Establishing Cost-Effective Allocation of Proton Therapy for Patients With Mediastinal Hodgkin Lymphoma.

PURPOSE: For curative treatment of Hodgkin lymphoma, radiation therapy benefit must be weighed against toxicity. Although more costly, proton radiation therapy reduces dose to healthy tissue, potentially improving the therapeutic ratio compared with photons. We sought to determine the cost-effectiveness of proton versus photon therapy for mediastinal Hodgkin lymphoma (MHL) based on reduced heart disease. METHODS AND MATERIALS: Our model approach was 2-fold: (1) Use patient-level dosimetric information for a cost-effectiveness analysis using a Markov cohort model. (2) Use population-based data to develop guidelines for policymakers to determine thresholds of proton therapy favorability for a given photon dose. The HD14 trial informed relapse risk; coronary heart disease risk was informed by the Framingham risk calculator modified by the mean heart dose (MHD) from radiation. Sensitivity analyses assessed model robustness and identified the most influential model assumptions. A 30-year-old adult with MHL was the base case using 30.6-Gy proton therapy versus photon intensity modulated radiation therapy. RESULTS: Proton therapy was not cost-effective in the base case for male ($129,000/ quality-adjusted life years [QALYs]) or female patients ($196,000/QALY). A 5-Gy MHD decrease was associated with proton therapy incremental cost-effectiveness ratio <$100,000/QALY in 40% of scenarios. The hazard ratio associating MHD and heart disease was the most influential clinical parameter. CONCLUSIONS: Proton therapy may be cost-effective a select minority of patients with MHL based on age, sex, and MHD reduction. We present guidance for clinicians using MHD to aid decision-making for radiation therapy modality.

Radiotherapy for extranodal classic Hodgkin lymphoma of the maxillary sinus: Case report and literature review.

BACKGROUND: Classic Hodgkin lymphoma is a malignant neoplasm of the lymphatic system that commonly presents with cervical and mediastinal lymphadenopathy. Primary extranodal disease of the head and neck is rare, with only a few cases reported in the literature. In this case report, we describe the presentation, treatment, and clinical outcome of a patient who presented with extranodal Hodgkin lymphoma of the maxillary sinus. METHODS: We report a case of extranodal classic Hodgkin lymphoma of the maxillary sinus treated with 2 cycles of chemotherapy and consolidative radiotherapy (RT). We also reviewed the literature. RESULTS: The patient tolerated treatment without complications and has experienced no evidence of recurrence 2 years after treatment. CONCLUSION: This is one of the few reports of extranodal Hodgkin lymphoma of the maxillary sinus. To our knowledge, this report represents the longest follow-up of any patient with this presentation.

Medical educational culture: introducing patients to applicants as part of the medical school interview: feasibility and initial impact show and tell.

INTRODUCTION: The College of Medicine at our institution underwent a major curricular revision in order to develop a patient-centered context for learning. The admission process was revised to reflect this change, adopting a holistic review process, with the hope of attracting students who were particularly well suited to a patient-centered curriculum and learning culture. METHODS: Patients from a single practitioner, who were accustomed to working with medical students, were asked if they would like to select the next generation of physicians. The patient's experience included a brief didactic presentation related to the patient's diagnosis and treatment. This was followed by an informal session with the applicants and the physician, where they shared their story in a small group setting. They were encouraged to share their experiences with the healthcare system, both positive and negative. The goal was to allow applicants to glean the importance of the human aspects of disease in our institutional culture of learning. RESULTS: The response and experience were overwhelmingly positive for the patients who donated their time to participate and for our applicants. Follow-up surveys indicated that our applicants found the experience to be unique and positive. Many of the students who chose to attend our university cited the interview experience and learning culture as factors that influenced their choice of medical schools. In addition, the Liaison Committee on Medical Education cited the favorability of the admission process in their recent site visit. DISCUSSION: Now in its fifth year, we can say that the inclusion of patients as part of the interview day is feasible as part of our admission process. We continue to make changes and monitor our progress, and we have added several other faculty members and specialties in order to ensure the program is sustainable.

Involved-node proton therapy in combined modality therapy for Hodgkin lymphoma: results of a phase 2 study.

