Prednisone, etoposide, procarbazine, and cyclophosphamide (PEP-C) oral combination chemotherapy regimen for recurring/refractory lymphoma: low-dose metronomic, multidrug therapy

BACKGROUND: Many patients with recurrent lymphoma are unable to tolerate intensive therapies, or have disease that is refractory. Metronomic chemotherapy offers a novel, potentially less toxic yet effective treatment strategy. METHODS: An analysis was performed on 75 lymphoma patients who were treated with the PEP-C regimen at a single institution. The program consisted of oral prednisone 20 mg after breakfast, cyclophosphamide 50 mg after lunch, etoposide 50 mg after dinner, and procarbazine 50 mg at bedtime with an oral antiemetic. All medications were administered daily until the white blood cell count fell to less than 3.0 x 10(9)/L, whereupon treatment was withheld until recovery from the nadir. Therapy was then reinstituted on a daily, alternate day, or fractionated weekly basis (eg, 5 of 7 days), depending on patient tolerance. Doses given per day were held constant. RESULTS: Eighty percent of patients had previously received 2 or more treatments. Overall, 69% achieved an objective response after PEP-C treatment, with 36% complete responses and 33% partial responses. Subjects with indolent histologies had superior overall responses, complete responses, and time on therapy relative to those with aggressive histologies. The regimen was generally well tolerated. CONCLUSIONS: Metronomic therapy with low-dose oral agents administered in combination for continuous, prolonged periods with minimal drug-free intervals represents a novel, active, easily tolerated approach to management of patients with recurrent lymphoma, particularly those with indolent histologies.     

Response of brain tumors to chemotherapy,evaluated in a clinically relevant xenograft model

Summary Chemotherapy for brain tumors remains unsatisfactory. Despite increasing participation in clinical trials, there is a clear need for pre-clinical models. Heterotransplantation of surgical specimens directly into the anterior chamber of the nude mouse eye has been demonstrated to produce evaluable xenografts. Drug access in this model is considered to mimic the blood-brain barrier.Five clinical specimens in 3 children with primitive neuroectodermal tumor/medulloblastoma were the sources of 293 intraocular xenografts (5 cohorts by source). Each tumor-bearing mouse received 1 of 5 drugs or normal saline, by intraperitoneal injection, weekly for 5 weeks. Response was monitored for up to 22 weeks, using a staging system which estimates the proportion of the anterior chamber filled by tumor.Results were analysed both as response rates (shrinkage in excess of 50%) at the conclusion of the treatment course and as time to tumor progression by the life table method. Comparison of response rates within cohorts by source of xenografts (exact chi-square test for overall and 2-sided Fisher's exact test for paired comparisons) indicated cyclophosphamide to be the most effective single agent. In logrank analyses cyclophosphamide achieved significantly longer delays to progression than all other drugs in one cohort and longer delays than all but diaziquone in 2 other cohorts.The intraocular xenograft model is a clinically relevant system for the study of therapeutic agents in brain tumors. The effectiveness of intensive dosage cyclophosphamide in a model dependent on access across the blood-aqueous barrier is important and consistent with recent clinical data.     

Salmonella choleraesuis as an anticancer agent in a syngeneic model of orthotopic hepatocellular carcinoma

Some anaerobic and facultative anaerobic bacteria represent novel therapeutic agents that have been recently applied in cancer therapy. Previously, we found that Salmonella choleraesuis in combination with cisplatin could retard tumor growth in the murine subsutaneous hepatocellular carcinoma (HCC) model. In this regard, we investigated the antitumor activity of S. choleraesuis in the ML-1 orthotopic tumor model. Systemically administered S. choleraesuis accumulated within not only subcutaneous but also orthotopic tumors for at least 30 days, forming tumor-to-normal tissue ratios exceeding 1,000-10,000 to 1. The antitumor effects of S. choleraesuis were evaluated in mice bearing subcutaneous and orthotopic ML-1 tumors. Compared with the control treatment, S. choleraesuis significantly prolonged the animal survival, reduced the tumor size, as well as upregulated interferon (IFN)-gamma and induced IFN-inducible chemokines CXCL10 (IP-10) productions. Furthermore, immunohistochemical staining of the tumors revealed decreased intratumoral microvessel density, increased infiltration of neutrophils, CD4(+) and CD8(+) T cells, and induced cell death in tumor microenvironment. In conclusion, these results suggest that tumor-targeted therapy using S. choleraesuis, which exerts tumoricidal and antiangiogenic activities, represents a potential strategy for the treatment of HCC.     

