Kevin S. Oh

Combined-Modality Therapy With Gemcitabine and Radiation Therapy as a Bladder Preservation Strategy: Long-Term Results of a Phase I Trial

PURPOSE A Phase I trial of twice-weekly gemcitabine and concurrent radiation therapy (RT) was performed in patients with muscle-invasive bladder cancer. We present the final analysis of bladder-intact survival (BIS), disease-specific survival (DSS), and overall survival (OS). METHODS AND MATERIALS Eligible patients had muscle-invasive transitional cell carcinoma (cT2-3) and were candidates for cystectomy. Patients underwent maximal transurethral resection of bladder tumor followed by twice-weekly gemcitabine with concurrent RT to the bladder (total of 60 Gy over 6 weeks). Gemcitabine doses ranged from 10 to 33 mg/m(2). RESULTS Median follow-up was 5.6 years (range, 0.6-9.5 years). Twenty-three of 24 patients were evaluable for response. All patients were clinical stage T2. Locoregional failure occurred in seven patients (30%), which were successfully salvaged by radical cystectomy (n = 5) or intravesical therapy (n = 2). Four local failures occurred > 5 years after therapy. Most local failures were noninvasive tumors (Ta or Tis, n = 6). Ten patients (43%) experienced optimal outcome (no failures and bladder intact). The 5-year actuarial estimates of survival are BIS 62%, OS 76%, and DSS 82%. CONCLUSION Twice-weekly gemcitabine with concurrent RT is well tolerated and provides rates of survival and bladder preservation that are comparable to the existing literature. All locoregional failures were successfully salvaged by either radical cystectomy or intravesical therapy. Given the high proportion of late local failures, we recommend long-term monitoring when using this regimen. Future studies comparing the safety and efficacy of gemcitabine- vs. platinum-based bladder preservation protocols are pending.

Outcomes after whole brain reirradiation in patients with brain metastases.

PURPOSE Patients with brain metastases are often treated with whole brain radiation therapy (WBRT) for purposes of palliation. The treatment of those who experience subsequent intracranial disease progression can include a second course of WBRT, although there is controversy surrounding its safety and efficacy. This study examines the outcomes in patients at Massachusetts General Hospital who underwent reirradiation. PATIENTS AND METHODS We examined the medical records of 17 patients at Massachusetts General Hospital with brain metastases who were initially treated with WBRT between 2002 and 2008 and were subsequently retreated with a second course of WBRT. The median dose for the first course of WBRT was 35 Gy (range, 28-40 Gy), with a fraction size of 2 to 3 Gy (median, 2.5 Gy). The median dose at reirradiation was 21.6 Gy (range, 14-30 Gy), with a fraction size of 1.5 to 2 Gy (median, 1.8 Gy). RESULTS The second course of WBRT was administered upon radiographic disease progression in all patients. Of 10 patients with complete follow-up data, 8 patients experienced complete or partial symptom resolution, and 2 did not show clinical improvement. The time to radiographic progression was 5.2 months. The median overall survival for all patients after diagnosis of metastases was 24.7 months. The median survival time after initiation of reirradiation was 5.2 months (95% CI, 1.3-8.7). In 6 patients with stable extracranial disease, the median survival time after retreatment was 19.8 months (95% CI, 2.7-∞), compared with 2.5 months (95% CI, 0.8-5.5) for those with extracranial disease progression (p = 0.05). Acute adverse reactions occurred in 70.5% of patients but were mild to moderate in severity. CONCLUSION In select patients and especially those with stable extracranial disease, reirradiation may be an appropriate and effective intervention to provide symptomatic relief and slow intracranial disease progression. Side effects were minimal and did not cause substantial changes in quality of life.

