Bassam I. Mattar

A placebo-controlled, double-blind trial of infliximab for cancer-associated weight loss in elderly and/or poor performance non-small cell lung cancer patients (N01C9)

PURPOSE This study tested whether infliximab, a chimeric IgG1kappa monoclonal antibody that blocks tumor necrosis factor (TNF) alpha, improves/stabilizes weight loss in elderly and/or poor performance status patients with metastatic non-small cell lung cancer (NSCLC). METHODS This double-blind trial randomly assigned patients to infliximab/docetaxel (n=32) versus placebo/docetaxel (n=29). The primary endpoint was > or = 10% weight gain. RESULTS Groups were balanced with respect to age, number of prior chemotherapy regimens, baseline weight loss, and performance status. No patient gained > or = 10% baseline weight, and early evidence of the lack of efficacy prompted early trial closure. Appetite improvement was negligible in both arms. However, infliximab-/docetaxel-treated patients developed greater fatigue and worse global quality of life scores. Other outcomes, such as tumor response rate (<10% in both groups) and overall survival, were not statistically different between groups. There were no statistically significant differences in adverse events, although one death was attributed to infliximab. Genotyping for the TNF alpha -238 and -308 polymorphisms revealed no clinical significance of these genotypes, as relevant to the loss of weight or appetite. CONCLUSIONS This trial closed early because infliximab did not prevent or palliate cancer-associated weight loss. Infliximab was associated with increased fatigue and inferior global quality of life.

A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma

There is increasing evidence that paclitaxel and carboplatin are clinically active in the treatment of metastatic melanoma (MM). ABI‐007 is an albumin‐bound formulation of paclitaxel that has demonstrated single‐agent activity against metastatic melanoma.

The relationship between numbness, tingling and shooting/burning pain in patients with chemotherapy-induced peripheral neuropathy (CIPN) as measured by the EORTC QLQ-CIPN20 instrument, N06CA

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is characterized by numbness, tingling, and shooting/burning pain. This analysis was performed to describe the relationship between numbness, tingling, and shooting/burning pain in patients with CIPN, as reported using the EORTC QLQ-CIPN20 (CIPN20).MethodsBaseline CIPN20 data were provided for all patients on a prospective trial designed to treat patients with bothersome CIPN. Baseline frequencies for the items on the CIPN20 are primarily described by descriptive statistics and histograms, with correlational analyses between individual items.ResultsA majority of the 199 patients accrued to this study reported “quite a bit” to “very much” numbness (57%) or tingling (63%) in the hands compared to “a little” or “not at all” (numbness (43%), tingling (38%)). Fewer patients reported “quite a bit” to “very much” shooting/burning pain in the hands (18%). Numbness and tingling in the hands were highly correlated (r = 0.69), while neither were highly correlated with shooting/burning pain. Similar results were observed in the feet. More severe ratings for tingling and shooting/burning pain were ascribed to the lower extremities, as opposed to the upper extremities.ConclusionsIn patients with CIPN, severe sensory neuropathy symptoms (numbness, tingling) commonly exist without severe neuropathic pain symptoms (shooting/burning pain), while the reverse is not common. Symptoms in the feet should be evaluated distinctly from those in the hands as the experience of symptoms is not identical, for individual patients, in upper versus lower extremities.

Does Sunscreen Prevent Epidermal Growth Factor Receptor (EGFR) Inhibitor–Induced Rash? Results of a Placebo-Controlled Trial from the North Central Cancer Treatment Group (N05C4)

PURPOSE Rash occurs in >50% of patients prescribed epidermal growth factor receptor (EGFR) inhibitors. This study was undertaken to determine whether sunscreen prevents or mitigates these rashes. METHODS This placebo-controlled, double-blinded trial enrolled rash-free patients starting an EGFR inhibitor. Patients were randomly assigned to sunscreen with a sun protection factor of 60 applied twice a day for 28 days versus placebo. They were then monitored for rash and quality of life (Skindex-16) during the 4-week intervention and for an additional 4 weeks. RESULTS Fifty-four patients received sunscreen, and 56 received placebo; the arms were balanced at baseline. During the 4-week intervention, physician-reported rash occurred in 38 (78%) and 39 (80%) sunscreen-treated and placebo-exposed patients, respectively (p = 1.00); no significant differences in rash rates emerged over the additional 4 weeks. There were no significant differences in rash severity, and patient-reported outcomes of rash yielded similar conclusions. Adjustment for sun intensity by geographical zone, season, and use of photosensitivity medications did not yield a significant difference in rash across study arms (p = .20). Quality of life scores declined but remained comparable between arms. CONCLUSIONS Sunscreen, as prescribed in this trial, did not prevent or attenuate EGFR inhibitor-induced rash.

Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy

BACKGROUND Postmenopausal women with osteoporosis/osteopenia are at increased risk of fracture. Aromatase inhibitors further increase bone loss in these patients. This study evaluates whether zoledronic acid prevents the bone loss expected when these patients initiate letrozole. PATIENTS AND METHODS Postmenopausal women with estrogen and/or progesterone receptor-positive breast cancer and a bone mineral density (BMD) T-score <-2.0 were given letrozole 2.5mg/vitamin D 400 international units daily, calcium 500mg twice daily, and 4mg zoledronic acid every 6 months. The BMD was assessed at baseline and 1 year. The primary endpoint was the mean change in lumbar spine (LS) BMD at 1 year. RESULTS Forty-six patients completed 1 year of treatment. LS BMD increased by 2.66% (p=0.01), femoral neck (FN) by 4.81% (p=0.01), and any measured endpoint by 4.55% (p=0.0052). CONCLUSIONS Zoledronic acid prevents bone loss in postmenopausal women with osteoporosis/osteopenia starting letrozole and is associated with improvements in BMD.

The use of Valeriana officinalis (Valerian) in improving sleep in patients who are undergoing treatment for cancer: a phase III randomized, placebo-controlled, double-blind study (NCCTG Trial, N01C5).

Sleep disorders are a substantial problem for cancer survivors, with prevalence estimates ranging from 23% to 61%. Although numerous prescription hypnotics are available, few are approved for long-term use or have demonstrated benefit in this circumstance. Hypnotics may have unwanted side effects and are costly, and cancer survivors often wish to avoid prescription drugs. New options with limited side effects are needed. The purpose of this trial was to evaluate the efficacy of a Valerian officinalis supplement for sleep in people with cancer who were undergoing cancer treatment. Participants were randomized to receive 450 mg of valerian-or placebo orally 1 hour before bedtime for 8 weeks. The primary end point was area under the curve (AUC) of the overall Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes included the Functional Outcomes of Sleep Questionnaire, the Brief Fatigue Inventory (BFI), and the Profile of Mood States (POMS). Toxicity was evaluated with both self-reported numeric analogue scale questions and the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Questionnaires were completed at baseline and at 4 and 8 weeks. A total of 227 patients were randomized into this study between March 19, 2004, and March 9, 2007, with 119 being evaluable for the primary end point. The AUC over the 8 weeks for valerian was 51.4 (SD = 16), while that for placebo was 49.7 (SD = 15), with a P value of 0.6957. A supplemental, exploratory analysis revealed that several fatigue end points, as measured by the BFI and POMS, were significantly better for those taking valerian over placebo. Participants also reported less trouble with sleep and less drowsiness on valerian than placebo. There were no significant differences in toxicities as measured by self-report or the CTCAE except for mild alkaline phosphatase increases, which were slightly more common in the placebo group. This study failed to provide data to support the hypothesis that valerian, 450 mg, at bedtime could improve sleep as measured by the PSQI. However, exploratory analyses revealed improvement in some secondary outcomes, such as fatigue. Further research with valerian exploring physiologic effects in oncology symptom management may be warranted.

A phase I/II study of bortezomib in combination with paclitaxel, carboplatin, and concurrent thoracic radiation therapy for non-small-cell lung cancer: North Central Cancer Treatment Group (NCCTG)-N0321.

