Impact of the radiosurgery prescription dose on the local control of small (2 cm or smaller) brain metastases


Abstract

OBJECTIVE

The impact of the stereotactic radiosurgery (SRS) prescription dose (PD) on local progression and radiation necrosis for small (≤ 2 cm) brain metastases was evaluated.

METHODS

An institutional review board–approved retrospective review was performed on 896 patients with brain metastases ≤ 2 cm (3034 tumors) who were treated with 1229 SRS procedures between 2000 and 2012. Local progression and/or radiation necrosis were the primary end points. Each tumor was followed from the date of radiosurgery until one of the end points was reached or the last MRI follow-up. Various criteria were used to differentiate tumor progression and radiation necrosis, including the evaluation of serial MRIs, cerebral blood volume on perfusion MR, FDG-PET scans, and, in some cases, surgical pathology. The median radiographic follow-up per lesion was 6.2 months.

RESULTS

The median patient age was 56 years, and 56% of the patients were female. The most common primary pathology was non–small cell lung cancer (44%), followed by breast cancer (19%), renal cell carcinoma (14%), melanoma (11%), and small cell lung cancer (5%). The median tumor volume and median largest diameter were 0.16 cm3 and 0.8 cm, respectively. In total, 1018 lesions (34%) were larger than 1 cm in maximum diameter. The PD for 2410 tumors (80%) was 24 Gy, for 408 tumors (13%) it was 19 to 23 Gy, and for 216 tumors (7%) it was 15 to 18 Gy. In total, 87 patients (10%) had local progression of 104 tumors (3%), and 148 patients (17%) had at least radiographic evidence of radiation necrosis involving 199 tumors (7%; 4% were symptomatic). Univariate and multivariate analyses were performed for local progression and radiation necrosis. For local progression, tumors less than 1 cm (subhazard ratio [SHR] 2.32; p < 0.001), PD of 24 Gy (SHR 1.84; p = 0.01), and additional whole-brain radiation therapy (SHR 2.53; p = 0.001) were independently associated with better outcome. For the development of radiographic radiation necrosis, independent prognostic factors included size greater than 1 cm (SHR 2.13; p < 0.001), location in the corpus callosum (SHR 5.72; p < 0.001), and uncommon pathologies (SHR 1.65; p = 0.05). Size (SHR 4.78; p < 0.001) and location (SHR 7.62; p < 0.001)—but not uncommon pathologies—were independent prognostic factors for the subgroup with symptomatic radiation necrosis.

CONCLUSIONS

A PD of 24 Gy results in significantly better local control of metastases measuring < 2 cm than lower doses. In addition, tumor size is an independent prognostic factor for both local progression and radiation necrosis. Some tumor pathologies and locations may also contribute to an increased risk of radiation necrosis.

The transformation of oncology


When I was trained at a prominent New York medical center in the 1960s, cancer was relegated to a minor place in the curriculum. Cancer patients were housed in a separate hospital, rarely visited by students or the medical house staff. If not amenable to surgery or radiotherapy, most cancers were regarded as hopeless. Research on cancer was not accorded the attention received by infectious, endocrine, autoimmune, cardiovascular, or neuropsychiatric disorders.

Now things are dramatically different in research, teaching, and care. Much of the new optimism comes from an understanding of cancer’s pathophysiology. Research has shown that cancers are intimately entwined with basic life processes—diseases of the genome, with perturbations of signaling pathways and essential cell functions. New diagnostic categories are based on genetic profiles, not just morphology. Effective prevention occurs through viral vaccines and behavioral changes that reduce exposure to mutagens; screening detects some cancers early enough for curative surgery. Therapeutic strategies are increasingly informed by underlying genomic damage or by the immunological responses to cancer-associated antigens. Such knowledge has driven annual reductions of 1 to 2% in age-adjusted cancer mortality rates in the United States for many years.

A close-up look at cancer

“Can…attention from national leaders be helpful without additional funds…?”

These encouraging signs have stimulated local, national, and even global efforts to hasten progress against cancer, with clearer strategies than were possible when President Nixon signed the National Cancer Act in 1971 and launched what is still called the “war on cancer.” President Obama’s 2015 decision to devote a third of his Precision Medicine Initiative to oncology was predicated on the new promise of using genomics, informatics, and redesigned clinical trials to revise cancer diagnostics, improve prognostic tools, and develop new therapeutics. The Administration’s more recent announcement of a cancer “moonshot,” led by Vice President Biden, aspires to move cancer research more quickly—accomplishing 10 years of work in 5 years—by leaping fences between disciplines, connecting health centers, and interweaving the academic and industrial sectors. Implausible goals that tarnished earlier campaigns, such as the elimination or cure of certain cancers by a certain date—the equivalent of a true moonshot—have been conspicuously absent.

Can such attention from national leaders be helpful without additional funds to support research? After all, despite this year’s $2 billion increase, the budget of the U.S. National Institutes of Health remains about 20% below its value a decade ago, and fundamental problems in cancer biology remain unsolved. One prominent example—how cancer cells metastasize from primary to distant sites—is addressed by several articles in this special issue of Science (see page 162). Expanded work on such questions requires expanded resources, yet provision of such funds remains uncertain.

Still, there are important things to do, even without enlarged Congressional appropriations. The White House is already using its convening power to encourage greater collaboration, information sharing, and team efforts. The vice president could use his popularity and bully pulpit to move beyond research to emphasize cancer prevention: the life-saving values of vaccines for human papilloma and hepatitis B viruses, the avoidance of tobacco use, the control of obesity. The Administration could also exercise its regulatory authority—most potently, to direct the Centers for Medicare and Medicaid Services (CMS) to allow reimbursement for molecular profiling of cancers. That would vastly increase the data available for analysis, accelerate interpretation of genetic profiles, provide a test bed for true sharing of clinical information, and allow future coverage determinations by CMS to be made more quickly and sensibly.

We are living in a remarkable time for cancer research, with synergies among its components and strong backing from the nation’s leaders. Let us take advantage of this moment, even without the certainty of additional dollars.

Clinical analysis of spinal stereotactic radiosurgery in the treatment of neurogenic tumors


Abstract

OBJECT

In this study the authors sought to evaluate clinical outcomes after using stereotactic radiosurgery (SRS) to treat benign and malignant spinal neurogenic tumors.

METHODS

The authors reviewed a total of 66 procedures of spinal SRS performed between 2001 and 2013 for 110 tumors in 58 patients with spinal neurogenic tumors, which included schwannomas, neurofibromas, and malignant peripheral nerve sheath tumors (MPNSTs). The clinical and radiological findings were evaluated in patients with benign neurogenic tumors. For the 4 patients with MPNSTs, the authors reported overall survival and results of additional immunohistochemical staining to predict the survival difference among the patients.

RESULTS

Of the 92 benign neurogenic tumors, 65 tumors that were serially followed up using MRI after SRS showed significant change in mean tumor volume, from a mean of 12.0 ± 2.6 cm3 pre-SRS to 10.8 ± 2.5 cm3 post-SRS (p = 0.027), over an average of 44 months. The local control rate of benign neurogenic tumors was 95.4%. The 34 patients who presented with clinical symptoms of pain showed a significant symptomatic improvement. The initial mean visual analog scale (VAS) score was 6.0 and decreased dramatically to 1.0 after SRS during an average follow-up period of 10.9 months (median of 8.1 months). Although the proportions of transient swelling and loss of intramural enhancement were significantly different among the groups, there was no statistically significant correlation between those 2 factors and local tumor control (p = 0.253 and 0.067, respectively; Fisher’s exact text). Cross-table analysis also indicated that there was no statistically significant relationship between groups with loss of intramural enhancement and transient swelling. The median survival of neurofibromatosis Type 1 (NF1)-related and sporadic MPNSTs was 1.13 and 5.8 years, respectively. Immunohistochemical results showed that S100 was expressed in a sporadic MPNST or neurofibroma, whereas topoisomerase-IIa was expressed in NF1-related MPNSTs.

CONCLUSIONS

SRS is an effective treatment modality for benign neurogenic tumors, while MPNSTs showed heterogeneity in their responses to SRS.

