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1.  Stereotactic Ablative Radiotherapy for Oligometastatic Disease in Liver 
BioMed Research International  2014;2014:340478.
Liver metastasis in solid tumors, including colorectal cancer, is the most frequent and lethal complication. The development of systemic therapy has led to prolonged survival. However, in selected patients with a finite number of discrete lesions in liver, defined as oligometastatic state, additional local therapies such as surgical resection, radiofrequency ablation, cryotherapy, and radiotherapy can lead to permanent local disease control and improve survival. Among these, an advance in radiation therapy made it possible to deliver high dose radiation to the tumor more accurately, without impairing the liver function. In recent years, the introduction of stereotactic ablative radiotherapy (SABR) has offered even more intensive tumor dose escalation in a few fractions with reduced dose to the adjacent normal liver. Many studies have shown that SABR for oligometastases is effective and safe, with local control rates widely ranging from 50% to 100% at one or two years. And actuarial survival at one and two years has been reported ranging from 72% to 94% and from 30% to 62%, respectively, without severe toxicities. In this paper, we described the definition and technical aspects of SABR, clinical outcomes including efficacy and toxicity, and related parameters after SABR in liver oligometastases from colorectal cancer.
doi:10.1155/2014/340478
PMCID: PMC4020541  PMID: 24868526
2.  Review and Uses of Stereotactic Body Radiation Therapy for Oligometastases 
The Oncologist  2012;17(8):1100-1107.
The radiobiologic, technical, and clinical aspects of stereotactic body radiation therapy are reviewed for various anatomical sites of oligometastases.
Learning Objectives
After completing this course, the reader will be able to: Assess stereotactic body radiation therapy (SBRT) as an emerging modality in the treatment of oligometastatic patients.Discuss data on safety and efficacy of SBRT in the oligometastatic setting.Evaluate SBRT as a competitive option in patients with a low burden of disease in the metastatic setting.
This article is available for continuing medical education credit at CME.TheOncologist.com
In patients with proven distant metastases from solid tumors, it has been a notion that the condition is incurable, warranting palliative care only. The term “oligometastases” was coined to refer to isolated sites of metastasis, whereby the entire burden of disease can be recognized as a finite number of discrete lesions that can be potentially cured with local therapies. Stereotactic body radiation therapy (SBRT) is a novel treatment modality in radiation oncology that delivers a very high dose of radiation to the tumor target with high precision using single or a small number of fractions. SBRT is the result of technological advances in patient and tumor immobilization, image guidance, and treatment planning and delivery. A number of studies, both retrospective and prospective, showed promising results in terms of local tumor control and, in a limited subset of patients, of survival. This article reviews the radiobiologic, technical, and clinical aspects of SBRT for various anatomical sites.
doi:10.1634/theoncologist.2012-0092
PMCID: PMC3425528  PMID: 22723509
Radiotherapy; Image-guided; Metastases; Neoplasm; Health care economics
3.  Concurrent chemoradiation of metastases with capecitabine and oxaliplatin and 3D-CRT in patients with oligometastatic colorectal cancer: results of a phase I study 
Background
Local control appears to be an important treatment aim in patients with limited metastases (oligometastases) of colorectal cancer (CRC). Those patients show a favourable prognosis, if - in addition to the local effective treatment - an occurrence of new metastases may also be postponed by effective systemic therapy. The purpose of this dose escalation phase I study was to establish the efficacy of local radiotherapy (RT) of oligometastatic CRC with a concurrent standard chemotherapy regimen.
Methods
Patients with first-, second- or third-line therapy of oligometastatic CRC (1–3 metastases or local recurrence plus max. 2 metastases) received capecitabine (825 mg/m2/d BID d 1–14; 22–35) and oxaliplatin (50 mg/m2 d 1, 8, 22, 29). 3D-conformal RT of all metastatic lesions was delivered in 2.0 Gy up to 36 Gy to 50 Gy (3 dose levels). Primary endpoint was the maximal tolerable dose (MTD) of RT defined as the level at which two or more of six patients experienced dose-limiting toxicity (DLT).
Results
Between 09/2004 and 08/2007, 9 patients (7 male, 2 female, 50–74 years) were enrolled, 6 patients treated at dose level 1 (36 Gy), 3 patients at dose level 2 (44 Gy). 1 patient from the first cohort experienced DLT (oxaliplatin-related hypersensitivity reaction). No radiation-induced DLT occurred. 6/9 patients achieved objective response (partial remission). One year after initiation, all patients were alive, 6 patients survived (16 to 54 months) patients died of tumor progression (14 to 23 months). The phase II part of the trial had to be closed due to recruitment failure.
