Simon S. Lo

Palliative radiotherapy for bone metastases: An ASTRO evidence-based guideline

PURPOSE To present guidance for patients and physicians regarding the use of radiotherapy in the treatment of bone metastases according to current published evidence and complemented by expert opinion. METHODS AND MATERIALS A systematic search of the National Library of Medicines PubMed database between 1998 and 2009 yielded 4,287 candidate original research articles potentially applicable to radiotherapy for bone metastases. A Task Force composed of all authors synthesized the published evidence and reached a consensus regarding the recommendations contained herein. RESULTS The Task Force concluded that external beam radiotherapy continues to be the mainstay for the treatment of pain and/or prevention of the morbidity caused by bone metastases. Various fractionation schedules can provide significant palliation of symptoms and/or prevent the morbidity of bone metastases. The evidence for the safety and efficacy of repeat treatment to previously irradiated areas of peripheral bone metastases for pain was derived from both prospective studies and retrospective data, and it can be safe and effective. The use of stereotactic body radiotherapy holds theoretical promise in the treatment of new or recurrent spine lesions, although the Task Force recommended that its use be limited to highly selected patients and preferably within a prospective trial. Surgical decompression and postoperative radiotherapy is recommended for spinal cord compression or spinal instability in highly selected patients with sufficient performance status and life expectancy. The use of bisphosphonates, radionuclides, vertebroplasty, and kyphoplasty for the treatment or prevention of cancer-related symptoms does not obviate the need for external beam radiotherapy in appropriate patients. CONCLUSIONS Radiotherapy is a successful and time efficient method by which to palliate pain and/or prevent the morbidity of bone metastases. This Guideline reviews the available data to define its proper use and provide consensus views concerning contemporary controversies or unanswered questions that warrant prospective trial evaluation.

Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline

Purpose To systematically review the evidence for the radiotherapeutic and surgical management of patients newly diagnosed with intraparenchymal brain metastases. Methods and Materials Key clinical questions to be addressed in this evidence-based Guideline were identified. Fully published randomized controlled trials dealing with the management of newly diagnosed intraparenchymal brain metastases were searched systematically and reviewed. The U.S. Preventative Services Task Force levels of evidence were used to classify various options of management. Results The choice of management in patients with newly diagnosed single or multiple brain metastases depends on estimated prognosis and the aims of treatment (survival, local treated lesion control, distant brain control, neurocognitive preservation). Single brain metastasis and good prognosis (expected survival 3 months or more): For a single brain metastasis larger than 3 to 4 cm and amenable to safe complete resection, whole brain radiotherapy (WBRT) and surgery (level 1) should be considered. Another alternative is surgery and radiosurgery/radiation boost to the resection cavity (level 3). For single metastasis less than 3 to 4 cm, radiosurgery alone or WBRT and radiosurgery or WBRT and surgery (all based on level 1 evidence) should be considered. Another alternative is surgery and radiosurgery or radiation boost to the resection cavity (level 3). For single brain metastasis (less than 3 to 4 cm) that is not resectable or incompletely resected, WBRT and radiosurgery, or radiosurgery alone should be considered (level 1). For nonresectable single brain metastasis (larger than 3 to 4 cm), WBRT should be considered (level 3). Multiple brain metastases and good prognosis (expected survival 3 months or more): For selected patients with multiple brain metastases (all less than 3 to 4 cm), radiosurgery alone, WBRT and radiosurgery, or WBRT alone should be considered, based on level 1 evidence. Safe resection of a brain metastasis or metastases causing significant mass effect and postoperative WBRT may also be considered (level 3). Patients with poor prognosis (expected survival less than 3 months): Patients with either single or multiple brain metastases with poor prognosis should be considered for palliative care with or without WBRT (level 3). It should be recognized, however, that there are limitations in the ability of physicians to accurately predict patient survival. Prognostic systems such as recursive partitioning analysis, and diagnosis-specific graded prognostic assessment may be helpful. Conclusions Radiotherapeutic intervention (WBRT or radiosurgery) is associated with improved brain control. In selected patients with single brain metastasis, radiosurgery or surgery has been found to improve survival and locally treated metastasis control (compared with WBRT alone).

Stereotactic body radiation therapy: a novel treatment modality

Stereotactic body radiation therapy (SBRT) involves the delivery of a small number of ultra-high doses of radiation to a target volume using very advanced technology and has emerged as a novel treatment modality for cancer. The role of SBRT is most important at two cancer stages—in early primary cancer and in oligometastatic disease. This modality has been used in the treatment of early-stage non-small-cell lung cancer, prostate cancer, renal-cell carcinoma, and liver cancer, and in the treatment of oligometastases in the lung, liver, and spine. A large body of evidence on the use of SBRT for the treatment of primary and metastatic tumors in various sites has accumulated over the past 10–15 years, and efficacy and safety have been demonstrated. Several prospective clinical trials of SBRT for various sites have been conducted, and several other trials are currently being planned. The results of these clinical trials will better define the role of SBRT in cancer management. This article will review the radiobiologic, technical, and clinical aspects of SBRT.

Brachial plexopathy from stereotactic body radiotherapy in early-stage NSCLC: Dose-limiting toxicity in apical tumor sites

BACKGROUND AND PURPOSE We report frequency of brachial plexopathy in early-stage non-small cell lung cancer treated with stereotactic body radiotherapy. MATERIALS AND METHODS 276 T1-T2, N0 or peripheral T3, N0 lesions were treated in 253 patients with stereotactic radiotherapy at Indiana University and Richard L. Roudebush VAMC from 1998 to 2007. Thirty-seven lesions in 36 patients were identified as apical lesions, defined as epicenter of lesion superior to aortic arch. Brachial plexus toxicity was scored for these apical lesions according to CTCAE v. 3.0 for ipsilateral shoulder/arm neuropathic pain, motor weakness, or sensory alteration. RESULTS The 37 apical lesions (19 Stage IA, 16 IB, and 2 IIB) were treated with stereotactic body radiotherapy to a median total dose of 57 Gy (30-72). The associated brachial plexus of 7/37 apical lesions developed grade 2-4 plexopathy (4 pts--grade 2, 2 pts--grade 3, 1 pt--grade 4). Five patients had ipsilateral shoulder/arm neuropathic pain alone, one had pain and upper extremity weakness, and one had pain progressing to numbness of the upper extremity and paralysis of hand and wrist. The median of the maximum brachial plexus doses of patients developing brachial plexopathy was 30 Gy (18-82). Two-year Kaplan-Meier risk of brachial plexopathy for maximum brachial plexus dose >26 Gy was 46% vs 8% for doses 26 Gy (p=0.04 for likelihood ratio test). CONCLUSIONS Stereotactic body radiotherapy for apical lesions carries a risk of brachial plexopathy. Brachial plexus maximum dose should be kept <26 Gy in 3 or 4 fractions.

A Generalized Linear-Quadratic Model for Radiosurgery, Stereotactic Body Radiation Therapy, and High–Dose Rate Brachytherapy

A generalized mathematical model for the relation between radiation dose and tumor cell death enables better treatment planning and dose schedule designs for current targeted high-dose radiation therapies in cancer. Better Aim Through Better Math More like a laser-guided missile than a conventional bomb, current radiation therapy for cancer hits small targets and tries to minimize collateral damage. Better imaging and delivery, and new ways to keep patients immobilized, have improved our ability to irradiate small, defined areas. Because the doses can be higher when the radiation beams are highly focused (and normal tissue is less likely to suffer), new radiation therapies are given in fewer, larger doses than the long series of low-dose treatments used in the past. But the use of large doses has been problematic, because the calculations used historically to devise the dose and schedule for therapy do not work well with large shots of radiation. Wang et al. have now derived a general equation that applies to both low- and high-dose treatment situations, and so will improve further the effectiveness of current radiation treatments for cancer. When radiation oncologists develop a treatment plan for a cancer patient, they make assumptions about how much radiation is needed to kill the tumor cells. Guided by past experiments, the linear-quadratic equation has defined this dose-response relationship for decades. But this equation does not account for the fact that at high radiation doses there is less sublethal damage to DNA (and more lethal damage). The resulting error in the calculation grows as the doses get higher, causing the effectiveness of a given amount of radiation to be overestimated, potentially leading to inadequate treatment of patients. The general form of the linear-quadratic equation (gLQ) that is derived here by Wang et al. is valid at both low and high doses and accurately calculates the amount of sublethal damage to DNA. They show that the traditional LQ model is an instance of the general model, as is another model used for high radiation doses, called the target model. Experiments taken from the literature, which measure the effects of a wide dose range of radiation on cells grown in vitro and in animals, confirm that the gLQ model accurately predicts the killing effects of radiation through the whole dose range (up to 13 Gy, the highest amount given to animals). When used to predict high-dose responses, the standard LQ model does not conform to the actual data. The gLQ will be a boon to physicians for designing ever more sophisticated, specialized high-dose cancer therapies. With this approach, unusual treatment regimes that use one or a few large doses can be more accurately administered, and the abundant clinical experience in the low-dose range can be extrapolated to high doses. The gLQ, combined with newer image-guided radiation therapy, should markedly enable improvements in radiation ablation of solid cancers. Conventional radiation therapy for cancer usually consists of multiple treatments (called fractions) with low doses of radiation. These dose schemes are planned with the guidance of the linear-quadratic (LQ) model, which has been the most prevalent model for designing dose schemes in radiation therapy. The high-dose fractions used in newer advanced radiosurgery, stereotactic radiation therapy, and high–dose rate brachytherapy techniques, however, cannot be accurately calculated with the traditional LQ model. To address this problem, we developed a generalized LQ (gLQ) model that encompasses the entire range of possible dose delivery patterns and derived formulas for special radiotherapy schemes. We show that the gLQ model can naturally derive the traditional LQ model for low-dose and low–dose rate irradiation and the target model for high-dose irradiation as two special cases of gLQ. LQ and gLQ models were compared with published data obtained in vitro from Chinese hamster ovary cells across a wide dose range [0 to ~11.5 gray (Gy)] and from animals with dose fractions up to 13.5 Gy. The gLQ model provided consistent interpretation across the full dose range, whereas the LQ model generated parameters that depended on dose range, fitted only data with doses of 3.25 Gy or less, and failed to predict high-dose responses. Therefore, the gLQ model is useful for analyzing experimental radiation response data across wide dose ranges and translating common low-dose clinical experience into high-dose radiotherapy schemes for advanced radiation treatments.

Complications associated with double balloon enteroscopy at nine US centers.

BACKGROUND & AIMS Double balloon enteroscopy (DBE) was introduced into the US in 2004. Potential complications include perforation, pancreatitis, and gastrointestinal bleeding. Prevalence and risk factors for complications have not been described in a US population. METHODS We conducted a retrospective study of DBE complications in 9 US centers. We obtained detailed information for each complication including patient history, maneuvers performed during the DBE, and presence of altered surgical anatomy. RESULTS We collected data from 2478 DBE examinations performed from 2004 to 2008. The dataset included 1691 (68%) anterograde DBE, 722 (29%) retrograde DBE (including 5 per-stomal DBEs), and 65 (3%) DBE-facilitated endoscopic retrograde cholangiopancreatography ERCP cases. There were a total of 22 (0.9%) major complications including perforation in 11 (0.4%), pancreatitis in 6 (0.2%), and bleeding in 4 (0.2%) patients. One of 6 cases of pancreatitis occurred post retrograde DBE. Perforations occurred in 3/1691 (0.2%) anterograde examinations and 8/719 (1.1%) retrograde DBEs (P = .004). Eight (73%) perforations occurred during diagnostic DBE examinations. Four of 8 retrograde DBE perforations occurred in patients with prior ileoanal or ileocolonic anastomoses. In the subset of 219 examinations performed in patients with surgically altered anatomy, perforations occurred in 7 (3%), including 1/159 (0.6%) anterograde DBE examinations, 6/60 (10%) retrograde DBEs, and 1 of 5 (20%) peristomal DBE examinations (P < .005 compared with patients without surgically altered anatomy). CONCLUSIONS DBE is associated with a higher complication rate compared with standard endoscopic procedures. The perforation rate was significantly elevated in patients with altered surgical anatomy undergoing diagnostic retrograde DBE examinations.