New Information about Mesothelioma Diagnosis and Treatment at Memorial Sloan-Kettering.


Most oncologists see very few people withmesothelioma, a relatively rare cancer. The illness originates in a membrane called the mesothelium, which forms a lining that protects many of the body’s internal organs. It has been linked to exposure to asbestos once commonly used in building materials and is diagnosed in just 2,000 to 3,000 people in the United States each year.

As a hospital with one of the nation’s largest volumes of patients with mesothelioma, Memorial Sloan-Kettering offers a unique breadth of understanding and experience in diagnosing and treating the disease.

In our newly updated guide to mesothelioma you can learn about improvements in treatments and supportive care that have dramatically lengthened and improved the quality of life for patients over the past few decades.

High Volume and Advanced Care

Our surgeons have been leaders in establishing surgical approaches used to treat pleural mesothelioma, a common subtype of the disease that forms in the pleura, the sac that protects the lungs. Pleural mesothelioma can cause symptoms such as shortness of breath and pain in the chest area.

We oversee a vast patient database — the world’s largest — that generates information helpful to physicians in selecting not only who is a good candidate for surgery, but which type of operation will be most effective.

In addition, we have pioneered a multimodal approach for pleural mesothelioma that combines surgical removal of cancerous tissue along with chemotherapy or radiation treatment. Our radiation oncologists have developed cutting-edge radiation techniques, such as intensity-modulated radiation therapy (IMRT) that enables radiation to be targeted to tumors with better precision while minimizing damage to the normal tissue.

Our surgical and medical oncology experts also collaborate in advancing the treatment ofperitoneal mesothelioma, a subtype that affects the lining of the abdomen and can lead to abdominal swelling and pain, diarrhea, and constipation. We are actively attempting to identify genetic mutations that might help us find new treatments for these cancers.

A Team Approach

Because we diagnose and treat a relatively large number of people with mesothelioma, we are able to offer many patients the option to enroll in clinical trials that test new drugs and novel approaches.

Through our multidisciplinary team approach we are able to design customized and timely treatment plans for each of our patients.

We have found that the quality and length of life of people with mesothelioma is also improved by the follow-up care and support provided by our team of physicians as well as our nurses and social workers. For relief from symptoms such as pain, fatigue, and shortness of breath, for example, many people also take advantage of our symptom and pain management services.

Source: MSKCC

Effects of Sulfonylureas on Tumor Growth.


Type 2 diabetes mellitus patients are at higher cancer risk, probably because of hyperinsulinemia and insulin growth factor 1 pathway activation. The effects of antidiabetic drugs on cancer risk have been described and discussed in several studies suggesting opposite effects of the biguanide metformin and sulfonylureas on cancer incidence and mortality. The anticancer mechanisms of metformin have been clarified, and some clinical studies, particularly in breast cancer patients, have been published or are currently ongoing; however, data about the effects of sulfonylureas on cancer growth are less consistent. The aims of this work are to review preclinical evidence of second-generation sulfonylureas effects on tumor growth, to clarify the potential mechanisms of action, and to identify possible metabolic targets for patient selection. Most evidence is on the adenosine triphosphate-sensitive potassium channels inhibitor glibenclamide, which interacts with reactive oxygen species production thus inducing cancer cell death. Among diarylsulfonylureas, next-generation DW2282 derivatives are particularly promising because of the proapoptotic activity in multidrug-resistant cells.

 

Source: The Oncologist.

 

Gene Patents and Personalized Cancer Care: Impact of the Myriad Case on Clinical Oncology.


Genomic discoveries have transformed the practice of oncology and cancer prevention. Diagnostic and therapeutic advances based on cancer genomics developed during a time when it was possible to patent genes. A case before the Supreme Court,Association for Molecular Pathology v Myriad Genetics, Inc seeks to overturn patents on isolated genes. Although the outcomes are uncertain, it is suggested here that the Supreme Court decision will have few immediate effects on oncology practice or research but may have more significant long-term impact. The Federal Circuit court has already rejected Myriad’s broad diagnostic methods claims, and this is not affected by the Supreme Court decision. Isolated DNA patents were already becoming obsolete on scientific grounds, in an era when human DNA sequence is public knowledge and because modern methods of next-generation sequencing need not involve isolated DNA. The Association for Molecular Pathology v Myriad Supreme Court decision will have limited impact on new drug development, as new drug patents usually involve cellular methods. A nuanced Supreme Court decision acknowledging the scientific distinction between synthetic cDNA and genomic DNA will further mitigate any adverse impact. A Supreme Court decision to include or exclude all types of DNA from patent eligibility could impact future incentives for genomic discovery as well as the future delivery of medical care. Whatever the outcome of this important case, it is important that judicial and legislative actions in this area maximize genomic discovery while also ensuring patients’ access to personalized cancer care.

Source: JCO

Use of the Word “Cure” in Oncology.


Purpose: Use of the word “cure” in cancer care reflects a balance of physician and patient optimism, realism, medico-legal concerns, and even superstition. This study surveyed a group of oncology specialists regarding the frequency and determinants of using the word cure.

Methods: Oncology clinicians at the Dana-Farber Cancer Institute (n = 180) were invited to complete a survey regarding the word cure in cancer care. Participants completed a 19-question survey regarding how commonly their patients are cured, how often they use the word cure in their practice, and details about its use. Three case scenarios were presented to elicit participants’ views.

Results: Of the 117 participants (65%) who provided responses, 81% were hesitant to tell a patient that they are cured, and 63% would never tell a patient that they are cured. Only 7% felt that greater than 75% of their patients are, or will be, cured. The participating clinicians reported that only 34% of patients ask if they are cured. For 20-year survivors of testicular cancer, large-cell lymphoma, and estrogen receptor–positive breast cancer, 84%, 76%, and 48% of clinicians, respectively, believed that the patients were cured, and 35%, 43%, and 56% recommended annual oncology follow-up of the patients. Twenty-three percent of oncology clinicians believed that patients should never be discharged from the cancer center.

Conclusion: Oncology clinicians report that patients are hesitant to ask whether they are cured, and the clinicians are hesitant to tell patients they are cured. Annual oncology follow-up was frequently endorsed, even after 20 years in remission.

Source: JOP

Comparative Effectiveness Research in Oncology.


Although randomized controlled trials represent the gold standard for comparative effective research (CER), a number of additional methods are available when randomized controlled trials are lacking or inconclusive because of the limitations of such trials. In addition to more relevant, efficient, and generalizable trials, there is a need for additional approaches utilizing rigorous methodology while fully recognizing their inherent limitations. CER is an important construct for defining and summarizing evidence on effectiveness and safety and comparing the value of competing strategies so that patients, providers, and policymakers can be offered appropriate recommendations for optimal patient care. Nevertheless, methodological as well as political and social challenges for CER remain. CER requires constant and sophisticated methodological oversight of study design and analysis similar to that required for randomized trials to reduce the potential for bias. At the same time, if appropriately conducted, CER offers an opportunity to identify the most effective and safe approach to patient care. Despite rising and unsustainable increases in health care costs, an even greater challenge to the implementation of CER arises from the social and political environment questioning the very motives and goals of CER. Oncologists and oncology professional societies are uniquely positioned to provide informed clinical and methodological expertise to steer the appropriate application of CER toward critical discussions related to health care costs, cost-effectiveness, and the comparative value of the available options for appropriate care of patients with cancer.

Source: the oncologist

The Next Big Thing for Metastatic Breast Cancer.


The drug-antibody conjugate trastuzumab emtansine demonstrated single-agent activity in patients with previously treated HER2-positive disease.

Even with the recent approval of pertuzumab as a component (along with trastuzumab and docetaxel) of a first-line regimen for patients with human epidermal growth factor receptor 2 (HER2)–positive, metastatic breast cancer, the anticipated approval of trastuzumab emtansine (T-DM1) is eagerly awaited by oncologists as a treatment for patients with progressive HER2-positive breast cancer following treatment with trastuzumab. Indeed, clinical experience with T-DM1 — a fusion molecule combining trastuzumab with a cytotoxic (maytansine) utilizing a stable linker (see illustration) — has shown robust clinical activity following prior anti-HER2 therapy with relatively modest toxicity (J Clin Oncol 2011 Feb; 29:398).

