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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., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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)., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Rituximab, a chimeric antibody that targets CD20(+) B cells, produces a 48% response rate in patients with refractory low-grade non-Hodgkin lymphoma. In this phase II trial, patients with low-grade non-Hodgkin lymphoma who had previously received no systemic therapy were treated with rituximab, 375 mg/m(2), administered by IV infusion for 4 consecutive weeks. Patients with objective response or stable disease received repeat 4-week courses of rituximab at 6-month intervals. At the time of initial reevaluation at 6 weeks, 21 of 39 patients (54%) had objective response to treatment, and an additional 14 patients (36%) had stable disease or minor response. Response rates were similar in patients with follicular and small lymphocytic (CLL-type) lymphoma (52% versus 57%, respectively). At present, follow-up is short and only 13 patients have undergone a second course of rituximab treatment. However, 4 additional responses were documented either prior to the second course of rituximab (2 patients) or following the second course (2 patients) and 4 patients improved from partial to complete response. The current response rate is 64%, with 6 complete responses (15%). Treatment with rituximab was well tolerated, with only 1 patient experiencing grade 3/4 infusion-related toxicity. Rituximab is well tolerated and highly active in patients with low-grade non-Hodgkin lymphoma previously untreated with systemic therapy. Although further follow-up is required, the demonstration of minimal toxicity and considerable activity of this new biologic agent represents an important beginning of more specific, less toxic treatment for this important group of cancer patients.

Purpose: To evaluate the toxicity, response rate and short-term survival associated with the chemotherapy combinations of docetaxel plus cisplatin or carboplatin when used for the treatment of patients with metastatic carcinoma of unknown primary site., Patients and Methods: Twenty-six patients were treated with docetaxel 75 mg/m2 i.v. and cisplatin 75 mg/m2 i.v. given every three weeks (study A) and subsequently, 47 patients were treated with docetaxel 65 mg/m2 and carboplatin (AUC dose = 6) every three weeks (study B). Stable or responding patients received a maximum of eight courses of therapy. Patients who were known to be in treatable subset groups were excluded from these trials. The majority of patients had two or more sites of metastasis; about 45% had adenocarcinoma and 50% poorly differentiated carcinoma., Results: In study A, 6 of 23 (26%) assessable patients had a major response to therapy. The median survival was eight months and one-year survival 42%. Seven patients were removed from the study early for grade 3 or 4 nausea and vomiting. In study B, 9 of 40 assessable patients (22%) had a major response to therapy. Median survival was eight months and one-year survival 29%. Toxicity associated with this regimen was predominantly myelosuppression. Comparisons of the two sequential trials showed no differences in response rates or survivals (P = 0.75)., Conclusions: Docetaxel and cisplatin (study A) is an active combination in carcinoma of unknown primary site, but associated with substantial gastrointestinal toxicity. A combination of docetaxel plus carboplatin (study B) is better tolerated and produced a similar response rate, median survival and one-year survival. Comparative phase III trials will be necessary to unequivically prove a survival advantage for any form of therapy in these patients. However, the survival for patients with carcinoma of unknown primary site receiving docetaxel-based chemotherapy is comparable to the survivals for several other groups of advanced cancer patients, such as non-small cell lung cancer, receiving various types of chemotherapy.

The newer or 'third generation' chemotherapeutic agents (paclitaxel, docetaxel, vinorelbine, gemcitabine, irinotecan, topotecan) have all recently been shown to have substantial activity against non-small-cell lung cancer (NSCLC). Many of these agents are now being incorporated into the therapy for patients with advanced disease. Paclitaxel was the first 'third generation' drug to be studied. The use of paclitaxel and carboplatin has proven to be a well tolerated and quite active regimen with one-year survival in patients with stage IV disease of about 40% and two-year survival of about 20%. These survival rates are at least twice as good as previous platinum-based regimens. We have simplified the administration of paclitaxel by using a one-hour infusion and many other investigators and clinicians have followed suit. The results are equivalent to a three-hour infusion schedule. Given the degree of activity in patients with stage IV disease, it is imperative to begin neoadjuvant and adjuvant trials with the newer drugs and drug combinations. We and others have started a neoadjuvant strategy which has proven to be feasible and most patients tolerate surgery well. While the results are quite preliminary, we have seen some complete pathologic responses (about 20%) and are encouraged by these early data. In addition, we have routinely used adjuvant paclitaxel and carboplatin in patients with stage IB-IIIA disease who have been previously resected. Radiotherapy and a weekly schedule of paclitaxel and carboplatin have been incorporated for patients with stages II-IIIB (selected IIIB patients). Randomized comparisons are certainly needed in the neoadjuvant and adjuvant arena and the other 'third generation' drugs need to be quickly evaluated. We have chosen to add a third agent to paclitaxel and carboplatin. The evaluation of several triple combinations including the addition of gemcitabine, vinorelbine and topotecan, respectively to the paclitaxel-carboplatin combination has been completed. Preliminary results from these trials will be briefly summarized and plans for additional studies of the newer agents will also be discussed. Studies to learn the appropriate combinations, doses and schedules of the newer drugs in concert with radiotherapy and/or resection are also urgently needed. Since the newer 'third generation' drugs appear to genuinely improve the survival of patients with stage IV disease, it is likely that incorporation of these more active agents into therapy for lower stages of disease will make an even greater impact on overall survival for patients with this common neoplasm.