Significance of targeted therapy and genetic alterations in EGFR, ALK, or KRAS on survival in patients with non–small cell lung cancer treated with radiotherapy for brain metastases

BACKGROUND We determined the impact of genetic alterations in EGFR, ALK, or KRAS on survival after radiotherapy for brain metastases in non-small cell lung cancer (NSCLC). METHODS Of 172 genotyped NSCLC patients treated with radiotherapy for brain metastases in 2005-2012, 54 had cancers with EGFR mutations, 12 had ALK rearrangements, 38 had KRAS mutations, and 68 were wild-type (WT). Overall survival (OS) was determined. RESULTS Median follow-up was 8.6 months. Median OS was 13.6 months for patients with EGFR mutations and 26.3 months for patients with ALK rearrangements, in contrast to 5.7 months for KRAS-mutant patients and 5.5 months for WT patients (P = .001). On multivariate analysis, adjusting for receipt of targeted therapy after cranial radiotherapy, ALK rearrangements were associated with improved OS (HR, 0.31; 95% CI, 0.13-0.74; P = .008). EGFR mutations were not significantly associated with improved OS on multivariate analysis (HR, 0.71; 95% CI, 0.37-1.38; P = .3). KRAS mutations were also not associated with improved OS (HR, 0.93; 95% CI, 0.59-1.47; P = .8). Receipt of targeted therapy after cranial radiotherapy was independently associated with improved OS (HR, 0.30; 95% CI, 0.17-0.54; P < .001). Receipt of chemotherapy after cranial radiotherapy, number of brain metastases, extracranial metastases, age, and performance status were also associated with OS. CONCLUSIONS NSCLC patients with genetic alterations in ALK have improved survival outcomes after radiotherapy for brain metastases compared with EGFR, KRAS, or WT. Subsequent receipt of targeted therapy was associated with additional improvement in OS.

Vertebral compression fractures after stereotactic body radiation therapy: a large, multi-institutional, multinational evaluation

OBJECTIVE The purpose of this study was to identify factors contributing to an increased risk for vertebral compression fracture (VCF) following stereotactic body radiation therapy (SBRT) for spinal tumors. METHODS A total of 594 tumors were treated with spinal SBRT as primary treatment or re-irradiation at 8 different institutions as part of a multi-institutional research consortium. Patients underwent LINAC-based, image-guided SBRT to a median dose of 20 Gy (range 8-40 Gy) in a median of 1 fraction (range 1-5 fractions). Median patient age was 62 years. Seventy-one percent of tumors were osteolytic, and a preexisting vertebral compression fracture (VCF) was present in 24% of cases. Toxicity was assessed following treatment. Univariate and multivariate analyses were performed using a logistic regression method to determine parameters predictive for post-SBRT VCF. RESULTS At a median follow-up of 10.1 months (range 0.03-57 months), 80% of patients had local tumor control. At the time of last imaging follow-up, at a median of 8.8 months after SBRT, 3% had a new VCF, and 2.7% had a progressive VCF. For development of any (new or progressive) VCF following SBRT, the following factors were predictive for VCF on univariate analysis: short interval from primary diagnosis to SBRT (less than 36.8 days), solitary metastasis, no additional bone metastases, no prior chemotherapy, preexisting VCF, no MRI used for target delineation, tumor volume of 37.3 cm(3) or larger, equivalent 2-Gy-dose (EQD2) tumor of 41.8 Gy or more, and EQD2 spinal cord Dmax of 46.1 Gy or more. Preexisting VCF, solitary metastasis, and prescription dose of 38.4 Gy or more were predictive on multivariate analysis. The following factors were predictive of a new VCF on univariate analysis: solitary metastasis, no additional bone metastases, and no MRI used for target delineation. Presence of a solitary metastasis and lack of MRI for target delineation remained significant on multivariate analysis. CONCLUSIONS A VCF following SBRT is more likely to occur following treatment for a solitary spinal metastasis, reflecting a more aggressive treatment approach in patients with adequately controlled systemic disease. Higher prescription dose and a preexisting VCF also put patients at increased risk for post-SBRT VCF. In these patients, pre-SBRT cement augmentation could be considered to decrease the risk of subsequent VCF.

