Oligometastatic Stage Research Articles

The clinical study of chest radiotherapy and optimal timing of intervention in oligometastatic stage IV NSCLC

Objective To clarify the significance of chest radiotherapy in the treatment of oligometastatic stage ⅠV non-small cell lung cancer (NSCLC) and to explore the optimal time of interventional therapy during chest radiotherapy. Methods A total of 192 patients with oligometastatic stage ⅠV NSCLC admitted to Shanxi Provincial Cancer Hospital from 2008 to 2014 were randomly and evenly divided into the chemotherapy alone, radiotherapy+ early intervention, radiotherapy+ middle intervention and radiotherapy+ late intervention groups. Survival analysis was performed with Kanplan-Meier method. Results The median survival of 192 patients with oligometastatic stage ⅠV NSCLC was 14.50 months, and the 1-, 2-and 3-year survival rates were 57.4%, 24.0% and 10.7%, respectively. The median survivalin the chemotherapy alone, radiotherapy+ early intervention, radiotherapy+ middle intervention and radiotherapy+ late intervention groups was 10, 21, 18 and 13 months, respectively. The 1-year survival rates were 34%, 73%, 71% and 51%, 10%, 40%, 32% and 13% for the 2-year survival rates, and 0%, 24%, 16% and 3% for the 3-year survival rates (P=0.000). The median survival of patients with radiotherapy dose ≥ 60 Gy and< 60 Gy was 21 and 13 months, 76% and 53% for the 1-year survival rates, 34% and 21% for the 2-year survival rates, and 17% and 10% for the 3-year survival rates (P=0.002). Conclusion Early interventional therapy and high-dose radiotherapy can improve the local control rate and prolong the survival time of patients with oligometastatic stage ⅠV NSCLC. Key words: Lung neoplasm/radiotherapy; Oligometastasis; Intervention timing; Prognosis

Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma

BackgroundClinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment. MethodsThe International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines. ResultsBased on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy–treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated. ConclusionsStandardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.

Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial

Dual BRAF and MEK inhibition produces a response in a large number of patients with stage IV BRAF-mutant melanoma. The existing standard of care for patients with clinical stage III melanoma is upfront surgery and consideration for adjuvant therapy, which is insufficient to cure most patients. Neoadjuvant targeted therapy with BRAF and MEK inhibitors (such as dabrafenib and trametinib) might provide clinical benefit in this high-risk p opulation. We undertook this single-centre, open-label, randomised phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible participants were adult patients (aged ≥18 years) with histologically or cytologically confirmed surgically resectable clinical stage III or oligometastatic stage IV BRAFV600E or BRAFV600K (ie, Val600Glu or Val600Lys)-mutated melanoma. Eligible patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, a life expectancy of more than 3 years, and no previous exposure to BRAF or MEK inhibitors. Exclusion criteria included metastases to bone, brain, or other sites where complete surgical excision was in doubt. We randomly assigned patients (1:2) to either upfront surgery and consideration for adjuvant therapy (standard of care group) or neoadjuvant plus adjuvant dabrafenib and trametinib (8 weeks of neoadjuvant oral dabrafenib 150 mg twice per day and oral trametinib 2 mg per day followed by surgery, then up to 44 weeks of adjuvant dabrafenib plus trametinib starting 1 week after surgery for a total of 52 weeks of treatment). Randomisation was not masked and was implemented by the clinical trial conduct website maintained by the trial centre. Patients were stratified by disease stage. The primary endpoint was investigator-assessed event-free survival (ie, patients who were alive without disease progression) at 12 months in the intent-to-treat population. This trial is registered at ClinicalTrials.gov, number NCT02231775. Between Oct 23, 2014, and April 13, 2016, we randomly assigned seven patients to standard of care, and 14 to neoadjuvant plus adjuvant dabrafenib and trametinib. The trial was stopped early after a prespecified interim safety analysis that occurred after a quarter of the participants had been accrued revealed significantly longer event-free survival with neoadjuvant plus adjuvant dabrafenib and trametinib than with standard of care. After a median follow-up of 18·6 months (IQR 14·6-23·1), significantly more patients receiving neoadjuvant plus adjuvant dabrafenib and trametinib were alive without disease progression than those receiving standard of care (ten [71%] of 14 patients vs none of seven in the standard of care group; median event-free survival was 19·7 months [16·2-not estimable] vs 2·9 months [95% CI 1·7-not estimable]; hazard ratio 0·016, 95% CI 0·00012-0·14, p<0·0001). Neoadjuvant plus adjuvant dabrafenib and trametinib were well tolerated with no occurrence of grade 4 adverse events or treatment-related deaths. The most common adverse events in the neoadjuvant plus adjuvant dabrafenib and trametinib group were expected grade 1-2 toxicities including chills (12 patients [92%]), headache (12 [92%]), and pyrexia (ten [77%]). The most common grade 3 adverse event was diarrhoea (two patients [15%]). Neoadjuvant plus adjuvant dabrafenib and trametinib significantly improved event-free survival versus standard of care in patients with high-risk, surgically resectable, clinical stage III-IV melanoma. Although the trial finished early, limiting generalisability of the results, the findings provide proof-of-concept and support the rationale for further investigation of neoadjuvant approaches in this disease. This trial is currently continuing accrual as a single-arm study of neoadjuvant plus adjuvant dabrafenib and trametinib. Novartis Pharmaceuticals Corporation.

