Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study.

Background: In the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the prespecified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2. Patients and methods: The RADIANT-2 trial compared everolimus (10 mg/day, orally; n = 216) versus placebo (n = 213), both in conjunction with octreotide LAR (30 mg, intramuscularly, every 28 days). Patients, unblinded at the time of progression or after end of double-blind core phase following primary analysis, were offered open-label everolimus with octreotide LAR (open-label phase). In the open-label phase, patients had similar safety and efficacy assessments as those in the core phase. For OS, hazard ratios (HRs) with 95% CIs using unadjusted Cox model and a Cox model adjusted for prespecified baseline covariates were calculated. Results: A total of 170 patients received open-label everolimus (143 crossed over from the placebo arm; 27 in the everolimus arm continued to receive the same treatment after unblinding). The median OS (95% CI) after 271 events was 29.2 months (23.8-35.9) for the everolimus arm and 35.2 months (30.0-44.7) for the placebo arm (HR, 1.17; 95% CI, 0.92-1.49). HR adjusted for baseline covariates was 1.08 (95% CI, 0.84-1.38). The most frequent drug-related grade 3 or 4 AEs reported during the open-label phase were diarrhea (5.3%), fatigue (4.7%), and stomatitis (4.1%). Deaths related to pulmonary or cardiac failure were observed more frequently in the everolimus arm. Conclusion: No significant difference in OS was observed for the everolimus plus octreotide LAR and placebo plus octreotide LAR arms of the RADIANT-2 study, even after adjusting for imbalances in the baseline covariates. Clinical Trial Number: NCT00412061, www.clinicaltrials.gov.

Disease characteristics, treatment patterns, and outcomes of follicular lymphoma in patients 40 years of age and younger: an analysis from the National Lymphocare Study†.

BACKGROUND: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma, with median age at diagnosis in the seventh decade. FL in young adults (YAs), defined as diagnosis at ≤40 years, is uncommon. No standard approaches exist guiding the treatment of YA FL, and little is known about their disease characteristics and outcomes. To gain further insights into YA FL, we analyzed the National LymphoCare Study (NLCS) to describe characteristics, initial treatments, and outcomes in this population versus patients aged >40 years. PATIENTS AND METHODS: Using the NLCS database, we stratified FL patients by age: 18-40 (YA), 41-60, 61-70, 71-80, and >80 years. Survival probability was estimated using Kaplan-Meier methodology. We examined associations between age and survival using hazard ratios and 95% confidence intervals (CIs) from multivariable Cox models. RESULTS: Of 2652 eligible FL patients in the NLCS, 164 (6%) were YAs. Of YA patients, 69% had advanced disease, 80% had low-grade histology, and 50% had good-risk disease according to the Follicular Lymphoma International Prognostic Index (FLIPI). Nineteen percent underwent observation, 12% received rituximab monotherapy, and 46% received chemoimmunotherapy [in 59% of these: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone)]. With a median follow-up of 8 years, overall survival (OS) at 2, 5, and 8 years was 98% (95% CI 93-99), 94% (95% CI 89-97), and 90% (95% CI 83-94), respectively. Median progression-free survival (PFS) was 7.3 years (95% CI 5.6-not reached). CONCLUSIONS: In one of the largest cohorts of YA FL patients treated in the rituximab era, disease characteristics and outcomes were similar to patients aged 41-60 years, with favorable OS and PFS in YAs. Longer-term outcomes and YA-specific survivorship concerns should be considered when defining management. These data may not support the need for more aggressive therapies in YA FL. CLINICAL TRIAL NUMBER: Roche/Genentech ML01377 (U2963n).

Improved time to treatment failure with an intermittent oxaliplatin strategy: results of CONcePT.

BACKGROUND: Oxaliplatin is an integral component of colorectal cancer treatment, but its use is limited by neurotoxicity. The Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT) tested intermittent oxaliplatin (IO) administration and the use of concurrent calcium and magnesium salts (Ca/Mg), two modifications intended to reduce neurotoxicity and extend the duration of treatment. PATIENTS AND METHODS: In this trial involving double randomization, 140 patients were randomized to receive modified FOLFOX7 plus bevacizumab with IO (eight-cycle blocks of oxaliplatin treatment) versus continuous oxaliplatin (CO); and Ca/Mg versus placebo (pre- and postoxaliplatin infusion). The primary end point was time-to-treatment failure (TTF). RESULTS: One hundred thirty-nine patients were entered and treated up to the point of early study termination due to concerns by the data-monitoring committee (DMC) that Ca/Mg adversely affected tumor response. Tumor response was not a study end point. Given DMC concerns, an additional independent, blinded radiology review of all images showed no adverse effect of treatment schedule or Ca/Mg on response by Response Evaluation Criteria In Solid Tumors. The IO schedule was superior to CO [hazard ratio (HR) = 0.581, P = 0.0026] for both TTF and time-to-tumor progression (TTP) (HR = 0.533, P = 0.047). CONCLUSIONS: An IO dosing schedule had a significant benefit on both TTF and TTP versus CO dosing in this trial despite the very attenuated sample. There was no effect of Ca/Mg on response.