Outcomes of Multidisciplinary Management in Pediatric Low-grade Gliomas

PURPOSE To evaluate the outcomes in pediatric low-grade gliomas managed in a multidisciplinary setting. METHODS AND MATERIALS We conducted a single-institution retrospective study of 181 children with Grade I-II gliomas. Log-rank and stepwise Cox proportional hazards models were used to analyze freedom from progression (FFP) and overall survival (OS). RESULTS Median follow-up was 6.4 years. Thirty-four (19%) of patients had neurofibromatosis Type 1 (NF1) and because of their favorable prognosis were evaluated separately. In the 147 (81%) of patients without NF1, actuarial 7-year FFP and OS were 67 ± 4% (standard error) and 94 ± 2%, respectively. In this population, tumor location in the optic pathway/hypothalamus was associated with worse FFP (39% vs. 76%, p < 0.0003), but there was no difference in OS. Age ≤5 years was associated with worse FFP (52% vs. 75%, p < 0.02) but improved OS (97% vs. 92%, p < 0.05). In those with tissue diagnosis, gross total resection (GTR) was associated with improved 7-year FFP (81% vs. 56%, p < 0.02) and OS (100% vs. 90%, p < 0.03). In a multivariate model, only location in the optic pathway/hypothalamus predicted worse FFP (p < 0.01). Fifty patients received radiation therapy (RT). For those with less than GTR, adjuvant RT improved FFP (89% vs. 49%, p < 0.003) but not OS. There was no difference in OS between patient groups given RT as adjuvant vs. salvage therapy. In NF1 patients, 94% of tumors were located in the optic pathway/hypothalamus. With a conservative treatment strategy in this population, actuarial 7-year FFP and OS were 73 ± 9% and 100%, respectively. CONCLUSIONS Low-grade gliomas in children ≤5 years old with tumors in the optic pathway/hypothalamus are more likely to progress, but this does not confer worse OS because of the success of salvage therapy. When GTR is not achieved, adjuvant RT improves FFP but not OS. Routine adjuvant RT can be avoided and instead reserved as salvage.

Proton therapy for low-grade gliomas: Results from a prospective trial.

In this prospective study, the authors evaluated potential treatment toxicity and progression‐free survival in patients with low‐grade glioma who received treatment with proton radiation therapy.

Case 21-2013: A 68-Year-Old Man with Metastatic Melanoma

Dr. Donald P. Lawrence: A 68-year-old man was seen in the cancer center at this hospital because of metastatic melanoma. Eleven years earlier, a superficial spreading melanoma had been excised from the right lower leg. The patient had been well until approximately 5 weeks before presentation to this hospital, when pain and swelling developed in the right leg and groin. Four weeks before presentation, he was seen in the emergency department at another hospital. Examination revealed a mass in the right groin, with surrounding erythema. A course of cephalexin was administered, with resolution of pain and erythema but persistence of the mass. Computed tomography (CT) of the pelvis reportedly revealed an irregular mass (3.1 cm in diameter) in the right groin. One week later, combination positron-emission tomography (PET) and CT (PET-CT) reportedly revealed hypermetabolic lymph nodes involving the right external iliac, femoral, and inguinal regions, and the medial right thigh. Eight days before presentation to this hospital, an ultrasound-guided biopsy of a lymph node in the right groin was performed at the other hospital. Pathological examination showed metastatic melanoma. The patient was referred to the cancer center at this hospital. The patient reported feeling well, with no pain, fatigue, nausea, weight loss, headaches, cough, or dyspnea. He had a history of hypertension, gastroesophageal reflux disease, diverticulitis, cardiomyopathy, coronary artery disease (he had undergone placement of a stent 1 year earlier), and hearing loss. He had a history of extensive sun exposure. Medications included aspirin, metoprolol, digoxin, hydrochlorothiazide, valsartan, clopidogrel, and a multivitamin, as well as acetaminophen and nitroglycerin spray, as needed. He had no known allergies. He lived with his wife and was retired, having previously worked as a landscaper and mechanic. He remained physically active, performing farm work. He had smoked three packs of cigarettes daily for 20 years (stopping 20 years earlier), drank alcohol infrequently, and did not use illicit drugs. His sister had had uterine cancer, and his maternal grandmother had had breast cancer; there was no family history of melanoma.

