Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2.

BACKGROUND: The best treatment for patients with advanced non-small cell lung cancer (NSCLC) and a poor performance status is not well defined. In this phase 2 trial, patients were randomized to receive treatment with either single-agent pemetrexed or 1 of 2 combination regimens. METHODS: Patients with newly diagnosed, histologically confirmed nonsquamous NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 were stratified by age and serum albumin level and were randomized (1:1:1) to 1 of 3 regimens: pemetrexed (arm 1), pemetrexed and bevacizumab (arm 2), or pemetrexed, carboplatin, and bevacizumab (arm 3). The response to treatment was assessed every 2 cycles; responding and stable patients continued treatment until progression or unacceptable toxicity. RESULTS: One hundred seventy-two patients were randomized, 162 patients began the study treatment, and 146 patients completed 2 cycles and were evaluated for their response. The median progression-free survival (PFS) was 2.8 months in arm 1, 4.0 months in arm 2, and 4.8 months in arm 3. The overall response rates were 15% in arm 1, 31% in arm 2, and 44% in arm 3. The overall survival was similar in the 3 treatment arms. All 3 regimens were relatively well tolerated. Patients receiving bevacizumab had an increased incidence of hypertension, proteinuria, and bleeding episodes, but most events were mild or moderate. CONCLUSIONS: All 3 regimens were feasible for patients with advanced NSCLC and an ECOG performance status of 2. The addition of bevacizumab to pemetrexed increased the overall response rate. The efficacy of pemetrexed/carboplatin/bevacizumab (median PFS, 4.8 months) approached the prespecified study PFS goal of 5 months. Larger studies will be necessary to define the role of bevacizumab in addition to standard pemetrexed and carboplatin in this population. Cancer 2018;124:1982-91. © 2018 American Cancer Society.

Erlotinib plus either pazopanib or placebo in patients with previously treated advanced non-small cell lung cancer: A randomized, placebo-controlled phase 2 trial with correlated serum proteomic signatures.

BACKGROUND: This study compared the efficacy and safety of treatment with erlotinib plus pazopanib versus erlotinib plus placebo in patients with previously treated advanced non-small cell lung cancer (NSCLC). METHODS: Patients with progressive-stage IV NSCLC after either 1 or 2 previous chemotherapy regimens were randomized to receive erlotinib (150 mg by mouth daily) with either pazopanib (600 mg by mouth daily) or placebo. During treatment, patients were evaluated every 8 weeks until disease progression or unacceptable toxicity. After a study amendment, pretreatment serum specimens for the VeriStrat assay were collected. The predictive value of the VeriStrat score (good vs poor) for progression-free survival (PFS) and overall survival (OS) was assessed in the overall population and in each treatment group. RESULTS: One hundred ninety-two eligible patients were randomized between February 2010 and February 2011. PFS was prolonged with erlotinib plus pazopanib versus erlotinib plus placebo (median, 2.6 vs 1.8 months; hazard ratio, 0.58; P = .001). There was no difference in the OS of the 2 groups. A good VeriStrat score predicted longer PFS and OS in the entire group and predicted longer PFS in the subgroup receiving erlotinib plus pazopanib. The addition of pazopanib increased toxicity, and this was consistent with the known toxicity profile. CONCLUSIONS: The addition of pazopanib to erlotinib in an unselected group of patients with previously treated NSCLC improved PFS and increased treatment-related toxicity, but it had no influence on OS. The efficacy of both regimens was modest. Patients receiving erlotinib plus pazopanib had longer PFS if they had a good VeriStrat score versus a poor one. Cancer 2018;124:2355-64. © 2018 American Cancer Society.

First-Line Carboplatin, Pemetrexed, and Panitumumab in Patients with Advanced Non-Squamous KRAS Wild Type (WT) Non-Small-Cell Lung Cancer (NSCLC).

BACKGROUND: We added panitumumab to standard combination chemotherapy as first-line treatment for patients with advanced KRAS WT non-squamous NSCLC. METHODS: Patients received panitumumab 9 mg/kg IV, pemetrexed 500 mg/m2 IV, and carboplatin AUC = 6 IV every 21 days. After 6 cycles, maintenance therapy with panitumumab and pemetrexed was administered every 21 days until progressive disease or unacceptable toxicity. RESULTS: 29 of 66 patients (44%) had objective responses. The median TTP was 6 months; median overall survival (OS) was 17 months. Panitumumab increased treatment-related toxicity, notably skin rash. CONCLUSIONS: The addition of panitumumab increased toxicity, and had no discernible impact on efficacy.

Paclitaxel/carboplatin with or without belinostat as empiric first-line treatment for patients with carcinoma of unknown primary site: A randomized, phase 2 trial.

BACKGROUND: The objective of this study was to evaluate the efficacy of belinostat, a histone deacetylase inhibitor, when added to paclitaxel/carboplatin in the empiric first-line treatment of patients with carcinoma of unknown primary site (CUP). METHODS: In this randomized phase 2 trial, previously untreated patients with CUP were randomized to receive belinostat plus paclitaxel/carboplatin (group A) or paclitaxel/carboplatin alone (group B) repeated every 21 days. Patients were re-evaluated every 2 cycles, and those without disease progression continued treatment for 6 cycles. Patients in group A then continued receiving single-agent belinostat, whereas patients in group B stopped treatment. The primary endpoint was progression-free survival (PFS): The authors postulated that the addition of belinostat would improve PFS from 5 months (expected with paclitaxel/carboplatin) to 8 months. RESULTS: In total, 89 patients were randomized (group A, n = 44; group B, n = 45), and the demographics and disease characteristics were balanced between the 2 groups. The addition of belinostat to paclitaxel/carboplatin did not improve PFS (group A, 5.4 months [95% confidence interval, 3.0-6.0 months]; group B, 5.3 months [95% confidence interval, 2.8-6.6 months]; P = .85). Overall survival was 12.4 months for group A versus 9.1 months for group B (P = .20). The response rate favored the belinostat group (45% vs 21%; P = .02). Belinostat resulted in a modest increase in treatment toxicity. CONCLUSIONS: The addition of belinostat to paclitaxel/carboplatin did not improve the PFS of patients with CUP who were receiving first-line therapy, although the patients who received belinostat had a higher investigator-assessed response rate. Future trials in CUP should focus on specific subsets, defined either by the predicted tissue of origin or by the identification of targetable molecular abnormalities.

A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors.

Introduction The PI3 kinase (PI3K) pathway is a commonly dysregulated pathway in cancers and is an attractive target for antitumor therapy. BEZ235 is a potent, highly specific and selective dual PI3K/mTOR inhibitor. Methods Patients were enrolled in a 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetics (PK) of BEZ235 when administered twice-daily as an oral sachet. For intrapatient PK comparison, patients were to receive a lead in of the total daily dose in a QD schedule for the first 8 days of the initial 28 day cycle. Patients continued treatment until unacceptable toxicity or disease progression occurred. Results Thirty-three patients received BEZ235. Initial dose levels of 200 and 400 mg BID had no DLTs. At the 600 mg BID dose level with 1200 mg QD lead in dose two DLTs of grade 3 mucositis occurred early in the first treatment cycle, the lead-in QD dosing was eliminated. Fatigue and mucositis limited dosing at 600 mg BID in subsequent patients. The 400 mg BID dose level was re-explored, with DLTs of grade 3 hyperglycemia, dehydration, fatigue, and grade 3 thrombocytopenia. Twelve patients were enrolled at an intermediate dose of 300 mg BID; a grade 3 mucositis DLT was reported in 1 patient, and this dose was declared the MTD. Preliminary PK data demonstrate a consistent increase in PK parameters (Cmax and AUC) with dose level compared to QD dosing. Fifteen patients experienced stable disease as their best response, including 10 (colorectal [4 patients], endometrial [3 patients], carcinoid NOS, pancreas, and melanoma) who had disease control for ≥16 weeks. Conclusions The recommended dose of BEZ235 administered BID as an oral sachet formulation is 300 mg BID. Toxicities seen have been reported for other dual PI3K/mTOR inhibitors.

Molecular diagnosis of the tissue of origin in cancer of unknown primary site: useful in patient management.