Introduction: Despite the advances in radiation techniques and chemotherapy, survival with current platinum-based chemotherapy and concomitant thoracic radiation remains dismal. Bortezomib, a proteasome inhibitor, modulates apoptosis and cell cycle through disruption of protein degradation. The combination of bortezomib and carboplatin/paclitaxel and concurrent radiation in unresectable stage III non–small-cell lung cancer was evaluated in this phase I/II study. Methods: Patients with histologic or cytologic confirmed stage III nonmetastatic non–small-cell lung cancer who were candidates for radiation therapy were eligible. In the phase I portion, patients received escalating doses of bortezomib, paclitaxel, and carboplatin concomitantly with thoracic radiation (60 Gy/30 daily fractions) using a modified 3 + 3 design. The primary endpoint for the phase II portion was the 12-month survival rate (12MS). A one-stage design with an interim analysis yielded 81% power to detect a true 12MS of 75%, with a 0.09 level of significance if the true 12MS was 60% using a sample size of 60 patients. Secondary endpoints consisted of adverse events (AEs), overall survival, progression-free survival, and the confirmed response rate. Results: Thirty-one patients enrolled during the phase I portion of the trial, of which four cancelled before receiving treatment, leaving 27 evaluable patients. Of these 27 patients, two dose-limiting toxicities were observed, one (grade 3 pneumonitis) at dose level 1 (bortezomib at 0.5 mg/m2, paclitaxel at 150 mg/m2, and carboplatin at area under the curve of 5) and one (grade 4 neutropenia lasting ≥8 days) at dose level 6 (bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2, and carboplatin at area under the curve of 6). During the phase I portion, the most common grade 3 of 4 AEs were leukopenia (44%), neutropenia (37%), dyspnea (22%), and dysphagia (11%). Dose level 6 was declared to be the recommended phase II dose (RP2D) and the phase II portion of the study opened. After the first 26 evaluable patients were enrolled to the RP2D, a per protocol interim analysis occurred. Of these 26 patients, 23 (88%) survived at least 6 months (95% confidence interval [CI], 70–98%), which was enough to continue to full accrual per study design. However, due to slow accrual, the study was stopped after 27 evaluable patients were enrolled (6—phase I RP2D; 21—phase II). Of these 27 patients, the 12MS was 73% (95% CI, 58–92%), the median overall survival was 25.0 months (95% CI, 15.6–35.8), and the median progression-free survival was 8.4 months (95% CI, 4.1–10.5). The confirmed response rate was 26% (seven of 27; 95% CI, 11–46%), consisting of four partial responses and three complete responses. Grade 3+ and grade 4+ AEs occurred in 82% and 56% of patients, respectively. One patient experienced grade 5 pneumonitis that was possibly related to the treatment. Grade 3 and 4 hematological toxicities were observed in 82% and 56% patients, respectively. Conclusions: The addition of bortezomib to concurrent carboplatin/paclitaxel and radiation seemed to be feasible, although associated with increased hematological toxicities. A favorable median overall survival of 25 months suggests a potential benefit for this regimen.

Unexplained hemopericardium as a presenting feature of primary cardiac angiosarcoma: A case report and a review of the diagnostic dilemma

This report describes a patient diagnosed with a cardiac angiosarcoma. The patient presented with cardiac tamponade. A pericardiocentesis revealed a bloody effusion, but cytology was nondiagnostic and a chest computed tomography showed only mediastinal lymphadenopathy. His pericardial effusion recurred 3 weeks later, at which time he was found to have a large right atrial mass which proved to be a cardiac angiosarcoma. This case report underscores the difficulties encountered in the diagnosis of cardiac angiosarcoma.

A Phase II trial of docetaxel and carboplatin administered every 2 weeks as preoperative therapy for stage II or III breast cancer: NCCTG study N0338.

Objective:We conducted a multicenter phase II trial to assess the efficacy and toxicity of docetaxel and carboplatin combination as neoadjuvant therapy for stage II or III breast cancer (BC). Methods:Patients received 75 mg/m2 of docetaxel and AUC 6 of carboplatin on day 1 followed by pegfilgrastim on day 2, every 14 days for 4 cycles, followed by definitive breast surgery. The primary endpoint was the proportion of patients achieving pathologic complete remission (pCR), defined as disappearance of all invasive and in situ tumors in the breast and axilla after chemotherapy. Results:A total of 57 women (median age, 53 y) were enrolled. Thirty-eight (67%) had ER+, 31 (54%) PR+, and 6 (11%) HER2+ disease; 9 had triple negative BC (TNBC). Forty-three (75%; 95% confidence interval, 62%-86%) of 57 eligible patients had clinical response (15 clinical complete response, 28 clinical partial response). Nine (16%; 90% confidence interval, 10%-28%) patients achieved pCR. Four of 9 (44%) patients with TNBC achieved pCR. Thrombocytopenia (5%) was the only grade 4 adverse event. The most common grade 3 adverse events were thrombocytopenia (19%), fatigue (12%), and anemia (9%). Conclusions:Four cycles of 2-weekly Docetaxel and Carboplatin are feasible with acceptable toxicity and a pCR rate of 16%. This regimen can be considered for neoadjuvant therapy of BC, particularly for patients not eligible for anthracycline therapy. A high pCR rate of 44% noted in a subset of patients with TNBC is encouraging and needs to be validated in large prospective trials.

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

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