Treatment-related hemophagocytic lymphohistiocytosis due to atezolizumab: a case report and review of the literature.

BACKGROUND: Immune checkpoint inhibitors avoid inhibition of T-cell responses, upregulating antitumor immune response. Moreover, a dysregulation with hyperactive immune response can be caused, some of them underdiagnosed. Hemophagocytic lymphohistiocytosis is a rare and often fatal syndrome of uncontrolled and ineffective hyperinflammatory response that triggers an inflammatory cascade that can lead in many cases to death. CASE PRESENTATION: We report the case of a 67-year-old Caucasian man with stage IV lung adenocarcinoma who developed hemophagocytic lymphohistiocytosis after initiation of atezolizumab, an antagonist of programmed death-ligand 1. Even with early diagnosis and proper treatment, death occurs in approximately half of all cases reported. CONCLUSION: Key markers are needed to better identify patients at risk of developing severe immune-related adverse events. In addition to key markers, a higher degree of suspicion and early intervention are needed to improve outcomes in acquired hemophagocytic lymphohistiocytosis, especially with the increasingly and expanding use of immune activation.

Dose-response relationship in phase i clinical trials: a European Drug Development Network (EDDN) Collaboration Study.

INTRODUCTION: Because a dose-response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors. EXPERIMENTAL DESIGN: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005-2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available. RESULTS: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%-80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003). CONCLUSION: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%-80% of MTD).

The role of capecitabine in locally advanced rectal cancer treatment: an update.

Preoperative infusional 5-fluorouracil (5-FU) and concurrent radiation therapy (RT) followed by total mesorectal surgery is the current standard of care for locally advanced rectal cancer (LAR). When compared with postoperative 5-FU-based chemoradiation, this strategy is associated with significantly lower rates of local relapse, lower toxicity and better compliance. Capecitabine is a rationally designed oral prodrug that is converted into 5-FU by intracellular thymidine phosphorylase. Substitution of infusional 5-FU with capecitabine is an attractive option that provides a more convenient administration schedule and, possibly, increased efficacy. Indeed, incorporation of capecitabine in combined modality neoadjuvant therapy for LAR has been under intense investigation during the last 10 years. Phase I and II clinical trials showed that a regimen consisting of capecitabine 825mg/m(2) twice daily for 7 days/week continuous oral administration in combination with RT is an active and well tolerated regimen, thereby being the preferred concurrent regimen. The definitive demonstration that efficacy of capecitabine/RT is similar to 5-FU/RT has been provided by the NSABP-R-04 and the German Margit trials. One approach to improve outcomes in rectal cancer is to deliver a second RT-sensitizing drug with effective systemic activity. Oxaliplatin and irinotecan are therefore good candidates. However, two phase III trials demonstrated that incorporation of oxaliplatin to capecitabine with RT did not improve early outcomes and, by contrast, increased toxicity. Capecitabine has also been combined with irinotecan. This regimen showed encouraging results in phase I and II clinical trials, which led to an ongoing phase III clinical trial. New strategies with induction chemotherapy with or without chemoradiation prior to surgery are currently under investigation. Whether or not capecitabine has a role in this setting is being investigated in ongoing trials. Incorporation of agents directed towards new targets, such as anti-epidermal growth factor receptor (EGFR) antibodies or antiangiogenic agents, in combination preoperative regimens, is being hampered by results of early trials in which efficacy outcomes with cetuximab were poor and an excessive rate of surgical complications with bevacizumab was observed. The lack of improvements in efficacy with the addition of cetuximab or bevacizumab in the adjuvant treatment of colon cancer led to concerns about further development of these agents in rectal cancer. The role of capecitabine in the postoperative adjuvant setting is the aim of the ongoing Dutch SCRIPT trial. The prediction of response associated with capecitabine has been based on expression of thymidylate synthase and dihydropyrimidine dehydrogenase, as well as on gene expression arrays. All these procedures require further validation and should be considered as investigational. In conclusion, capecitabine can safely and effectively replace intravenous continuous infusion of 5-FU in the preoperative chemoradiation setting for rectal cancer management. The addition of other new antineoplastic agents to a fluoropyrimidine-based regimen remains investigational.

Combining antiangiogenics to overcome resistance: rationale and clinical experience.

Antiangiogenic therapies are now well established in oncology clinical practice; however, despite initial optimism, the results of late-phase trials, especially in the adjuvant setting, have largely proved disappointing. In the context of metastatic disease, resistance to antiangiogenic agents arises through a range of mechanisms, including the development of alternative angiogenic pathways. One of the proposed strategies to overcome this resistance is to combine antiangiogenic agents with different mechanisms of action. Early-phase clinical trials assessing the tolerability and efficacy of different combinations of antiangiogenic drugs, including those that target the VEGF pathway or the angiopoietins, as well as vascular disrupting agents, are increasing in number. An example of this strategy is the combination of sorafenib and bevacizumab, which has elicited major responses in different tumor types, including ovarian carcinoma and glioblastoma. However, overlapping and cumulative toxicities pose a real challenge. This review summarizes the preclinical rationale for this approach and current clinical experience in combining antiangiogenic therapies.

Outcomes of patients with metastatic melanoma treated with molecularly targeted agents in phase I clinical trials.

INTRODUCTION: First-line treatment options utilizing chemotherapy and cytokine-based treatments for patients with metastatic melanoma (MM) are unsatisfactory. We analyzed the clinical outcomes of patients with MM treated in phase I trials of novel agents. We hypothesized that patients included in phase I clinical trials did not have worse outcomes than with the chemotherapy and cytokine-based first-line treatment. METHODS: Data of patients with MM treated at The Drug Development Unit between 2004 and 2010 were collected. The response rate (RR) and time to progression (TTP) for first-line therapy were compared to those of phase I trial therapy. Patients acted as their own controls for statistical analyses. RESULTS: Sixty-five patients were treated in 31 phase I trials. First-line treatment included dacarbazine or temozolomide in 58 (89%) cases and interferon-α in 5 patients (8%) and cisplatin-based treatment in 2 patients (3%). There was no significant difference in either the RR (11 vs. 14%, p = 0.87) or TTP (90 vs. 53 days, p = 0.15) in patients treated with first-line treatment versus phase I treatment, respectively. CONCLUSION: Phase I clinical trials of molecularly targeted agents show clinical activity that is not dissimilar to that of treatment with existing chemotherapy and cytokine-based treatment.

KRAS mutations in primary colorectal cancer tumors and related metastases: a potential role in prediction of lung metastasis.

BACKGROUND: KRAS mutations in colorectal cancer primary tumors predict resistance to anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody therapy in patients with metastatic colorectal cancer, and thus represent a true indicator of EGFR pathway activation status. METHODOLOGY/PRINCIPAL FINDINGS: KRAS mutations were retrospectively studied using polymerase chain reactions and subsequent sequencing of codons 12 and 13 (exon 2) in 110 patients with metastatic colorectal tumors. These studies were performed using tissue samples from both the primary tumor and their related metastases (93 liver, 84%; 17 lung, 16%). All patients received adjuvant 5-Fluorouracil-based polychemotherapy after resection of metastases. None received anti-EGFR therapy. Mutations in KRAS were observed in 37 (34%) of primary tumors and in 40 (36%) of related metastases, yielding a 94% level of concordance (kappa index 0.86). Patients with primary tumors possessing KRAS mutations had a shorter disease-free survival period after metastasis resection (12.0 vs 18.0 months; P = 0.035) than those who did not. A higher percentage of KRAS mutations was detected in primary tumors of patiens with lung metastases than in patients with liver metastases (59% vs 32%; p = 0.054). To further evaluate this finding we analyzed 120 additional patients with unresectable metastatic colorectal cancer who previously had their primary tumors evaluated for KRAS mutational status for clinical purposes. Separately, the analysis of these 120 patients showed a tendency towards a higher degree of KRAS mutations in primary tumors of patients with lung metastases, although it did not reach statistical significance. Taken together the group of 230 patients showed that KRAS was mutated significantly more often in the primary tumors of patients with lung metastases (57% vs 35%; P = 0.006). CONCLUSIONS/SIGNIFICANCE: Our results suggest a role for KRAS mutations in the propensity of primary colorectal tumors to metastasize to the lung.

Meningeal relapse by follicular lymphoma as a single mass.

Follicular lymphoma is the second most common lymphoma throughout the world. Its course is usually indolent. Affection of Central Nervous System by a follicular lymphoma is usually as primary disease, and secondary affection is usually due to high-grade transformation. In this case-report we describe a young patient who presented a follicular lymphoma which secondary affected the central nervous system without high grade transformation.