Abstract CT156: Novel neoadjuvant targeted therapy trial yields insight into molecular mechanisms of response

Abstract Background: Major advances have been made in the treatment of metastatic melanoma through the use of molecularly targeted therapy and immunotherapy, and trials incorporating these agents are now being extended to patients with earlier-stage disease. The current standard of care (SOC) therapy for high-risk resectable melanoma (stage IIIB/IIIC) is upfront surgery and SOC adjuvant therapy; however, relapse rates are high (~70%). We hypothesized that treatment with neoadjuvant + adjuvant targeted therapy (dabrafenib + trametinib) in this patient population would result in lower relapse rates and prolonged survival over SOC therapy. Methods: To test this hypothesis, we designed a randomized clinical trial (NCT02231775) in patients with resectable Stage IIIB/C or oligometastatic stage IV BRAF-mutant melanoma. Patients were randomized 1:2 to SOC (Arm A) versus neoadjuvant + adjuvant D+T (Arm B, 8 wks neoadjuvant + 44 wks adjuvant). The primary endpoint was relapse-free survival (RFS) with additional secondary endpoints. Importantly longitudinal sampling of tumor tissue was obtained (at baseline, week 3, and surgery) and molecular profiling was performed to gain insights into mechanisms of therapeutic response. Results: 21 of 84 patients were enrolled (arm A=7, arm B=14). Arms were well matched, and toxicity to targeted therapy was limited. RECIST response rate to 8 wks D+T was 77%, with a pathologic complete response rate (pCR) of 58%. Interim analysis revealed a significantly higher RFS in the D+T arm over SOC (p&amp;lt;0.0001), substantiating early stoppage of the trial. Notably, achievement of a pCR correlated with durable clinical benefit. Tumor mutational load was similar in those achieving a pCR versus those who did not, however known recurrent gene alterations in melanoma were noted to be more abundant in those who failed to achieve a pCR. Transcriptomic profiling in longitudinal tumor samples revealed differentially expressed genes (DEGs) that were highly correlated with achieving a pCR. Initial functional analysis of DEGs implicate multiple cancer cell-intrinsic (differentiation, MAPK pathway and metabolic) features and immune microenvironmental factors to be associated with response to neoadjuvant targeted therapy. Conclusion: Neoadjuvant + adjuvant D+T is associated with a high pCR rate and improved RFS over SOC in patients with high-risk resectable metastatic melanoma. Pathological and molecular correlative analysis revealed both pre- and on-treatment tumor features to be highly associated with the high pCR rate. Citation Format: Scott E. Woodman, Peter Prieto, Miles C. Andrews, Rodabe N. Amaria, Michael Tetzlaff, Adi Diab, Sapna P. Patel, Hwu Wen-Jen, Isabella Glitza, Hussein Tawbi, Patrick Hwu, Janice Cormier, Anthony Lucci, Richard Royal, Jeffrey Lee, Roland Bassett, Lauren Simpson, Elizabeth Burton, Li Zhao, Elizabeth Grimm, Alexandre Reuben, Christine Spencer, Junna Oba, Merrick Ross, Jeffrey Gershenwald, Michael Davies, Jennifer A. Wargo. Novel neoadjuvant targeted therapy trial yields insight into molecular mechanisms of response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT156. doi:10.1158/1538-7445.AM2017-CT156

Relapse-free survial and target identification to enhance response with neoadjuvant and adjuvant dabrafenib + trametinib (D+T) treatment compared to standard-of-care (SOC) surgery in patients (pts) with high-risk resectable BRAF-mutant metastatic melanoma.

9587 Background: Targeted and immune therapies have dramatically improved outcomes in stage IV metastatic melanoma pts. These agents are now being tested in earlier-stage disease. SOC surgery for high-risk resectable melanoma (AJCC stage IIIB/IIIC), with or without adjuvant therapy, is associated with a high risk of relapse (~70%). We hypothesized that neoadjuvant (neo) + adjuvant treatment with D+T improves RFS in these pts. Longitudinally collected biospecimens from pts receiving this treatment were analyzed to identify candidate strategies to further improve outcomes. Methods: A prospective single-institution randomized clinical trial (NCT02231775) was conducted in BRAF-mutant pts with resectable Stage IIIB/C or oligometastatic stage IV melanoma. Pts were randomized 1:2 to SOC (Arm A) versus neo + adjuvant D+T (Arm B; 8 wks neo + 44 wks adjuvant). The primary endpoint was RFS. Tumor biopsies were collected at baseline, week 3, and at surgery for molecular and immune profiling (whole exome sequencing, gene expression profiling, IHC, flow cytometry). Results: 21 of a planned 84 patients were enrolled (Arm A = 7, Arm B = 14). Arms were well balanced for standard prognostic factors, and toxicity was manageable. RECIST response rate with neo D+T was 77%, and the pathologic complete response rate (pCR) was 58%. First interim analysis revealed significantly improved RFS in the D+T arm over SOC (HR 62.5, p &lt; 0.0001), leading to early closure to enrollment. Pts with a pCR at surgery had significantly improved RFS versus pts without pCR (p = 0.04) on neo D+T. Tumor profiling revealed incomplete MAPK pathway blockade and higher levels of CD8+ T cells expressing immunomodulators Tim-3 and Lag-3 in pts who did not achieve a pCR. Conclusions: Neo + adjuvant D+T is associated with a high pCR rate and markedly improved RFS over SOC in pts with high-risk resectable BRAF-mutant metastatic melanoma. pCR at surgery is associated with improved RFS. Tumor analyses reveal candidate targets for testing in future trials to enhance responses to neo D+T. Clinical trial information: NCT02231775.

68Ga-prostate-specific membrane antigen-positron emission tomography/computed tomography in advanced prostate cancer: Current state and future trends.

The early and accurate detection of prostate cancer is important to ensure timely management and appropriate individualized treatment. Currently, conventional imaging has limitations particularly in the early detection of metastases and at prostate-specific antigen (PSA) levels < 2.0 ng/mL. Furthermore, disease management such as salvage radiotherapy is best at low PSA levels. Thus, it is critical to capture the disease in the oligometastatic stage as disease progression and commencement of systemic therapies can be delayed by metastasis-directed therapy. Prostate-specific membrane antigen (PSMA) is overexpressed in prostatic cancer cells. Novel imaging modalities using radiolabeled tracers with PSMA such as 68Ga-PSMA-positron emission tomography (PET)/computed tomography (CT) have shown promising results. We review the literature regarding 68Ga-PSMA-PET/CT in the setting of primary prostate cancer and biochemical recurrence. At present, the best utilization of 68Ga-PSMA-PET/CT appears to be in biochemical recurrence. 68Ga-PSMA-PET/CT has high diagnostic accuracy for lymph node metastases and has been shown to have superior detection rates to conventional imaging, especially at low PSA levels.The exact role of 68Ga-PSMA-PET/CT in primary prostate cancer is not yet entirely clear. It has an improved detection rate for smaller lesions and may be able to identify nodal or distant metastatic disease at an earlier stage. While still experimental, there may also be value in combining 68Ga-PSMA-PET to multiparametric magnetic resonance imaging for staging of intraprostatic disease. To date, 68Ga-PSMA-PET/CT has been shown to have considerable clinical value and to impact treatment selection for patients with prostate cancer. Still in its infancy, the results of future clinical trials will be excitedly awaited.

Radical surgery of oligometastatic pancreatic cancer

BackgroundIn metastatic disease (M1), chemotherapy (expected survival: 6–10 months) is considered the only treatment option. The aim of this study was to evaluate the outcome of curative M1 PDAC resections. MethodsProspective data of all patients undergoing primary tumour and metastasis resection for stage IV PDAC during a 12-year period was analysed regarding localisation (liver or distant interaortocaval lymph nodes; ILN), morbidity and survival. Patients were stratified with regard to syn- or metachronous metastases resection. ResultsPatients (n = 128) undergoing PDAC and metastases resection (intention-to-treat, oligometastatic stage; liver n = 85; ILN n = 43) were included. Surgical morbidity and 30-day mortality after synchronous resection of M1 tumours were 45% and 2.9%, respectively. Overall median survival after M1 resection was 12.3 months in both groups. Long-term outcome showed a 5-year survival of 8.1% after surgery for both liver metastases and 10.1% following ILN resection. ConclusionsThe present collective is the largest series of resected metastatic PDAC and shows that resection of liver or ILN metastases can be done safely and should be considered as it may be superior to palliative treatment, and it is associated with long-term survival of 10% in selected patients. Further studies to stratify patients for these procedures are warranted.

Outcomes of a Highly Selective Surgical Approach to Oligometastatic Lung Cancer

A highly selected subset of patients with oligometastatic non-small cell lung cancer (NSCLC) will be cured after all sites of established disease (primary and metastases) have been eliminated by surgery or radiation (ie, "curative intent" approach). Mediastinal lymph node metastases (N2) have been found retrospectively to predict a poor prognosis in this setting (5-year survival of 4% for N2-positive versus 31% for N2-negative). Hence, our institution has programmatically limited the use of curative intent local therapy to oligometastatic NSCLC patients confirmed to be free of N2 disease. However, it is unclear whether the exclusion of N2-positive patients is an effective prospective selection step to aggressively treat oligometastatic NSCLC. A prospectively maintained institutional tumor registry was reviewed for oligometastatic stage IV NSCLC patients evaluated for curative intent treatment from 2005 to2014. All synchronous oligometastatic NSCLC cases were evaluated by invasive mediastinal staging before treatment. Twenty-two patients without N2 disease underwent curative intent treatment, and 13 patients with N2 disease were treated palliatively. The groups were similar by bivariate analyses. The N2-negative patients treated with curative intent had a superior 5-year survival compared with N2-positive patients treated palliatively (58% versus 0%, respectively; p= 0.028). Using invasive mediastinal staging to exclude N2 disease has a role in surgical decision making and achieving long-term survival among oligometastatic NSCLC patients. Further study is warranted to determine whether a subset of patients with N2 disease also have the potential for long-term survival with local therapy.

Abstract B03: A small-molecule antagonist of CX3CR1 impairs homing and colonization of breast cancer cells in the skeleton

Abstract Therapeutic approaches aimed to prevent breast cancer cells from spreading to distant sites are commonly neglected, based on the indication that dissemination from primary tumors can occur early. However, mounting evidence indicates that cancer cells recirculating from established bone lesions could further seed and colonize both skeleton and soft-tissue organs, thus precipitating metastatic dissemination and accelerating disease progression. We have previously shown that breast circulating tumor cells (CTCs) rely on the chemokine receptor CX3CR1 for lodging to the skeleton. Here, we show that this receptor is overexpressed by all four main subtypes of breast adenocarcinoma and also abundantly detected in bone metastatic lesions from breast cancer patients. We have recently synthesized JMS-17-2, a novel small molecule inhibitor of CX3CR1. We tested this compound in pre-clinical animal models of metastases in which human breast cancer cells, labeled with fluorescent and bioluminescent markers, are converted into CTCs by direct grafting in the arterial blood circulation. Pre-incubating cancer cells with JMS-17-2 or treating animals with this compound (10 mg/Kg, i.p.) were equally effective in dramatically decreasing the number of breast CTCs that lodged to the skeleton. These disseminated tumor cells (DTCs) were detected 24 hours after grafting and enumerated by multispectral fluorescence microscopy of sequential bone tissue sections spanning the entire width of tibiae and femora. Notably, when animals were examined at two weeks after grafting, JMS-17-2 completely prevented metastases, indicating that the reduction in number of DTCs directly translates to an impaired tumor growth in the long term. Finally, JMS-17-2 was administered to animals harboring a limited number of small metastases in bone and soft-tissues and monitored by bioluminescence imaging for three weeks before sacrifice. Animals treated with the CX3CR1 antagonist remained at an oligometastatic stage whereas control animals showed a sharp increase in the number of metastatic lesions and overall tumor burden. The work presented here should generate a conceptual shift in the treatment strategies for breast cancer patients, paving the way to approaches aimed to counteract the seeding of additional lesions from existing metastases. We also introduce JMS-17-2 as the first CX3CR1 antagonist and lead compound of a class of potentially new drugs with a novel mechanism of action that could be added to the arsenal of therapies currently used to treat advanced breast adenocarcinoma. Citation Format: Fei Shen, Yun Zhang, Danielle Jernigan, Jie Yan, Fernando Garcia, Olimpia Meucci, Joseph Salvino, Alessandro Fatatis. A small-molecule antagonist of CX3CR1 impairs homing and colonization of breast cancer cells in the skeleton. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B03.

Recurrence and Survival Outcomes After Percutaneous Thermal Ablation of Oligometastatic Melanoma

ObjectivesTo evaluate focal treatment of melanoma metastases and to explore whether any potential extended survival benefit exists in a select patient population. Patients and MethodsAll patients who underwent image-guided local thermal ablation of metastatic melanoma over an 11-year period (January 1, 2002, to December 31, 2013) were retrospectively identified using an internally maintained clinical registry. Only patients with oligometastatic stage IV disease amenable to complete ablation of all clinical disease at the time of ablation were included in the analysis. Overall survival and median progression-free survival periods were calculated. ResultsThirty-three patients with primary ocular or nonocular melanoma had 66 metastases treated in the lungs, liver, bones, or soft tissues. Eleven (33%) patients were on systemic medical therapy at the time of the procedure. The median survival time was 3.8 years (range, 0.5-10.5 years), with a 4-year estimated survival of 44.1% (95% CI, 28%-68%). Local recurrence at the ablation site developed in 15.1% (5 of 33) of the patients and 13.6% of the tumors (9 of 66). The median progression-free survival time was 4.4 months (95% CI, 1.4 months to 10.5 years), with an estimated 1-year progression-free survival of 30.3% (95% CI, 18%-51%). A subgroup analysis identified 11 patients with primary ocular melanoma and 22 with nonocular melanoma, with a median survival time of 3.9 years (range, 0.9-4.7 years) and 3.8 years (range, 0.5-10.5 years), respectively (P=.58). There were no major complications and no deaths within 30 days of the procedure. ConclusionSelective use of image-guided thermal ablation of oligometastatic melanoma may provide results similar to surgical resection in terms of technical effectiveness and oncologic outcomes with minimal risk.

Neoadjuvant Cytoreductive Treatment of Regionally Advanced Melanoma With BRAF/MEK Inhibition: Study Protocol of the REDUCTOR (Cytoreductive Treatment of Dabrafenib Combined With Trametinib to Allow Complete Surgical Resection in Patients With BRAF Mutated, Prior Unresectable Stage III or IV Melanoma) Trial

BackgroundLocally advanced (unresectable or high risk of R1 resection) regionally metastatic melanoma occurs in approximately 5% of patients with regionally metastatic disease. Cytoreductive treatment with sufficient downsizing of the tumor could enable radical resection in these patients. BRAF + MEK combination treatment has shown quick responses in most patients with BRAF-mutated melanoma. The aim of the present study, therefore, was to evaluate the ability of short-term cytoreductive neoadjuvant BRAF + MEK inhibition to allow for complete surgical resection in patients with BRAF-mutated, locally advanced stage III or oligometastatic stage IV melanoma. Patients and MethodsThe REDUCTOR (cytoreductive treatment of dabrafenib combined with trametinib to allow complete surgical resection in patients with BRAF mutated, prior unresectable stage III or IV melanoma) trial is a phase II trial in which 25 patients with BRAF-mutated, locally advanced, stage III or oligometastatic stage IV melanoma (≤ 3 metastases) will receive neoadjuvant cytoreductive dabrafenib and trametinib combination therapy. The patients will be treated for 8 weeks. The positron emission tomography/computed tomography response evaluation will occur at 2 and 8 weeks. In the case of sufficient tumor downsizing, surgery will be performed. Biopsies for translational research purposes will occur at baseline and 2 weeks, and the dissection specimen will be stored at 8 weeks. ConclusionThe primary endpoint of the present trial is the percentage of patients in whom an R0 resection (microscopically radical) can be performed, as evaluated by pathologic examination. The secondary endpoints are recurrence-free survival, time to next treatment, and overall survival. Translational research will focus primarily on the assessment of treatment-induced changes in exome mutations within the tumor and changes in gene expression profiles.

A prospective phase II study of consolidation chemotherapy after concurrent chemoradiotherapy for oligometastatic stage IV non-small cell lung cancer

Objective To evaluate the efficacy and safety of consolidation chemotherapy after thoracic radical concurrent chemoradiotherapy for patients with oligometastatic non-small cell lung cancer (NSCLC). Methods Sixty-six NSCLC patients with more than five metastases from 2008 to 2013 were enrolled, and image-guided radiotherapy with conventionally fractionated or hypofractionated doses were performed for these patients. Platinum-based doublets chemotherapy was applied for both concurrent chemoradiotherapy and consolidation chemotherapy. Short-term outcome, adverse reactions, and survival rate were assessed for the patients after treatment. Results Sixty-four patients completed the treatment. The median biologically equivalent dose for planning target volume of thoracic primary tumor lesions was 72 Gy, with a median number of chemotherapy cycles of 4. The objective response rate for thoracic lesions was 70%. The follow-up rate was 97%. The 1-, 2-, and 3-year overall survival (OS) rates were 72%, 53%, and 31%, respectively, with a median OS time of 25 months; the 1-, 2-, and 3-year progression-free survival (PFS) rates were 56%, 26%, and 7%, respectively, with a median PFS time of 14 months. The incidence of grade 2-3 acute radiation pneumonitis and radiation esophagitis was 1% and 17%, respectively, and the incidence of grade 3-4 decreases in leukocytes, hemoglobin, and platelet count was 39%, 11%, and 16%, respectively. Conclusions Radical radiotherapy combined with concurrent and consolidation chemotherapy for oligometastatic NSCLC can achieve good short-term outcome and long-term survival, with tolerable adverse effects. Key words: Lung neoplasms/radiochemotherapy; Oligometastatic; Treatment outcome; Toxicity

Local control rates with five fractions of stereotactic body radiotherapy for primary lung tumors: a single institution experience of 153 consecutive patients

Background: We report our institutional experience with stereotactic body radiotherapy (SBRT) for treatment of non-small cell lung cancer (NSCLC). Methods: One hundred and fifty-three consecutive patients diagnosed with NSCLC were treated with image-guided SBRT between 2008 and 2012. Stage I patients were treated in lieu of resection, stage II-III patients were not candidates for concurrent chemoradiation and had disease amenable to SBRT and stage IV patients had oligometastatic disease. The median prescribed isocenter dose was 50 Gy in five fractions (range, 40-60 Gy) with the majority (n=121) receiving 50 Gy in five fractions. The 80% isodose line covered the planning target volume (PTV) [defined as gross tumor volume (GTV) + 7-11 mm volumetric expansion). Follow-up ranged from 1-46 months with a median of 13 months. Results: The 1- and 2-year local control (LC) rates for all patients were 92% and 85% respectively. For 111 patients with stage I NSCLC, 1- and 2-year LC was 95% and 85%, with all local recurrence (LR) occurring within 2 years. LC at 1- and 2-year was 87% for both stage II (n=19) and stage III (n=14), with all LR occurring within 10 months. For oligometastatic stage IV (n=9) patients, LC at 1- and 2-year was 71%, with all LR occurring within 5 months. Two-year LC among patients with tumors 1 cm. Tumor histology, prescribed dose, patient age, and prior radiotherapy (RT) or surgery had no significant impact on LC rates. Prior chemotherapy had a significant negative impact on LC with 1- and 2-year LC of 59%, compared to 1- and 2-year LC of 93% and 85%, respectively (P=0.015). n multivariate analysis, stage was the only significant predictor of LC. Among stage I NSCLC patients, 6 of 111 developed LR, 13 developed distant failures (of whom 5 also developed LR). Of these 111 patients, 5 died from NSCLC and 2 died from causes other than NSCLC; no patient died from treatment-related toxicity. Conclusions: SBRT plays a vital role and offers excellent LC in medically-inoperable NSCLC patients, with treatment during the early stage of the disease determined as the single most significant predictor of LC on multivariate analysis.

Abstract 4116: A small-molecule antagonist of CX3CR1 impairs homing and colonization of breast cancer cells in the skeleton

Abstract Therapeutic approaches aimed to prevent breast cancer cells from spreading to distant sites are commonly neglected, based on the indication that dissemination from primary tumors can occur early. However, mounting evidence indicates that cancer cells recirculating from established bone lesions could further seed and colonize both skeleton and soft-tissue organs, thus precipitating metastatic dissemination and accelerating disease progression. We have previously shown that breast circulating tumor cells (CTCs) rely on the chemokine receptor CX3CR1 for lodging to the skeleton. Here, we show that this receptor is overexpressed by all four main subtypes of breast adenocarcinoma and also abundantly detected in bone metastatic lesions from breast cancer patients. We have recently synthesized JMS-17-2, a novel small molecule inhibitor of CX3CR1. We tested this compound in pre-clinical animal models of metastases in which human breast cancer cells, labeled with fluorescent and bioluminescent markers, are converted into CTCs by direct grafting in the arterial blood circulation. Pre-incubating cancer cells with JMS-17-2 or treating animals with this compound (10 mg/Kg, i.p.) were equally effective in dramatically decreasing the number of breast CTCs that lodged to the skeleton. These disseminated tumor cells (DTCs) were detected 24 hours after grafting and enumerated by multispectral fluorescence microscopy of sequential bone tissue sections spanning the entire width of tibiae and femora. Notably, when animals were examined at two weeks after grafting, JMS-17-2 completely prevented metastases, indicating that the reduction in number of DTCs directly translates to an impaired tumor growth in the long term. Finally, JMS-17-2 was administered to animals harboring a limited number of small metastases in bone and soft-tissues and monitored by bioluminescence imaging for three weeks before sacrifice. Animals treated with the CX3CR1 antagonist remained at an oligometastatic stage whereas control animals showed a sharp increase in the number of metastatic lesions and overall tumor burden. The work presented here should generate a conceptual shift in the treatment strategies for breast cancer patients, paving the way to approaches aimed to counteract the seeding of additional lesions from existing metastases. We also introduce JMS-17-2 as the first CX3CR1 antagonist and lead compound of a class of potentially new drugs with a novel mechanism of action that could be added to the arsenal of therapies currently used to treat advanced breast adenocarcinoma. Citation Format: Fei Shen, Yun Zhang, Danielle Jernigan, Jie Yan, Fernando Garcia, Olimpia Meucci, Joseph Salvino, Alessandro Fatatis. A small-molecule antagonist of CX3CR1 impairs homing and colonization of breast cancer cells in the skeleton. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4116. doi:10.1158/1538-7445.AM2015-4116

