0.001), second-look cytoreduction (P = 0.003), perioperative intraperitoneal chemotherapy (P = 0.008) and postoperative chemotherapy (P= 0.01), either intraperitoneal or systemic. CONCLUSIONS: Peritoneal carcinomatosis from an unknown primary site is a rare subset of primary peritoneal malignancy. Aggressive treatment may provide prolonged palliation with occasional long-term survival.     

Class III β-tubulin is a marker of paclitaxel resistance in carcinomas of unknown primary site

PURPOSE: In this study, we determine the prevalence and the prognostic value of the class III beta-tubulin microtubule protein examined immunohistochemically, in tumors of 40 patients with carcinomas of unknown primary site treated with paclitaxel-based chemotherapy. METHODS: Immunohistochemical intensity of staining and percentage of cells were quantified. Clinical characteristics, response to chemotherapy, progression-free survival, and overall survival were assessed for relationships with the expression of class III beta-tubulin. RESULTS: The response rate was 17.9% (seven partial responses among 39 valuable patients), while eleven patients had a stable disease (28.2%) and 21 patients progressed on therapy (53.8%). Patients with high class III beta-tubulin expression were more resistant to taxane-based chemotherapy, defined as progression under treatment, while patient characteristics were not found to be correlated with response to chemotherapy. Patients whose tumors expressed high levels of class III beta-tubulin isotype had shorter overall survival, while there was a trend for an association with progression free survival. Multivariate analysis showed that class III beta-tubulin expression was independently correlated with progression free survival and overall survival. CONCLUSIONS: These findings suggest that a high level of expression of class III beta-tubulin in tumor cells is associated with resistance to paclitaxel and decreased survival in patients with carcinomas of unknown primary receiving paclitaxel-based chemotherapy.     

Phase II trial of intraperitoneal carboplatin in ovarian carcinoma patients with macroscopic residual disease at second-look laparotomy: A multicentre study of the French Federation Nationale des Centres de Lutte Contre le Cancer

BACKGROUND: Because of its antitumour activity and its pharmacological advantagewhen administered by the intraperitoneal route, carboplatinwas studied in a phase II multicen-tric trial. The aim of thestudy was to determine the response rate and the toxicity ofcarboplatin administered intraperito-neally and to determineif pathological complete response could be attained in womenwith macroscopic residual ovarian cancer at second-look laparotomyafter intravenous cis-platin chemotherapy. PATIENTS AND METHODS: Twenty-nine patients with macroscopical residual disease afterintravenous cisplatin-based chemotherapy at second-look laparotomy,were treated at that time with 300 mg/m² of carboplatin administeredin the abdominal cavity every four weeks for six cycles. Ininstances of negative findings at physical and CT scan examination,laparotomy evaluation was performed and the catheter was removed.The dose of carboplatin was increased or decreased accordingto hematological toxicity. RESULTS: Efficacy is evaluable in 25 pts: 2 pts had pathological completeresponses and 1 pt had microscopic disease (12% response rateof evaluable patients). Toxicity is evaluable for 135 cyclesin 29 patients. No grade 4 hematological toxicity was observed,2 pts had grade 3 leukopenia and 3 pts had grade 3 thrombocytopenia;grade 3 vomiting was observed in 11% of cycles. No peritonealcomplication was observed; catheter dysfunction occurred afterthe first cycle in one patient who refused a surgical procedureto remove the catheter and to pursue treatment. CONCLUSION: Intraperitoneal carboplatin demonstrates efficacy in patientswith macroscopical residual disease at second-look laparotomyafter first-line cisplatin chemotherapy. The recommended dosefor further studies is 300 mg/m² administered every 4 weeks.A low response rate does not favour a randomised study. ovarian cancer, intraperitoneal chemotherapy, carboplatin, second look     

Curative combination chemotherapy for patients with advanced poorly differentiated carcinoma of unknown primary site

We have previously reported complete responses and long-term survival following cisplatin-based combination chemotherapy in some patients with advanced poorly differentiated carcinomas of unknown primary site. In order to better define the clinical and pathologic characteristics of the chemotherapy-responsive subgroup, we have reviewed the case histories of our 32 patients who achieved complete response to combination chemotherapy. Initial light microscopic diagnoses were as follows: poorly differentiated carcinoma (23 patients), poorly differentiated adenocarcinoma (eight patients), or poorly differentiated large cell carcinoma (one patient). The median age was 37 years (range, 19-70); 25 of 32 patients were male. All patients had unresectable neoplasms at the time of diagnosis. Twenty-two patients had metastases at two or more locations. In 27 of 32 patients (84%), the predominant site of tumor involvement was either in the mediastinum, retroperitoneum, lymph nodes, or lungs. Six patients were assigned more specific diagnoses at some time during their clinical course on the basis of further pathologic evaluation, additional biopsy material, or autopsy: germinal tumors, two patients; adenocarcinoma of the lung, one patient; carcinoid tumor of the lung, one patient; and malignant melanoma, two patients. Eighteen patients (56%) remain continuously disease free at a median of 77 months following diagnosis and are considered unlikely to recur. All patients with poorly differentiated carcinomas and tumor location in the mediastinum, retroperitoneum, lungs, or lymph nodes should be considered for treatment with intensive cisplatin-containing combination chemotherapy, since some of these patients have potentially curable malignancies.     

