A phase 1 trial of autologous stem cell transplantation conditioned with melphalan 200 mg/m2 and total marrow irradiation (TMI) in patients with relapsed/refractory multiple myeloma.

In this phase 1 study, we tested increasing doses of total marrow irradiation (TMI) in addition to standard intravenous melphalan at 200 mg/m2 (Mel200) in the conditioning regimen prior to autologous stem cell transplant (ASCT) for multiple myeloma (NCT02043847). Twelve patients aged 18-75 with relapsed myeloma were enrolled in the study and received Mel200 and TMI 3 Gy (n = 3), 6 Gy (n = 3), or 9 Gy (n = 6) prior to transplant. There were no grade 4 extra-hematologic toxicities and a maximum tolerated dose was not reached. Median time to neutrophil and platelet engraftment was 11 and 13 d, respectively. At day 90, 73% of patients were in CR or VGPR. Median progression free survival (PFS) was 449 d and median overall survival (OS) was 966 d. We conclude that TMI at a dose of 9 Gy can be safely combined with Mel200 in therapeutic regimens for autologous transplant. Initial clinical results will prompt a phase 2 study.

MicroRNAs in glioblastoma pathogenesis and therapy: A comprehensive review.

Glioblastoma (GBM), also known as grade IV astrocytoma, is the most aggressive primary intracranial tumor of the adult brain. MicroRNAs (miRNAs), a class of small non-coding RNA species, have critical functions across various biological processes. A great deal of progress has been made recently in dissecting miRNA pathways associated with the pathogenesis of GBM. miRNA expression signatures called gene signatures also characterize and contribute to the phenotypic diversity of GBM subclasses through their ability to regulate developmental growth and differentiation. miRNA molecules have been identified as diagnostic and prognostic biomarkers for patient stratification and may also serve as therapeutic targets and agents. This review summarizes: (i) the current understanding of the roles of miRNAs in the pathogenesis of GBM, (ii) the potential use of miRNAs in GBM diagnosis and glioma grading, (iii) further prospects of developing miRNAs as novel biomarkers and therapeutic targets for GBM, and (iv) important practical considerations when considering miRNA therapy for GBM patients.

A validated, transitional and translational porcine model of hepatocellular carcinoma.

Difficult questions are confronting clinicians attempting to improve hepatocellular carcinoma (HCC) outcomes. A large animal model with genetic, anatomical, and physiological similarities to humans is required to transition from mouse models to human clinical trials to address unmet clinical needs. To validate our previously reported inducible porcine cancer model (Oncopig) as a transitional HCC model, Oncopig hepatocyte cultures were transformed using Cre recombinase. The resulting porcine HCC cells (pHCC) expressed oncogenic TP53R167H and KRASG12D, and displayed nuclear pleomorphisms with pale to granular cytoplasm arranged in expanded plates similar to human HCC histopathology. Human HCC transcriptional hallmarks were detected in pHCC cells using RNA-seq, including TERT reactivation, apoptosis evasion, angiogenesis activation, and Wnt signaling activation. Master regulators of gene expression were conserved across Oncopig and 18 human HCC cell lines. pHCC injection into SCID mice resulted in tumors recapitulating human HCC characteristics, including thick trabeculae formation, pseudoacini patterning, and sheets of well-vascularized stroma. Finally, autologous injection of pHCC cells subcutaneously yielded a tumor histologically characterized as Edmondson Steiner (HCC nuclear grade assessment system) grade 2 HCC with trabecular patterning and T-lymphocyte infiltration. These data demonstrate the Oncopig HCC model's utility for improving detection, treatment, and biomarker discovery relevant to human HCC.

Rapid and Sensitive Detection of Breast Cancer Cells in Patient Blood with Nuclease-Activated Probe Technology.

A challenge for circulating tumor cell (CTC)-based diagnostics is the development of simple and inexpensive methods that reliably detect the diverse cells that make up CTCs. CTC-derived nucleases are one category of proteins that could be exploited to meet this challenge. Advantages of nucleases as CTC biomarkers include: (1) their elevated expression in many cancer cells, including cells implicated in metastasis that have undergone epithelial-to-mesenchymal transition; and (2) their enzymatic activity, which can be exploited for signal amplification in detection methods. Here, we describe a diagnostic assay based on quenched fluorescent nucleic acid probes that detect breast cancer CTCs via their nuclease activity. This assay exhibited robust performance in distinguishing breast cancer patients from healthy controls, and it is rapid, inexpensive, and easy to implement in most clinical labs. Given its broad applicability, this technology has the potential to have a substantive impact on the diagnosis and treatment of many cancers.