OPINION STATEMENT: Cancer of unknown primary site (CUP) is a clinicopathologic syndrome consisting of many types of cancer and accounting for approximately 3 % of all patients with advanced cancers. This syndrome has frustrated patients and physicians for decades, because a primary site or tissue of origin has not been possible to identify clinically, despite the presence of metastatic tumor. Favorable subsets (approximately 20 % of all CUP) with a presumptive occult primary site have been recognized for several decades based on clinical and standard pathologic features; site-specific therapy in these patients improves their survival compared with the majority of other (approximately 80 %) CUP patients. These other patients, most with adenocarcinomas, have been difficult to treat because the tissue of origin was unknown. Broad-spectrum empiric chemotherapy became the standard approach for these patients in the past 30 years. More recently, new diagnostic technology (evolving immunohistochemistry and emergent gene-expression profiling) has enabled us to establish accurately a tissue of origin in most (90 %+) CUP patients. Gene-expression profiling assays complement standard pathology and for the majority of biopsy specimens accurately identify the primary site or tissue of origin; clinical studies have supported the value of site-directed therapy. When the tissue of origin is in doubt after standard pathologic examination, a gene expression assay is frequently diagnostic, and the outcome of many CUP patients is improved with site-specific therapy. The era of empiric therapy has ended in favor of site-specific therapy, based on the precise diagnosis of the tumor type present in each patient.

International consensus on the initial diagnostic workup of cancer of unknown primary.

BACKGROUND: Although the incidence of Cancer of Unknown Primary (CUP) is estimated to be 1-2 % of all cancers worldwide, no international standards for diagnostic workup are yet established. Such an international guideline would facilitate international comparison, provide adequate incidence and survival rates, and ultimately improve care of patients with CUP. METHODS: Participants for a four round modified Delphi study were selected via a CUP literature search in PubMed and an international network of cancer researchers. A total of 90 CUP experts were invited, and 34 experts from 15 countries over four continents completed all Delphi survey rounds. FINDINGS: The Delphi procedure resulted in a multi-layer CUP classification for the diagnostic workup. Initial diagnostic workup should at least consist of history and physical examination, full blood count, analysis of serum markers, a biopsy of the most accessible lesion, a CT scan of chest/abdomen/pelvis, and immunohistochemical testing. Additionally, the expert panel agreed on the need of an ideal diagnostic lead time for CUP patients. There was no full consensus on the place in diagnostic workup of symptom-guided MRI or ultrasound, a PET/CT scan, targeted gene panels, immunohistochemical markers, and whole genome sequencing. INTERPRETATION: Consensus was reached on the contents of the first diagnostic layer of a multi-layer CUP classification. This is a first step towards full consensus on CUP diagnostics, that should also include supplementary and advanced diagnostics.

Phase 1 results from a study of romidepsin in combination with gemcitabine in patients with advanced solid tumors.

Romidepsin is a potent histone deacetylase inhibitor; preclinical studies showed potential synergy with the nucleoside analog gemcitabine. This phase 1 trial was conducted to determine the maximum tolerated dose for two schedules of romidepsin plus gemcitabine in patients with advanced solid tumors in which gemcitabine had previously demonstrated clinical activity. The recommended phase 2 dose was 12 mg/m(2) romidepsin plus 800 mg/m(2) gemcitabine on days 1 and 15 every 28 days. Results suggest additive hematologic toxicities of romidepsin plus gemcitabine, but the level of antitumor activity observed warrants more formal trials of this combination to further assess safety and efficacy.

Cancer of unknown primary site: evolving understanding and management of patients.

Cancer of unknown primary site is a common clinicopathologic syndrome representing a very heterogeneous group of patients with metastatic cancers and clinically undetectable primary tumor sites. The standard treatment for these patients for the last 15 years has been empiric "broad-spectrum" chemotherapy. In recent years, improved immunocytochemistry and the emergence of gene expression profiling have provided the diagnostic tools necessary to accurately define the tissue of origin in the majority of patients. Recent data have confirmed the ability of molecular profiling assays to complement standard pathologic diagnosis, and a large prospective study has documented a survival improvement for patients treated with site-specific therapy directed by the molecular assay diagnoses of their tissues of origin compared to empiric chemotherapy. The clinicopathologic evaluation of patients is now more standardized. The era of empiric chemotherapy administered to all patients is coming to an end, and customized therapies are favored. The management of patients has evolved with the ability to confidently define the tissue of origin. Further delineation of the molecular aberrations in advanced solid tumors, regardless of the primary tumor site, signals a more precise and perhaps more effective therapy for each patient.

Systematic review of the CUP trials characteristics and perspectives for next-generation studies.

BACKGROUND: Research on therapeutic strategies for patients with unknown primary cancer (CUP) has been underwhelming. This paper summarized and evaluated the CUP therapeutic research over the previous five years. Based on this evaluation, recommendations for clinical trial designs are made to improve the impact of CUP research on patients. METHODS: Published and ongoing research were evaluated. PubMed was searched from January 1, 2015, to November 1, 2021. The start date of 2015 was chosen to identify research published after ESMO issued new diagnostic and therapeutic guidelines. The US National Library of Medicine indexed ongoing clinical trials. FINDINGS: Of the 244 CUP studies indexed in PubMed, 11.9% were prospective studies, and 4.9% were clinical trials. The review protocol deemed 65 publications eligible for full-text review. Eleven studies evaluating therapeutic regimens were retained. The two prospective studies and non-randomized trials showed promising outcomes for site-specific treatments. Randomized clinical trials were less promising; however, the trials had recruitment challenges resulting in biased accrual and the inability to keep pace with advancing diagnostics and therapeutics. Most of the 35 ongoing studies were phase II single-arm trials assessing immune checkpoint inhibitors (ICI) or site-specific therapies among CUP patients with suspected favorable prognoses. CONCLUSION: Our evaluation suggests two prospective clinical trial designs that addressed recent study design and recruitment challenges. A visionary approach uses a multi-arm, multistage randomized trial to address rapid advancements in diagnosis and therapy. A pragmatic approach utilizes a single-arm trial with historical controls to overcome comparison group and recruitment challenges.

A phase I trial to determine the safety of imatinib in combination with vatalanib in patients with advanced malignancies.

The role of tyrosine kinase inhibitors (TKIs) in the treatment of advanced malignancies is well established. Imatinib and vatalanib are oral TKIs with different mechanisms of action. This trial sought to establish the safety, tolerability, and maximum tolerated dose (MTD) of the two agents in combination. Secondary objectives included determination of potential pharmacologic interactions among vatalanib and imatinib and observation of antitumor activity. Patients with biopsy-proven advanced refractory solid tumors were enrolled in this single-center dose-escalation trial. Patients initially received imatinib and vatalanib once daily following a 14-day run-in period of daily oral vatalanib only, and were observed for a full 28-day treatment cycle prior to dose escalation. An amendment divided the vatalanib dose into two daily doses and gradually escalated the dose over a 2-3 week period. Patients continued combination therapy until disease progression or intolerable toxicity. Forty-five patients were enrolled between September 2004 and November 2007. As of September 2009, a total of 247 cycles of treatment had been administered (range: 1 -44+, median = 2 ). The MTD was determined to be vatalanib 1250 mg daily and imatinib 400 mg daily. Thirty-five patients (78%) were evaluable for response; 2 patients achieved PR, while 14 patients had SD ( 10 had stable disease ≥ 6 cycles). The combination of vatalanib and imatinib was well tolerated. Twice-daily vatalanib dosing improved tolerability and ease of full-dose administration. These results suggest that vatalanib-containing combinations may be active and tolerable, warranting further study.

A pilot study of adjuvant doxorubicin and cyclophosphamide followed by paclitaxel and sorafenib in women with node-positive or high-risk early-stage breast cancer.

PURPOSE: To examine the safety of sorafenib combined with standard adjuvant treatment in patients with node-positive or otherwise high-risk breast cancer. PATIENTS AND METHODS: Eligibility: mastectomy/breast-conserving surgery; axillary node assessment for stage I/II/IIIA/IIIC (T1-3, N3a only) breast cancer; node-positive/high-risk node-negative (tumor size >2 cm; hormone-receptor negative; grade 2/3; or age <35 years); Eastern Cooperative Oncology Group performance status (ECOG-PS) 0-1; and adequate organ function. TREATMENT: doxorubicin (60 mg/m(2) intravenous) and cyclophosphamide (600 mg/m(2) intravenous; AC) on day 1, every 3 weeks (x 4 cycles), followed by paclitaxel 175 mg/m(2) intravenous on day 1, (every 3 weeks x 4 cycles) or 80 mg/m(2) intravenous (every week/x 12 cycles), combined with sorafenib (400 mg oral twice a week; TS) for 12 months or less. RESULTS: Forty-five patients were enrolled from 5/07-1/08. Baseline characteristics included: median age of 54 years (range, 35-74 years); 93% of patients with ECOG-PS 0; 84% node-positive; 33% hormone-receptor negative. All patients completed AC treatment and were eligible to receive TS; of these, 8 (13%) patients came off study due to physician/patient decision; 21 (47%) patients came off study due to toxicity; 2 (4%) patients completed TS but did not proceed with maintenance sorafenib; and 14 (31%) patients completed TS and entered the maintenance phase of sorafenib treatment. Sorafenib was taken for 6.1 weeks during the paclitaxel phase and 15 weeks during maintenance. Severe toxicities during sorafenib therapy were limited, including neutropenia, anorexia, arthralgia, diarrhea, and dyspnea. After a median follow-up of 21.0 months (range, 18.9-25.9), all patients were alive and without recurrence. CONCLUSION: Sorafenib was generally associated with limited severe toxicity when combined with paclitaxel following AC. However, many patients discontinued sorafenib early due to grade 1/2 toxicity, physician/patient decision, and treatment compliance. Additional studies of sorafenib in breast cancer in the neoadjuvant and triple-negative settings are warranted.