PURPOSE: This study describes the early clinical outcomes of a prospective phase 2 study of consolidative involved-node proton therapy (INPT) as a component of combined-mode therapy in patients with stages I to III Hodgkin lymphoma (HL) with mediastinal involvement. METHODS AND MATERIALS: Between September 2009 and June 2013, 15 patients with newly diagnosed HL received INPT after completing chemotherapy in an institutional review board-approved protocol comparing the dosimetric impact of PT with those of three-dimensional conformal radiation therapy (3DCRT) and intensity modulated RT. Based on (18)F-Fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) response, 5 children received 15 to 25.5 cobalt Gy equivalent (CGE) of INPT after receiving 4 cycles of Adriamycin, Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide or Vincristine, adriamycin, methotrexate, Prednisone chemotherapy, and 10 adults received 30.6 to 39.6 CGE of INPT after 3 to 6 cycles of Adriamycin, Bleomycine, Vinblastine, Dacarbazine. Patients were routinely evaluated for toxicity during and after treatment, using Common Terminology Criteria for Adverse Events, version 3.0, and for relapse by physical examination and routine imaging. Relapse-free survival (RFS) and event-free survival (EFS) rates were calculated using the Kaplan-Meier method from the time of diagnosis. RESULTS: The median follow-up was 37 months (range, 26-55). Two events occurred during follow-up: 1 relapse (inside and outside the targeted field) and 1 transformation into a primary mediastinal large B cell lymphoma. The 3-year RFS rate was 93%, and the 3-year EFS rate was 87%. No acute or late grade 3 nonhematologic toxicities were observed. CONCLUSIONS: Although decades of follow-up will be needed to realize the likely benefit of PT in reducing the risk of radiation-induced late effects, PT following chemotherapy in patients with HL is well-tolerated, and disease outcomes were similar to those of conventional photon therapy.

Managing cetuximab hypersensitivity-infusion reactions: incidence, risk factors, prevention, and retreatment.

Cetuximab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody approved by the US Food and Drug Administration for the treatment of colorectal (CRC) and head and neck (H&N) cancers. Hypersensitivity-infusion reactions (HIRs) confer moderate morbidity and potential mortality. HIRs have a wide geographic incidence with few identifiable risk factors. Limited data regarding risk-reduction interventions for HIR or post-HIR retreatment are available. All patients treated with cetuximab at a single Veterans Affairs facility were monitored for development of HIRs, with baseline clinical, demographic, and supportive care data recorded. All received standard premedication based on cohort assignment. A total of 51 consecutive patients (30 CRC; 21 H&N) received at least one dose of cetuximab. Grades II-IV HIRs occurred in 14 patients (27%; 6 grade II, 6 grade Ill, 2 grade IV). There was no grade V HIR. All HIRs occurred during the first infusion. There were no differences between age, race, diagnosis, stage, concurrent chemotherapy, or radiotherapy with cetuximab, allergy history, or military service era of patients developing HIRs versus those who did not.There were no identifiable risk factors that predicted the severity of HIR. Neither premedication modifications (P = 0.34) nor bronchodilator use (P= 0.12) impacted the incidence or severity of HIR. A cetuximab test dose successfully elicited an HIR and resulted in an 87% cost savings. None of five patients receiving subsequent retreatment with anti-EGFR MoAb had recurrence of an HIR. An HIR during cetuximab infusion can be a serious and underestimated toxicity. The relatively high incidence reported here is consistent with that previously identified in the Southeastern United States. No clinical, demographic, or historic variables reliably predicted HIR in our population. Use of a test dose to elicit a HIR appears to be feasible and cost-effective. Use of panitumumab after a cetuximab HIR in select patients with CRC appears to be feasible and safe.

Long-term outcomes for stage I-II aggressive non-Hodgkin lymphoma of Waldeyer's ring.