Vascular targeting by EndoTAG™‐1 enhances therapeutic efficacy of conventional chemotherapy in lung and pancreatic cancer

Cationic lipid complexed paclitaxel (EndoTAG?‐1) is a novel vascular targeting agent for the treatment of cancer. Here, the aim was to investigate intratumoral drug distribution after EndoTAG?‐1 therapy and analyze the impact of EndoTAG?‐1 scheduling on antitumoral efficacy. The therapeutic effect of EndoTAG?‐1 in combination with conventional gemcitabine or cisplatin therapy was evaluated in L3.6pl orthotopic pancreatic cancer and a subcutaneous Lewis lung (LLC‐1) carcinoma model. Oregon Green paclitaxel encapsulated in cationic liposomes in combination with intravital fluorescence microscopy clearly exhibited delivery of the drug by EndoTAG?‐1 to the tumor endothelium, whereas Oregon Green paclitaxel dissolved in cremophor displayed an interstitial distribution pattern. The therapeutic efficacy of EndoTAG?‐1 was critically dependent on the application schedule with best therapeutic results using a metronomic rather than a maximum tolerated dose application sequence. The combination of EndoTAG?‐1 therapy and cytotoxic chemotherapy significantly enhanced antitumoral efficacy in both tumor models. Interestingly, only EndoTAG?‐1 in combination with gemcitabine was able to inhibit the incidence of metastasis in pancreatic cancer. In conclusion, vascular targeting tumor therapy by EndoTAG?‐1 combined with standard small molecular chemotherapy results in markedly enhanced antitumoral efficacy. Therefore, this combination represents a promising novel strategy for clinical cancer therapy.     

Treatment of melanoma with a serotype 5/3 chimeric oncolytic adenovirus coding for GM‐CSF: Results in vitro,in rodents and in humans

Metastatic melanoma is refractory to irradiation and chemotherapy, but amenable to immunological approaches such as immune‐checkpoint‐inhibiting antibodies or adoptive cell therapies. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules. Therefore, oncolytic immuno‐virotherapy of malignant melanoma is an appealing approach, which was recently validated by a positive phase 3 trial. We investigated the potency of oncolytic adenovirus Ad5/3‐D24‐GMCSF on a panel of melanoma cell lines and animal models, and summarized the melanoma‐specific human data from the Advanced Therapy Access Program (ATAP). The virus effectively eradicated human melanoma cells in vitro and subcutaneous SK‐MEL‐28 melanoma xenografts in nude mice when combined with low‐dose cyclophosphamide. Furthermore, virally‐expressed granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) stimulated the differentiation of human monocytes into macrophages. In contrast to human cells, RPMI 1846 hamster melanoma cells exhibited no response to oncolytic viruses and the chimeric 5/3 fiber failed to increase the efficacy of transduction, suggesting limited utility of the hamster model in the context of viruses with this capsid. In ATAP, treatments appeared safe and well‐tolerated. Four out of nine melanoma patients treated were evaluable for possible therapy benefit with modified RECIST criteria: one patient had minor response, two had stable disease, and one had progressive disease. Two patients were alive at 559 and 2,149 days after treatment. Ad5/3‐D24‐GMCSF showed promising efficacy in preclinical studies and possible antitumor activity in melanoma patients refractory to other forms of therapy. This data supports continuing the clinical development of oncolytic adenoviruses for treatment of malignant melanoma.     

Five‐year safety and efficacy data from a phase Ib study of nivolumab and chemotherapy in advanced non‐small‐cell lung cancer

Combination antiprogrammed death 1/programmed death‐ligand 1 Ab and platinum‐based chemotherapy is standard first‐line treatment for advanced non‐small‐cell lung cancer without targetable oncogene alterations. We describe the long‐term safety and efficacy data from a previously reported phase Ib study of nivolumab and chemotherapy. Japanese patients with non‐small‐cell lung cancer were assigned to a treatment arm based on histology and treatment history. Nivolumab (10 mg/kg, i.v.) and chemotherapy (4 arms) were given every 3 weeks: arm A, 4 cycles of cisplatin and gemcitabine (first‐line); arm B, 4 cycles of cisplatin and pemetrexed followed by pemetrexed maintenance therapy (first‐line); arm C, 4‐6 cycles of carboplatin, paclitaxel, and bevacizumab followed by bevacizumab (first‐line); and arm D, docetaxel (second‐ or third‐line). Study treatments were continued every 3 weeks as maintenance therapy until disease progression. Minimum follow‐up period was 57.9 months. Median progression‐free survival (median [range, plus sign indicates censored data]) was 6.3 (0.7+‐47.8), 11.8 (1.4‐65.1+), 40.7 (5.3‐60.8+), and 3.2 (1.9‐10.9) months, and 5‐year progression‐free survival was observed in 0/6, 1/6, 1/6, and 0/6 patients in arms A, B, C, and D, respectively. Median overall survival was 13.2 (11.0‐55.4), 28.5 (14.6‐66.2+), not reached (24.2‐67.4+), and 12.5 (9.8‐16.9) months; the number of patients surviving 5 years were 0/6, 1/6, 4/6, and 0/6 in arms A, B, C, and D, respectively. No unexpected severe adverse events or treatment‐related deaths occurred. Nivolumab and platinum‐based chemotherapy combinations showed long‐term tolerability. A moderate proportion of patients in arm C showed 5‐year progression‐free and overall survival.     

Preconditioning chemotherapy with paclitaxel and cisplatin enhances the antitumor activity of cytokine induced-killer cells in a murine lung carcinoma model

Adoptive cell therapy involving the use of ex vivo generated cytokine-induced killer cells (CIKs) provides a promising approach to immunotherapy. However, the therapeutic activity of CIKs is limited by the immunosuppressive factors active in the host. It has become increasingly apparent that manipulation of the recipient immune system with the preconditioning regimen is essential to guarantee the antitumor effect of subsequent adoptive cell therapy. In our study, paclitaxel (PTX) and cisplatin (DDP) were used as preconditioning drugs combined with CIKs to illustrate the potential mechanisms underlying the synergic antitumor effect against Lewis lung cancer cells in vitro and in vivo. We found that 3LL cells displayed an increased sensitization to CIKs-induced lysis after treatment with PTX or DDP in vitro. Significant inhibition of tumor growth was observed in mice treated with combinatorial chemo-immunotherapy with respect to untreated or single regimen treated ones. Prior chemotherapy markedly enhanced the intratumoral accumulation of CD3(+) T lymphocytes and the homing of CIKs to the spleen and tumor. Moreover, the frequencies of intratumoral and splenic regulatory T cells (Tregs) were significantly decreased after chemotherapy pretreatment. Our findings provide a new rationale for combining immunotherapy and chemotherapy to induce a synergistic antitumor response in patients with lung cancer.     

Therapeutic efficacy of targeting chemotherapy using local hyperthermia and thermosensitive liposome: evaluation of drug distribution in a rat glioma model

A method was developed of targeting chemotherapy using thermosensitive liposomes to treat malignant gliomas. Using the brain heating system, when the tumour core is heated to >43°C, the tumour infiltrating zone is exposed to mild hyperthermia (40–43°C). Thermosensitive liposomes were designed to release their contents at 40°C to target both the tumour core and tumour infiltrating zone. The present study investigated the anti-tumour effect on rat glioma models in tumour drug uptake and tumour growth delay studies. Elevated accumulation of ADR in the rat C6 glioma after treatment was obtained in the area heated to >40°C. However, there was no significant difference between the areas heated to 40–42°C and >43°C. Furthermore, it was found that ADR concentrations in the mildly hyperthermic areas were significantly higher following treatment with liposomal ADR than with free ADR. The animals treated with the new combination therapy had significantly longer overall survival time in comparison to those receiving other treatments. Thus, thermosensitive liposomes release their contents in response to mild hyperthermia and this combination therapy has a greater therapeutic efficacy for malignant brain tumours. This method is a promising approach for the treatment of malignant glioma patients.     

CC-chemokine ligand 17 gene therapy induces tumor regression through augmentation of tumor-infiltrating immune cells in a murine model of preexisting CT26 colon carcinoma

Chemokines, which regulate leukocyte trafficking and infiltration of local sites, are attractive candidates for improving the efficacy of cancer immunotherapy by enhancing the accumulation of immune cells in tumor tissue. Herein, we evaluated the antitumor effects of intratumoral injection of RGD fiber-mutant adenoviral vectors (AdRGDs) encoding the chemokines CCL17, CCL19, CCL20, CCL21, CCL22, CCL27, XCL1 or CX3CL1 in a murine model of preexisting CT26 colon carcinoma. Among these 8 chemokine-expressing AdRGDs, injection of AdRGD-CCL17 most effectively induced tumor regression and generated specific immunity in rechallenge experiments. Tumor elimination activity by intratumoral injection of AdRGD-CCL17 depended on both the vector dose and the number of injections, and mainly required CD8+ CTLs in an effector phase as confirmed by analysis using BALB/c nude mice and an in vivo depletion assay. In addition, CCL17 gene transduction induced significant increases in the number of infiltrating macrophages and CD8+ T cells in CT26 tumors, and changed the tumor microenvironment to an immunologic activation state in which there was enhanced expression of lymphocyte activation markers and cell adhesion molecules. Thus, our data provide evidence that CCL17 gene transduction of local tumor sites is a promising approach for the development of a cancer immunogene therapy that can recruit activated tumor-infiltrating immune effector cells.     