Recurrence and survival outcomes following percutaneous thermal ablation of oligometastatic melanoma.

e20040 Background: Focal treatment of melanoma metastases has been demonstrated to provide extended survival in a very select patient population. To our knowledge, percutaneous image-guided thermal ablation of metastatic lesions has not been described for patients with stage IV melanoma. Methods: All patients who underwent image-guided local thermal ablation of metastatic melanoma over an 11-year period (2002-2013) were retrospectively identified using an internally maintained clinical registry. Only patients with oligometastatic stage IV disease amenable to complete ablation of all clinical disease at the time of ablation were included in our analysis. Progression of disease was followed with contrast-enhanced CT, MRI or PET/CT for identification of local recurrence at the ablation site, recurrent organ specific and/or new metastatic disease outside the previously treated organ. Overall survival and median progression-free survival (including local recurrence at the ablation site, treated organ recurrence and new metastatic disease) were calculated. Results: Thirty-three patients with primary ocular or cutaneous melanoma had 67 metastases treated in the lungs, liver, bones or soft tissues. Thirteen (39.4%) patients were on systemic medical therapy at the time of the procedure. The median survival time was 3.8 years with 5-year estimated survival of 27.5% (95% Cl: 14.6 to 51.9%). Local recurrence at the ablation site developed in 15.1% (5/33) of patients and 13.4% of tumors (9/67). Median progression-free survival time was 4.4 months with estimated 1-year progression-free survival of 30.3% (95% Cl:18.1 to 50.8%). There were no major complications and no deaths within 30 days post procedure. Conclusions: We demonstrate that image-guided thermal ablation of metastatic melanoma amenable to complete ablation of all clinical disease confers a potential survival benefit with minimal risk.

Radiothérapie stéréotaxique extracrânienne et oligométastases

In stage IV cancers, locoregional management of primitive tumours as surgery and/or radiotherapy improved both progression-free survival and overall survival. Among metastatic cancer patients, some of them are considered as oligometastatic stage as they present few metastatic sites associated with low tumor aggressiveness. For those patients, metastatic local control, and therefore prolonged time to progression should be reached through local treatments as surgery and/or radiofrequency ablation and/or stereotactic radiotherapy. Here we propose a review of oligometastatic stage and results from extracranial stereotactic radiotherapy in terms of efficacy and tolerance.

Definitive thoracic radiotherapy in oligometastatic stage IV non-small cell lung cancer (NSCLC).

e18032 Background: Intrathoracic tumor control in patients (pts) with metastatic NSCLC is controversial as most die of distant disease. But a subset of good performance status pts with minimal burden of extrathoracic disease may benefit aggressive treatment. We report outcomes in a subset of pts with oligometastatic NSCLC treated with definitive radiotherapy (RT) to the primary tumor. Methods: We identified29 stage IV pts from 01/04 - 08/10 who had ECOG ≤2 and ≤4 metastases who received ≥50 Gy thoracic RT with chemotherapy. Pts were assessed for local control, overall survival and toxicity. An exploratory analysis was performed matching these pts to pts receiving chemotherapy (CT) alone. Results: In the 29 chemoradiotherapy (CRT) pts, median age was 57 yrs, 72% had ECOG 1 and 91% were staged with PET. Median survival was 22 months. Eight patients had grade 2+ pneumonitis. Nineteen patients had grade 2+ esophagitis. Next, 2 CT pts were matched with each CRT pt on 4 factors: age, ECOG, and presence of multi-organ or contralateral lung disease. We excluded 4 CRT pts who did not match 2 CT controls. Median survival was 22 vs 9 months (p &lt;0.01) for patients given CRT vs CT. Median time to local failure was 18 vs 6 months (p = 0.01). Median survival in locally controlled pts was 39 vs 19 months in pts with local failure (p = 0.02). On multivariable analysis, radiation (p &lt;0.01, OR = 0.33), multiple metastatic organs at diagnosis (p &lt;0.01, OR = 2.14), and gender (p &lt;0.01, OR = 0.41) were associated with overall survival. Conclusions: Treatment ofNSCLC patients with oligometastatic disease with definitive dose radiation therapy may provide a local control and overall survival benefit in a subset of patients with minimal extrathoracic burden of disease.