The Oncopig Cancer Model: An Innovative Large Animal Translational Oncology Platform.

Despite an improved understanding of cancer molecular biology, immune landscapes, and advancements in cytotoxic, biologic, and immunologic anti-cancer therapeutics, cancer remains a leading cause of death worldwide. More than 8.2 million deaths were attributed to cancer in 2012, and it is anticipated that cancer incidence will continue to rise, with 19.3 million cases expected by 2025. The development and investigation of new diagnostic modalities and innovative therapeutic tools is critical for reducing the global cancer burden. Toward this end, transitional animal models serve a crucial role in bridging the gap between fundamental diagnostic and therapeutic discoveries and human clinical trials. Such animal models offer insights into all aspects of the basic science-clinical translational cancer research continuum (screening, detection, oncogenesis, tumor biology, immunogenicity, therapeutics, and outcomes). To date, however, cancer research progress has been markedly hampered by lack of a genotypically, anatomically, and physiologically relevant large animal model. Without progressive cancer models, discoveries are hindered and cures are improbable. Herein, we describe a transgenic porcine model-the Oncopig Cancer Model (OCM)-as a next-generation large animal platform for the study of hematologic and solid tumor oncology. With mutations in key tumor suppressor and oncogenes, TP53R167H and KRASG12D , the OCM recapitulates transcriptional hallmarks of human disease while also exhibiting clinically relevant histologic and genotypic tumor phenotypes. Moreover, as obesity rates increase across the global population, cancer patients commonly present clinically with multiple comorbid conditions. Due to the effects of these comorbidities on patient management, therapeutic strategies, and clinical outcomes, an ideal animal model should develop cancer on the background of representative comorbid conditions (tumor macro- and microenvironments). As observed in clinical practice, liver cirrhosis frequently precedes development of primary liver cancer or hepatocellular carcinoma. The OCM has the capacity to develop tumors in combination with such relevant comorbidities. Furthermore, studies on the tumor microenvironment demonstrate similarities between OCM and human cancer genomic landscapes. This review highlights the potential of this and other large animal platforms as transitional models to bridge the gap between basic research and clinical practice.

ß-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q).

Deletion of the chromosome 5q [del(5q)] is one of the most common cytogenetic abnormalities observed in patients with de novo myelodysplastic syndromes (MDS) and therapy-related MDS or acute myeloid leukemia (t-MDS/tAML). Emerging evidence indicates that activation of the Wnt/ß-catenin pathway contributes to the development of myeloid neoplasms with del(5q). Whether ß-catenin is a potential therapeutic target for myeloid neoplasms with del(5q) has yet to be evaluated. Here, we report that genetic deletion of a single allele of ß-catenin rescues ineffective hematopoiesis in an Apc haploinsufficient mouse model, which recapitulates several characteristic features of the preleukemic stage of myeloid neoplasms with a -5/del(5q). In addition, loss of a single allele of ß-catenin reversed the defective self-renewal capacity of Apc-haploinsufficient hematopoietic stem cells and reduced the frequency of apoptosis induced by Apc haploinsufficiency. Suppression of ß-catenin by indomethacin or ß-catenin shRNA reduced proliferation and survival of human leukemia cell lines with del(5q) but not of control leukemia cell lines in vitro; ß-catenin inactivation also inhibited leukemia progression in vivo in xenograft mice reconstituted with del(5q) leukemia cell lines. Inhibition of ß-catenin also stunted growth and colony-forming abilities of primary bone marrow cells from del(5q) AML patients in vitro Overall, our data support the idea that ß-catenin could serve as a therapeutic target for the treatment of myeloid neoplasms with del(5q). Cancer Res; 77(15); 4116-26. ©2017 AACR.

Symptomatic Massive Splenomegaly in Persistent Polyclonal B-cell Lymphocytosis Requiring Splenectomy.