Carcinoma of unknown primary with gastrointestinal profile: immunohistochemistry and survival data for this favorable subset.

BACKGROUND: Carcinoma of unknown primary with a "gastrointestinal profile" is an emerging, favorable entity. Distinguishing this entity is of increasing significance given the progress in the treatment of colorectal cancer. PATIENTS AND METHODS: 74 carcinoma of unknown primary (CUP) patients with CDX2+ tumors were chosen from the databases at M.D. Anderson and Sarah Cannon Cancer Centers between 2004 and 2010. Data on clinical and pathological characteristics including therapy and survival were recorded. RESULTS: 20 patients had ascites on presentation; the predominant sites of metastases included liver (30 %), carcinomatosis (50 %), and nodes (51 %). Based on immunohistochemistry, 2 cohorts were created: Cohort 1-"consistent with lower GI profile" included 34 patients [CDX-2+, CK20+, CK7-] and Cohort 2-"probable lower GI profile" included 40 patients [CDX2+, irrespective of CK7/CK20 status]. Excluding 6 outliers, Cohorts 1 and 2 had 32 and 36 patients, respectively; their median survivals were 37 and 21 months, respectively. On multivariate Cox regression analysis, only liver metastases were found to negatively influence survival. CONCLUSIONS: Our retrospective study provides encouraging indications that CUP patients with gastrointestinal profiles benefit from site-specific therapy. We recommend all CUP patients, especially those with abdominal nodes, isolated carcinomatosis or liver metastases, to undergo optimal immunohistochemistry (IHC) to check for a gastrointestinal profile of CUP.

Kinetics of N-[(4-chlorophenyl)amino]carbonyl-2,3-dihydro-1H-indene-5-sulfonamide (LY186641) in humans.

The metabolism and disposition of LY186641, a diarylsulfonylurea with antineoplastic activity identified in preclinical tests, was determined in 21 patients who received 23 courses of orally administered drug. A linear correlation was found between the dose of drug administered and LY186641 peak plasma concentrations and LY186641 area under the curve measurements. Clearance (135 +/- 36 ml/h/m2), terminal half-life (31 +/- 11 h), and volume of distribution (10.2 +/- 2.8 liters) were independent of drug dose. No LY186641 was excreted in urine. Hydroxy and keto metabolites of LY186641 were identified in plasma and urine samples. Urinary excretion of these metabolites during the initial 48 h following drug administration accounted for 20% of LY186641 disposition. Plasma half-life of the hydroxy and keto metabolites was longer than that of parent drug (3.3 and 3.1 days, respectively). Plasma concentrations of parent drug correlated with the presence of methemoglobinemia, the dose-limiting toxicity found with LY186641.

Potential utility of serum neuron-specific enolase levels in small cell carcinoma of the lung.

To assess the value of neuron-specific enolase (NSE) as a possible biomarker of small cell lung cancer, serum levels were determined by radioimmunoassay in 93 newly diagnosed untreated patients and were compared to the NSE levels of 20 healthy adult controls [9.6 +/- 0.7 (S.E.) ng/ml]. Serum NSE was elevated (greater than 20 ng/ml) in 73% of all patients including 23 of 39 (59%) with limited-stage disease and 45 of 54 (83%) with extensive-stage disease. The mean serum NSE was significantly higher in extensive-stage disease (94.5 +/- 13.8 ng/ml) compared to the mean value for limited-stage disease (33.7 +/- 4.7 ng/ml) (p less than 0.001). NSE was elevated in all patients with three or more sites of metastatic disease. Serial NSE determinations were obtained on 57 small cell lung cancer patients. NSE levels fell in 40 of 50 (80%) of patients responding to treatment, increased in 5 of 7 (71%) of patients with progressive disease, and increased in 30 of 35 (86%) of patients who relapsed. A persistent rise in serum NSE occurred as many as 12 weeks before the clinical recognition of relapse in 15 of 23 (65%) of patients for whom adequate serial NSE data were available. These findings indicate that serum NSE may be a useful marker for staging, monitoring treatment, and predicting relapse in patients with small cell lung cancer.