Endoscopic full-thickness plication for the treatment of GERD: 12-month follow-up for the North American open-label trial

BACKGROUND The aim of this study was to assess the intermediate-term (12-month) safety and efficacy of endoscopic full-thickness plication in patients with symptomatic GERD. METHODS Sixty-four patients with chronic heartburn that required maintenance antisecretory therapy received a single, endoscopically placed, full-thickness plication in the gastric cardia 1 cm distal to the gastroesophageal junction. At baseline and 12 months after plication, patients completed the GERD Health Related Quality of Life questionnaire, Gastrointestinal Symptom Rating Scale, and SF-36 Health Survey, as well as a medication use diary. Ambulatory 24-hour pH monitoring and esophageal manometry were obtained at baseline and 3 months after plication. At 6 months after plication, the 24-hour pH study was repeated. RESULTS Of the 57 patients who completed the 12-month follow-up, 40 (70%) were no longer taking a proton pump inhibitor. Median GERD Health Related Quality of Life scores were improved compared with baseline while taking medication (19.0 vs. 5.0; p < 0.0001) and while not taking medication (13.0 vs. 5.0; p < 0.002). At 6 months after the procedure, an improvement in distal esophageal acid exposure was demonstrated in 40 of 51 patients (80%), with a decrease of 39% in the median percentage of time the pH was less than 4 (p < 0.0001). Normal pH scores were observed in 30% of patients. All procedure-related adverse events occurred acutely, as previously reported, and no new adverse event was observed during extended follow-up. CONCLUSIONS Full-thickness plication at the gastroesophageal junction is an effective endoscopic procedure for treatment of patients with symptoms caused by GERD. It reduces reflux symptoms and antisecretory medication use over at least a 1-year period.

Phase IB Study of Gene-Mediated Cytotoxic Immunotherapy Adjuvant to Up-Front Surgery and Intensive Timing Radiation for Malignant Glioma

PURPOSE Despite aggressive therapies, median survival for malignant gliomas is less than 15 months. Patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) fare worse, presumably because of temozolomide resistance. AdV-tk, an adenoviral vector containing the herpes simplex virus thymidine kinase gene, plus prodrug synergizes with surgery and chemoradiotherapy, kills tumor cells, has not shown MGMT dependency, and elicits an antitumor vaccine effect. PATIENTS AND METHODS Patients with newly diagnosed malignant glioma received AdV-tk at 3 × 10(10), 1 × 10(11), or 3 × 10(11) vector particles (vp) via tumor bed injection at time of surgery followed by 14 days of valacyclovir. Radiation was initiated within 9 days after AdV-tk injection to overlap with AdV-tk activity. Temozolomide was administered after completing valacyclovir treatment. RESULTS Accrual began December 2005 and was completed in 13 months. Thirteen patients were enrolled and 12 completed therapy, three at dose levels 1 and 2 and six at dose level 3. There were no dose-limiting or significant added toxicities. One patient withdrew before completing prodrug because of an unrelated surgical complication. Survival at 2 years was 33% and at 3 years was 25%. Patient-reported quality of life assessed with the Functional Assessment of Cancer Therapy-Brain (FACT-Br) was stable or improved after treatment. A significant CD3(+) T-cell infiltrate was found in four of four tumors analyzed after treatment. Three patients with MGMT unmethylated glioblastoma multiforme survived 6.5, 8.7, and 46.4 months. CONCLUSION AdV-tk plus valacyclovir can be safely delivered with surgery and accelerated radiation in newly diagnosed malignant gliomas. Temozolomide did not prevent immune responses. Although not powered for efficacy, the survival and MGMT independence trends are encouraging. A phase II trial is ongoing.

Predicting Control of Primary Tumor and Survival by DCE MRI During Early Therapy in Cervical Cancer

Purpose:To assess the early predictive power of MRI perfusion and volume parameters, during early treatment of cervical cancer, for primary tumor control and disease-free-survival. Materials and Methods:Three MRI examinations were obtained in 101 patients before and during therapy (at 2–2.5 and 4–5 weeks) for serial dynamic contrast enhanced (DCE) perfusion MRI and 3-dimensional tumor volume measurement. Plateau Signal Intensity (SI) of the DCE curves for each tumor pixel of all 3 MRI examinations was generated, and pixel-SI distribution histograms were established to characterize the heterogeneous tumor. The degree and quantity of the poorly-perfused tumor subregions, which were represented by low-DCE pixels, was analyzed by using various lower percentiles of SI (SI%) from the pixel histogram. SI% ranged from SI2.5% to SI20% with increments of 2.5%. SI%, mean SI, and 3-dimensional volume of the tumor were correlated with primary tumor control and disease-free-survival, using Student t test, Kaplan-Meier analysis, and log-rank test. The mean post-therapy follow-up time for outcome assessment was 6.8 years (range: 0.2–9.4 years). Results:Tumor volume, mean SI, and SI% showed significant prediction of the long-term clinical outcome, and this prediction was provided as early as 2 to 2.5 weeks into treatment. An SI5% of <2.05 and residual tumor volume of ≥30 cm3 in the MRI obtained at 2 to 2.5 weeks of therapy provided the best prediction of unfavorable 8-year primary tumor control (73% vs. 100%, P = 0.006) and disease-free-survival rate (47% vs. 79%, P = 0.001), respectively. Conclusions:Our results show that MRI parameters quantifying perfusion status and residual tumor volume provide very early prediction of primary tumor control and disease-free-survival. This functional imaging based outcome predictor can be obtained in the very early phase of cytotoxic therapy within 2 to 2.5 weeks of therapy start. The predictive capacity of these MRI parameters, indirectly reflecting the heterogeneous delivery pattern of cytotoxic agents, tumor oxygenation, and the bulk of residual presumably therapy-resistant tumor, requires future study.

Multicenter results of stereotactic body radiotherapy (SBRT) for non-resectable primary liver tumors

Abstract Background. An excess of 100 000 individuals are diagnosed with primary liver tumors every year in USA but less than 20% of those patients are amenable to definitive surgical management due to advanced local disease or comorbidities. Local therapies to arrest tumor growth have limited response and have shown no improvement on patient survival. Stereotactic body radiotherapy (SBRT) has emerged as an alternative local ablative therapy. The purpose of this study was to evaluate the tumor response to SBRT in a combined multicenter database. Study design. Patients with advanced hepatocellular carcinoma (HCC, n = 21) or intrahepatic cholangiocarcinoma (ICC, n = 11) treated with SBRT from four Academic Medical Centers were entered into a common database. Statistical analyses were performed for freedom from local progression (FFLP) and patient survival. Results. The overall FFLP for advanced HCC was 63% at a median follow-up of 12.9 months. Median tumor volume decreased from 334.2 to 135 cm3 (p < 0.004). The median time to local progression was 6.3 months. The 1- and 2-years overall survival rates were 87% and 55%, respectively. Patients with ICC had an overall FFLP of 55.5% at a median follow-up of 7.8 months. The median time to local progression was 4.2 months and the six-month and one-year overall survival rates were 75% and 45%, respectively. The incidence of grade 1–2 toxicities, mostly nausea and fatigue, was 39.5%. Grade 3 and 4 toxicities were present in two and one patients, respectively. Conclusion. Higher rates of FFLP were achieved by SBRT in the treatment of primary liver malignancies with low toxicity.