Dat C. Pham

Proton Radiation Therapy Offers Reduced Normal Lung and Bone Marrow Exposure for Patients Receiving Dose-Escalated Radiation Therapy for Unresectable Stage III Non-Small-Cell Lung Cancer: A Dosimetric Study

INTRODUCTION The purpose of this study was to determine the potential benefit of proton radiation therapy over photon radiation therapy in patients with unresectable stage III non-small-cell lung cancer. MATERIALS AND METHODS Optimized 3-dimensional conformal photon (3DCRT), intensity-modulated radiation therapy (IMRT) and proton therapy (PT) plans were generated for 8 consecutive patients with unresectable stage III non-small-cell lung cancer using the same target goals and normal tissue constraints. The radiation exposure to non-targeted normal structures, including lung, bone marrow, esophagus, heart, and spinal cord, were compared. Photon doses are expressed in gray (Gy). Proton doses are expressed in cobalt gray equivalents (CGE). RESULTS In all patients, 3DCRT, IMRT, and PT plans, achieved the dose goals for the target volumes. Compared with the 3DCRT plans, proton plans offered a median 29% reduction in normal lung V(20) Gy (CGE), a median 33% reduction in mean lung dose (MLD), and a median 30% reduction in the volume of bone marrow receiving a dose of 10 Gy (CGE). Compared with the IMRT plans, the proton plans offered a median 26% reduction in normal lung V(20) Gy (CGE), a median 31% reduction in MLD, and a median 27% reduction in the volume of bone marrow receiving a dose of 10 Gy (CGE). CONCLUSION By reducing the volumes of normal structures irradiated, protons can potentially improve the therapeutic index for patients with unresectable stage III non-small-cell lung cancer receiving combined radiation therapy and chemotherapy.

HIV-associated primary cervical non-Hodgkin’s lymphoma and two other cases of primary pelvic non-Hodgkin’s lymphoma☆

BACKGROUND Although there have been few case series of primary pelvic non-Hodgkins lymphoma (NHL) reported over the past two decades, no patient with acquired immunodeficiency syndrome (AIDS)-related primary pelvic NHL has been reported. CASE We report a human immunodeficiency virus (HIV)-infected patient with primary cervical NHL. After surgical biopsy, she received standard NHL combination chemotherapy plus standard HIV highly active antiretroviral therapy (HAART), and remains disease free 38 months since therapy. We also report two other cases of primary pelvic NHL. CONCLUSIONS Primary pelvic NHL is rare, with clinical presentation similar to other common gynecologic malignancies. It is treated with combination chemotherapy and pelvic radiotherapy, and generally has good prognosis. Adding HAART to other standard therapies for patients with AIDS-related pelvic lymphoma may improve the prognosis of this category of patients.

Proton Therapy With Concurrent Chemotherapy for Non–Small-Cell Lung Cancer: Technique and Early Results

BACKGROUND Proton therapy can deliver a more conformal dose distribution than photon radiation and may allow safe dose escalation in stage III lung cancer. Early outcomes are presented here for patients who received proton therapy with concurrent chemotherapy for non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS Nineteen patients with regionally advanced NSCLC were treated with concurrent chemotherapy (carboplatin and paclitaxel [n = 18]) and proton therapy from August 2008 to April 2010 either with (n = 7) or without (n = 12) induction chemotherapy. Eighteen patients had stage III NSCLC, and 1 patient had stage IIB disease. The median proton therapy dose was 74 cobalt gray equivalent (CGE) in 2 CGE fractions with 18 patients who received ≥70 CGE. Twelve patients also received selective nodal proton therapy to the adjacent uninvolved nodal regions, with a median dose of 40 CGE (range, 40-46 CGE). The patients were routinely evaluated for treatment-related toxicity and disease progression every 3 months, with a history, physical, and computed tomography or positron emission tomography-computed tomography. RESULTS The median follow-ups for living patients were 15 and 16 months (range, 7-26 months), respectively. Nonhematologic and hematologic acute grade 3+ toxicity (<90 days) developed in 1 and 4 patients, respectively. Two of 16 patients assessable for late toxicity (≥90 days) developed a significant grade 3+ nonhematologic late toxicity, whereas 1 patient developed a grade 3+ hematologic late toxicity. Local progression was the site of first relapse in one patient. CONCLUSION Mediastinal proton therapy with concomitant chemotherapy was associated with acceptable toxicity. Although encouraging, longer follow-up with more patients is needed to confirm the long-term efficacy of this treatment.

Protons safely allow coverage of high-risk nodes for patients with regionally advanced non-small-cell lung cancer.