Now, investigators have conducted an industry-supported, single-arm, phase II clinical trial to evaluate the effectiveness of T-DM1 (3.6 mg/kg intravenously, every 3 weeks) in 110 patients with metastatic HER-2-positive breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. Patients had previously received a median of seven prior nonendocrine agents.

At median follow-up of 17.4 months, the objective response rate (the primary objective) was 34.5%, the clinical benefit rate (inclusive of stable disease) was 48.2%, and median progression-free survival (PFS) was 6.9 months. T-DM1 was well tolerated. Most adverse events were grade 1 or 2. The most common events of any grade were fatigue, nausea, and thrombocytopenia. Grade 3 or 4 thrombocytopenia occurred in 9.1% of patients, and grade 3 fatigue occurred in 4.5%.

Comment: T-DM1 was recently shown to be superior to combination capecitabine and lapatinib in metastatic breast cancer patients who were not as heavily pretreated as those in the current study (JW Oncol Hematol Jul 3 2012). T-DM1 will be rapidly embraced by clinical oncologists once it is approved, and the future development of this agent will likely move to earlier-stage breast cancer and be used in combination with other HER2-targeted agents such as pertuzumab.

Source:Journal Watch Oncology and Hematology

 

Ultrasound-assisted convection-enhanced delivery to the brain in vivo with a novel transducer cannula assembly.


In convection-enhanced delivery (CED), drugs are infused locally into tissue through a cannula inserted into the brain parenchyma to enhance drug penetration over diffusion strategies. The purpose of this study was to demonstrate the feasibility of ultrasound-assisted CED (UCED) in the rodent brain in vivo using a novel, low-profile transducer cannula assembly (TCA) and portable, pocket-sized ultrasound system.

Methods

Forty Sprague-Dawley rats (350–450 g) were divided into 2 equal groups (Groups 1 and 2). Each group was divided again into 4 subgroups (n = 5 in each). The caudate of each rodent brain was infused with 0.25 wt% Evans blue dye (EBD) in phosphate-buffered saline at 2 different infusion rates of 0.25 μl/minute (Group 1), and 0.5 μl/minute (Group 2). The infusion rates were increased slowly over 10 minutes from 0.05 to 0.25 μl/minute (Group 1) and from 0.1 to 0.5 μl/minute (Group 2). The final flow rate was maintained for 20 minutes. Rodents in the 4 control subgroups were infused using the TCA without ultrasound and without and with microbubbles added to the infusate (CED and CED + MB, respectively). Rodents in the 4 UCED subgroups were infused without and with microbubbles added to the infusate (UCED and UCED + MB) using the TCA with continuous-wave 1.34-MHz low-intensity ultrasound at a total acoustic power of 0.11 ± 0.005 W and peak spatial intensity at the cannula tip of 49.7 mW/cm2. An additional 4 Sprague-Dawley rats (350–450 g) received UCED at 4 different and higher ultrasound intensities at the cannula tip ranging from 62.0 to 155.0 mW/cm2 for 30 minutes. The 3D infusion distribution was reconstructed using MATLAB analysis. Tissue damage and morphological changes to the brain were assessed using H & E.

Results

The application of ultrasound during infusion (UCED and UCED + MB) improved the volumetric distribution of EBD in the brain by a factor of 2.24 to 3.25 when there were no microbubbles in the infusate and by a factor of 1.16 to 1.70 when microbubbles were added to the infusate (p < 0.001). On gross and histological examination, no damage to the brain tissue was found for any acoustic exposure applied to the brain.

Conclusions

The TCA and ultrasound device show promise to improve the distribution of infused compounds during CED. The results suggest further studies are required to optimize infusion and acoustic parameters for small compounds and for larger molecular weight compounds that are representative of promising antitumor agents. In addition, safe levels of ultrasound exposure in chronic experiments must be determined for practical clinical evaluation of UCED. Extension of these experiments to larger animal models is warranted to demonstrate efficacy of this technique.

Source: Journal of neurosurgery.