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.

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 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.

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). METHODS: Five consecutive patients with regionally advanced NSCLC underwent treatment planning for high-dose involved-field (IF) treatment (positron emission tomography-positive gross disease) with or without selective/elective nodal irradiation, defined as the extended field (EF). Four treatment plans were developed for each patient: i) IMRT to treat IF to 74 Gy (IFrT); ii) IMRT to treat high-risk nodes to 44 Gy and IF to 74 Gy (EFrT); iii) PT to treat IF to 74CGE (IFpT); and iv) PT to treat high-risk nodes to 44CGE and IF to 74CGE (EFpT). High-risk nodes were defined as mediastinal, hilar, and supraclavicular lymph node stations adjacent to foci of PET-positive gross disease. The IMRT and PT plans were isoeffective. Dose to organs at risk (OARs), including the lung, esophagus, heart and spinal cord, were evaluated. RESULTS: The average IF clinical target volume (CTV) was 397 cc (344-428), while the average EF CTV was 642 cc (530-753 cc). Comparing IMRT with PT, mean lung dose reduced 3.4 Gy/CGE and 3.7 Gy/CGE; lung V20 reduced 4% and 5% for EF and IF, respectively. CONCLUSIONS: Selective/elective nodal irradiation with protons reduces normal-lung exposure compared to selective/elective nodal irradiation with IMRT.

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.

Cytomorphology of a solitary left chest wall mass: an unusual presentation from unknown primary hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) may present in various ways, but only very rarely with symptoms of distant metastases or evolve from ectopic liver tissue. This report describes a case of a 62-year-old white man who was admitted for hemoptysis and a large left chest wall mass that was growing for about a year. The patient underwent Fine-needle aspiration (FNA) of the mass that revealed poorly differentiated large-cell carcinoma. A lung primary was suspected initially; however, further workup of this patient showed an elevated serum alpha-fetoprotein (AFP) level of 16,425 ng/ml. A computerized tomography (CT) scan of the abdomen showed cirrhotic liver, evidence of esophageal varices, but no evidence of a liver mass. The FNA findings were reviewed and ancillary studies were performed, including pan cytokeratin (AE1/3), Hepatocyte Paraffin 1 (HepPar-1), AFP, CD10, CD34, and polyclonal CEA. The results confirmed the diagnoses of HCC probably from occult primary or from ectopic liver tissue. The former was suggested, since serum AFP was dropped to 6,640 ng/ml following resection of the tumor. We concluded that HCC should be considered in the list of differential diagnosis of chest wall mass. HCC may present as metastatic disease from a clinically and radiologically unrecognized liver mass. FNA, coupled with ancillary studies, provides a rapid and accurate diagnostic tool in challenging cases.

Chest wall abscess: an unusual presentation of Hodgkin's lymphoma.

A chest wall abscess is a very rare presentation of extranodal Hodgkin's lymphoma (HL); only one case has been reported to date. Here, we describe a case of a 38-yr-old man with HL whose initial presentation was a chest wall abscess. The diagnosis of HL was suggested by cytological examination of the purulent discharge and was confirmed subsequently by excisional biopsy of cervical lymph node.

Timing of coronary artery bypass graft surgery following acute myocardial infarction: a critical literature review.

Despite more than 30 years' experience with coronary artery bypass surgery, controversy still exists about the optimal timing of surgical revascularization following acute myocardial infarction. To review the published information on this topic, a Medline search of the literature published between 1984 and October 2000 was performed. After reviews and individual case reports we re excluded, 11 retrospective and prospective studies remained for analysis. Pervasive heterogeneity with respect to inclusion criteria, outcome measurement, definitions, variance among studies of measured time between myocardial infarction (MI) and coronary artery bypass graft (CABG), differences in study endpoints, and evolution of surgical techniques and medical regimens over this time precluded formal meta-analysis. Although prospective randomized trials are lacking, the preponderance of data from the 11 retrospective and prospective observational studies suggests that timing of bypass surgery after infarction is not an independent predictor of outcome and that delaying coronary bypass surgery for an arbitrary period of time following acute MI is unwarranted. Rather, ventricular function, post-infarction ischemia, noncardiac comorbid conditions, and the urgency of the surgery itself constitute the important predictors of perioperative mortality, and these clinical factors should be used to estimate perioperative risk and decide upon the risk:benefit relationship for CABG in this patient population.