Peripheral monocytes and neutrophils predict response to immune checkpoint inhibitors in patients with metastatic non-small cell lung cancer.

We carried out a retrospective cohort study on patients with metastatic non-small cell lung cancer (mNSCLC) to identify the peripheral blood count parameters associated with response to immune checkpoint inhibitors (ICIs). There were 17 males and 15 females. Their median age was 64.5 years (range 20-84). History of smoking was present in 25/32 (78%) patients. Twelve patients received pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial responses. There was no difference in the distribution of sex, age, and smoking status between responders and non-responders. The median time to response (TTR) was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of responders, those with AMCs > 700/mm3 had a significantly shorter median TTR than those with AMCs ≤ 700/mm3 (8 weeks vs 12 weeks; p = 0.048). Although baseline absolute neutrophil counts (ANCs) did not have any prognostic value, ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs ≤ 4200/mm3 after first dose were more likely to respond than those with ANCs > 4200/mm3 (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC before and during therapy may, therefore, provide an easy method to identify those mNSCLC patients most likely to benefit from ICI therapy.

Farnesyl transferase expression determines clinical response to the docetaxel-lonafarnib combination in patients with advanced malignancies.

BACKGROUND: Lonafarnib (LNF) is a protein farnesyl transferase (FTase) inhibitor that has shown synergistic activity with taxanes in preclinical models and early stage clinical trials. Preclinical findings suggested tubulin acetylation and FTase expression levels may be important determinants of drug sensitivity that would help identify patient populations more likely to benefit from this regimen. This pilot study evaluated the biological effects of LNF and docetaxel (DTX) combination therapy in refractory solid tumors by comparing pretreatment and post-treatment tumor biopsies. METHODS: Patients with histologically confirmed locally advanced or metastatic solid malignancies refractory to standard therapies or with no effective therapies available were eligible. Patients were randomized to 1 of 4 dosing cohorts: 1) 30 mg/m², 100 mg; 2) 36 mg/m², 100 mg; 3) 30 mg/m², 150 mg; or 4) 36 mg/m², 150 mg of DTX intravenously weekly, LNF orally twice daily, respectively. RESULTS: Of the 38 patients enrolled, 36 were treated, and 29 were evaluable for toxicity and response assessment. The combination of LNF and DTX was tolerated in all cohorts with the exception of a 28% incidence of grade 3/4 diarrhea, which was manageable with aggressive antidiarrheal regimens. Seven patients derived clinically meaningful benefit from this combination treatment; these patients had significantly lower basal FTase-beta mRNA expression levels than the mean study population level (P < .05). Correlation of clinical benefit with tubulin acetylation content as well as basal acetyl-tubulin content were evaluated. However, no significant correlation was found. CONCLUSIONS: Despite the small number of patients, these findings support our preclinical mechanistic studies and warrant further clinical investigations using FTase-beta mRNA expression as a potential predictive biomarker to select for an enriched patient population to study the effects of taxane and FTase inhibitor combination therapies.

Phase I combination study of trabectedin and doxorubicin in patients with soft-tissue sarcoma.

PURPOSE: To determine the dose of trabectedin plus doxorubicin with granulocyte colony-stimulating factor support associated with manageable neutropenia and acceptable dose-limiting toxicities (DLT) in patients with recurrent or persistent soft-tissue sarcoma. METHODS: In this phase I, open-label, multicenter trial, patients previously treated with 0-1 prior chemotherapy regimens excluding doxorubicin, an Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function received a 10- to 15-min i.v. infusion of doxorubicin 60 mg/m(2) immediately followed by a 3-h i.v. infusion of trabectedin 0.9 to 1.3 mg/m(2) on day 1 of a 3-week cycle. Because four of the first six patients experienced DLT-defining neutropenia during cycle 1, all subsequent patients received primary prophylactic granulocyte colony-stimulating factor. The maximum tolerated dose was the highest dose level with six or more patients in which less than one-third of the patients experienced severe neutropenia or DLT. Blood was collected during cycle 1 for pharmacokinetic analyses. Adverse events, tumor response, and survival were assessed. RESULTS: Patients (N = 41) received a median of six cycles of treatment (range, 2-13). The maximum tolerated dose was trabectedin 1.1 mg/m(2) and doxorubicin 60 mg/m(2). Common grade 3/4 treatment-emergent adverse events were neutropenia (71%), alanine aminotransferase increase (46%), and thrombocytopenia (37%). Overall, 5 (12%) patients achieved a partial response and 34 (83%) maintained stable disease. Median progression-free survival was 9.2 months. Doxorubicin and trabectedin pharmacokinetics were not altered substantially with concomitant administration. CONCLUSION: The combination of doxorubicin 60 mg/m(2) followed by trabectedin 1.1 mg/m(2) every 21 days is safe and active in patients with soft-tissue sarcoma.

Paraneoplastic syndromes in lung cancer and their management.

Paraneoplastic syndromes are most frequently associated with lung cancer. This review considers a variety of paraneoplastic syndromes associated with lung cancer and discusses their pathophysiology, clinical features and management options.

Cardiac Immune-Related Adverse Events in Immune Checkpoint Inhibition Therapy.

Immune checkpoint inhibitors present clinicians with both an exciting step forward in cancer treatment and the unknown possibilities of an unshackled immune system. The latter phenomena, known as immune-related adverse events (irAEs), are of particular interest because they may affect any organ system with autoimmune-like pathologies, such as hepatitis and colitis. Within the cardiovascular system, irAEs associated with immune checkpoint blockade exist as a broad clinical spectrum, with autoimmune myocarditis being the best-characterized entity at this time. In general, irAEs are often reversible with immunosuppression. However, irAEs that affect the cardiovascular system pose the possibility of a rapid and fatal clinical deterioration. The mortality attributed to immune checkpoint blockade-associated autoimmune myocarditis, as reported in the WHO database, exists from 36% to 67%, dependent on the therapeutic regimen. Yet, despite the potential severity such events pose, guidelines dictating the identification of immune checkpoint inhibition irAEs do not exist, providing a stark contrast with other anticancer medications with known cardiovascular effects. The lack of guidelines may be related to the perceived rarity of these events, yet a recent study of immune checkpoint inhibition-associated autoimmune myocarditis suggests that this clinical entity may be more prevalent than initially believed. Until more standardized information regarding these potentially serious events is available, the study of documented cases is instructive to improve identification of such phenomena, as well as the outcomes for patients who develop them.

Role of bevacizumab in the management of the patient with malignant pleural effusion: more questions than answers.

INTRODUCTION: Malignant pleural effusion (MPE) is a feature of metastatic cancer associated with significant morbidity and cost. The typical management of MPE is systemic chemotherapy and mechanical intervention. Vascular endothelial growth factor (VEGF), an inducer of vascular permeability, has been shown to mediate fluid formation. Therefore, bevacizumab, an inhibitor of VEGF, offers theoretical promise for abolishing fluid formation in MPE. Areas covered: This review begins with a summary of VEGF physiology and evidence of its role in MPE pathogenesis. This is followed by an overview of bevacizumab and major trials that put it on the map of non-small cell lung cancer (NSCLC). The majority of the article is devoted to a review of the current evidence base for the use of bevacizumab for MPE control in metastatic pleural malignancy. The review concludes with considerations of patient selection and toxicity. Expert commentary: Evidence in support of bevacizumab administration for MPE management remains flawed. Small studies suggest efficacy of both intravenous and intrapleural routes, but their design raises bias concerns. Bevacizumab appears to be safe in properly selected cases. The future of MPE management may de-emphasize VEGF inhibition in favor of precise molecular therapeutics that could address the root cause of tumorigenesis.

Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors.

We carried out a retrospective cohort study on patients with advanced cancer treated with immune checkpoint inhibitors (ICIs) to determine whether antibiotics affect treatment outcome. Sixty consecutive patients were identified, and 17 received systemic antibiotics within 2 weeks before and/or after first dose of ICI. Antibiotic-treated patients were significantly younger (p = 0.0008) and less likely to receive nivolumab (p = 0.08) or had neutrophil:lymphocyte ratio < 5 (p = 0.08). They had a lower response rate (RR) (29.4% vs 62.8%) (p = 0.024) and more inferior progression-free survival (PFS) (p = 0.048). Narrow-spectrum antibiotics did not affect the RR. However, broad-spectrum antibiotics were associated with a lower RR (25% vs 61%) (p = 0.02) and a trend towards longer time to response (median: 14 weeks vs 12 weeks) (p = 0.1). They also had shorter PFS (p = 0.012). Multivariate analysis identified antibiotics as the only factor affecting RR (p = 0.0038) and PFS (p = 0.01). We next examined the 21 patients whose PFS lasted for 12 weeks or more. Five of the 21 patients received broad-spectrum antibiotics within 10 weeks before disease progression. There was a trend towards shorter PFS in these patients (p = 0.1). Finally, antibiotic-treated patients experienced shorter overall survival (OS) (median: 24 months vs 89 months) (p = 0.003). Multivariate analysis found age (p = 0.035) and antibiotics (p = 0.038) to be the only factors affecting OS. Our results point to a detrimental effect of broad-spectrum antibiotics on treatment outcome to ICI therapy.