Our objective was to determine if protons allow for the expansion of treatment volumes to cover high-risk nodes in patients with regionally advanced non-small-cell lung cancer. In this study, 5 consecutive patients underwent external-beam radiotherapy treatment planning. Four treatment plans were generated for each patient: 1) photons (x-rays) to treat positron emission tomography (PET)-positive gross disease only to 74 Gy (XG); 2) photons (x-rays) to treat high-risk nodes to 44 Gy and PET-positive gross disease to 74 Gy (XNG); 3) protons to treat PET-positive gross disease only to 74 cobalt gray equivalent (PG); and 4) protons to treat high-risk nodes to 44 CGE and PET-positive gross disease to 74 CGE (PNG). We defined high-risk nodes as mediastinal, hilar, and supraclavicular lymph nodal stations anatomically adjacent to the foci of PET-positive gross disease. Four-dimensional computed tomography was utilized for all patients to account for tumor motion. Standard normal-tissue constraints were utilized. Our results showed that proton plans for all patients were isoeffective with the corresponding photon (x-ray) plans in that they achieved the desired target doses while respecting normal-tissue constraints. In spite of the larger volumes covered, median volume of normal lung receiving 10 CGE or greater (V10Gy/CGE), median V20Gy/CGE, and mean lung dose were lower in the proton plans (PNG) targeting gross disease and nodes when compared with the photon (x-ray) plans (XG) treating gross disease alone. In conclusion, proton plans demonstrated the potential to safely include high-risk nodes without increasing the volume of normal lung irradiated when compared to photon (x-ray) plans, which only targeted gross disease.

Argatroban in heparin-induced thrombocytopenia: rationale for use and place in therapy

Heparin-induced thrombocytopenia (HIT) is a recognized complication of heparin and requires urgent detection and treatment. HIT can be divided into two types, type I and type II, with type I being a transient decrease in platelet count without clinical consequence. For the purpose of this review, the term HIT refers to the immune-mediated type II that causes paradoxical thrombo-emboli. The aim of this review is to familiarize clinicians with a specific direct thrombin inhibitor, argatroban, in the treatment of HIT. Argatroban has been successfully employed in treating HIT in many different subsets of patients, including those with endstage renal disease on hemodialysis and in patients undergoing percutaneous coronary intervention and those with multiorgan dysfunction syndrome.

A Phase 2 Trial of Concurrent Chemotherapy and Proton Therapy for Stage III Non-Small Cell Lung Cancer: Results and Reflections Following Early Closure of a Single-Institution Study

PURPOSE Proton therapy has been shown to reduce radiation dose to organs at risk (OAR) and could be used to safely escalate the radiation dose. We analyzed outcomes in a group of phase 2 study patients treated with dose-escalated proton therapy with concurrent chemotherapy for stage 3 non-small cell lung cancer (NSCLC). METHODS AND MATERIALS From 2009 through 2013, LU02, a phase 2 trial of proton therapy delivering 74 to 80 Gy at 2 Gy/fraction with concurrent chemotherapy for stage 3 NSCLC, was opened to accrual at our institution. Due to slow accrual and competing trials, the study was closed after just 14 patients (stage IIIA, 9 patients; stage IIIB, 5 patients) were accrued over 4 years. During that same time period, 55 additional stage III patients were treated with high-dose proton therapy, including 7 in multi-institutional proton clinical trials, 4 not enrolled due to physician preference, and 44 who were ineligible based on strict entry criteria. An unknown number of patients were ineligible for enrollment due to insurance coverage issues and thus were treated with photon radiation. Median follow-up of surviving patients was 52 months. RESULTS Two-year overall survival and progression-free survival rates were 57% and 25%, respectively. Median lengths of overall survival and progression-free survival were 33 months and 14 months, respectively. There were no acute grade 3 toxicities related to proton therapy. Late grade 3 gastrointestinal toxicity and pulmonary toxicity each occurred in 1 patient. CONCLUSIONS Dose-escalated proton therapy with concurrent chemotherapy was well tolerated with encouraging results among a small cohort of patients. Unfortunately, single-institution proton studies may be difficult to accrue and consideration for pragmatic and/or multicenter trial design should be considered when developing future proton clinical trials.

Dosimetric rationale and early experience at UFPTI of thoracic proton therapy and chemotherapy in limited-stage small cell lung cancer

Abstract Background. Concurrent chemoradiotherapy (CRT) is the standard of care in patients with limited-stage small cell lung cancer (SCLC). Treatment with conventional x-ray therapy (XRT) is associated with high toxicity rates, particularly acute grade 3+ esophagitis and pneumonitis. We present outcomes for the first known series of limited-stage SCLC patients treated with proton therapy and a dosimetric comparison of lung and esophageal doses with intensity-modulated radiation therapy (IMRT). Material and methods. Six patients were treated: five concurrently and one sequentially. Five patients received 60–66 CGE in 30–34 fractions once daily and one patient received 45 CGE in 30 fractions twice daily. All six patients received prophylactic cranial irradiation. Common Terminology Criteria for Adverse Events, v3.0, was used to grade toxicity. IMRT plans were also generated and compared with proton plans. Results. The median follow-up was 12.0 months. The one-year overall and progression-free survival rates were 83% and 66%, respectively. There were no cases of acute grade 3+ esophagitis or acute grade 2+ pneumonitis, and no other acute grade 3+ non-hematological toxicities were seen. One patient with a history of pulmonary fibrosis and atrial fibrillation developed worsening symptoms four months after treatment requiring oxygen. Three patients died: two of progressive disease and one after a fall; the latter patient was disease-free at 36 months after treatment. Another patient recurred and is alive, while two patients remain disease-free at 12 months of follow-up. Proton therapy proved superior to IMRT across all esophageal and lung dose volume points. Conclusion. In this small series of SCLC patients treated with proton therapy with radical intent, treatment was well tolerated with no cases of acute grade 3+ esophagitis or acute grade 2+ pneumonitis. Dosimetric comparison showed better sparing of lung and esophagus with proton therapy. Proton therapy merits further investigation as a method of reducing the toxicity of CRT.

Proton therapy for lung cancer

Proton therapy is an emerging radiotherapy technology with the potential to improve the therapeutic index in the treatment of lung cancer patients. Since charged particles, such as protons, have a penetration length that can be modified by using different energies, protons offer the clinician the ability to modulate radiation dose deposition along the beam path. This facilitates an increase of the dose to the tumor target while minimizing the volume of normal tissue irradiation. Such precise delivery is particularly relevant in the setting of lung cancer where the targeted tissues are in close proximity to moderately radiation‐sensitive organs like the spinal cord, heart, and esophagus, but are also effectively surrounded by the normal lung, which is extremely sensitive to radiation damage. Proton therapy has been investigated for the treatment of surgically curable yet medically inoperable patients as well as patients with regionally advanced disease.

Selective nodal irradiation of regionally advanced non‐small‐cell lung cancer with proton therapy and IMRT: A dosimetric comparison

Objectives:  Evaluate the dosimetric impact of selective/elective nodal treatment with dose‐escalated radiotherapy for regionally advanced non‐small‐cell lung cancer (NSCLC) using proton therapy (PT) or intensity‐modulated radiotherapy (IMRT).

Refractory idiopathic pure red cell aplasia complicated by immune thrombocytopenia successfully treated with subcutaneous alemtuzumab

To the Editor: Only rare case reports of patients with pure red cell aplasia (PRCA) responding to alemtuzumab exist; however, most are secondary PRCA with only one being idiopathic [1]. We report a man with refractory idiopathic PRCA complicated by ITP, successfully treated with subcutaneous alemtuzumab. In Jan 2007, a 69-year-old man presented with idiopathic PRCA, refractory to treatments from 1993 to 2001 with anti-thymocyte globulin, prednisone, cyclosporine, cyclophosphamide, and rituximab 375 mg/m weekly 3 8. He required 2–3 units of red blood cells monthly with mean Hb 5–7 g/dl prior to transfusion. In 2005, he developed asymptomatic ITP with platelet count (PLT) 60–80 3 10/l, which dropped to 20–40 3 10/l over 2 years. Bone marrow biopsy and aspirate in Feb 2007 showed absence of erythroid precursors, presence of normal myeloid cells, and megakaryocytes. He was then treated with subcutaneous alemtuzumab with baseline Hb 6.8 g/dl, PLT 22 3 10/l, and WBC 5.3 3 10/l. He received test doses of 3 mg on Day 1, and 10 mg on Day 4. WBC then dropped to 1.2 3 10/l, which necessitated G-CSF 480 mcg daily until it normalized. On Day 18, he received alemtuzumab 30 mg, followed by pegfilgrastim 6 mg the next day for anticipated neutropenia. This was then repeated every 2 weeks on Days 32, 46, 60, 74, and 88. The cumulative dose was 193 mg. PLT rose to 83 3 10/l on Day 31, reached 180 3 10/l on Day 46, then stayed in the normal range. Hb increased to 8.6 g/dl on Day 88, reached 11.7 g/dl on Day 153, and then remained in the 11–12 g/dl range (Fig. 1). He became transfusion independent since Day 46. Bone marrow biopsy and aspiration on Day 153 showed presence of erythroid precursors, and decreased myeloid cells. At the most recent visit, he remained transfusion independent with Hb 12.1 g/ dl, PLT 161 3 10/l, and WBC 3.5 3 10/l. No major toxicity of alemtuzumab was noted other than asymptomatic leukopenia. Alemtuzumab has been shown to be effective in treating PRCA (idiopathic or secondary) and ITP, although the experience for these conditions is very limited [1–3]. It appears to be more effective than rituximab in treating PRCA, underlying the importance of T-cell modulation in PRCA [3]. Previous reports of PRCA involved intravenous use of alemtuzumab and did not document any patient with both idiopathic PRCA and ITP effectively treated with alemtuzumab. Our patient was, however, successfully treated with subcutaneous alemtuzumab despite 14 years since diagnosis. Subcutaneous alemtuzumab is an effective treatment option for refractory PRCA with durable remission, helps patients to become transfusion independent, and should be studied as a treatment for ITP. The dose and schedule of alemtuzumab for PRCA are not known due to limited anecdotal experience; however, a total dose of less than 200 mg can provide durable remission. Patients should be monitored closely, take prophylactic antibiotics, and receive granulocytes growth factor support as needed.