Phase I clinical study of N-[(4-chlorophenyl)amino]carbonyl-2,3-dihydro-1H-indene-5-sulfonamide (LY186641).

Between February 1987 and July 1988, 45 patients with advanced refractory cancer were treated with LY186641, a diarylsulfonylurea that has shown a broad spectrum of activity in preclinical testing. Patients received a weekly p.o. dose of LY186641 for 6 consecutive weeks; responding and stable patients continued weekly therapy until progression occurred. Using a standard phase I study design, the first three patients received LY186641 at 30 mg/m2 week; the dose was escalated in subsequent patients until dose-limiting toxicity occurred. Methemoglobinemia was the major toxicity observed and was dose related. Methemoglobin levels peaked approximately 24 h after LY186641 was administered and fell to low levels after 48 h. Six patients developed fatigue, cyanosis, and dyspnea associated with serum methemoglobinemia levels of greater than 20%; four of these patients were subsequently removed from the study. Hemolytic anemia was also observed but was clinically significant in only 10 patients. Other side effects were mild and infrequent. The maximum tolerated dose of LY186641, when given at this schedule, was 2550 mg/m2/week. No objective tumor responses were observed.

Combination intraventricular chemotherapy for meningeal neoplasia.

Twenty two patients with meningeal neoplasia were treated with biweekly combination intraventricular chemotherapy using methotrexate, cytosine arabinoside, and thiotepa. Patients with the following malignancies were included: breast cancer, ten patients; lung cancer, seven; non-Hodgkin's lymphoma, two; malignant melanoma, one; transitional cell carcinoma of the bladder, one; and malignant glioma, one. Eight of 22 patients (36%) had a Karnofsky performance status of less than 50%. Eleven of 22 patients received radiotherapy to symptomatic areas, and seven received systemic chemotherapy in addition to combination intraventricular therapy. Patients were evaluated for both toxicity and response to therapy. Myelosuppression was the major toxic condition and occurred in 17 of 22 patients (77%). Ten patients (45%) had a nadir WBC count of less than 1000/microL or a platelet count of less than 25,000/microL. No patient achieved a complete response (CR), although nine patients (41%) had partial responses (PRs) lasting 4 to 24 + weeks. Median survival for the entire group was 10 weeks (range, 6 to 24+ weeks). In this small group of patients, simultaneous triple-drug intraventricular chemotherapy caused unacceptable myelosuppression without increasing the response rate, response duration, or survival when compared with single-agent methotrexate and radiotherapy.

Poorly differentiated carcinoma of unknown primary site: correlation of light microscopic findings with response to cisplatin-based combination chemotherapy.

We have previously reported complete responses and long-term survival in patients with metastatic poorly differentiated carcinoma (PDC) of unknown primary site who received intensive cisplatin-containing chemotherapy regimens. We reviewed the light microscopic specimens from 113 patients with PDC in an attempt to identify common histopathologic features in the chemotherapy-responsive subgroup, and to rule out the presence of previously unrecognized germ cell tumors. Relatively few diagnoses more specific than PDC could be made. We could identify no histopathologic features by light microscopy that distinguished responsive from unresponsive neoplasms. Only one patient was found to have a previously unrecognized yolk sac carcinoma, and in five other patients the possibility of a germ cell neoplasm was considered in the differential diagnosis by at least one reviewer. The remaining tumors had no histologic features suggestive of germ cell neoplasms. Ninety-six patients had received combination chemotherapy (89 with cisplatin-containing regimens); 27 patients (28%) achieved complete remission, and 16 remain free of disease at a median of 65 months after completion of therapy. Patients with PDC of unknown primary site who are responsive to cisplatin-containing chemotherapy regimens cannot be reliably identified by light microscopy. At present, all such patients should be considered for an empiric trial of chemotherapy with cisplatin-based regimens, since cure is achievable in a minority.

High-dose VP-16-213 monotherapy for refractory germinal malignancies: a phase II study.