PURPOSE: To determine the long-term outcome of patients treated at the University of Florida for aggressive non-Hodgkin lymphoma (NHL) of Waldeyer's ring. MATERIALS AND METHODS: Forty-six patients treated with radiotherapy (RT) at the University of Florida from 1964 to 2006 for biopsy-proven aggressive NHL of Waldeyer's ring were included in this study. Of this group, 20 patients were treated with RT alone and 26 with combined-modality therapy (CMT) with the addition of chemotherapy: 24 patients with induction and 2 with concurrent or adjuvant chemotherapy. RESULTS: The 5-year and 10-year in-field control rates were 95% and 85%, respectively, and the out-of-field control rates were 67% and 63%, respectively. The 10-year disease-free survival (DFS), cause-specific survival, and overall survival (OS) rates were 47%, 50%, and 37%, respectively. The CMT group had superior 10-year DFS compared with the RT-alone group (57% vs. 37%), but this difference was not statistically significant. No difference in 10-year OS was seen between the CMT group and the RT-alone group. CONCLUSIONS: Similar to other sites, out-of-field recurrences are the primary pattern of failure for NHL of Waldeyer's ring. DFS was superior with CMT compared with RT alone and remains the standard of care.

Clinical presentation and outcomes of lymphocyte-predominant Hodgkin disease at the University of Florida.

OBJECTIVE: To examine the clinical presentation and treatment outcomes of lymphocyte-predominant Hodgkin disease (LPHD) at the University of Florida over a 37-year period. METHODS AND MATERIALS: A retrospective review of the clinical presentation and treatment outcomes in 34 patients with LPHD treated at the University of Florida from 1968 to 2005 was conducted. The end points of absolute survival, cause-specific survival, and relapse-free survival were assessed and late treatment sequelae were identified. RESULTS: Ninety-six percent of patients presented with stage I/II disease. None had mediastinal disease, 4 (12%) had bulky disease (>6 cm in maximum tumor dimension), and only 1 (3%) had B symptoms. Eighty percent of patients were treated with radiation therapy (RT) alone and 20% with RT and chemotherapy. At 5, 10, and 15 years, absolute survival was 97%, 85%, and 76%; cause-specific survival was 100%, 95%, and 95%; and relapse-free survival was 93%, 81%, and 74%. No patients died with Hodgkin disease, but 1 patient's death was attributed to treatment-related late sequelae. There were 6 treatment failures, including 2 within the RT field; all failures were successfully salvaged. The median time to relapse was 5.8 years (range, 2.9-14.6 years). Three secondary malignancies were observed. CONCLUSION: LPHD patients typically present at an early stage without B symptoms, mediastinal, or bulky disease. First-line treatment with RT alone yields excellent results in appropriately selected patients and remains the standard of care. Relapses often occur late and long-term follow-up is needed to successfully diagnose and treat late relapses.

Discordant expression of CD20 by flow cytometry and immunohistochemistry in a patient responding to rituximab: an unusual mechanism.

Immunohistochemistry using the L26 antibody recognizes an intracellular domain of CD20, whereas the L27 antibody used for surface CD20 staining by flow cytometry (FC) recognizes an extracellular domain and would be expected to be a better predictor of response to rituximab. We present a 75-year-old man who was initially treated for CD20- diffuse large B-cell lymphoma based on FC and, at relapse, still had CD20- disease by FC but CD20+ disease by immunohistochemistry. The patient responded to rituximab alone. On further study, it was shown that the malignant B cells, but not normal B cells, expressed the L27 surface binding site only within the intracellular domain. Therefore, it appears that the rituximab binding site is distinct from the surface binding site, and when there is a disparity between the methods to detect CD20 expression, consideration should be given to include rituximab in the treatment plan.

Lethal midline granuloma-nasal natural killer/T-cell lymphoma.

PURPOSE: The purpose of this paper is to discuss lethal midline granuloma (LMG)-nasal natural killer (NK) T-cell lymphoma (LMG-NTL). METHODS: Literature review. RESULTS: LMG is a rare entity that usually arises in the nasal cavity, exhibits a male preponderance, and has a wide age range. The majority of LMGs are LMG-NTLs. The optimal treatment of LMG-NTL is unclear and is most likely moderate-dose radiotherapy. The prognosis for patients with LMG-NTL is significantly worse than for patients with other types of head and neck non-Hodgkin lymphomas (NHL). The 5-year survival rate is approximately 20% but may be higher, depending on whether patients with less aggressive forms of NHL are included. Initial local-regional disease progression is the predominant pattern of treatment failure. Late failures after 5 years are uncommon. CONCLUSIONS: LMG-NTL is a rare nasal NK/T-cell lymphoma that can be difficult to distinguish from other benign and malignant entities. Its clinical course, however, is extremely aggressive. The patterns of failure suggest a role for more aggressive local-regional treatment, as well as more effective chemotherapy.