Phase 2 trial results with the novel neurokinin‐1 receptor antagonist casopitant in combination with ondansetron and dexamethasone for the prevention of chemotherapy‐induced nausea and vomiting in cancer patients receiving moderately emetogenic chemotherapy

BACKGROUND:

This randomized, double‐blind, dose‐ranging, placebo‐controlled, phase 2 trial evaluated the neurokinin‐1 receptor antagonist casopitant mesylate in combination with ondansetron/dexamethasone (ond/dex) for the prevention of chemotherapy‐induced nausea and vomiting (CINV) related to moderately emetogenic chemotherapy (MEC).

METHODS:

Chemotherapy‐naive patients who were receiving MEC (N = 723) were randomized to receive either oral placebo or casopitant at doses of 50 mg, 100 mg, or 150 mg daily (on Days 1‐3) plus ondansetron (on Days 1‐3) and dexamethasone (Day 1). Two exploratory arms evaluated single‐dose casopitant (150 mg) plus ond/dex and a 3‐day casopitant regimen with once‐daily ondansetron and dexamethasone. Primary endpoints were rates of complete response (CR) (no vomiting, retching, rescue therapy, or premature discontinuation) and significant nausea (SN) (≥25 mm on a visual analog scale) over the first 120 hours after Cycle 1 of MEC. Secondary endpoints included acute and delayed CR and SN rates, rates of nausea, vomiting, and safety.

RESULTS:

All casopitant doses that were tested significantly increased the proportion of patients with CR: The CR rates were 80.8% with casopitant 50 mg, 78.5% with casopitant 100 mg, and 84.2% with casopitant 150 mg compared with 69.4% in the control group (P = .0127); casopitant 150 mg was identified as the minimally effective dose. In exploratory analyses, single‐dose casopitant demonstrated a 79.2% CR rate, and once‐daily ondansetron plus casopitant produced an 83.5% CR rate. Vomiting rates in the first 5 days after MEC were reduced with casopitant‐containing regimens (from 23% to 10%‐16%). Rates of SN did not differ among treatment arms (range, 28%‐29%). Casopitant appeared to be well tolerated with no notable differences in overall adverse event frequency.

CONCLUSIONS:

Casopitant plus ond/dex was more effective than ond/dex alone for the prevention of CINV. Cancer 2009. © 2009 American Cancer Society.     

The use of paediatric chemotherapy protocols at full dose is both a rational and feasible treatment strategy in adults with Ewing's family tumours

Background: Ewing's sarcoma and primitive neuroectodermal tumour (ES/PNET) are rare, limiting opportunities for therapy studies in adults. Chemotherapy regimens adapted from paediatric studies are often used for adults but concerns about poor outcome and treatment toxicity may adversely affect drug dose intensity. We present our experience using a paediatric protocol at full dose.Patients and methods: Records of 34 patients with ES/PNET who received the IVAD chemotherapy regimens were reviewed. Received drug dose intensity, toxicity and survival data were collected.Results: Received dose intensity in 30 evaluable patients was 0.92 compared to the standard IVAD schedule. Myelosuppression was the major toxicity, 83% of patients experienced grade 4 neutropenia. There was no major renal or cardiac toxicity. In patients without metastases at presentation, five-year overall survival was 63% and progression free survival was 39%. Tumour burden at presentation was statistically significantly associated with survival (P = 0.002). The five-year survival rate of 80% in patients presenting with low volume non metastatic disease was equivalent to published paediatric series.Conclusions: Although the IVAD chemotherapy regimens are myelotoxic in adults, they can be given safely. We recommend that adults with ES/PNET should be included in current multicentre, multidisciplinary treatment studies directed at children.     

Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide.

BACKGROUND: Effective adjuvant or neoadjuvant regimens of chemotherapy have dramatically improved the prognosis of patients with high-grade osteosarcoma of the extremity, localized at diagnosis. Currently, little is known about patients with metastatic disease at presentation. PATIENTS AND METHODS: From May 1995 to May 2000, 57 patients with osteosarcoma of the extremity, metastatic at presentation, were treated according to the following scheme: primary chemotherapy, restaging, simultaneous resection of primary tumor and metastatic lesions, and maintenance chemotherapy. RESULTS: Thirty-five patients achieved remission. At a follow-up ranging from 2 to 7 years, seven remained continuously free of disease, one died of chemotherapy-related toxicity and 27 patients relapsed. Twenty-one of the 22 patients who never achieved remission died as a result of the tumor, as well as 20 of the 27 who achieved remission but then relapsed. Of the remaining seven relapsing patients, six are alive with uncontrolled disease, while one is alive and free of disease 24 months after the last post-relapse treatment. Two-year event-free survival (EFS) and overall survival (OS) were 21% and 55%, respectively. These results are significantly poorer than those achieved in 128 contemporary patients with non-metastatic disease at presentation, treated with the same chemotherapy protocol (2-year EFS and OS of 75% and 94%, respectively). CONCLUSIONS: The results of our study confirm that the prognosis of patients with osteosarcoma of the extremity, metastatic at presentation, remains poor, despite the use of aggressive treatments.