Immune Effects of Chemotherapy, Radiation, and Targeted Therapy and Opportunities for Combination With Immunotherapy

There have been significant advances in cancer treatment over the past several years through the use of chemotherapy, radiation therapy, molecularly targeted therapy, and immunotherapy. Despite these advances, treatments such as monotherapy or monomodality have significant limitations. There is increasing interest in using these strategies in combination; however, it is not completely clear how best to incorporate molecularly targeted and immune-targeted therapies into combination regimens. This is particularly pertinent when considering combinations with immunotherapy, as other types of therapy may have significant impact on host immunity, the tumor microenvironment, or both. Thus, the influence of chemotherapy, radiation therapy, and molecularly targeted therapy on the host anti-tumor immune response and the host anti-host response (ie, autoimmune toxicity) must be taken into consideration when designing immunotherapy-based combination regimens. We present data related to many of these combination approaches in the context of investigations in patients with melanoma and discuss their potential relationship to management of patients with other tumor types. Importantly, we also highlight challenges of these approaches and emphasize the need for continued translational research.

Case 21-2013

Dr. Donald P. Lawrence: A 68-year-old man was seen in the cancer center at this hospital because of metastatic melanoma. Eleven years earlier, a superficial spreading melanoma had been excised from the right lower leg. The patient had been well until approximately 5 weeks before presentation to this hospital, when pain and swelling developed in the right leg and groin. Four weeks before presentation, he was seen in the emergency department at another hospital. Examination revealed a mass in the right groin, with surrounding erythema. A course of cephalexin was administered, with resolution of pain and erythema but persistence of the mass. Computed tomography (CT) of the pelvis reportedly revealed an irregular mass (3.1 cm in diameter) in the right groin. One week later, combination positron-emission tomography (PET) and CT (PET-CT) reportedly revealed hypermetabolic lymph nodes involving the right external iliac, femoral, and inguinal regions, and the medial right thigh. Eight days before presentation to this hospital, an ultrasound-guided biopsy of a lymph node in the right groin was performed at the other hospital. Pathological examination showed metastatic melanoma. The patient was referred to the cancer center at this hospital. The patient reported feeling well, with no pain, fatigue, nausea, weight loss, headaches, cough, or dyspnea. He had a history of hypertension, gastroesophageal reflux disease, diverticulitis, cardiomyopathy, coronary artery disease (he had undergone placement of a stent 1 year earlier), and hearing loss. He had a history of extensive sun exposure. Medications included aspirin, metoprolol, digoxin, hydrochlorothiazide, valsartan, clopidogrel, and a multivitamin, as well as acetaminophen and nitroglycerin spray, as needed. He had no known allergies. He lived with his wife and was retired, having previously worked as a landscaper and mechanic. He remained physically active, performing farm work. He had smoked three packs of cigarettes daily for 20 years (stopping 20 years earlier), drank alcohol infrequently, and did not use illicit drugs. His sister had had uterine cancer, and his maternal grandmother had had breast cancer; there was no family history of melanoma.

Alectinib Dose Escalation Reinduces Central Nervous System Responses in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer Relapsing on Standard Dose Alectinib

The central nervous system (CNS) is an important and increasingly recognized site of treatment failure in anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC) patients receiving ALK inhibitors. In this report, we describe two ALK-positive patients who experienced initial improvements in CNS metastases on standard dose alectinib (600 mg twice daily), but who subsequently experienced recurrences with symptomatic leptomeningeal metastases. Both patients were dose-escalated to alectinib 900 mg twice daily, resulting in repeat clinical and radiographic responses. Our results suggest that dose intensification of alectinib may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis.