James M. Larner

Chest Wall Volume Receiving >30 Gy Predicts Risk of Severe Pain and/or Rib Fracture After Lung Stereotactic Body Radiotherapy

PURPOSE To identify the dose-volume parameters that predict the risk of chest wall (CW) pain and/or rib fracture after lung stereotactic body radiotherapy. METHODS AND MATERIALS From a combined, larger multi-institution experience, 60 consecutive patients treated with three to five fractions of stereotactic body radiotherapy for primary or metastatic peripheral lung lesions were reviewed. CW pain was assessed using the Common Toxicity Criteria for pain. Peripheral lung lesions were defined as those located within 2.5 cm of the CW. A minimal point dose of 20 Gy to the CW was required. The CW volume receiving >or=20, >or=30, >or=40, >or=50, and >or=60 Gy was determined and related to the risk of CW toxicity. RESULTS Of the 60 patients, 17 experienced Grade 3 CW pain and five rib fractures. The median interval to the onset of severe pain and/or fracture was 7.1 months. The risk of CW toxicity was fitted to the median effective concentration dose-response model. The CW volume receiving 30 Gy best predicted the risk of severe CW pain and/or rib fracture (R(2) = 0.9552). A volume threshold of 30 cm(3) was observed before severe pain and/or rib fracture was reported. A 30% risk of developing severe CW toxicity correlated with a CW volume of 35 cm(3) receiving 30 Gy. CONCLUSION The development of CW toxicity is clinically relevant, and the CW should be considered an organ at risk in treatment planning. The CW volume receiving 30 Gy in three to five fractions should be limited to <30 cm(3), if possible, to reduce the risk of toxicity without compromising tumor coverage.

A phase I-II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme

Malignant gliomas are thought to be highly dependent on the mevalonate pathway for cell growth. Lovastatin, a cholesterol-lowering drug, inhibits not only the rate-limiting step in the mevalonate pathway (hepatic hydroxymethyl glutaryl coenzyme A reductase), but also the prenylation of several key regulatory proteins including ras and the small guanosine triphosphate binding proteins. Therefore, from August 1994 through March 1996, 18 patients with either anaplastic glioma or glioblastoma multiforme were entered into a trial testing the safety of high-dose lovastatin with or without radiation. Although the response data is too premature to evaluate activity, the fact that high doses of lovastatin are well tolerated with concurrent radiation suggests that central nervous system toxicity will not be a significant limiting toxicity as more selective farnesyltransferase inhibitors are brought into the clinic as radiation sensitizers.

Special Treatment Issues in Non-small Cell Lung Cancer: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND This guideline updates the second edition and addresses patients with particular forms of non-small cell lung cancer that require special considerations, including Pancoast tumors, T4 N0,1 M0 tumors, additional nodules in the same lobe (T3), ipsilateral different lobe (T4) or contralateral lung (M1a), synchronous and metachronous second primary lung cancers, solitary brain and adrenal metastases, and chest wall involvement. METHODS The nature of these special clinical cases is such that in most cases, meta-analyses or large prospective studies of patients are not available. To ensure that these guidelines were supported by the most current data available, publications appropriate to the topics covered in this article were obtained by performing a literature search of the MEDLINE computerized database. Where possible, we also reference other consensus opinion statements. Recommendations were developed by the writing committee, graded by a standardized method, and reviewed by all members of the Lung Cancer Guidelines panel prior to approval by the Thoracic Oncology NetWork, Guidelines Oversight Committee, and the Board of Regents of the American College of Chest Physicians. RESULTS In patients with a Pancoast tumor, a multimodality approach appears to be optimal, involving chemoradiotherapy and surgical resection, provided that appropriate staging has been carried out. Carefully selected patients with central T4 tumors that do not have mediastinal node involvement are uncommon, but surgical resection appears to be beneficial as part of their treatment rather than definitive chemoradiotherapy alone. Patients with lung cancer and an additional malignant nodule are difficult to categorize, and the current stage classification rules are ambiguous. Such patients should be evaluated by an experienced multidisciplinary team to determine whether the additional lesion represents a second primary lung cancer or an additional tumor nodule corresponding to the dominant cancer. Highly selected patients with a solitary focus of metastatic disease in the brain or adrenal gland appear to benefit from resection or stereotactic radiosurgery. This is particularly true in patients with a long disease-free interval. Finally, in patients with chest wall involvement, provided that the tumor can be completely resected and N2 nodal disease is absent, primary surgical resection should be considered. CONCLUSIONS Carefully selected patients with more uncommon presentations of lung cancer may benefit from an aggressive surgical approach.

The role of preoperative adjuvant treatment in the management of esthesioneuroblastoma: the University of Virginia experience.

OBJECTIVE Multidisciplinary management of esthesioneuroblastoma has effected markedly increased survival during the past 20 years. The potential for radical craniofacial surgery for complete en bloc resection, the availability of advanced neuroimaging modalities, and the incorporation of neoadjuvant therapy into treatment strategies for tumor remission have all contributed to this accomplishment. However, a standard protocol for the management of these lesions has not been accepted; preoperative radiation and chemotherapy have been advocated, but neither radiographic nor clinical response has been quantified. METHODS Thirty-four consecutive patients with biopsy-proven esthesioneuroblastoma treated at one institution from 1976 to 1994 were reviewed to determine the effects of preoperative radiation therapy, with or without chemotherapy, on tumor size and long-term survival. RESULTS In a multivariate regression analysis, advanced age was predictive of decreased disease-free survival (P=0.008), whereas advanced Kadish stage was associated with a borderline higher rate of disease-related mortality (P=0.056). Two-thirds of the patients showed a significant reduction in tumor burden with adjuvant therapy. Patients with response to neoadjuvant therapy demonstrated a significantly lower rate of disease-related mortality (P=0.050). In this series, the overall 5- and 10-year survival rates were 81.0 and 54.5%, respectively. CONCLUSION Preoperative neoadjuvant therapy provides a valuable complement to radical craniofacial resection, leading to reduction in tumor burden. Patients experiencing reduction in tumor volume by neoadjuvant therapy demonstrate an improved prognosis.

Gamma Knife radiosurgery to the surgical cavity following resection of brain metastases.

OBJECT This study evaluated the efficacy of postoperative Gamma Knife surgery (GKS) to the tumor cavity following gross-total resection of a brain metastasis. METHODS A retrospective review was conducted of 700 patients who were treated for brain metastases using GKS. Forty-seven patients with pathologically confirmed metastatic disease underwent GKS to the postoperative resection cavity following gross-total resection of the tumor. Patients who underwent subtotal resection or who had visible tumor in the resection cavity on the postresection neuroimaging study (either CT or MR imaging with and without contrast administration) were excluded. Radiographic and clinical follow-up was assessed using clinic visits and MR imaging. The radiographic end point was defined as tumor growth control (no tumor growth regarding the resection cavity, and stable or decreasing tumor size for the other metastatic targets). Clinical end points were defined as functional status (assessed prospectively using the Karnofsky Performance Scale) and survival. Primary tumor pathology was consistent with lung cancer in 19 cases (40%), melanoma in 10 cases (21%), renal cell carcinoma in 7 cases (15%), breast cancer in 7 cases (15%), and gastrointestinal malignancies in 4 cases (9%). The mean duration between resection and radiosurgery was 15 days (range 2-115 days). The mean volume of the treated cavity was 10.5 cm3 (range 1.75-35.45 cm3), and the mean dose to the cavity margin was 19 Gy. In addition to the resection cavity, 34 patients (72%) underwent GKS for 116 synchronous metastases observed at the time of the initial radiosurgery. RESULTS The mean radiographic follow-up duration was 14 months (median 10 months, range 4-37 months). Local tumor control at the site of the surgical cavity was achieved in 44 patients (94%), and tumor recurrence at the surgical site was statistically related to the volume of the surgical cavity (p=0.04). During follow-up, 34 patients (72%) underwent additional radiosurgery for 140 new (metachronous) metastases. At the most recent follow-up evaluation, 11 patients (23%) were alive, whereas 36 patients had died (mean duration until death 12 months, median 10 months). Patients who showed good systemic control of their primary tumor tended to have longer survival durations than those who did not (p=0.004). At the last clinical follow-up evaluation, the mean Karnofsky Performance Scale score for the overall group was 78 (median 80, range 40-100). CONCLUSION Radiosurgery appears to be effective in terms of providing local tumor control at the resection cavity following resection of a brain metastasis, and in the treatment of synchronous and metachronous tumors. These data suggest that radiosurgery can be used to prevent recurrence following gross-total resection of a brain metastasis.

Size matters: a comparison of T1 and T2 peripheral non-small-cell lung cancers treated with stereotactic body radiation therapy (SBRT).

OBJECTIVE The purpose of this study was to compare the outcomes and local control rates of patients with peripheral T1 and T2 non-small-cell lung cancer treated with stereotactic body radiation therapy. METHODS The records of 40 consecutive patients treated with 3- or 5-fraction lung stereotactic body radiation therapy for peripheral, clinical stage I non-small-cell lung cancer were reviewed. Stereotactic body radiation therapy was delivered at a median dose of 60 Gy. Doses to organs at risk were limited based on the Radiation Therapy Oncology Group 0236 treatment protocol. Patients were staged clinically. Median follow was 12.5 months. RESULTS Twenty-seven (67%) patients and 13 (33%) patients had T1 and T2 tumors, respectively. Thirty-seven (94%) patients were medically inoperable. Nine (23%) patients had chest wall pain after stereotactic body radiation therapy. Symptomatic pneumonitis developed in 4 (10%) patients. Increasing tumor size correlated with worse local control and overall survival. The median recurrence-free survival for T1 and T2 tumors was 30.6 months (95% confidence interval [CI], 26.9-34.2) and 20.5 months (95% CI, 14.3-26.5), respectively (P = .038). Local control at 2 years was 90% and 70% in T1 and T2 tumors, respectively (P = .03). The median survival for T1 and T2 tumors was 20 months (95% CI, 20.1-31.6) and 16.7 months (95% CI, 10.8-21.2), respectively (P = .073). CONCLUSIONS Stereotactic body radiation therapy for T2 non-small-cell lung cancer has a higher local recurrence rate and trended toward a worse survival than did T1 lesions. Tumor size is an important predictor of response to stereotactic body radiation therapy and should be considered in treatment planning.