INTRODUCTION: Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare lymphoproliferative hematological disease characterized by binucleated lymphocytes, CD 19+ CD 5-lymphocytosis, and elevated levels of serum immunoglobulin M (IgM). It can rarely be associated with splenomegaly, though the disease usually remains indolent. CASE PRESENTATION: We present a case of PPBL in a young man with massive splenomegaly that mimicked isolated splenic lymphoma requiring splenectomy for persistent pain, symptoms, and diagnosis. DISCUSSION: Determining the etiology of splenomegaly in these patients is often confounding due to a lack of a tissue diagnosis and the limited morphological and immuno-histochemical features of PPBL, therefore, the presentation remains highly concerning for lymphoma. CONCLUSION: The presentation, surgical treatment, tissue and peripheral blood molecular analysis, and flow cytometry integral to managing these patients and to prevent an assumptive and misleading diagnosis are reviewed.

miR-let-7f-1 regulates SPARC mediated cisplatin resistance in medulloblastoma cells.

Our previous studies indicate that Secreted Protein Acidic and Rich in Cysteine (SPARC) expression suppressed medulloblastoma tumor growth in vitro and in vivo. Here we sought to determine the effect of SPARC expression in medulloblastoma cells to chemotherapeutic agents. In this study, we show that SPARC expression induces cisplatin resistance in medulloblastoma cells. We also demonstrate that the autophagy was involved in SPARC expression mediated resistance to cisplatin. Suppression of autophagy by either autophagy inhibitor, 3-methyladenosine (3MA) or Atg5 siRNA enhanced cisplatin sensitivity in SPARC expressed cells. Further, SPARC expression suppressed miR-let-7f-1 expression which resulted in disrupted repression of High Mobility Group Box 1 (HMGB1), a critical regulator of autophagy. We also show that HMGB1 is a direct target of miR-let-7f-1 and forced expression of HMGB1 cDNA enhanced cisplatin sensitivity in SPARC expressed cells. In summary, our results suggest that SPARC modulates cisplatin resistance by modulating the Let-7f-1 miRNA/HMGB1 axis in medulloblastoma cells.

Costs of care for lung and colon cancer patients receiving chemotherapy following FDA policy changes.

PURPOSE: Use of erythropoiesis-stimulating agents (ESAs) in US cancer care declined amidst post-marketing evidence of adverse effects and the Food and Drug Administration's (FDA) addition of a "black-box" warning to product labeling in March 2007. Because reduced ESA use may have led to more transfusions or increased anemia-related health care needs, we measured the policy's impact on health care costs of lung and colon cancer patients receiving chemotherapy. METHODS: In a retrospective cohort study of 13,630 lung and 3,198 colon cancer patients in the Department of Veterans Affairs (VA) between 2002 and 2008, we calculated anemia treatment (ESA and transfusion), cancer- and non-cancer-related, and total health care costs for the chemotherapy episode of care. We used multivariable regression to examine health care costs and utilization between patients whose chemotherapy was administered before (PRE) or after (POST) March 1, 2007. RESULTS: ESA costs declined and transfusion costs were similar, resulting in lower overall POST-period anemia treatment costs (lung, $526 lower, P < 0.01; colon, $504 lower, P < 0.01). Other cancer-related health care costs increased, resulting in markedly higher POST-period total health care costs (lung, $4,706 higher, P < 0.01; colon, $11,414 higher, P < 0.01). CONCLUSIONS: Although chemotherapy episode anemia treatment costs declined after the black-box warning, the savings were offset by increases in other cancer-related costs. Those increases were mainly in outpatient services and pharmacy, suggesting that likely drivers include adoption of new high-cost diagnostic approaches and therapeutic modalities. Additional research is needed to determine the effects of anemia management changes on patient outcomes and to more fully understand cost-benefit relationships in cancer treatment.

MicroRNA 203 Modulates Glioma Cell Migration via Robo1/ERK/MMP-9 Signaling.