A phase I study of panobinostat in combination with gemcitabine in the treatment of solid tumors.

PURPOSE: To evaluate the safety and tolerability of the combination of orally administered panobinostat with gemcitabine in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received oral panobinostat administered 2 or 3 times weekly (continuous or intermittent dosing in combination with intravenous gemcitabine administered on days 1, 8, and 15 every 28 days or on days 1 and 8 every 21 days). Toxicity assessments were ongoing, and disease assessments were repeated every 2 treatment cycles. RESULTS: A total of 63 cycles of study treatment were administered to 17 patients over 5 different dose levels. Dose-limiting toxicities occurred at all dose levels. In all instances, dose-limiting toxicities were due to grade 4 myelosuppression or myelosuppression warranting dose modifications during the first treatment cycle. Nonhematologic toxicities were mild to moderate in intensity and consisted of anorexia, constipation, diarrhea, fatigue, nausea, vomiting, and rash. One patient with ovarian cancer had an unconfirmed partial response, and 5 patients had stable disease lasting more than 4 cycles. CONCLUSION: Dosing of the combination regimen of panobinostat and gemcitabine is limited by myelosuppression. The recommended doses for further study are intermittent oral panobinostat administered at a dose of 10 mg 3 times weekly for 2 weeks in combination with gemcitabine 800 mg/m2 administered intravenously on days 1 and 8 every 21 days.

Development and Validation of a Novel Nomogram for Individualized Prediction of Survival in Cancer of Unknown Primary.

PURPOSE: Prognostic uncertainty is a major challenge for cancer of unknown primary (CUP). Current models limit a meaningful patient-provider dialogue. We aimed to establish a nomogram for predicting overall survival (OS) in CUP based on robust clinicopathologic prognostic factors. EXPERIMENTAL DESIGN: We evaluated 521 patients with CUP at MD Anderson Cancer Center (MDACC; Houston, TX; 2012-2016). Baseline variables were analyzed using Cox regression and nomogram developed using significant predictors. Predictive accuracy and discriminatory performance were assessed by calibration curves, concordance probability estimate (CPE ± SE), and concordance statistic (C-index). The model was subjected to bootstrapping and multi-institutional external validations using two independent CUP cohorts: V1 [MDACC (2017), N = 103] and V2 (BC Cancer, Vancouver, Canada and Sarah Cannon Cancer Center/Tennessee Oncology, Nashville, TN; N = 302). RESULTS: Baseline characteristics of entire cohort (N = 926) included: median age (63 years), women (51%), Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 (64%), adenocarcinomas (52%), ≥3 sites of metastases (30%), and median follow-up duration and OS of 40.1 and 14.7 months, respectively. Five independent prognostic factors were identified: gender, ECOG PS, histology, number of metastatic sites, and neutrophil-lymphocyte ratio. The resulting model predicted OS with CPE of 0.69 [SE: ± 0.01; C-index: 0.71 (95% confidence interval: 0.68-0.74)] outperforming Culine/Seve prognostic models (CPE: 0.59 ± 0.01). CPE for external validation cohorts V1 and V2 were 0.67 (± 0.02) and 0.70 (± 0.01), respectively. Calibration curves for 1-year OS showed strong agreement between nomogram prediction and actual observations in all cohorts. CONCLUSIONS: Our user-friendly CUP nomogram integrating commonly available baseline factors provides robust personalized prognostication which can aid clinical decision making and selection/stratification for clinical trials.

A phase I study of weekly topotecan in combination with pemetrexed in patients with advanced malignancies.