A phase II study of gemcitabine in patients with relapsed or refractory low-grade non-Hodgkin lymphoma.

PURPOSE: The purpose of this study was to determine the tolerability, clinical response rate, and time to disease progression of gemcitabine treatment in patients with low-grade non-Hodgkin lymphoma. (NHL) PATIENTS AND METHODS: Twenty patients with low-grade NHL and progression of disease after at least 1 prior treatment regimen were prospectively enrolled. The treatment regimen consisted of 1200 mg/m2 gemcitabine intravenously administered weekly for 7 weeks followed by a 1-week rest. Subsequent treatment was given weekly for 3 weeks followed by a 1-week rest and repeated for a maximal treatment of 6 cycles until disease progression or unacceptable toxicity. RESULTS: The predominant histologic subtypes among our patients were small lymphocytic (8 of 20) and follicular (7 of 20). Grade III/IV hematologic toxicity was observed in 15 of 20 patients and dose reductions or treatment delays occurred in 19 of 20 patients. Fatigue and asthenia were treatment-limiting in many patients. There were no complete or partial responses observed and only 2 patients had stable disease after 12 weeks of treatment. The average time to progression or off-study status was 2.3 months (95% confidence interval, 1.7-2.9) with 8 patients showing progression of disease. Twelve patients were taken off the study as a result of unacceptable toxicity before observed progression of disease. No patient completed the planned course of therapy. With a median follow up of 10.2 months, 10 of 20 patients remained alive. CONCLUSION: Gemcitabine as a single agent, in this dosage and schedule, has minimal clinical activity in relapsed or refractory low-grade lymphomas and was associated with considerable toxicity. Therefore, further study of gemcitabine in this setting is not justified.

Phase II trial of individualized rituximab dosing for patients with CD20-positive lymphoproliferative disorders.

PURPOSE: To determine the feasibility and efficacy of pharmacokinetic (PK) -based maintenance dosing of rituximab and possibly design a more rational maintenance schedule. PATIENTS AND METHODS: Patients with CD20-positive lymphoproliferative disorders were treated with four weekly infusions of rituximab 375 mg/m(2). All patients without progressive disease were then monitored for 1 year and received a single infusion of 375 mg/m(2) when the level decreased below 25 microg/mL. RESULTS: Twenty-nine of 31 patients were assessable with a variety of histologic subtypes. The overall response rate (ORR) for the entire group was 59% with 27% complete responses (CRs) and 32% partial responses. The median PFS for all patients was 19 months, with a median follow-up of 25 months. In 22 patients with low-grade non-Hodgkin's lymphoma (LGNHL), the ORR was 63% with 36% CR and median progression-free survival (PFS) has not been reached. Of 29 assessable patients, 22 were available for PK-based maintenance. The median time to repeat bolus was 5 months (range, 1 to 9 months) for the first, 3.5 months (range, 2 to 5 months) for the second, and 3 months (range, 2 to 4 months) for the third infusion. Ninety-five percent of patients required three or fewer infusions to be maintained in the therapeutic range. CONCLUSION: Individualized PK dosing for rituximab produced efficacy comparable to other published maintenance strategies. PK data from this trial suggest that a rational maintenance strategy in patients with LGNHL would be a single dose of 375 mg/m(2) of rituximab every 3 to 4 months.

Paraneoplastic manifestations of lymphoma.

Paraneoplastic syndromes are manifestations of malignancies that have produced effects that are distant from the primary tumor or metastases. Paraneoplastic syndromes are not caused by local effects of compression or infiltration into tissues, but are generally due to ectopic hormone production, autoimmune phenomena, or overproduction of cytokines. Paraneoplasia may be the presenting symptom of underlying malignancy and can affect almost any organ system, such as the neurologic syndromes associated with small-cell lung cancer or hypercalcemia associated with squamous cell carcinomas. Lymphoproliferative disorders are also associated with many paraneoplastic disorders; however, to date, most published information has been in the form of case reports and series of small numbers of patients. In this review, the most common paraneoplastic syndromes associated with non-Hodgkin's lymphoma and Hodgkin's disease will be discussed.