VP-16-213 at standard dose is one of the more active agents for the treatment of germ cell tumors. In previous phase I studies, VP-16-213 has been investigated in suprastandard dose when hematopoietic reconstitution was assured by autologous bone marrow transplantation (ABMT). This phase II study was performed to explore the possibility that an augmented dose of VP-16-213 may be more active than standard dose against germ cell tumors. Eleven patients with progressive refractory germ cell tumors were treated with high-dose VP-16-213: 2,400 mg/m2 with ABMT every three to four weeks followed by 1,200 mg/m2 without ABMT. Seven patients had received VP-16-213 at standard dose prior to high-dose VP-16-213. Toxicity to high-dose VP-16-213 included severe myelosuppression, nausea, vomiting, alopecia, mucositis, and hepatitis. Of 10 evaluable patients, two complete responses and four partial responses, all of short duration, were obtained. However, some patients unresponsive to standard-dose VP-16-213 exhibited responses to the augmented-dose VP-16-213. Therefore, although more myelosuppressive, VP-16-213 may have increased activity against germ cell tumors when administered at augmented dose. High-dose VP-16-213 may be considered in designing new approaches for initial management of patients with germ cell tumors not expected to be cured with standard chemotherapy.

Paclitaxel in combination chemotherapy with radiotherapy in patients with unresectable stage III non-small-cell lung cancer.

PURPOSE: The addition of combination chemotherapy to standard radiation therapy has improved treatment for locally unresectable non-small-cell lung cancer. In this phase II study, we evaluated the toxicity and efficacy of a novel chemotherapy regimen that included paclitaxel, cisplatin, and etoposide plus concurrent radiation therapy in this group of patients. PATIENTS AND METHODS: Thirty-three patients with previously untreated, unresectable stage III non-small-cell lung cancer (stage IIIA, 11 patients; stage IIIB, 22 patients) initially received two courses of chemotherapy, which included paclitaxel 135 mg/m2 by 1-hour infusion on day 1, cisplatin 60 mg/m/ intravenously (i.v.) on day 2, and etoposide 100 mg/m2 i.v. on days 1, 2 and 3. On week 6, radiation therapy (60 Gy in 30 fractions) was initiated in conjunction with two additional courses of chemotherapy: paclitaxel 135 mg/m2 i.v. by 1-hour infusion on day 1, cisplatin 5 mg/m2 i.v. on days 2- to 10, and etoposide 25 mg/m2 on days 1 to 10. RESULTS: This combined modality program was feasible and well tolerated by most patients. During the two courses of induction chemotherapy, grade 3 or 4 myelosuppression occurred in only six patients (18%). Esophagitis was common during combined modality therapy (grade 3, 10 patients; grade 4 five patients). Forty-two percent of patients had partial response after two courses of induction therapy, and 82% of patients had an objective response at completion of therapy. Twelve patients (36%) had a complete response. Nineteen patients remain progression-free at a median of 8 months; the median survival time has not been reached. CONCLUSION: This paclitaxel-containing combined modality therapy is feasible and highly active in patients with inoperable stage III lung cancer. Esophagitis is the most common severe toxicity with this program. Further studies with paclitaxel-containing combination regimens in patients with stage III non-small-cell lung cancer are indicated.

Mitoxantrone, fluorouracil, and high-dose leucovorin: an effective, well-tolerated regimen for metastatic breast cancer.

Between September 1988 and August 1990, we treated 35 women with metastatic breast cancer with a novel regimen containing mitoxantrone, fluorouracil (5-FU), and high-dose leucovorin. This regimen was designed to take full advantage of the favorable toxicity profiles of these agents while maintaining a high level of activity. All patients had received previous chemotherapy (adjuvant only, 15 patients; at least one metastatic regimen, 20 patients). Seven patients had received previous doxorubicin, but none within 6 months of study entry. Of 31 assessable patients, 20 (65%) had objective responses (two complete, 18 partial), with a median response duration of 6 months (range, 3 to 16+ months). Four patients with bone metastases (abnormal bone scan only) and pain were not considered assessable by strict response criteria; two of these patients had sustained symptomatic relief for 6 and 8 months, respectively. Myelosuppression was the most frequent toxicity but was mild in most patients; only four hospitalizations for fever and neutropenia were required (2% of courses). No severe thrombocytopenia occurred and no RBC transfusions were required. Alopecia, mucositis, and nausea/vomiting were uncommon and were not severe in any patient. The combination of mitoxantrone, 5-FU, and high-dose leucovorin is well tolerated and active as a first- or second-line treatment for metastatic breast cancer. Comparison with other standard regimens for breast cancer is indicated.