INTRODUCTION: This phase I study evaluated the safety, tolerability, preliminary antitumor activity, and pharmacokinetic interaction of weekly topotecan (days 1 and 8) in combination with pemetrexed (day 1 only) in patients with advanced solid tumors. METHODS: Patients received topotecan (3.0-4.0 mg/m(2) i.v. days 1 and 8) and pemetrexed (375-500 mg/m(2) i.v. day 1) over 21-day cycles. Patients were accrued across five different dose levels and were observed for safety, tolerability, and preliminary activity. RESULTS: Twenty-six patients received 120 cycles of pemetrexed and topotecan, including five patients who received 8, 8, 10, 12, and 17 cycles without dose reductions, confirming a lack of cumulative myelosuppression. Four patients received topotecan (4.0 mg/m(2) i.v.) and pemetrexed (500 mg/m(2) i.v.), but experienced two dose-limiting toxicities (febrile neutropenia, grade 4 thrombocytopenia). As a result, the topotecan (3.5 mg/m(2) i.v.) and pemetrexed (500 mg/m(2) i.v.) group was expanded to 12 patients. The only grade 3 or 4 nonhematologic toxicity was one episode of grade 3 fatigue; no grade 3 or 4 nausea/vomiting/diarrhea, mucositis, or rash was reported. One non-small cell lung cancer (NSCLC) patient (12 months) and one soft tissue sarcoma patient (6 months) achieved a partial response. CONCLUSIONS: Weekly topotecan plus every-3-week pemetrexed was well tolerated and active. Full doses of topotecan plus pemetrexed caused brief reversible myelosuppression with minimal dose delays/reductions; no grade 3 or 4 nausea/vomiting/diarrhea, mucositis, or rash was reported. All six NSCLC patients at the recommended phase II dose had at least stable disease as a best response, including one partial response lasting 12 months. There was no evidence of an effect of pemetrexed on topotecan pharmacokinetics. Collectively, these data suggest that further phase II exploration of weekly topotecan plus every-3-week pemetrexed for advanced malignancies is indicated.

Molecular profiling in unknown primary cancer: accuracy of tissue of origin prediction.

INTRODUCTION: This retrospective, multi-institutional study evaluated the accuracy of tissue-of-origin prediction by molecular profiling in patients with carcinoma of unknown primary site (CUP). METHODS: Thirty-eight of 501 patients (7.6%) with CUP, seen in 2000-2008, had their latent primary site tumor subsequently identified during life. Twenty-eight of these patients (73.7%) had adequate initial tissue biopsies available for molecular profiling with a reverse transcriptase-polymerase chain reaction (RT-PCR) assay (Cancer Type ID; bioTheranostics, Inc., San Diego, CA). The assay was performed on formalin-fixed paraffin-embedded biopsy specimens in a blinded fashion, and the assay results were compared with clinicopathologic data and the actual latent primary sites. RESULTS: Twenty of the 28 (71.4%) RT-PCR assays were successfully completed (eight biopsies had either insufficient tumor or poorly preserved RNA). Fifteen of the 20 assay predictions (75%) were correct (95% confidence interval, 60%-85%), corresponding to the actual latent primary sites identified after the initial diagnosis of CUP. Primary sites correctly identified included breast (four patients), ovary/primary peritoneal (four patients), non-small cell lung (three patients), colorectal (two patients), gastric (one patient), and melanoma (one patient). Three predictions were incorrect (intestinal, testicular, sarcoma) in patients with gastroesophageal, pancreatic, and non-small cell lung cancer, respectively, and two were unclassifiable in patients with non-small cell lung cancer. Clinicopathologic findings were helpful in suggesting the correct primary site in some patients and appear to complement the molecular assay findings. CONCLUSIONS: These data validate the reliability of this assay in predicting the primary site in CUP patients and may form the basis for more successful site-directed therapy, when used in concert with clinicopathologic data.

Phase II study of capecitabine in combination with thalidomide in patients with metastatic breast cancer.

We examined the toxicity/efficacy of capecitabine with thalidomide, administered over 21-day cycles, in 24 previously treated metastatic breast cancer (MBC) patients. This regimen was poorly tolerated: grade 3/4 neutropenia (13%); grade 3 nausea (22%), vomiting (17%), and diarrhea (13%); and grade 2/3 hand-foot syndrome (38%). In addition, the response rate was lower than expected: partial response (13%), stable disease (17%), and progressive disease at first evaluation (35%). The median time to progression and overall survival were 2.7 and 11.0 months, respectively. These results do not support further investigation of thalidomide for MBC. The role of angiogenesis inhibition in breast cancer treatment should continue to be defined using more efficacious and specific inhibitors.