Management of neurotropic low-grade B-cell lymphoma: report of two cases.

BACKGROUND: Low-grade lymphomas do not commonly involve the central or peripheral nervous system. METHODS: Case report and review of the literature of two cases of B-cell lymphoma of the extranodal marginal zone type involving the head and neck region with evidence of extensive neurotropism are detailed in this report. RESULTS: One patient was initially seen with a mass in the temporalis muscle and the other with a masticator space mass. The clinical course was indolent in both cases, although associated imaging studies suggested a more aggressive tumor. Both patients were treated with moderate-dose radiotherapy only. At the time of writing, one patient has no evidence of disease 6.5 years after treatment and the other at 6 months. CONCLUSIONS: This suggests that some marginal zone lymphomas exhibit a low-grade clinical course despite an aggressive radiographic pattern of perineural and neurotropic spread. This type of lymphoma might be effectively treated with moderate-dose radiotherapy.

Dose-intense ifosfamide/doxorubicin/cisplatin based chemotherapy for osteosarcoma in adults.

The efficacy of neoadjuvant and adjuvant chemotherapy has been clearly established in the treatment of osteosarcoma; however, the most active regimen remains to be identified. This prospective study evaluated the efficacy and toxicity of a dose-intense ifosfamide, doxorubicin, and cisplatin-based neoadjuvant regimen in adults with osteosarcoma. We prospectively treated 20 patients with osteogenic sarcoma with two cycles of ifosfamide/doxorubicin followed by two cycles of doxorubicin/cisplatin every 2 weeks. Surgical specimens were analyzed for percent tumor necrosis. Patients who demonstrated a "good response" (GR) to chemotherapy received the same combination postoperatively at a lower dose rate. Patients who demonstrated a "poor response" (PR) received four cycles of high-dose methotrexate alternating with two cycles of ifosfamide/etoposide and two cycles of cisplatin/etoposide after the surgery. Neoadjuvant chemotherapy was well tolerated with moderate hematologic toxicity. Twelve of 19 evaluable patients (63%) were treated according to the GR arm and 7 according to the PR arm. At median follow-up of 5.5 years, disease-free survival (DFS) and overall survival (OS) are 68% and 74%, respectively. Patients treated on the GR arm had DFS and OS of 75% and 83%, respectively, whereas patients on the PR arm had DFS and OS of 57%. Intensive neoadjuvant chemotherapy is effective and moderately well tolerated in patients with de novo osteosarcoma. The outcome data suggest that lack of a near complete response to preoperative chemotherapy reflects inherent biologic resistance to chemotherapy and hence a poor prognosis.

Phase II study of fludarabine combined with interferon-alpha-2a followed by maintenance therapy with interferon-alpha-2a in patients with low-grade non-hodgkin's lymphoma.

Randomized trials suggest improved disease-free survival in low-grade non-Hodgkin's lymphoma (LGNHL) when interferon is combined with multiagent chemotherapy. This phase II trial was conducted to investigate the feasibility of combining fludarabine monophosphate (fludarabine) and IFN in a regimen for treatment of LGNHL. Twenty-one patients were evaluable. Median age was 55 years, and patients had been treated with an average of 1.7 chemotherapy regimens before enrollment. Patients received 25 mg/m2 of fludarabine intravenously on days 1 through 5 followed by 2 x 10(6) U/m2 of interferon-alpha-2a subcutaneously on days 22 through 26. Cycles were repeated every 4 weeks with delays and dose modifications for significant cytopenias. Patients were restaged after cycles 4 and 8, and those with at least a partial response to therapy were given maintenance therapy consisting of 2 x 10(6) U/m2 interferon-alpha-2a subcutaneously three times per week for 6 months. The overall response rate was 76% with a 25% complete response (CR) rate. Overall response rates were 75% (3/4 with 2 CR's) for chemotherapy-naive patients and 76% (13/17 with 3 CR's) for previously treated patients. Median time to progression was 12 months, and currently two patients are without evidence of progression at a median follow-up of 55 months. Grade III or greater toxicities included neutropenia (39%), anemia (17%), thrombocytopenia (5%), fevers/chills (5%), and fatigue (5%). Fludarabine and interferon can be effectively and safely combined in a regimen with significant activity against LGNHL. A modification of this regimen may be suitable for further study.