Paclitaxel by 1-hour infusion: an active drug in metastatic non-small-cell lung cancer.

PURPOSE: Paclitaxel is an active single agent when administered as a 24-hour continuous infusion in the treatment of stage IV non-small-cell lung cancer. We evaluated the efficacy and toxicity of paclitaxel administered by 1-hour infusion in the outpatient setting to patients with stage IV or relapsed non-small-cell lung cancer. PATIENTS AND METHODS: Fifty-nine patients with stage IV or relapsed non-small-cell lung cancer were treated with 1-hour infusions of paclitaxel. The first 17 patients received a dose of 135 mg/m2 and the remaining 42 patients received 200 mg/m2. By random assignment, 31 patients received a single-day, 1-hour infusion of paclitaxel, and 28 patients received a 3-day, divided-dose schedule, with each dose administered by 1-hour infusion. Both regimens were repeated every 21 days. All patients received premedication with dexamethasone, diphenhydramine, and cimetidine. Cytokines were not routinely used. RESULTS: Thirteen of 53 assessable patients (25%) had partial responses to treatment. An additional five patients had minor responses. The median survival duration of the entire group was 8 months and the actuarial 1-year survival rate was 33%. Patients who received 200 mg/m2 of paclitaxel had a higher response rate than those who received 135 mg/m2 (31% v 12%, respectively). Six of 16 patients (38%) previously treated with cisplatin-based regimens responded to 200 mg/m2 of paclitaxel. No significant differences in activity were seen when the 1-day and 3-day paclitaxel schedules were compared. Paclitaxel was well tolerated at both doses and schedules, and no severe hypersensitivity reactions occurred. Only 18 of 154 courses (12%) given at 200 mg/m2 resulted in grade 3 or 4 leukopenia. CONCLUSION: Paclitaxel administered by 1-hour infusion is an active and well-tolerated new agent in the treatment of metastatic non-small-cell lung cancer. These results suggest that a paclitaxel dose of 200 mg/m2 is more effective than 135 mg/m2 and can produce responses in patients previously treated with cisplatin-based regimens. Incorporation into combination regimens is indicated.

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.

Overexpression of Her-2 in patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site.

PURPOSE: To determine the frequency of Her-2 overexpression in patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site. PATIENTS AND METHODS: Tumor specimens from 100 patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma were stained for the Her-2 protein using the Dako immunohistochemical method. Clinical and pathologic characteristics of patients with and without Her-2 overexpression were compared. RESULTS: Staining for Her-2 overexpression was successful in 94 of 100 patients. Ten (11%) of 94 tumor specimens overexpressed Her-2. Eight of 10 overexpressors had poorly differentiated adenocarcinoma, and all overexpressors had predominant tumor location above the diaphragm, usually in the mediastinum or lungs. CONCLUSION: Her-2 overexpression occurs in a minority of patients with poorly differentiated carcinoma/adenocarcinoma of unknown primary site. Because most overexpressors had poorly differentiated adenocarcinoma, further evaluation of patients with adenocarcinoma of unknown primary site is necessary to determine the frequency of Her-2 overexpression in this common subgroup. Evaluation of the efficacy of trastuzumab in Her-2 overexpressors with carcinoma of unknown primary site is indicated.

Chronic daily administration of oral etoposide--a phase I trial.

In this phase I study, we administered etoposide (VP-16) orally for 21 consecutive days to patients with advanced refractory cancers. All patients had received previous chemotherapy, and 50% of patients had received more than one combination regimen. When given for 21 consecutive days, the maximum-tolerated dose of oral VP-16 was 50 mg/m2/d. Myelosuppression was the dose-limiting toxicity, and occurred between days 21 and 28. In most patients, blood counts had recovered sufficiently by day 35 to begin another 3-week course. WBC count nadirs of less than 1,000/microL occurred in four of 20 courses at this dose, and three patients required hospitalization for treatment of neutropenia and fever. Alopecia occurred in most patients; gastrointestinal (GI) and other toxicities were uncommon. Five of 16 patients with measurable tumor had partial responses of 3 to 4 months duration. Four of these five patients had malignancies that are usually unresponsive to VP-16 when administered by previously investigated schedules. This method of VP-16 administration is well tolerated, convenient, and may optimize antitumor efficacy by exploiting the schedule dependency of this drug. Phase II studies are necessary to define the level of activity of this schedule of VP-16.