Single agent vinflunine in the salvage treatment of patients with castration-resistant prostate cancer: a phase II trial of the Sarah Cannon research consortium.

Patients with metastatic prostate cancer resistant to hormones and docetaxel were treated with vinflunine (320 mg/m(2) every 21 days), a new vinca alkaloid with improved preclinical activity. Only 1 of 36 patients (3%) had partial response; the median progression-free survival (PFS) was 2.1 months. Treatment was well tolerated, with myelosuppression as the only frequent toxicity. Vinflunine has a low level of activity in the treatment of refractory metastatic prostate cancer, and should not be further developed for this indication.

Phase II trial of FOLFOX6, bevacizumab, and cetuximab in the first-line treatment of metastatic colorectal cancer.

PURPOSE: To examine FOLFOX/bevacizumab/cetuximab in the first-line treatment of metastatic colorectal cancer (mCRC). DESIGN: Randomized phase II trial aimed at achieving a 60% objective response rate (ORR). Due to frequent cetuximab-related hypersensitivity reactions the trial was amended to a single-arm design. Eligibility: Previously untreated mCRC, measurable disease, Eastern Cooperative Oncology Group performance status (ECOG-PS) 0-1. TREATMENT: Modified FOLFOX6 (oxaliplatin 85 mg/m², leucovorin 350 mg, and 5-fluorouracil 400 mg/m² bolus; 2.4 g/m² infusion, 46 h) day 1; bevacizumab 5 mg/kg on day 1; cetuximab 400 mg/m² on day 1, then 250 mg/m² on days 1 and 8, every 14 days (1 cycle) until progressive disease (PD); restaging occurred every 4 cycles. RESULTS: With emerging negative progression-free survival (PFS) data from a similarly designed trial, this trial closed early. Enrollment (N=31) was from August 2005-June 2008. PATIENT CHARACTERISTICS: Median age was 55 years (29-78); 58% were male; 71% were ECOG-PS 0. Ten cycles (median) were completed (range 2-62). The ORR was 55% (95% confidence interval [CI], 36-73%); 11 patients (35%) had stable disease; 1 patient (3%) had PD; 2 patients (6%) were unevaluable. Median PFS was 9 months (95% CI, 8.3-15.2 months); median overall survival was 25.7 months (95% CI, 15.4-27.6 months). Grade 3/4 toxicities (>1 patient) included neutropenia (25%), rash (23%; grade 2 events, 45%), diarrhea (19%), fatigue (16%), pain (16%), anemia (13%), sensory neuropathy (13%), deep-vein thrombosis (10%), nausea (10%), pulmonary embolism (7%), anorexia (6%), and vomiting (6%). CONCLUSION: In this limited trial, it is unclear whether cetuximab contributed to FOLFOX/bevacizumab efficacy, although the response rate, PFS, and overall survival were high. The regimen was generally well-tolerated, with expected skin effects; thromboembolic rates should be assessed in larger analyses. Cetuximab's role in first-line mCRC treatment is likely best guided by K-RAS testing in future clinical trials.

The role of site-specific therapy for cancers of unknown of primary: A meta-analysis.

Cancers of unknown primary (CUP) are among the most common causes of death due to cancer, are associated with a poor prognosis and have few therapeutic options available. Molecularly-guided site-specific treatments were explored based on the assumption that CUP are similar in their response to treatment of predicted primary tumours. Given the discordant results between these studies, a meta-analysis using a random-effects model and the inverse variance method was performed. MEDLINE and conference abstracts of American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) meetings were searched from inception until November 2019. A trend towards improved OS was noted with site-specific versus empiric treatment for CUP (HR = 0.73; 95% confidence interval (CI) 0.52-1.02). There was significant heterogeneity across the four studies (I [2] = 79%; p = 0.002) but no significant difference was noted between the treatment effect in the two subgroups (randomised vs. non-randomised; p = 0.07). The test for overall effect for progression free survival, which had only been reported for the two randomised studies, was not statistically significant (HR = 0.93; 95% CI 0.74-1.17), with little heterogeneity between studies (I [2] = 0%; p = 0.77). The results of this meta-analysis highlight the significant heterogeneity between the prospective studies comparing molecularly tailored to empiric therapy for CUP and the need for other randomised studies including only primary tumors with available effective therapies.