Taxanes in the treatment of non-small cell lung cancer.

Paclitaxel and docetaxel, drugs that bind tightly to beta-tubulin and disrupt microtubule dynamics, are widely used in the treatment of non-small cell lung cancer (NSCLC), the most common cause of cancer death in men and women living in the US. These well tolerated drugs, alone or in combination with another cytotoxic agent, have been shown to increase the survival of patients with metastatic disease or malignant effusions. Both paclitaxel and docetaxel can be combined with concurrent chest irradiation for patients with locally advanced NSCLC. The combination of carboplatin and paclitaxel, when given postoperatively to patients with stage IB NSCLC, improved survival compared with surgery alone, with little toxicity. Taxane combinations are undergoing study as adjuvant therapy for patients with other stages of operable disease. Except for a recent trial with bevacizumab, efforts to improve the efficacy of taxane/platinum combinations in patients with advanced disease by adding a third 'targeted' drug have thus far been unsuccessful.

Hypoglycemia in the setting of advanced gastrointestinal stromal tumor.

We report a rare case of symptomatic hypoglycemia in a patient with intra-abdominal recurrence of a previously resected gastrointestinal stromal tumor (GIST). The patient is a 65-year-old woman who underwent resection of a large abdominal mass arising from the stomach, histologically diagnosed as a high-grade leiomyosarcoma. She was lost to follow up. Five years later, the mass recurred; core biopsy demonstrated a CD 117-positive, spindle-cell tumor, consistent with a GIST. She was placed on Gleevec, as there was evidence of multifocal disease, but imaging revealed only mild improvement. Subsequently, her clinical status deteriorated, and she was hospitalized for dehydration, vomiting, and mental status changes. Her blood glucose on admission was 22 mg/dL, and a dextrose infusion (50%) was necessary to maintain adequate blood glucose levels. Measurements of insulin, proinsulin, c-peptide, beta-hydroxybutyrate, and thyroid-stimulating hormone were normal, as were cosyntropin stimulation and glucagon response tests. Suspicions arose for tumor-secreted insulin-like factor. She underwent resection of the dominant 44-cm recurrence, with immediate rebound hyperglycemia, followed by complete normalization of her blood glucose levels. She was discharged on postoperative Day 5 without symptoms or insulin, and is alive with disease at 20 months. Paraneoplastic syndromes occur in only 15 per cent of patients with known malignancies (e.g., lung cancer and metastatic carcinoid), and are rarely reported in the setting of GIST. Hypoglycemia is most often observed in presence of insulinoma and only isolated case reports in GIST patients exist. Overexpression of insulin-like growth factor II is thought to be the mechanism of action. Supportive management and palliative resection or debulking is recommended when possible.

Update on the management of connective tissue malignancies.

Approximately 11,000 new cases of connective tissue malignancies are anticipated in 2004. These diseases can be divided into soft-tissue sarcomas, sarcomas of bone, and gastrointestinal stromal tumors. Optimal management of these diseases requires a multidisciplinary team with expertise in surgery, pathology, radiotherapy, and chemotherapy. Over half of patients with stage III soft tissue and bone sarcomas are cured, as are some patients with metastatic disease. Imatinib mesylate has been an important advance in the treatment of gastrointestinal stromal tumors.

Chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck.

Recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN) are difficult problems and likely to become more challenging as concurrent chemotherapy and radiation are more widely used. Randomized studies reported in 1992 established the combination of cisplatin and infusional 5-fluorouracil (5-FU) as the reference regimen for chemotherapy-naive, good-performance status patients. Subsequently, a randomized study of 194 patients comparing cisplatin and 5-FU to cisplatin and paclitaxel found better tolerance, better pain relief, and improved quality of life with the newer regimen, but no survival differences (medians of 9 months) were detected. Phase II studies of a platinum/taxane combination with a third drug have reported response rates of greater than 50%, including 15% complete responses. A number of non-platinum-containing regimens are active in pretreated patients. Gefitinib has shown median survival times comparable to those achieved with cisplatin and paclitaxel, and appears especially promising for patients who recur after cytotoxic chemotherapy. Newer antifolates, agents that target or restore deficient p53, and other signal transduction inhibitors are under study.

Recent advances of novel targeted therapy in non-small cell lung cancer.