Preliminary results of treatment of Ewing's sarcoma of bone in children and young adults: six months of intensive combined modality therapy without maintenance

Thirty-one previously untreated patients with Ewing's sarcoma were treated with an intensive chemotherapy program of vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cyclosphosphamide (VADRIAC) in combination with radiation therapy to the primary site (greater than 50 Gy) and bone metastases (45 to 50 Gy). An intensified regimen with one further cycle of chemotherapy (VADRIAC), total body irradiation (TBI), and autologous bone marrow transplantation was given to patients with primary tumors of the pelvis, humerus, femur, and chest wall without metastases and to all patients with metastases at diagnosis. Patients with primary tumors of the distal extremity and other sites without metastases at diagnosis were treated on a less intensive chemotherapy regimen of VADRIAC without the intensification. Therapy was completed within 6 to 7 months in all patients. Thirteen patients had metastatic disease at diagnosis; only two of these had the lung as the sole site of metastatic disease. Eighteen patients had no evidence of metastatic disease at diagnosis: ten of these patients had tumors that arose in central axis and proximal extremity sites, and eight had tumors that arose in distal extremity and other sites. Thirty of the 31 patients achieved a complete remission, although two patients underwent amputation: one before chemotherapy and radiation and one after chemotherapy and radiation because of persistent local disease. Seventeen remain in their first complete remission at a median time on study of 30 months and a median time after completion of therapy of 24 months. Fourteen patients have relapsed (13) or progressed (1): ten in metastatic sites and four in the primary site. One patient had persistent local disease after radiation requiring amputation. Nine of the 13 patients with metastatic disease at diagnosis have relapsed compared with five of the 18 patients without metastatic disease. For the entire group, the actuarial survival is 78% (65% to 87%) at 30 months, and the actuarial disease-free survival is 58% (46% to 69%) at 30 months.     

Cisplatin and gemcitabine with either vinorelbine or paclitaxel in the treatment of carcinomas of unknown primary site : results of an Italian multicenter, randomized, phase II study

BACKGROUND.: To date, the standard treatment for patients who have carcinoma of unknown primary site has not been established. METHODS.: In this randomized Phase II study, 66 previously untreated patients (33 patients per arm) with carcinomas of unknown primary site received cisplatin (35 mg/m2) and gemcitabine (1000 mg/m2) with either paclitaxel (70 mg/m2) or vinorelbine (25 mg/m2), and all drugs were administered intravenously on Days 1 and 8 of a 21-day cycle. Twenty-nine patients (44%) presented with > or =2 involved sites. The pathologic diagnosis was mainly adenocarcinoma (48 patients; 72.7%) and squamous carcinoma (7 patients; 10.6%). RESULTS.: In the first arm, 16 patients (48.5%) experienced an objective response, and 9 patients (27.2%) had disease stabilization. In the vinorelbine-containing arm, 14 patients (42.3%) experienced an objective response, and 8 patients (24.2%) had disease stabilization. The median response duration and the median time to progression were similar in both treatment arms; the median overall survival was 9.6 months (95% confidence interval, 7.11-12.09 months) for patients who received the cisplatin/gemcitabine/paclitaxel regimen and 13.6 months (95% confidence interval, 6.61-20.59 months) for patients who received the vinorelbine combination. Grade 3 and 4 toxicities were more frequent in the paclitaxel-containing arm. CONCLUSIONS.: Both combinations satisfied the 2-step design, demonstrating antitumor activity without relevant differences in response rates or response duration; however, the vinorelbine-containing regimen yielded superior results both in terms of overall survival (13.6 months vs 9.6 months) and in terms of treatment tolerability. Therefore, according to a pick the winner attitude, the combination of cisplatin/gemcitabine/vinorelbine may be considered in the design of future randomized, Phase III trials for patients with carcinomas of unknown primary site.     