Glioblastoma (GBM) is the most common and malignant primary adult brain cancer. Allelic deletion on chromosome 14q plays an important role in the pathogenesis of GBM, and this site was thought to harbor multiple tumor suppressor genes associated with GBM, a region that also encodes microRNA-203 (miR-203). In this study, we sought to identify the role of miR-203 as a tumor suppressor in the pathogenesis of GBM. We analyzed the miR-203 expression data of GBM patients in 10 normal and 495 tumor tissue samples derived from The Cancer Genome Atlas data set. Quantitative real-time PCR and in situ hybridization in 10 high-grade GBM and 10 low-grade anaplastic astrocytoma tumor samples showed decreased levels of miR-203 expression in anaplastic astrocytoma and GBM tissues and cell lines. Exogenous expression of miR-203 using a plasmid expressing miR-203 precursor (pmiR-203) suppressed glioma cell proliferation, migration, and invasion. We determined that one relevant target of miR-203 was Robo1, given that miR-203 expression decreased mRNA and protein levels as determined by RT-PCR and Western blot analysis. Moreover, cotransfection experiments using a luciferase-based transcription reporter assay have shown direct regulation of Robo1 by miR-203. We also show that Robo1 mediates miR-203 mediated antimigratory functions as up-regulation of Robo1 abrogates miR-203 mediated antimigratory effects. We also show that miR-203 expression suppressed ERK phosphorylation and MMP-9 expression in glioma cells. Furthermore, we demonstrate that miR-203 inhibits migration of the glioma cells by disrupting the Robo1/ERK/MMP-9 signaling axis. Taken together, these studies demonstrate that up-regulation of Robo1 in response to the decrease in miR-203 in glioma cells is responsible for glioma tumor cell migration and invasion.

Quantitative FRET imaging to visualize the invasiveness of live breast cancer cells.

Matrix metalloproteinases (MMPs) remodel tumor microenvironment and promote cancer metastasis. Among the MMP family proteases, the proteolytic activity of the pro-tumorigenic and pro-metastatic membrane-type 1 (MT1)-MMP constitutes a promising and targetable biomarker of aggressive cancer tumors. In this study, we systematically developed and characterized several highly sensitive and specific biosensors based on fluorescence resonant energy transfer (FRET), for visualizing MT1-MMP activity in live cells. The sensitivity of the AHLR-MT1-MMP biosensor was the highest and five times that of a reported version. Hence, the AHLR biosensor was employed to quantitatively profile the MT1-MMP activity in multiple breast cancer cell lines, and to visualize the spatiotemporal MT1-MMP activity simultaneously with the underlying collagen matrix at the single cell level. We detected a significantly higher level of MT1-MMP activity in invasive cancer cells than those in benign or non-invasive cells. Our results further show that the high MT1-MMP activity was stimulated by the adhesion of invasive cancer cells onto the extracellular matrix, which is precisely correlated with the cell's ability to degrade the collagen matrix. Thus, we systematically optimized a FRET-based biosensor, which provides a powerful tool to detect the pro-invasive MT1-MMP activity at single cell levels. This readout can be applied to profile the invasiveness of single cells from clinical samples, and to serve as an indicator for screening anti-cancer inhibitors.

Hemoglobin levels triggering erythropoiesis-stimulating agent therapy in patients with cancer: the shift after United States Food and Drug Administration policy changes.

STUDY OBJECTIVE: To determine whether the hemoglobin level at which health care providers prescribed erythropoiesis-stimulating agent (ESA) therapy (trigger hemoglobin level) for their patients receiving chemotherapy was lower after the United States Food and Drug Administration (FDA) mandated a black-box warning in March 2007. DESIGN: Retrospective analysis. DATA SOURCE: U.S. Department of Veterans Affairs Healthcare System (VA) national databases. PATIENTS: A total of 7450 patients who were diagnosed with cancer between 2002 and 2009, were undergoing chemotherapy, and who received an ESA within 12 months after their cancer diagnosis. MEASUREMENTS AND MAIN RESULTS: Data were collected on patients' demographic, clinical, environmental, and treatment-related factors. After controlling for these factors, multivariable regression analyses were used to compare the trigger hemoglobin level before and after the FDA-mandated labeling change. The average trigger hemoglobin level was 0.73 g/dl lower after the labeling change (95% confidence interval [CI] -0.84 to -0.63). Moreover, the decline in trigger hemoglobin levels began in mid-2006, when the average trigger hemoglobin level fell from 10.50 g/dl in early 2006 (95% CI 10.36-10.63) to 9.30 g/dl by late 2009 (95% CI 9.10-9.49). CONCLUSION: Even before the 2007 FDA-mandated changes in ESA product labeling, hemoglobin levels that triggered ESA treatment began declining for patients receiving cancer care within the VA. This highlights the critical importance of dissemination of postmarketing safety data to impact shifts in ESA use for anemia management.

Trends in anemia management in lung and colon cancer patients in the US Department of Veterans Affairs, 2002-2008.

PURPOSE: In 2007, growing concerns about adverse impacts of erythropoiesis-stimulating agents (ESAs) in cancer patients led to an FDA-mandated black box warning on product labeling, publication of revised clinical guidelines, and a Medicare coverage decision limiting ESA coverage. We examined ESA therapy in lung and colon cancer patients receiving chemotherapy in the VA from 2002 to 2008 to ascertain trends in and predictors of ESA use. METHODS: A retrospective study employed national VA databases to "observe" treatment for a 12-month period following diagnosis. Multivariable logistic regression analyses evaluated changes in ESA use following the FDA-mandated black box warning in March 2007 and examined trends in ESA administration between 2002 and 2008. RESULTS: Among 17,014 lung and 4,225 colon cancer patients, those treated after the March 2007 FDA decision had 65% (lung OR 0.35, CI(95%) 0.30-0.42) and 53% (colon OR 0.47, CI(95%) 0.36-0.63) reduced odds of ESA treatment compared to those treated before. Declines in predicted probabilities of ESA use began in 2006. The magnitude of the declines differed across age groups among colon patients (p = 0.01) and levels of hemoglobin among lung cancer patients (p = 0.04). CONCLUSIONS: Use of ESA treatment for anemia in VA cancer care declined markedly after 2005, well before the 2007 changes in product labeling and clinical guidelines. This suggests that earlier dissemination of research results had marked impacts on practice patterns with these agents.

Neratinib: an oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer.

BACKGROUND: The revolutionary success of imatinib, a specific inhibitor of the BCR-ABL tyrosine kinase (TK) in the treatment of chronic myelogenous leukemia ushered in the era of targeted therapies in cancer. The erythroblastic leukemia viral oncogene homolog family of receptor TKs, to which EGFR (HER1) and human epidermal growth factor receptor 2 (HER2)/neu TKs belong, has been implicated in a variety of cancers, and several agents that inhibit these TKs are in clinical use, with many more in various stages of development. OBJECTIVES: To summarize current knowledge about neratinib (HKI-272), an oral, irreversible dual inhibitor of EGFR and HER2 and to define its future clinical role, especially in the context of related agents that are either available or in the pipeline. METHODS: A Medline search using Pubmed was conducted using the keywords neratinib, HKI-272, EGFR, HER2, lapatinib, trastuzumab, erlotinib, gefitinib, cetuximab and panitumumab. Relevant abstracts presented at the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings were also reviewed. CONCLUSIONS: Both preclinical and human studies have shown that neratinib has promising activity in both advanced breast cancer and NSCLC with an acceptable safety profile. The data support its continued clinical development.

Management of platinum-based chemotherapy-induced acute nausea and vomiting: is there a superior serotonin receptor antagonist?

OBJECTIVE: The last decade has witnessed the great impact of 5-hydroxytryptamine-3 receptor (5-HT(3))antagonists in revolutionizing the management of platinum-based chemotherapy-induced acute nausea and vomiting (CINV). However, despite the availability of a variety of 5-HT(3) antagonists, little data is published to support superiority of one drug over another, leaving the choice of serotonin receptor antagonist largely empirical. The National Comprehensive Cancer Network and American Society of Clinical Oncology guidelines for management of chemotherapy-associated nausea and vomiting cleary endorse the use of serotonin receptor antagonist; however, no single agent is preferred over the rest. METHODS: Data for patients (n=159) receiving platinum-based chemotherapy regimens were retrospectively collected . Patients getting 5-HT(3) antagonists without steriods or those with known history of brain metastasis, gastroparesis, and intestinal obstruction were not eligible for the study. Patient characteristics including age, gender, primary diagnosis, history of heavy alcohol intake, chemotherapy regimen administered , number of cycles, and Eastern Cooperative Group performance status at the start of therapy were noted. Primary outcome was the complete control of platinum-induced acute nausea and vomiting. Secondary outcome measures included control of > or = grade 1 nausea or vomiting, comparison of two doses of dexamethasone, and antiemetic eficacy among various platinum drugs. National Cancer Institute Common Toxicity Criteria version 2.0 was used to assess toxicity. RESULTS: A total of 126 patients received 369 cycles of platinum-based therapy. Dolasetron ( n=157), granisetron ( n=81), and ondansetron ( n=131) achieved complete control of vomiting in 89.8, 95.5, and 92.3% (p=0.67) of cycles, respectively. Respectively, complete nausea control was observed in 68.1, 75.3 and, 69.4% (p=0.50). Dexamethasone 20 mg was not superior to 10 mg in complete control of nausea and vomiting ( p= 0.15 and p=0.63, respectively). However, complete nausea control was signinficantly better in the subgroup of patients getting cisplatin-compared with carboplatin-based regimens (78.8% vs. 67.7%, p<0.05). CONCLUSION: No significant difference exists in the antiemetic efficacy of the three 5-HT(3) antagonists studied in controlling CINV when administered in combination with dexamethasone. Choicce of antiemetic regimen should therefore be based on drug cost.

Low incidence of neutropenic events in patients with lymphoma receiving first-cycle pegfilgrastim with chemotherapy: results from a prospective community-based study.

BACKGROUND: Most alterations to chemotherapy dose and schedule are because of neutropenic events, which mainly occur in the first chemotherapy cycle. This prospective, community-based study evaluated the effectiveness of pegfilgrastim in patients with lymphoma who were also receiving chemotherapy. PATIENTS AND METHODS: Patients aged > or = 18 years with cancer other than leukemia or myelodysplastic syndromes were eligible, including patients with major comorbidities who were generally not eligible for most clinical trials. Key exclusions were weekly chemotherapy and concurrent radiation therapy. Patients received pegfilgrastim 6 mg approximately 24 hours after chemotherapy in each cycle (up to 8 cycles). Endpoints included neutropenic complications and serious adverse events. RESULTS: This open-label single-arm study enrolled 2249 patients at 319 sites. Of these 2249 patients, 325 patients with non-Hodgkin lymphoma (NHL) and 46 patients with Hodgkin disease were included in the primary analysis set. The median age was 65 years for patients with NHL and 41 years for patients with Hodgkin disease, and 31% and 26% had major comorbidities, respectively. Few patients experienced neutropenic complications, including grade 4 febrile neutropenia (patients with Hodgkin disease: 0 [95% confidence interval (CI), 0-8%]; patients with NHL: 13% [95% CI, 10%-17%]); febrile neutropenia-related hospitalization (patients with Hodgkin disease: 0 [95% CI, 0-8%]; patients with NHL: 10% [95% CI, 7%-14%]), neutropenia-related dose reduction (patients with Hodgkin disease: 0 [95% CI, 0-8%]; patients with NHL: 5% [95% CI, 3%-8%]), and neutropenia-related dose delay (patients with Hodgkin disease: 0 [95% CI, 0-8%]; patients with NHL: 5% [95% CI, 3%-8%]). Serious adverse events were consistent with those observed in patients receiving myelosuppressive chemotherapy. CONCLUSION: Patients with lymphoma receiving myelosuppressive chemotherapy supported by pegfilgrastim experienced few neutropenic complications or neutropenia-related alterations in chemotherapy dose and schedule.

Evaluation of the combination of docetaxel/carboplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN): a Southwest Oncology Group Phase II study.

Carboplatin/docetaxel chemotherapy was evaluated in advanced squamous cell carcinoma of the head and neck (SCCHN). Eligibility included patients with recurrent, persistent, or metastatic SCCHN with Zubrod performance status 0-2. Docetaxel 65 mg/m(2) and carboplatin (AUC of 6) were given IV in a 21-day cycle to 68 patients. Response probability was 25 percent (95%CI: 15-38). The major toxicity observed was neutropenia, with 36 patients (61 percent) experiencing Grade 3 or worse. Median progression-free survival was 3.8 months (95%CI, 3.1-4.8) Median overall survival was 7.4 months (95%CI, 6.2-8.9). The results of this study suggest this regimen is active for outpatient treatment of recurrent SCCHN patients with good performance status.