Conclusions
Local 3D-CRT to metastatic lesions in addition to standard chemotherapy was feasible, DLT was not documented. 3/9 patients survived for a period of 3.5 to 4.4 years (time at the last evaluation). Radiotherapy of metastatic lesions should be incorporated into subsequent trials.
doi:10.1186/1748-717X-7-83
PMCID: PMC3403841  PMID: 22681700
Oligometastatic colorectal cancer; Chemoradiation; Capecitabine; Oxaliplatin; Phase I study
4.  Role of stereotactic body radiotherapy for oligometastasis from colorectal cancer 
Systemic chemotherapy has enabled prolongation of survival in patients with stage IV colorectal cancer. This has subsequently increased the relative significance of local therapy for patients with oligometastases because they can be cured by removal of oligometastatic lesions. One of the most frequently reported tumor histologies for oligometastases is colorectal cancer. Resection is the standard therapy in most settings of oligometastases. Recently, studies have shown that stereotactic body radiotherapy (SBRT) may become a treatment option that provides high local control with minimal morbidity. Two-year local control rates following SBRT for hepatic and pulmonary oligometastases are almost over 80% and are even higher for patients treated with high-dose regimens. The indications of SBRT for other metastatic sites or conditions include isolated lymph nodes, spinal and adrenal metastasis, and post-surgical pelvic recurrence. Many retrospective studies have indicated that SBRT for various lesions results in good outcomes with low morbidity, both in the curative and palliative setting. However, few reports with a high level of evidence have indicated the efficacy of SBRT compared to standard therapy. Hereafter, the optimal indication of SBRT needs to be prospectively investigated to obtain convincing evidence.
doi:10.3748/wjg.v20.i15.4220
PMCID: PMC3989958  PMID: 24764660
Oligometastasis; Colorectal cancer; Radiation therapy; Stereotactic ablation body radiation therapy; Local therapy
5.  MicroRNA Expression Characterizes Oligometastasis(es) 
PLoS ONE  2011;6(12):e28650.
Background
Cancer staging and treatment presumes a division into localized or metastatic disease. We proposed an intermediate state defined by ≤5 cumulative metastasis(es), termed oligometastases. In contrast to widespread polymetastases, oligometastatic patients may benefit from metastasis-directed local treatments. However, many patients who initially present with oligometastases progress to polymetastases. Predictors of progression could improve patient selection for metastasis-directed therapy.
Methods
Here, we identified patterns of microRNA expression of tumor samples from oligometastatic patients treated with high-dose radiotherapy.
Results
Patients who failed to develop polymetastases are characterized by unique prioritized features of a microRNA classifier that includes the microRNA-200 family. We created an oligometastatic-polymetastatic xenograft model in which the patient-derived microRNAs discriminated between the two metastatic outcomes. MicroRNA-200c enhancement in an oligometastatic cell line resulted in polymetastatic progression.
Conclusions
These results demonstrate a biological basis for oligometastases and a potential for using microRNA expression to identify patients most likely to remain oligometastatic after metastasis-directed treatment.
doi:10.1371/journal.pone.0028650
PMCID: PMC3236765  PMID: 22174856
6.  Stereotactic body radiation therapy for abdominal oligometastases: a biological and clinical review 
Advances in imaging and biological targeting have led to the development of stereotactic body radiation therapy (SBRT) as an alternative treatment of extracranial oligometastases. New radiobiological concepts, such as ceramide-induced endothelial apoptosis after hypofractionated high-dose SBRT, and the identification of patients with oligometastatic disease by microRNA expression may yet lead to further developments. Key factors in SBRT are delivery of a high dose per fraction, proper patient positioning, target localisation, and management of breathing–related motion. Our review addresses the radiation doses and schedules used to treat liver, abdominal lymph node (LN) and adrenal gland oligometastases and treatment outcomes. Reported local control (LC) rates for liver and abdominal LN oligometastases are high (median 2-year actuarial LC: 61 -100% for liver oligometastases; 4-year actuarial LC: 68% in a study of abdominal LN oligometastases). Early toxicity is low-to-moderate; late adverse effects are rare. SBRT of adrenal gland oligometastases shows promising results in the case of isolated lesions. In conclusion, properly conducted SBRT procedures are a safe and effective treatment option for abdominal oligometastases.
doi:10.1186/1748-717X-7-126
PMCID: PMC3485144  PMID: 22852764
Cancer; Gastrointestinal; Liver; Radiotherapy; Radiation biology; Surgery
7.  A Call for the Aggressive Treatment of Oligometastatic and Oligo-Recurrent Non-Small Cell Lung Cancer 
Pulmonary Medicine  2012;2012:480961.
Metastatic non-small cell lung cancer (NSCLC) carries a dismal prognosis. Clinical evidence suggests the existence of an intermediate, or oligometastatic, state when metastases are limited in number and/or location. In addition, following initial curative therapy, many patients present with limited metastatic disease, or oligo-recurrence. Metastasis-directed, anti-cancer therapies may benefit these patients. A growing evidence-base supports the use of hypofractionated, image-guided radiotherapy (HIGRT) for a variety of malignant conditions including inoperable stage I NSCLC and many metastatic sites. When surgical resection is not possible, HIGRT offers an effective alternative for local treatment of limited metastatic disease. Early studies have produced promising results when HIGRT was delivered to all known sites of disease in patients with oligometastatic/oligo-recurrent NSCLC. In a population of patients formerly considered rapidly terminal, these studies report five year overall survival rates of 13–22%. HIGRT for metastatic NSCLC warrants further study. We call for large, intergroup, and even international randomized trials incorporating HIGRT and other metastasis-directed therapies into the treatment of patients with oligometastatic/oligo-recurrent NSCLC.
doi:10.1155/2012/480961
PMCID: PMC3483729  PMID: 23125927
8.  Stereotactic Body Radiotherapy for Metachronous Multisite Oligo-Recurrence: A Long-Surviving Case with Sequential Oligo-Recurrence in Four Different Organs Treated Using Locally Radical Radiotherapy and a Review of the Literature 
Pulmonary Medicine  2012;2012:713073.
Stereotactic body radiotherapy (SBRT) for oligometastases represents a recent trend in radiation oncology. While abundant data are available regarding the use of SBRT for the treatment of lung or liver oligometastases from various retrospective series and prospective trials, relatively little information has been accumulated for the treatment of oligometastases at sites other than the lungs and liver, particularly for sequential oligometastases in multiple organs. Oligometastases with primary lesions controlled is called “oligo-recurrence.” We describe herein the case of a lung cancer patient who developed repeated oligo-recurrence at multiple sites that were each controlled by radical radiotherapy and achieved long-term survival and discuss the merits of locally aggressive radiotherapy for this type of disease condition with reviewing the literature. Although further investigation should be undertaken to clarify the benefits, objectives, and methods of SBRT for the treatment of oligometastases, we believe utilization of SBRT may be worthwhile for patients with remote metastases who hope for treatment to acquire better local control and possible longer survival.
doi:10.1155/2012/713073
PMCID: PMC3486341  PMID: 23150822
9.  Stereotactic body radiation therapy for liver metastases 
Over the years, early diagnosis of metastatic disease has improved and the prevalence of oligometastatic patients is increasing. Liver is a most common site of progression from gastrointestinal, lung and breast cancer and in the setting of oligometastatic patients, surgical resection is associated with increased survival. Approximately 70-90% of liver metastases, however, are unresectable and an effective and safe alternative therapeutic option is necessary for these patients. The role of stereotactic body radiation therapy (SBRT) was investigated in the treatment of oligometastatic patients with promising results, thanks to the ability of this procedure to deliver a conformal high dose of radiation to the target lesion and a minimal dose to surrounding critical tissues. This paper was performed to review the current literature and to provide the practice guidelines on the use of stereotactic body radiotherapy in the treatment of liver metastases. We performed a literature search using Medical Subject Heading terms “SBRT” and “liver metastases”, considering a period of ten years.
doi:10.3978/j.issn.2078-6891.2014.039
PMCID: PMC4074953  PMID: 24982767
Liver metastases; stereotactic body radiation therapy (SBRT); oligometastases; stereotactic ablative radiotherapy (SABR)
10.  Prognostic Impact of Radiation Therapy to the Primary Tumor in Patients With Non-small Cell Lung Cancer and Oligometastasis at Diagnosis 
Purpose
We investigated prognostic factors associated with survival in patients with non-small cell lung cancer (NSCLC) and oligometastatic disease at diagnosis, particularly the influence of local treatment to the primary site on prognosis.
Methods and Materials
From January 2000 through June 2011, 78 consecutive patients with oligometastatic NSCLC (<5 metastases) at diagnosis underwent definitive chemoradiation therapy (≥45 Gy) to the primary site. Forty-four of these patients also received definitive local treatment for the oligometastases. Survival outcomes were estimated using the Kaplan-Meier method, and risk factors were identified by univariate and multivariate analyses.
Results
Univariate Cox proportional hazard analysis revealed better overall survival (OS) for those patients who received at least 63 Gy of radiation to the primary site (P=.002), received definitive local treatment for oligometastasis (P=.041), had a Karnofsky performance status (KPS) score >80 (P=.007), had a gross tumor volume ≤ 124 cm3 (P=.002), had adenocarcinoma histology (P=.002), or had no history of respiratory disease (P=.016). On multivariate analysis, radiation dose, performance status, and tumor volume retained significance (P=.004, P=.006, and P<.001, respectively). The radiation dose also maintained significance when patients with and without brain metastases were analyzed separately.
Conclusions
Tumor volume, KPS, and receipt of at least 63 Gy to the primary tumor are associated with improved OS in patients with oligometastatic NSCLC at diagnosis. Our results suggest that a subset of such patients may benefit from definitive local therapy.
doi:10.1016/j.ijrobp.2012.02.054
PMCID: PMC3919541  PMID: 22503522
11.  Stereotactic body radiotherapy for oligo-recurrence within the nodal area from colorectal cancer 
Recurrence of colorectal cancer (CRC) often presents as solitary metastases, oligometastases or oligo-recurrence. Surgical resection became the preferred treatment for patients with CRC lung and hepatic metastases. However, surgical treatment for oligo-recurrence within nodal area is not a widely accepted treatment due to due to their relative rarity and high postoperative morbidity. Stereotactic body radiotherapy (SBRT) is one of the emerging radiation treatment techniques in which a high radiation dose can be delivered to the tumor. High-dose SBRT can ablate the tumor with an efficacy similar to that achieved with surgery, especially for small tumors. However, there have been very few studies on SBRT for oligo-recurrence within nodal area, although several studies have evaluated the role of SBRT in the treatment of liver and lung metastases from CRC. This article reviews the current clinical status of and treatment methods for oligo-recurrence within nodal area from CRC, with particular emphasis on SBRT.
doi:10.3748/wjg.v20.i8.2005
PMCID: PMC3934470  PMID: 24587675
Colorectal cancer; Oligo-recurrence; Oligometastases; Stereotactic radiotherapy; Lymph node
12.  Oligometastases and Oligo-recurrence: The New Era of Cancer Therapy 
Recurrence or metastasis of cancer has been considered to occur in the last stage of the patient's life. However, the new notions of oligometastases and oligo-recurrence have been proposed and the paradigm shift in the conceptualization of cancer metastasis or cancer recurrence. Oligometastases is the state in which the patient shows distant relapse in only a limited number of regions. Local therapy such as surgery, radiotherapy and radiofrequency ablation for the relapsed sites could thus improve patient's survival. On the other hand, oligo-recurrence is a notion similar to oligometastases. However, the conditions of oligo-recurrence has a primary site of the cancer controlled, meaning that all gross recurrent or metastatic sites could be treated using local therapy.
doi:10.1093/jjco/hyp167
PMCID: PMC2813545  PMID: 20047860
oligometastases; oligo-recurrence; local therapy; systemic therapy; paradigm shift
13.  The role of radiation therapy for carcinoma of the lung. 
A large proportion of patients with carcinoma of the lung may benefit from the use of radiation therapy. Operable patients have not been shown to benefit from preoperative irradiation, but postoperative irradiation has improved survival in those found to have involvement of hilar or mediastinal lymph nodes. Radiation therapy is the only potentially curative treatment for patients who are inoperable, but do not have distant metastasis. Control of the local tumor is very dependent upon dose-fractionation-time relationships. Patients who are relatively asymptomatic, i.e., they have a high performance status, are curable if treated promptly with radiation therapy. Small cell carcinoma requires both radiation therapy and chemotherapy. The optimal method of combining the two modalities is yet to be determined, but prophylactic cranial irradiation is necessary to control microscopic metastases that are not affected by systemic chemotherapy, and thoracic irradiation is necessary to give the highest probability of control of the primary tumor. Prophylactic cranial irradiation has also been shown to reduce the frequency of brain metastasis in patients with squamous carcinoma, large cell carcinoma, and adenocarcinoma; it may become more important in these cell types when more effective chemotherapy is developed.
Images
PMCID: PMC2595953  PMID: 6270918
14.  Repeated stereotactic body radiotherapy for oligometastatic prostate cancer recurrence 
Purpose
To assess the outcome of prostate cancer (PCa) patients diagnosed with oligometastatic disease at recurrence and treated with stereotactic body radiotherapy (SBRT).
Methods
Non-castrate patients with up to 3 synchronous metastases (bone and/or lymph nodes) diagnosed on positron emission tomography - computed tomography, following biochemical recurrence after local curative treatment, were treated with (repeated) SBRT to a dose of 50 Gy in 10 fractions or 30 Gy in 3 fractions. Androgen deprivation therapy-free survival (ADT-FS) defined as the time interval between the first day of SBRT and the initiation of ADT was the primary endpoint. ADT was initiated if more than 3 metastases were detected during follow-up even when patients were still asymptomatic. Secondary endpoints were local control, progression free survival (PFS) and toxicity. Toxicity was scored using the Common Terminology Criteria for Adverse Events.
Results
With a median follow-up from time of SBRT of 2 years, we treated 50 patients with 70 metastatic lesions with a local control rate of 100%. The primary involved metastatic sites were lymph nodes (54%), bone (44%), and viscera (2%). The median PFS was 19 mo (95% CI: 13–25 mo) with 75% of recurring patients having ≤3 metastases. A 2nd and 3rd course of SBRT was delivered in 19 and 6 patients respectively. This results in a median ADT-FS of 25 months (20–30 mo). On univariate analysis, only a short PSA doubling time was a significant predictor for both PFS (HR: 0.90, 95% CI: 0.82 – 0.99) and ADT-FS (HR: 0.83; 95% CI: 0.71 – 0.97). Ten patients (20%) developed toxicity following treatment, which was classified as grade I in 7 and grade II in 3 patients.
Conclusion
Repeated SBRT for oligometastatic prostate cancer postpones palliative androgen deprivation therapy with 2 years without grade III toxicity.
doi:10.1186/1748-717X-9-135
PMCID: PMC4066290  PMID: 24920079
Oligometastases; Prostate cancer; Recurrence; Salvage therapy; Stereotactic body radiotherapy
15.  Radiosurgery for Recurrent Brain Metastases after Whole-Brain Radiotherapy : Factors Affecting Radiation-Induced Neurological Dysfunction 
Objective
We retrospectively analyzed survival, local control rate, and incidence of radiation toxicities after radiosurgery for recurrent metastatic brain lesions whose initial metastases were treated with whole-brain radiotherapy. Various radiotherapeutical indices were examined to suggest predictors of radiation-related neurological dysfunction.
Methods
In 46 patients, total 100 of recurrent metastases (mean 2.2, ranged 1-10) were treated by CyberKnife radiosurgery at average dose of 23.1 Gy in 1 to 3 fractions. The median prior radiation dose was 32.7 Gy, the median time since radiation was 5.0 months, and the mean tumor volume was 12.4 cm3. Side effects were expressed in terms of radiation therapy oncology group (RTOG) neurotoxicity criteria.
Results
Mass reduction was observed in 30 patients (65%) on MRI. After the salvage treatment, one-year progression-free survival rate was 57% and median survival was 10 months. Age (<60 years) and tumor volume affected survival rate (p=0.03, each). Acute (≤1 month) toxicity was observed in 22% of patients, subacute and chronic (>6 months) toxicity occurred in 21%, respectively. Less acute toxicity was observed with small tumors (<10 cm3, p=0.03), and less chronic toxicity occurred at lower cumulative doses (<100 Gy, p=0.004). "Radiation toxicity factor" (cumulative dose times tumor volume of <1,000 Gy×cm3) was a significant predictor of both acute and chronic CNS toxicities.
Conclusion
Salvage CyberKnife radiosurgery is effective for recurrent brain metastases in previously irradiated patients, but careful evaluation is advised in patients with large tumors and high cumulative radiation doses to avoid toxicity.
doi:10.3340/jkns.2009.45.5.275
PMCID: PMC2693786  PMID: 19516944
Brain; Metastasis; Radiotherapy; Toxicity; Radiosurgery; Recurrence
16.  The management of painful bone metastases with an emphasis on radionuclide therapy. 
OBJECTIVE: This review provides an update on the management of painful bone metastases, with an emphasis on radionuclide therapy, and introduces oligometastases and quantitative imaging evaluations for clinical trials. METHODS: The current use of radionuclides, alone and in combination with chemotherapy and radiation therapy for painful bone metastases, is discussed, including toxicity, cost and overall outcomes. RESULTS: Radionuclide therapy is shown to be a useful and cost-effective means of alleviating bone pain in metastatic disease and may be more effective when combined with chemotherapy, bisphosphonates and radiation therapy. Early use of radionuclides in pain therapy may limit cancer progression by inhibiting oligometastases development. Thus, radionuclides can significantly decrease patient morbidity, prolong patient survival, and may decrease the occurrence of new bone metastases. CONCLUSION: Palliative pain therapy is critical for effectively managing bone metastases, with treatment options including analgesics, external beam radiotherapy, chemotherapy and radionuclides. Radionuclide therapy is underutilized. Recent studies using radionuclides with chemotherapy and bisphosponates, or using newer radionuclides or combinations of radionuclides and treatment paradigms (e.g., higher activities, repetitive or cyclic administration, chemo sensitization, chemo supplementation), are encouraging. A comprehensive, inter-disciplinary clinical approach is needed. Clinical collaborations will optimize radionuclide therapy for pain palliation and increase awareness of its benefits.
PMCID: PMC2574338  PMID: 17668645
17.  Comparison of outcomes in patients with stage III versus limited stage IV non-small cell lung cancer 
Background
Standard therapy for metastatic non small cell lung cancer (NSCLC) includes palliative systemic chemotherapy and/or radiotherapy. Recent studies of patients with limited metastases treated with curative-intent stereotactic body radiation therapy (SBRT) have shown encouraging survival. We hypothesized that patients treated with SBRT for limited metastases have comparable outcomes with those treated with curative-intent radiation for Stage III NSCLC.
Methods
We retrospectively reviewed the records of NSCLC patients treated with curative-intent radiotherapy at the University of Rochester from 2000-2008. We identified 3 groups of patients with NSCLC: stage III, stage IV, and recurrent stage IV (initial stage I-II). All stage IV NSCLC patients treated with SBRT had ≤ 8 lesions.
Results
Of 146 patients, 88% had KPS ≥ 80%, 30% had > 5% weight loss, and 95% were smokers. The 5-year OS from date of NSCLC diagnosis for stage III, initial stage IV and recurrent stage IV was 7%, 14%, and 27% respectively. The 5-year OS from date of metastatic diagnosis was significantly (p < 0.00001) superior among those with limited metastases (≤ 8 lesions) versus stage III patients who developed extensive metastases not amenable to SBRT (14% vs. 0%).
Conclusion
Stage IV NSCLC is a heterogeneous patient population, with a selected cohort apparently faring better than Stage III patients. Though patients with limited metastases are favorably selected by virtue of more indolent disease and/or less bulky disease burden, perhaps staging these patients differently is appropriate for prognostic and treatment characterization. Aggressive local therapy may be indicated in these patients, though prospective clinical studies are needed.
doi:10.1186/1748-717X-6-80
PMCID: PMC3141527  PMID: 21718501
Stereotactic Body Radiotherapy; Oligometastases; Non-Small Cell Lung Cancer
18.  Oligometastatic Disease at Presentation or Recurrence for Nonsmall Cell Lung Cancer 
Pulmonary Medicine  2012;2012:396592.
Oligometastatic Non-Small Cell Lung Cancer (NSCLC) presents a unique opportunity for potential curative therapy. Improved cancer staging using PET/CT, MRI, and future cellular and molecular staging with circulating tumor cells and/or molecular markers will identify more patients with truly oligometastasis disease that will benefit from definitive local treatment. Recent development of noninvasive local ablative therapy such as stereotactic radiotherapy makes it possible to eradicate multiple local diseases with minimal side effect. Novel systemic therapy may also control systemic spread and therefore make it possible to improve survival by eliminating local diseases. More research, particularly prospective studies, is ideally randomized studies are needed to validate the concept of oligometastasis.
doi:10.1155/2012/396592
PMCID: PMC3413954  PMID: 22900169
19.  Kyphoplasty and intra-operative radiotheray, combination of kyphoplasty and intra-operative radiation for spinal metastases: technical feasibility of a novel approach 
International Orthopaedics  2012;36(6):1255-1260.
Purpose
To evaluate whether this new method is clinically applicable after theoretical and cadaver testing.
Methods
The incidence of spinal metastases requiring therapy is increasing, due to enhanced life expectancy. Due to results from studies with epidural compression a combined surgical and radiation therapy is often chosen. Minimal invasive cement augmentation is an increasingly used technique, due to fast pain relief and immediate stabilisation. On the other hand, stereotactic radiosurgery is considered to provide a more durable response and better local disease control than conventional radiotherapy with the application of higher doses. Therefore the combination of cement stabilisation and simultaneous intra-operative radiation with immediate stabilisation and high-dose radiation could be an interesting therapeutic option. The results of a clinical feasibility study are presented.
Results
17 patients could be treated with the new method. In two patients (10%) intra-operative radiation could not be applied. No surgical interventions for complications were required.
Conclusions
Summarizing Kypho-IORT is technically feasible with an intra-operative risk profile comparable to sole kyphoplasty and a shorter treatment time and hospitalisation for the patients compared to conventional multifraction radiation. Radiation could not be applied in 10% of cases due to technical difficulties. The results of this feasibility study permit further evaluation of this new technique by a dose escalation study which is currently in preparation.
doi:10.1007/s00264-011-1470-9
PMCID: PMC3353067  PMID: 22270861
20.  Role of HMG-CoA reductase inhibitors with curative radiotherapy in men with prostate cancer 
Brachytherapy and external beam radiotherapy are effective and commonly used treatment modalities in men with localized prostate cancer. In this review, we explore the role of radiation therapy in the curative management of prostate cancer, including the use of conformal therapeutic techniques to allow for the escalation of radiation doses to tumor, along with the use of combined radiation and hormonal therapy to enhance disease outcomes in men with aggressive disease. We also review the possible anticancer role of HMG-CoA reductase inhibiting agents (statins) in men with prostate cancer. Laboratory evidence suggests that statins may have antineoplastic effects when used alone and may sensitize cells to radiation therapy when given in combination. We explore the biologic basis for an anticancer effect and the clinical evidence suggesting statins may aid in improving outcomes with radiation therapy for localized prostate cancer.
doi:10.2147/OAJU.S14245
PMCID: PMC3818949  PMID: 24198641
HMG-CoA reductase inhibitors; statins; radiotherapy; prostate cancer
21.  Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors 
Background
Development of acquired resistance limits the utility of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for the treatment of EGFR mutant lung cancers. There are no accepted, targeted therapies for use after acquired resistance develops. Metastasectomy is used in other cancers to manage oligometastatic disease. We hypothesized that local therapy is associated with improved outcomes in patients EGFR mutant lung cancers with acquired resistance to EGFR TKI.
Methods
Patients who received non-CNS local therapy were identified by a review of data from a prospective biopsy protocol for patients with EGFR-mutant lung cancers with acquired resistance to EGFR TKI therapy and other institutional biospecimen registry protocols.
Results
Eighteen patients were identified that received elective local therapy (surgical resection, radiofrequency ablation or radiation). Local therapy was well-tolerated, with 85% of patients restarting TKI therapy within one month of local therapy. The median time to progression after local therapy was 10 months (95% Confidence interval [CI]: 2 to 27 months). The median time until a subsequent change in systemic therapy was 22 months (95% CI: 6 to 30 months). The median overall survival from local therapy was 41 months (95% CI: 26 to not reached).
Conclusions
EGFR- mutant lung cancers with acquired resistance to EGFR TKI therapy are amenable to local therapy to treat oligometastatic disease when used in conjunction with continued EGFR inhibition. Local therapy followed by continued treatment with an EGFR TKI is well tolerated, and associated with long PFS and OS. Further study in selected individuals in the context of other systemic options is required.
doi:10.1097/JTO.0b013e31827e1f83
PMCID: PMC3673295  PMID: 23407558
22.  Helical tomotherapy for spine oligometastases from gastrointestinal malignancies 
Radiation Oncology Journal  2011;29(4):219-227.
Purpose
This study evaluated the treatment effectiveness and proper radiation dose of helical tomotherapy (HT) in spine oligometastases from gastrointestinal cancers.
Materials and Methods
From 2006 to 2010, 20 gastrointestinal cancer patients were treated with HT for spine oligometastases (31 spine lesions). The gross tumor volume (GTV) was the tumor evident from magnetic resonance imaging images fused with simulation computed tomography images. Clinical target volume (CTV) encompassed involved vertebral bodies or dorsal elements. We assumed that the planning target volume was equal to the CTV. We assessed local control rate after HT for 31 spine metastases. Pain response was scored by using a numeric pain intensity scale (NPIS, from 0 to 10).
Results
Spine metastatic lesions were treated with median dose of 40 Gy (range, 24 to 51 Gy) and median 5 Gy per fraction (range, 2.5 to 8 Gy) to GTV with median 8 fractions (range, 3 to 20 fraction). Median biologically equivalent dose (BED, α/β = 10 Gy) was 52 Gy10 (range, 37.5 to 76.8 Gy10) to GTV. Six month local control rate for spine metastasis was 90.3%. Overall infield failure rate was 15% and outfield failure rate was 75%. Most patients showed pain relief after HT (93.8%). Median local recurrence free survival was 3 months. BED over 57 Gy10 and oligometastases were identified as prognostic factors associated with improved local progression free survival (p = 0.012, p = 0.041).
Conclusion
HT was capable of delivering higher BED to metastatic lesions in close proximity of the spinal cord. Spine metastases from gastrointestinal tumors were sensitive to high dose radiation, and BED (α/β = 10 Gy) higher than 57 Gy10 could improve local control.
doi:10.3857/roj.2011.29.4.219
PMCID: PMC3429906  PMID: 22984674
Spine metastasis; Helical tomotherapy
23.  Carcinoma of the Rectum and Rectosigmoid Colon: Role of Radiation Therapy 
Surgery is the modality of choice in curative treatment for cancer of the colon and rectum. Since a majority of the patients present advanced disease where the surgical outlook is poor, adjuvant therapy may be warranted. Clinical and experimental data demonstrate the benefits from preoperative radiation therapy and some clinical reports indicate the beneficial effects of postoperative radiotherapy. Two national studies are underway to determine the effectiveness of preoperative radiation therapy in moderate doses. A similar study is suggested to establish the effectiveness of postoperative radiation therapy.
For patients who are poor surgical risks, or for a tumor which is considered to be inoperable, and in a selected group, radiation therapy can be used as a curative procedure. Advantages include eliminating the need for a permanent colostomy. In case of failure, electrocoagulation and abdominal perineal resection are still available alternatives.
A modest amount of radiation therapy can afford maximum palliation with minimum discomfort to the patient. About 80-90 percent of patients with pain and bleeding and 50 percent of patients with symptomatic liver metastasis respond favorably.
PMCID: PMC2537166  PMID: 82620
24.  Ipilimumab and radiation therapy for melanoma brain metastases 
Cancer Medicine  2013;2(6):899-906.
Ipilimumab, an antibody that enhances T-cell activation, may augment immunogenicity of tumor cells that are injured by radiation therapy. We hypothesized that patients with melanoma brain metastasis treated with both ipilimumab and radiotherapy would have improved overall survival, and that the sequence of treatments may affect disease control in the brain. We analyzed the clinical and radiographic records of melanoma patients with brain metastases who were treated with whole brain radiation therapy or stereotactic radiosurgery between 2005 and 2012. The hazard ratios for survival were estimated to assess outcomes as a function of ipilimumab use and radiation type. Seventy patients were identified, 33 of whom received ipilimumab and 37 who did not. The patients who received ipilimumab had a censored median survival of 18.3 months (95% confidence interval 8.1–25.5), compared with 5.3 months (95% confidence interval 4.0–7.6) for patients who did not receive ipilimumab. Ipilimumab and stereotactic radiosurgery were each significant predictors of improved overall survival (hazard ratio = 0.43 and 0.45, with P = 0.005 and 0.008, respectively). Four of 10 evaluable patients (40.0%) who received ipilimumab prior to radiotherapy demonstrated a partial response to radiotherapy, compared with two of 22 evaluable patients (9.1%) who did not receive ipilimumab. Ipilimumab is associated with a significantly reduced risk of death in patients with melanoma brain metastases who underwent radiotherapy, and this finding supports the need for multimodality therapy to optimize patient outcomes. Prospective studies are needed and are underway.
doi:10.1002/cam4.140
PMCID: PMC3892394  PMID: 24403263
Brain metastases; immunotherapy; ipilimumab; melanoma; stereotactic radiosurgery
25.  Role of Radiation Therapy in the Management of Renal Cell Cancer 
Cancers  2011;3(4):4010-4023.
Renal cell carcinoma (RCC) is traditionally considered to be radioresistant; therefore, conventional radiotherapy (RT) fraction sizes of 1.8 to 2 Gy are thought to have little role in the management of primary RCC, especially for curative disease. In the setting of metastatic RCC, conventionally fractionated RT has been an effective palliative treatment in 50% of patients. Recent technological advances in radiation oncology have led to the clinical implementation of image-guided radiotherapy, allowing biologically potent doses to the tumors intra- and extra-cranially. As predicted by radiobiologic modeling, favorable outcomes have been observed with highly hypofractionated schemes modeled after the experience with intracranial stereotactic radiosurgery (SRS) for RCC brain metastases with reported local control rates averaging 85%. At present, both primary and metastatic RCC tumors may be successfully treated using stereotactic approaches, which utilize steep dose gradients to maximally preserve function and avoid toxicity of adjacent organs including liver, uninvolved kidney, bowel, and spinal cord regions. Future endeavors will combine stereotactic body radiation therapy (SBRT) with novel targeted therapies, such as tyrosine kinase inhibitors and targeted rapamycin (mTOR) inhibitors, to maximize both local and systemic control.
doi:10.3390/cancers3044010
PMCID: PMC3763407  PMID: 24213122
radiation therapy; stereotactic radiosurgery; renal cell carcinoma

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