A 66-Year-Old Woman With Newly Diagnosed Oligometastatic Non–Small Cell Lung Cancer

A 66-year-old woman presented with newly diagnosed stage IV non-small cell lung cancer (NSCLC) and a large adrenal metastasis. She initially had flu-like symptoms and dyspnea and was found to have a right upper lobe (RUL) lung nodule. Chest CT showed a 1.4-cm spiculated RUL lung nodule, peripheral right lung nodule, right perihilar mass, and 10.9-cm left adrenal mass. PET/CT showed enhancement of the RUL nodule, hilar mass, and left adrenal mass. She presented for evaluation of treatment options. This case was thought to represent an instance of oligometastatic stage IV NSCLC. Literature suggests that a select patient population with otherwise resectable disease may benefit from surgical resection of a lung primary and the isolated metastasis with improved survival. This seems to be most effective in patients who have undergone a complete staging evaluation with PET scan; CT of the chest, abdomen, and pelvis; and a brain MRI revealing T1-2, N0-1, M-oligo disease. This radical approach should be reserved for patients with potentially curative disease based on the staging evaluation and who are otherwise good surgical candidates.

Definitive Dose Thoracic Radiotherapy In Oligometastatic Stage IV Non-small Cell Lung Cancer (NSCLC)

Definitive Dose Thoracic Radiotherapy In Oligometastatic Stage IV Non-small Cell Lung Cancer (NSCLC)

Long-term survival after high-dose chemotherapy followed by peripheral stem cell rescue for high-risk locally advanced/inflammatory and metastatic breast cancer.

1048 Background: Patients (pts) with high-risk (HR) locally advanced/inflammatory breast cancer (LABC/IBC), and oligometastatic (≤ 3 sites) stage IV metastatic breast cancer (MBC) are likely to relapse/progress early. High dose chemotherapy (HDCT) followed by stem cell rescue (SCR) may prolong progression/relapse-free (PFS/RFS) and overall survival (OS) in selected pts. Methods: Between 1998 and 2009, 104 eligible pts were consented and treated sequentially on 2 City of Hope Cancer Center IRB-approved HDCT protocols. HDCT consisted of carboplatin, thiotepa, and cyclophosphamide (STAMP-V), doxorubicin, paclitaxel, and cyclophosphamide (ACT), or tandem melphalan and STAMP-V (administered to all pts with MBC and followed by targeted radiation therapy), supported by SCR. Results: Ninety-two pts were diagnosed with LABC/IBC (16 IBC), and 12 had MBC. Among the 92 HR pts, by AJCC 7th edition criteria,14 pts were treated for IIIA, 10 for IIIB, and 68 for IIIC BC. The median age for pts with LABC/IBC was 50 years (range 28−66). Neoadjuvant chemotherapy (NCT) was prescribed to 34% of pts. HDCT was prescribed a median of 8.1 (range 4.4−14.5) months (mos) after diagnosis. The median follow-up of alive LABC/IBC patients was 84 mths (range 6−136). Hormone receptors (HR) were positive in 74% of LABC/IBC pts, and HER2 was overexpressed in 23%. Hormone receptor status (HR) positively impacted the likelihood of RFS and OS (HR+ vs HR- 5-yr RFS 61% vs 32%, p=.008). Tumor grade, histopathology including IBC, HER2 and triple negative status, or receipt of NCT had no statistically significant effect on survival, although higher stage disease led to worse long term outcomes (5-yr RFS for Stage IIIA, IIIB, IIIC was 85%, 68%, 45%, p=.051, with 5-yr OS 92%, 90%, and 64%, respectively, p=.051). For MBC (12 pts), the median follow-up of alive pts is 40 months, (range 24−62), resulting in a 3-yr PFS of 49% 95% CI (19%−73%), and 3−yr OS of 73% 95% CI (38%−91%). One pt died of HDCT-associated sepsis, and 1 pt developed papillary thyroid cancer. Conclusions: The favorable long term PFS/RFS and OS in this selected pt population warrants validation in molecularly defined subgroups with LABC/IBC/MBC.