Cloning and characterization of Chinese hamster p53 cDNA

We have cloned and sequenced Chinese hamster p53 cDNA and have compared the p53 sequence in different Chinese hamster cell lines to several relevant phenotypes. Our results indicate that a mutation in CHO cells that changes Thr211 to Lys211 abrogates the ability to arrest in G1 and apparently renders cells capable of amplifying DNA. However, this mutation has no effect on the G2 checkpoint or on acute down-regulation of DNA replication after a radiation challenge.

Radiosurgery in the treatment of spinal metastases: tumor control, survival, and quality of life after helical tomotherapy.

OBJECTIVEThe effectiveness and limitations of spinal radiosurgery using a helical TomoTherapy system for the treatment of spinal metastases are reviewed in this article. METHODSThis is a retrospective review of patients who underwent stereotactic radiosurgery for spinal metastases between July 2004 and December 2007. Radiographic follow-up consisted of magnetic resonance imaging to assess tumor growth control as well as pre- and posttreatment x-rays, which were used to measure changes in segmental angulation and deformity. Clinical performance was assessed using the Karnofsky Performance Scale, Oswestry Disability Index, and visual analog scale. RESULTSForty patients were treated for 110 metastatic tumors (range, 1–6 tumors per patient). The mean age at the time of radiosurgical treatment was 67 years (age range, 35–81 years). Twenty-three patients (57.5%) had undergone previous surgical resection. Pain was the most common presenting symptom, seen in 32 patients (80%). The mean Oswestry Disability Index score at presentation was 43 (range, 20–90), and the mean visual analog scale score was 6.2 (range, 0–10). The mean radiosurgical dose to the tumor was 17.3 Gy (range, 10–24 Gy). At a mean follow-up duration of 12.7 months (range, 4–32 months), decreased or stable tumor volume was seen in 90 (82%) of the tumors treated. There was improvement in pain in 34 patients (85%). The mean postradiosurgical Oswestry Disability Index score was 25 (range, 10–90), whereas the postradiosurgical visual analog scale score was 3.2 (range, 0–9). Progression of kyphosis was the most common radiographic sequela, experienced by 73% of patients alive at 12 months, with a mean change in angulation of 7.3 ± 4.5 degrees. CONCLUSIONRadiosurgery is effective as either primary or adjunctive treatment of metastatic tumors of the spine.

Protein Phosphatase-1α Regulates Centrosome Splitting through Nek2

ATM is a central mediator of the cellular response to the DNA damage produced by ionizing radiation. We recently showed that protein phosphatase 1 (PP1) is activated by ATM. Because Nek2 is activated by autophosphorylation, and because its dephosphorylation is catalyzed by PP1, we asked if the radiation damage signal to Nek2 was mediated by PP1. Overexpression of Nek2 induces premature centrosome splitting probably by phosphorylating centrosome cohesion proteins C-Nap1 and Rootletin. In this study, we show isoform specificity of PP1 binding and regulation of Nek2. Although both PP1α and PP1γ coimmunoprecipitated with Nek2, only PP1α regulated Nek2 function. Ionizing radiation inhibited Nek2 activity, and this response was dependent on ATM and on PP1 binding to Nek2 and coincident with Thr320 dephosphorylation of PP1. Radiation-induced inhibition of centrosome splitting was abrogated in cells expressing Nek2 mutated in the PP1-binding motif outside the kinase domain. Conversely, cells depleted of PP1α by small interfering RNA showed enhanced centrosome splitting and loss of radiation-induced inhibition of centrosome splitting. The identification of a PP1-specific isoform mediating a checkpoint response opens up the possibility of selectively targeting phosphatases as novel radiation sensitizers. [Cancer Res 2007;67(3):1082–9]

MR‐guided focused ultrasound surgery, present and future

MR-guided focused ultrasound surgery (MRgFUS) is a quickly developing technology with potential applications across a spectrum of indications traditionally within the domain of radiation oncology. Especially for applications where focal treatment is the preferred technique (for example, radiosurgery), MRgFUS has the potential to be a disruptive technology that could shift traditional patterns of care. While currently cleared in the United States for the noninvasive treatment of uterine fibroids and bone metastases, a wide range of clinical trials are currently underway, and the number of publications describing advances in MRgFUS is increasing. However, for MRgFUS to make the transition from a research curiosity to a clinical standard of care, a variety of challenges, technical, financial, clinical, and practical, must be overcome. This installment of the Vision 20∕20 series examines the current status of MRgFUS, focusing on the hurdles the technology faces before it can cross over from a research technique to a standard fixture in the clinic. It then reviews current and near-term technical developments which may overcome these hurdles and allow MRgFUS to break through into clinical practice.