Rishi Agarwal

Validation of the Children's International Mucositis Evaluation Scale (ChIMES) in paediatric cancer and SCT.

Background:Objectives were to describe the reliability and validity of a new paediatric-specific mucositis scale, the Children’s International Mucositis Evaluation Scale (ChIMES).Methods:In a multi-centre prospective study, children aged 0 to ⩽18 years were eligible if they were receiving any of the following: myeloablative stem cell transplantation (SCT), ⩾60 mg m−2 course−1 doxorubicin or ⩾12 g m−2 methotrexate. Multiple measures of mucositis were included along with ChIMES. Respondents were parent proxy report for children aged <12 years, and child self-report for children aged 12–18 years and 8 to <12 years. Mucositis diaries were completed at baseline and on Days 7–17 following chemotherapy/conditioning. On Day 14, the respondent reported presence of mucositis and change since the previous day.Results:The 185 respondents included parents (N=98), children aged 12–18 years (N=66) and children aged 8 to <12 years (N=21). Test–retest reliability was excellent for ChIMES Total Score and ChIMES Percentage Score with r>0.8 for all respondent types. Criteria for construct validation were met across all measures. ChIMES also demonstrated responsiveness with significant differences between baseline and Day 14.Conclusion:ChIMES is a paediatric-specific measure of mucositis with favourable psychometric properties. It exhibits reliability, construct validity and responsiveness. ChIMES should be incorporated into clinical trials of mucositis prevention and treatment in paediatric cancer and SCT.

A phase I dose-escalation trial of high-dose melphalan with palifermin for cytoprotection followed by autologous stem cell transplantation for patients with multiple myeloma with normal renal function.

Melphalan 200 mg/m(2) is the standard conditioning regimen for patients with multiple myeloma (MM) with normal renal function (NRF) undergoing autologous stem cell transplant (ASCT). In an effort to escalate the dose of melphalan and to improve the efficacy, we designed a dose-escalation study of melphalan in conjunction with palifermin in patients with NRF, with the hope that a higher dose of melphalan can be administered with an acceptable degree of oral mucositis (OM). We enrolled 19 patients (18 evaluable) with NRF. Dose-escalation of melphalan administered on day -2 began at 200 mg/m(2) with palifermin administered at a fixed dose of 60 mcg/kg/day. Palifermin was given as an i.v. bolus on day -5, -4, and -3, and then on day +1, +2, and +3. Subsequent dose escalations of melphalan were done at 20 mg/m(2) increments up to a maximum dose of 280 mg/m(2). Of 18 evaluable patients, there were no treatment-related deaths by day 100. The median age was 48.5 years (range, 33-65 years). The most common adverse events related to palifermin included rash (18 events, no ≥ grade 3 events), elevation of amylase (10 events, 4 were grade 3 but asymptomatic), and lipase (5 events, 2 were grade 3 but asymptomatic), edema (11 events, no ≥ grade 3). The overall incidence of OM grade 3 was 44% (8/18) with a median duration of severe mucositis of 5 days (range, 3-6 days). Eleven patients (61%) required opioid analgesics. None of the patients received total parenteral nutrition (TPN)/nasogastric feeding. Two of 6 patients who were given melphalan 280 mg/m(2) did not develop OM. Cardiac dose-limiting toxicity (DLT) in the form of atrial fibrillation did occur in 1 of 6 patients treated with melphalan 280 mg/m(2). Palifermin has permitted safe dose escalation of melphalan up to 280 mg/m(2), thus reaching the cumulative dosage of melphalan administered in tandem ASCT. This higher dose of melphalan has the potential to improve the efficacy and, hopefully, outcomes of patients with MM with a single ASCT. A phase 2 trial is necessary to better delineate the antimyeloma efficacy of this regimen.

Combined Antiangiogenic and Mammalian Target of Rapamycin Inhibitor Targeted Therapy in Metaplastic Breast Cancer Harboring a PIK3CA Mutation.

Metaplastic breast cancer (MpBC) is an extremely rare breast cancer subtype, characterized by a heterogeneous phenotype. MpBC aggressive biology is attributed to its stem cell-like characteristics. Since these tumors are largely chemoresistant, novel targeted therapies should be explored. Herein, we report the clinical course of a 59-year-old African American woman with MpBC with a PIK3CA mutation in codon 545, exon 10 (GAG to AAG; p.Glu545Lys) and a TP53 mutation in codon 286, exon 8 (GAA to AAA; p.Glu286Lys). The same mutations were observed in the primary and secondary sites. The patient was treated with a molecularly matched therapy using a combined antiangiogenic and mammalian target of rapamycin kinase inhibitor strategy that included liposomal doxorubicin, bevacizumab, and temsirolimus. Partial remission was achieved. In this report, the scientific rationale underlying the activity of this combination was explored. In conclusion, patients may benefit from being offered molecular profiling early during the course of the disease to receive a therapy guided accordingly.

Advanced biliary tract cancer: clinical outcomes with ABC-02 regimen and analysis of prognostic factors in a tertiary care center in the United States

BACKGROUND Gemcitabine plus cisplatin (GC) is currently the standard regimen for advanced biliary tract cancers (BTC) based on the outcomes in ABC-02 trial. Multiple factors can affect outcomes in these patients. This retrospective review evaluates the University of Cincinnati experience with GC in advanced intrahepatic (IHC)/extrahepatic cholangiocarcinoma (EHC) and gall bladder carcinoma (GBC). METHODS In this study approved by University of Cincinnati IRB, retrospective analysis of advanced BTC patients seen between 01/2008 and 01/2015 was done. Kaplan Meyer method was used to calculate progression free survival (PFS), and overall survival (OS). Cox model was used to test the association between baseline variables and OS/PFS, adjusting for gender and age at diagnosis. Patients were identified using ICD code for BT tumors, 26 patients met inclusion criteria: histologically proven advanced BTC that received GC as their initial chemotherapy. GC was given as per ABC-02 protocol with appropriate modifications until disease progression or unacceptable toxicities. RESULTS Median age at diagnosis was 62 years (range, 31-81 years). Eighteen (69%) were IHC, 5 EHC, 3 GBC, 61% male, 73% whites. Performance status (PS): 0-1: 69%, PS 2: 31%. Baseline CA19-9 data was available for 21 patients, (range 1 to 69,543), and abnormal CA19-9 was seen in 14 patients (54%). PFS was 4.5 months (95% CI: 3.1-8.9 months) and OS was 10.5 months (95% CI: 7.9-18.8 months). OS at 6 and 12 months was 69% (18/26) and 42% (11/26). Thirty-eight percent (10/26) received 2nd line chemotherapy, of these 9/10 received 5FU based chemotherapy. Eleven percent (3/26) received 3rd line chemotherapy. Increase in baseline carcinoembryonic antigen (CEA), alanine aminotransferase, alkaline phosphatase (ALP) and total bilirubin was associated with increased risk of death while increase in baseline CEA and ALP was associated with increased risk of progression (P valve <0.05). In the group of patients who had all three major risk factors (PS ≥2, CEA >3, and stage IVb), the median survival was 2.9 months (95% CI: 2.6-9.3 months), which was significantly worse compared to rest of the population [median 18 months (95% CI: 5.4-19.5 months), P<0.01]. CONCLUSIONS Our data supports the use of GC as a first line regimen for advance BTC in a non-clinical trial setting. Results are comparable to those reported in ABC-02 trial, despite inclusion of PS 2 patients whom constituted 31% of our population. In the patient population studied, baseline CEA and liver function test appeared able to predict response to GC in advanced BTC. Patients with all three high risk factors (PS ≥2, CEA >3, and stage IVb) did poorly and may need careful selection prior to initiating chemotherapy.

Retreatment after secondary resistance or mixed response: a pilot study.

Objective: Oncologists usually avoid retreatment with drugs to which patients have shown secondary resistance or a mixed response. Here, we report our findings in a pilot study in patients rechallenged with agents previously producing prolonged stable disease (SD), partial or complete remission (PR/CR) or a mixed response, followed by progression. Results: Eleven individuals with advanced cancers (median number of prior systemic therapies in the metastatic setting = 4, range 2-7) were included (8 men; median age 57 years; median Eastern Cooperative Oncology Group performance status of 1). The median duration between initial treatment and retreatment was 92 weeks. Eight of 11 patients (73%) on a retreatment regimen showed SD ≥24 weeks/PR/CR. Of these 8 individuals, 2 were retreated with the same agent(s), 1 with a different agent possessing the same mechanism of action (e.g., in case of an epidermal growth factor receptor inhibitor, using gefitinib first, then erlotinib), and 5 with the same agent(s) in combination with other agents. Conclusion: Our pilot data suggest that patients who develop acquired resistance after durable SD/CR/PR or who have an initial mixed response may attain SD ≥6 months/PR/CR with a retreatment approach.

POEMS Syndrome Presentation with an Abscess within the Plasmacytoma-A Rare Case Report.

POEMS Syndrome is a rare cause of demyelinating and axonal mixed neuropathy. Plasmacytomas are usually seen in POEMS syndrome and can be osseous or extramedullary. Plasmacytomas presenting as an abscess has not been noted earlier. Our patient presented with localized hyperpigmented patch on the back and later developed progressive weakness in upper and lower limbs. Initially serum and urine protein electrophoresis were normal. The patient was thought to have Chronic Inflammatory Demyelinating Polyneuropathy and was treated accordingly without any improvement. Repeat serum protein electrophoresis showed monoclonal gammopathy. MRI of the back revealed an abscess in the paravertebral soft tissues reaching up to the skin. Needle biopsy was consistent with plasmacytoma. Later, he developed a purulent fungating lesion in the lower midback. Antibiotics were started and local resection was done followed by radiation. Pathology of the resected mass showed plasmacytoma extensively involving subcutaneous soft tissue and bone. The patient improved with the treatment. Cystic plasmacytomas and abscess within the plasmacytoma has not been reported earlier. Whether abscess formation is part of the disease spectrum due to infiltration of overlying tissue or is secondary to localized immunosuppression is unknown. Local treatment of a single plasmacytoma is useful in ameliorating systemic symptoms.

Phase I study of nab-paclitaxel, gemcitabine, and bevacizumab in patients with advanced cancers

BackgroundWe performed a phase I modified 3 + 3 dose escalation study to evaluate the safety and activity of bevacizumab plus gemcitabine and nab-paclitaxel in patients with advanced solid tumours.MethodsPatients were given fixed dose gemcitabine plus increasing doses of nab-paclitaxel and bevacizumab. Toxicity, response, and association with VEGF polymorphism was analysed.ResultsThe study enrolled 110 patients who had undergone a median of 3 prior lines of therapy. The median age was 60 years (range, 17–85 years), and 55 patients (50%) had gemcitabine-refractory disease. We observed 3 dose-limiting toxicities during dose escalation and 3 DLTs in expansion cohorts. Dose escalation to 150 mg/m2 nab-paclitaxel and 15 mg/kg bevacizumab with 1000 mg/m2 of gemcitabine was well tolerated with no MTD. One patient with gemcitabine-refractory peritoneal papillary carcinoma had a complete response, 13 patients (13%) had partial responses, and 54 patients (52%) had stable disease ≥12 weeks. Exploratory VEGF single nucleotide polymorphism (SNP) analysis was performed on 13 patients.ConclusionsThe combination of gemcitabine, nab-paclitaxel, and bevacizumab is safe, well-tolerated, and has activity in advanced malignancies, including gemcitabine-refractory tumours. Based on this study, the recommended phase 2 dose is gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2, and bevacizumab 15 mg/kg. VEGF polymorphism data should be evaluated in future bevacizumab-based trials.

Contents Vol. 85, 2013

A.B. Benson, Chicago, Ill. A. Chang, Singapore A.L. Cheng, Taipei J.F. Cleary, Madison, Wisc. M. Dietel, Berlin M.S. Ernstoff , Lebanon, N.H. M.G. Fakih, Duarte, Calif. J.J. Grau, Barcelona H. Gronemeyer, Illkirch D.F. Hayes, Ann Arbor, Mich. C.S. Johnson, Buff alo, N.Y. M.J. Kelley, Durham, N.C. P.J. Loehrer, Indianapolis, Ind. J.R. Marshall, Buff alo, N.Y. S. Monfardini, Milan R. Nagler, Haifa R. Ohno, Nagoya B. Pestalozzi, Zurich H.M. Pinedo, Amsterdam E.A. Repasky, Buff alo, N.Y. A. Semczuk, Lublin E.F. Smit, Amsterdam C.N. Sternberg, Rome R. Stupp, Zurich M.S. Tallman, Chicago, Ill. S. Tanaka, Hiroshima M. Tian, Houston, Tex. D.L. Trump, Buff alo, N.Y. T. Wiegel, Ulm W. Yasui, Hiroshima H. Zhang, Hangzhou City Editor-in-Chief

Abstract 1177: Retreatment after secondary resistance: A pilot study.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Retreatment with agents to which patients have shown secondary resistance or a mixed response is usually avoided by oncologists, though recent results suggest that continuing herceptin after secondary resistance is associated with a better outcome than discontinuation. Here we present preliminary results of a pilot study in which patients were retreated with agents that had previously produced prolonged stable disease (SD), partial or complete remission (PR/CR) or a mixed response,followed by progression.This study was performed according the guidelines of the MD Anderson Cancer Center Institutional Review Board. Eleven patients with diverse, advanced cancers (median number of prior systemic therapies in the metastatic setting = four (range, 2-7) have been included to date (number of men = 8; median age = 57 years; median ECOG performance status = 1)., The median duration between the initial treatment and the retreatment regimen was 95 weeks (range 5-323 weeks). Eight of 11patients (73%) on a retreatment regimen showed stable disease (SD) >24 weeks or a partial response. Of these eight, two were retreated with precisely the same agent(s); one, with a different agent that has the same mechanism of action (EGFR inhibitor; gefitinib first and then erlotinib); and five, with the same agent(s) but with additional agents added. | N | Diagnosis | No of prior therapies | Best Prior Treatment | Gap* (weeks) | Best Retreatment | |:-- | ------------------------------------- | --------------------- | ------------------------------------------ | --------------- | ---------------- | --- | | | | | Name | Duration(weeks) | Best Response | | Name | Duration (weeks) | Best Response | | 1 | Adenocystic Carcinoma | 3 | Erlotinib | 99 | PR | 54 | Erlotinib | 69 | SD | | 2 | Hepatic Cholangiocarcinoma | 2 | Sorafenib | 7 | Mixed | 15 | Bevacizumab plus Sorafenib | 36 | SD | | 3 | Myxoid Liposarcoma | 3 | Trabectedin | 58 | SD | 92 | Trabectedin | 4 | PD | | 4 | Ewings Sarcoma | 7 | IGF inhibitor | 148 | PR | 5 | IGF inhibitor plus mTOR inhibitor | 153+ | PR | | 5 | Rectal Adenocarcinoma | 5 | Capecitabine plus bevacizumab | 44 | SD | 95 | Capecitabine plus Bevacizumab | 24 | SD | | 6 | Ovarian Serous Carcinoma | 4 | Paclitaxel plus carboplatin | 18 | CR | 120 | Paclitaxel and Carboplatin (Bevacizumab added after 4 months) | 60+ | PR | | 7 | Colorectal Cancer | 3 | FOLFOX plus bevacizumab | 22 | CR | 26 | HAI Oxaliplatin plus HAI Irinotecan plus IV Bevacizumab | 3 | PD | | 8 | Squamous Cell Cancer of Head and Neck | 4 | Chemoradiation with Carboplatin and taxane | 7 | CR | 214 | Docetaxel plus Carboplatin plus 5FU | 6 | PR | | 9 | Colorectal Adenocarcinoma | 6 | FOLFIRI plus bevacizumab | 24 | PR | 104 | HAI Oxaliplatin and IV Bevacizumab and PO Capecitabine | 12 | SD | | 10 | Adenocystic Carcinoma | 7 | Gefitinib | 114 | SD | 322 | Erlotinib | 31+ | SD | | 11 | Invasive Ductal Carcinoma of Breast | 4 | Carboplatin plus Docetaxel plus Herceptin | 21 | CR | 383 | Carboplatin, Taxotere, Herceptin and Temsirolimus | 26 | PR | * *Gap in weeks between the previous treatment and initiation of the retreatment with some of the same drugs. Our pilot data suggest that retreatment with agents to which patients had previously shown durable SD/CR/PR or mixed response followed by secondary resistance can produce SD > = 24 weeks/ PR when given alone or in combination after a gap between initial treatment and retreatment. Plausible mechanisms accounting for this phenomenon include persistence of a suppressed clone alongside the new resistant clone, drug synergy,and epigenetic modulation during drug holidays. Further investigation of the effect of retreatment in patients with advanced metastatic disease is warranted. Citation Format: Rishi Agarwal, Aung Naing, Gerald Falchook, Jennifer Wheler, Siqing Fu, Razelle Kurzrock. Retreatment after secondary resistance: A pilot study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1177. doi:10.1158/1538-7445.AM2013-1177

Successful autologous stem cell collection with filgrastim and plerixafor after long-term lenalidomide therapy for multiple myeloma.

Novel agents such as lenalidomide have demonstrated responses similar to high-dose melphalan and autologous stem cell transplant in multiple myeloma. For patients who are started on lenalidomide, it is advisable to collect stem cells early if future transplant is contemplated. We are reporting a patient who underwent successful stem cell mobilization after 68 cycles of lenalidomide. A 60-year old male presented with back pain. He was diagnosed with stage IIA, IgA multiple myeloma. He was enrolled in a clinical trial and was randomized to receive lenalidomide plus dexamethasone. He received a total of 68 cycles of lenalidomide before progressing. He underwent mobilization of stem cells using filgrastim and plerixafor. He underwent successful stem cell transplant. Longer duration of lenalidomide adversely effects stem cell mobilization. To the best of our knowledge, there has been no other case reported in which stem cell mobilization was feasible after such a long (68 months) duration of uninterrupted lenalidomide therapy.