Combined small-cell and non-small-cell lung cancer.

Nine (2%) of 429 small-cell lung cancer (SCLC) patients seen at Vanderbilt University between 1977 and 1983 had a combined subtype SCLC at diagnosis (ie, small-cell carcinoma plus squamous cell or adenocarcinoma). Staging procedures and chemotherapy treatment were uniform for all 429 patients. The diagnosis of combined histology was established via bronchoscopy (six patients), needle aspiration biopsy (one), lymph node biopsy (one), and thoracotomy (one). The clinical characteristics of the combined subtype patients were similar to patients with other subtypes of SCLC (ie, there were no differences in median age, sex, performance status, and stage of disease). However, patients with a combined subtype histology had a higher incidence of peripheral lesions on chest x-ray (56% v 14%, P less than .001) and a lower median lactate dehydrogenase (LDH) (301 IU/L v 341 IU/L, P = .0002) at diagnosis. The overall response to chemotherapy (57% v 78; P = .5) and the median survival (8 months v 10 months; P = .4) of the combined subtype patients were similar to patients with other subtypes of SCLC. Two (22%) combined histology patients survived greater than or equal to 5 years. Both had had surgical resection in addition to chemotherapy. These data suggest that the combined subtype of SCLC is clinically similar to pure SCLCs and that surgery may play a prominent role in the management of these tumors. The possibility of a combined histology tumor should be considered in patients thought to have SCLC on the basis of limited biopsy material, such as a needle aspiration or bronchial biopsy, and when the primary lesion is peripherally located on chest x-ray.

Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide.

PURPOSE: To evaluate the efficacy and toxicity of a novel chemotherapy combination that includes paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of patients with carcinoma of unknown primary tumor site. PATIENTS AND METHODS: Fifty-five patients with carcinoma of unknown primary tumor site were treated with the following regimen, administered every 21 days: paclitaxel 200 mg/m2 by 1-hour intravenous (I.V.) infusion on day 1, carboplatin at an estimated area under the concentration-time curve (AUC) of 6.0 on day 1, and etoposide 50 mg alternated with 100 mg orally on days 1 through 10. Responding patients received a total of four courses of treatment. The following histologies were included: adenocarcinoma, 30 patients; poorly differentiated carcinoma (PDC) or poorly differentiated adenocarcinoma (PDA), 21; poorly differentiated neuroendocrine carcinoma, three; and squamous carcinoma, one. RESULTS: Twenty-five of 53 assessable patients (47%; 95% confidence interval [CI], 33% to 61%) had major objective responses to treatment (seven complete responses). Response rates were similar in patients with adenocarcinoma versus PDC (45% and 48%, respectively). The actuarial median survival time for the entire group was 13.4 months. The regimen was well tolerated, with only seven hospitalizations for treatment of neutropenia and fever (4% of courses) and no treatment-related deaths. CONCLUSION: The combination of paclitaxel, carboplatin, and extended-schedule etoposide is highly active and well tolerated in patients with carcinoma of unknown primary tumor site. Response rates and survival in this multicenter community-based trial compare favorably with all previously studied empiric regimens. In addition, this regimen is substantially less toxic and easier to administer than the cisplatin-based regimens previously used in this setting. If this level of efficacy is confirmed, this treatment should be considered standard first-line therapy in patients with carcinoma of unknown primary tumor site.

Successful treatment of resistant germinal neoplasms with VP-16 and cisplatin: results of a Southeastern Cancer Study Group trial.

Between July 1979 and May 1982, we treated 45 male patients with refractory germinal neoplasms. All patients had previously received intensive cisplatin-containing combination chemotherapy regimens. Patients received salvage chemotherapy with VP-16 and cisplatin +/- bleomycin +/- doxorubicin. Of 44 evaluable patients, 19 (43%) achieved complete remissions with salvage chemotherapy, 12 (27%) had partial remissions, and nine (21%) had no response. Four patients (9%) were not evaluable for response due to early death or noncompliance but are considered treatment failures. Ten patients (23%) remain alive and continuously disease free 20 to 39 months (median, 29 months) after completion of therapy. Hematologic toxicity was severe, with one death related to sepsis. Bleomycin-induced pulmonary fibrosis occurred in 17 patients with two fatalities. The addition of bleomycin and/or doxorubicin to this regimen increases toxicity and probably does not improve treatment results. Salvage chemotherapy with VP-16 and cisplatin offers potentially curative therapy to men with resistant germinal tumors.