Since the beginning of its clinical development 20 years ago, etoposide has become an important and widely used agent in clinical oncology. Its integral role in the treatment of germ cell tumors and small-cell lung cancer seems unlikely to diminish in the future, and its use in non-Hodgkin's lymphoma and in various high dose regimens will probably continue to increase. Active investigation continues regarding the optimal dose and schedule of etoposide, and it is likely that these investigations will result in further improvement of its clinical activity in patients with sensitive tumor types. Continued clinical investigation may result in the identification of active etoposide containing combination regimens for ovarian cancer, breast cancer, and some of the childhood malignancies. Exciting possibilities for the future include exploration of etoposide in combination with the topoisomerase I inhibitors, as well as the development of drugs to reverse drug resistance. During the next 10 years, the applications and importance of this unique drug will continue to increase.

Background: Metastatic breast cancer remains an incurable disease; therefore, both the efficacy and the toxicity of palliative chemotherapy are important considerations. Mitoxantrone and 5-fluorouracil (5-FU) with high dose leucovorin are active drugs in the treatment of breast cancer, and both can be given with relatively few side effects. We evaluated the efficacy and toxicity of these agents in a combination regimen for the treatment of metastatic breast cancer., Patients and Methods: In a phase II study, we treated 35 women with metastatic breast cancer with the following regimen: mitoxantrone 12 mg/m2 i.v. day 1; leucovorin 300 mg i.v. over 1 hour followed by 5-FU 350 mg/m2 i.v. push on days 1, 2 and 3; courses repeated every 21 days. Responding patients received a total of 6-8 courses. Most patients were receiving second-line chemotherapy for metastatic breast cancer, but some were receiving first-line therapy following failure of adjuvant chemotherapy., Results: Twenty of 31 assessable patients (65%) had objective responses; in addition, 2 of 4 patients with bone-only metastases had sustained symptomatic responses. Toxicity was mild and the regimen was well tolerated. The activity of this drug combination has been verified in several other phase II studies., Conclusions: The combination of mitoxantrone, 5-FU and high-dose leucovorin provides an attractive option for second-line chemotherapy of metastatic breast cancer. The efficacy of this combination in first-line therapy is currently being compared to cyclophosphamide, methotrexate and 5-FU (CMF) in a randomized trial.

We retrospectively compared the results of treatment with hexamethylmelamine (HMM), cyclophosphamide, doxorubicin, and cisplatin (H-CAP) to treatment results using cyclophosphamide, doxorubicin, and cisplatin (CAP) in patients with advanced ovarian cancer. The treatments were identical in dosage and schedule with the exception of the addition of HMM to one regimen. Fifty-five patients treated with H-CAP between August 1977 and March 1980 were compared with a subsequent group of 22 patients who received CAP between October 1984 and October 1987. Following 6 months of therapy, patients were restaged either with second-look laparotomy or with clinical restaging. Fifty-three of 55 patients (96%) and 14/21 (67%) patients had objective responses to H-CAP and CAP respectively (p = 0.001). The pathologic complete response rate as determined by second-look laparotomy was higher in the patients who received H-CAP (35% vs. 19%). The median survival of patients receiving H-CAP is 47 months compared to 21 months for the CAP patients. In limited residual disease patients (maximum tumor diameter less than or equal to 3 cm), the median survival also favored the H-CAP treatment (101 months vs. 21 months, p = 0.002). The median time to progression was greater in patients receiving H-CAP vs. those receiving CAP (67 months vs. 16 months, p = 0.045). Treatment-related toxicity was similar for the two regimens. These findings suggest that the addition of HMM to CAP chemotherapy prolongs the median survival for patients with limited residual disease advanced ovarian cancer.