Lung cancer is the leading cause of cancer deaths world-wide. Recent advances in cancer biology have led to the identification of new targets in neoplastic cells and the development of novel targeted therapies. At this time, two targeted agents are approved by the FDA in advanced non-small cell lung cancer (NSCLC): the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib, and the anitangiogenic bevacizumab. A third agent, cetuximab, which was recently shown to enhance survival when used with cisplatin and vinorelbine as first line therapy for advanced NSCLC, will likely be approved by regulatory agencies. With more than 500 molecularly targeted agents under development, the prospects of identifying novel therapies that benefit individual patients with lung cancer are bright.

Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected].

PURPOSE: Gemcitabine as a single agent and the combination of gemcitabine and docetaxel have activity in patients with metastatic soft tissue sarcoma. To determine if the addition of docetaxel to gemcitabine improved clinical outcome of patients with metastatic soft tissue sarcomas, we compared a fixed dose rate infusion of gemcitabine versus a lower dose of gemcitabine with docetaxel. PATIENTS AND METHODS: In this open-label phase II clinical trial, the primary end point was tumor response, defined as complete or partial response or stable disease lasting at least 24 weeks. A Bayesian adaptive randomization procedure was used to produce an imbalance in the randomization in favor of the superior treatment, accounting for treatment-subgroup interactions. RESULTS: One hundred nineteen of 122 randomly assigned patients had assessable outcomes. The adaptive randomization assigned 73 patients (60%) to gemcitabine-docetaxel and 49 patients (40%) to gemcitabine alone, indicating gemcitabine-docetaxel was superior. The objective Response Evaluation Criteria in Solid Tumors response rates were 16% (gemcitabine-docetaxel) and 8% (gemcitabine). Given the data, the posterior probabilities that gemcitabine-docetaxel was superior for progression-free and overall survival were 0.98 and 0.97, respectively. Median progression-free survival was 6.2 months for gemcitabine-docetaxel and 3.0 months for gemcitabine alone; median overall survival was 17.9 months for gemcitabine-docetaxel and 11.5 months for gemcitabine. The posterior probability that patients receiving gemcitabine-docetaxel had a shorter time to discontinuation for toxicity compared with gemcitabine alone was .999. CONCLUSION: Gemcitabine-docetaxel yielded superior progression-free and overall survival to gemcitabine alone, but with increased toxicity. Adaptive randomization is an effective method to reduce the number of patients receiving inferior therapy.

Randomized phase II study of bortezomib alone and bortezomib in combination with docetaxel in previously treated advanced non-small-cell lung cancer.

PURPOSE: To evaluate the efficacy and toxicity of bortezomib +/- docetaxel as second-line therapy in patients with relapsed or refractory advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomly assigned to bortezomib 1.5 mg/m2 (arm A) or bortezomib 1.3 mg/m2 plus docetaxel 75 mg/m2 (arm B). A treatment cycle of 21 days comprised four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, docetaxel on day 1. Patients could receive unlimited cycles. The primary end point was response rate. RESULTS: A total of 155 patients were treated, 75 in arm A and 80 in arm B. Baseline characteristics were comparable. Investigator-assessed response rates were 8% in arm A and 9% in arm B. Disease control rates were 29% in arm A and 54% in arm B. Median time to progression was 1.5 months in arm A and 4.0 months in arm B. One-year survival was 39% and 33%, and median survival was 7.4 and 7.8 months in arms A and B, respectively. Adverse effect profiles were as expected in both arms, with no significant additivity. The most common grade > or = 3 adverse events were neutropenia, fatigue, and dyspnea (4% and 53%, 19% and 26%, and 17% and 14% of patients in arms A and B, respectively). CONCLUSION: Bortezomib has modest single-agent activity in patients with relapsed or refractory advanced NSCLC using this schedule, with minor enhancement in combination with docetaxel. Additional investigation of bortezomib in NSCLC is warranted in combination with other drugs known to be active, or using different schedules.

Selective serotonin reuptake inhibitor-induced rhabdomyolysis associated with irinotecan.

A 74-year-old man was admitted with rhabdomyolysis after undergoing initial treatment for gastrointestinal cancer with irinotecan. The syndrome partially resolved after the discontinuation of all of his usual medications, including his chronic selective serotonin reuptake inhibitor (SSRI). The rhabdomyolysis was exacerbated upon reinitiation of the SSRI and disappeared when the SSRI was discontinued. The combination of irinotecan and SSRI resulted in potentially lethal rhabdomyolysis.