Salvage chemotherapy for recurrent spinal cord ependymona

BACKGROUND: Ependymomas are reported to constitute 4% of all primary central nervous system (CNS) malignancies in adults, 30% of which occur in the spinal cord. A prospective Phase II study to determine toxicity and response to chronic oral etoposide in patients with recurrent low-grade intramedullary spinal cord ependymoma (SCE) was conducted. METHODS: Ten patients (6 males and 4 females with a median age of 30 years) with recurrent SCE were treated with oral etoposide (50mg/m(2)/day given daily for 21 days followed by a 14-day break and then repeated constituted a cycle of therapy). All patients had failed surgery and radiotherapy and four patients had failed one prior chemotherapy. Blood counts were obtained weekly, and neurologic examination and a chemistry panel were performed monthly. Contrast-enhanced magnetic resonance imaging of the spine was performed every 8 weeks after a cycle of etoposide and before the next cycle of chemotherapy was initiated. RESULTS: Treatment-related complications included alopecia in 9 patients, nonbloody diarrhea in 6 patients, a baseline weight loss of > 10% in 5 patients, Grade (according to the National Cancer Institute Common Toxicity Scale) 3-4 neutropenia in 3 patients, Grade 3-4 thrombocytopenia in 3 patients, and Grade 3-4 anemia in 2 patients. There were no treatment-related deaths reported. After 1 cycle of etoposide, 3 patients (30%) demonstrated progressive disease, 2 patients (20%) achieved a partial response, and 5 patients (50%) maintained stable disease. The overall median response or stable disease duration (disease-free progression) was 15 months (range, 2.5-45+ months). The overall median survival was 17.5 months (range, 3-45+ months). CONCLUSIONS: Chronic oral etoposide appears to be well tolerated, has modest toxicity, and had apparent activity in the small cohort of adults in the current study with surgically and medically refractory, recurrent, intradural intramedullary SCE.     

Oral etoposide for refractory and relapsed neuroblastoma.

PURPOSE: To describe the efficacy of oral etoposide against resistant stage 4 neuroblastoma. PATIENTS AND METHODS: Patients with refractory or recurrent stage 4 neuroblastoma were treated with etoposide 50 mg/m(2) taken orally each day, in two or three divided doses, for 21 consecutive days. Treatment could be repeated after a 1-week period. Extent-of-disease studies included imaging with 131-iodine-metaiodobenzylguanidine and extensive bone marrow (BM) sampling. RESULTS: Oral etoposide was used in 20 children between the ages of 2 and 11 years (median, 6 years). Prior treatment included high doses of alkylating agents and a median of 4.5 cycles of etoposide-containing chemotherapy, with cumulative etoposide doses of 1,800 mg/m(2) to 3,935 mg/m(2) (median, 2,300 mg/m(2)). Oral etoposide produced antineuroblastoma effects in four of four children with disease refractory to intensive induction treatment; sampling variability could account for resolution (n = 3) or reduction (n = 1) of BM involvement, but improvement in other markers also occurred. Antineuroblastoma effects were also evident in five of five children with asymptomatic relapses after a long chemotherapy-free interval: BM disease resolved and all other disease markers significantly improved in two patients, and disease markers improved or stabilized in three patients on treatment for more than 6 months. In these nine patients, extramedullary toxicity was absent, neutropenia did not occur, transfusional support was not needed, and preliminary data suggested little immunosuppression (phytohemagglutinin responses). Oral etoposide was ineffective in all (11 of 11) patients with rapidly growing tumor masses. CONCLUSION: Given the absence of toxicity to major organs, the minimal myelosuppression or immunosuppression, and the antineoplastic activity in patients with low tumor burdens after high-dose chemotherapy, limited use of low-dose oral etoposide should be considered for inclusion in postinduction consolidative treatment programs aimed at eradicating minimal residual disease.     

Phase II trial of primary chemotherapy followed by reduced-dose radiation for CNS germ cell tumors.

PURPOSE: A prospective phase II study was initiated to assess the response rate, survival, and late effects of treatment in patients with newly diagnosed CNS germ cell tumors (GCT), using etoposide plus cisplatin followed by radiation therapy prescribed by extent of disease, histology, and response to chemotherapy. PATIENTS AND METHODS: Seventeen patients aged 8 to 24 years with histologically proven CNS GCT received etoposide (100 mg/m2/d) plus cisplatin (20 mg/m2/d) daily for 5 days every 3 weeks for four cycles, followed by radiation therapy. Nine patients had germinomas; eight had mixed GCT. Four patients (three with germinomas and one with mixed GCT) presented with leptomeningeal dissemination. RESULTS: Radiographically, 14 of 17 patients were assessable for response; 11 patients experienced complete regression, and three had major partial regression before radiation. Six of seven assessable patients with elevated CSF levels of alpha-fetoprotein or betahuman chorionic gonadotropin had normalization with chemotherapy alone; all normalized with combined chemotherapy and radiation therapy. All 17 patients are alive without evidence of disease (median follow-up, 51 months). One patient developed a relapse in the spinal leptomeninges and was rendered free of disease with spinal radiation more than 5 years ago. One patient developed carotid stenosis requiring surgery. Thus far, only minimal long-term deterioration in neurocognitive function has been detected as a consequence of protocol treatment. CONCLUSION: Conventional-dose intravenous chemotherapy with etoposide and cisplatin can effect tumor regression in a high proportion of patients with CNS GCT, including those with leptomeningeal metastases. Acute and long-term toxicities are acceptable. Progression-free survival and overall survival are excellent.