Six men undergoing potentially curative chemotherapy for advanced lymphomas received daily injections (50 micrograms) of an analogue of luteinizing hormone releasing hormone (LH-RHa) in an attempt to protect posttreatment gonadal function. The median duration of combined LH-RHa-chemotherapy administration was 25 weeks (range, 14 to 31 weeks). During the simultaneous administration of LH-RHa and chemotherapy, plasma testosterone levels decreased to subnormal levels, while both follicle-stimulating hormone (FSH) and luteinizing hormone levels declined to the lower limit of normal. All subjects became oligospermic or azoospermic within eight weeks of starting treatment. Following discontinuation of chemotherapy and LH-RHa, both plasma testosterone and LH promptly increased and stabilized within the normal range. FSH progressively increased to a level well above the normal range. Only one patient has recovered evidence of active spermatogenesis at 84 weeks postcessation of chemotherapy. No untoward side effects due to LH-RHa were experienced. Although LH-RHa can be administered safely during combination chemotherapy, no improvement in posttreatment fertility has yet been demonstrated.

Four patients with small cell lung cancer (SCC) presenting with Pancoast's syndrome are described. Superior sulcus tumors are usually caused by epidermoid carcinoma or adenocarcinoma of the lung, and are routinely treated with radiotherapy followed by radical surgery. SCC, on the other hand, is widely disseminated at diagnosis and is best treated with chemotherapy. Although not previously reported as a cause of Pancoast's tumor, these four cases of SCC presenting as such clearly indicate the need for pretreatment histologic diagnosis to avoid unnecessary surgical intervention. Transcutaneous needle aspiration biopsy is a means by which the diagnosis can be safely made in patients presenting with apical lung tumors.

Forty patients with limited-stage small cell carcinoma of the lung were prospectively evaluated for adjuvant surgery after intensive chemotherapy to determine resectability. All patients giving informed consent and having a Karnofsky performance status greater than or equal to 50% were included in the study, which ran from May, 1980, to September, 1982. Ages ranged from 40 to 70 years (median, 59 years). One patient was lost to follow-up. Thirty-nine patients were evaluated for operation 9 to 15 weeks after diagnosis and after having received two to four cycles of chemotherapy intravenously every 3 weeks (cyclophosphamide, 1,000 mg/m2; doxorubicin, 50 mg/m2; vincristine, 1 mg/m2; VP-16, 300 mg/m2). Two patients had clinical Stage I tumors; 12 patients, Stage II; and 25 patients, Stage III. At the time of reevaluation there were 13 (33%) complete responders, 21 (54%) partial responders, and 5 (13%) with stable disease. Eleven (28%) of the 39 patients underwent thoracotomy using standard resection criteria for non-small cell carcinoma. Eight of these 11 had resectable lesions (2, Stage I; 3, Stage II; 3, Stage III); five pneumonectomies and three lobectomies were performed. Tumor was present in six of eight specimens. Twenty-eight patients were not candidates for operation for various reasons: poor pulmonary function, 5; unresectable tumors, 10; refusal, 6; very poor medical condition, 6; and primary site not identified, 1. Median survival for complete responders was 17 months and for partial responders, 11 months. We have prospectively identified suitable candidates for adjuvant surgery among the total group (denominator population) of patients with limited-stage small cell carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Thirty-eight patients with primary malignant mediastinal tumors of all cell types are the basis for this review. Eleven of these patients had germ cell tumors. Five germ cell tumors were seminomas, two were malignant teratomas, and two were endodermal sinus tumors. Mean survival for all patients with germ cell tumors was 3.3 years. Eight children had surgical excision of mediastinal neuroblastomas, and all but 1 are alive for a mean survival of 6.7 years. Seven patients had lymphoproliferative disorders; 6 of these patients had nodular sclerosing Hodgkin's disease, and 1 had lymphoblastic (thymic) lymphoma. Mean survival was 5.1 years. There were five carcinomas of various cell types and one angiopericytoma. None of the patients with these lesions survived more than 2 years. Four patients had thymoma with an average survival of 3.7 years. Two patients had carcinoid tumors of thymic origin; neither survived more than 1 year. In 1972, we reported 5-year disease-free survival of 26% in a series of patients with primary mediastinal tumors. Our experience since 1970 shows current survival of 47.3% and 5-year disease-free survival of 34.2%. We use combined methods of therapy, including aggressive surgical resection, combination chemotherapy, and often mediastinal irradiation for most types of mediastinal tumors. Primary mediastinal malignancies should be treated aggressively using a multidisciplinary approach, since many of these tumors are curable.