Non-lung Metastases Research Articles

Improved local control following dose-escalated stereotactic ablative radiation therapy (SABR) for metastatic sarcomas: An international multi-institutional experience

BackgroundWe aimed to characterize local control (LC) and overall survival (OS) following stereotactic ablative radiation therapy (SABR) for extracranial sarcoma metastases. MethodsA prospectively-maintained institutional registry was queried for patients with metastases from sarcoma primaries managed with SABR. Kaplan-Meier analysis was utilized for univariate analyses to assess potential prognostic factors regarding LC and OS. A Cox proportional hazards multivariate (MVA) model was employed to further assess initially identified independent variables. ResultsA total of 94 patients with 118 lesions with LC information were identified. Common metastatic sites treated were lung (77), non-spinal bone (15), and spine (10). The median biologically effective dose (BED4) was 175 Gy4 (range56.3 Gy4–360 Gy4) with a median dose/fractionation schedule of 50 Gy/5 fractions. One- and 2-year OS rates were 81.3 % (95 % CI: 71.2–88.1 %6) and 50.5 % (95 % CI: 38.6–61.3 %, respectively. On Cox MVA, advanced age and non-lung metastases were associated with inferior OS (p < 0.03) with patients with 0–2 of these risk factors having estimated 2-year OS of 65.1 %, 38.9 %, and N/A, respectively. One- and 2-year LC rates were 85.3 % (95 % CI: 77.7–90.9 %) and 78.2 % (95 % CI: 67.9–85.6 %), respectively. On MVA, only BED4 < 175 Gy was associated with inferior LC (hazard ratio (HR) = 3.33; p = 0.01). Ten of 118 treated lesions had treatment-related toxicities (all Grade 1–2). ConclusionAge and lung vs. non-lung metastases were prognostic of OS and should be considered in patient selection for SABR. Dose escalation when feasible with BED4 ≥ 175 Gy is recommended given durable LC achieved without a subsequent increase in toxicity.

Distant metastasis without regional progression in non-muscle invasive bladder cancer: case report and pooled analysis of literature

BackgroundNon-muscle invasive bladder cancer (NMIBC) represents the majority of bladder neoplasms. It is unusual for NMIBC metastasizing distantly without regional progression, namely metastatic NMIBC (mNMIBC), which is still poorly understood and easily omitted based on current management policies. So far, description of mNMIBC is limited to a few case reports.MethodsWe reported a 70-year-old man with NMIBC who suffered from cervical metastasis without pelvic recurrence at 41 months after initial diagnosis. Then we performed a collective analysis of this case together with published mNMIBC cases searched from PubMed, Embase, and Web of Science, aiming to illustrate baseline clinicopathologic parameters, metastatic patterns, and treatment outcomes of these patients and analyze associated influencing factors.ResultsAfter scrupulous review, 45 cases previous reported and the one from our center were incorporated into the aggregated cohort of mNMIBC, including 34 males and 12 females. Primary tumors from 46.7% of patients were high-grade (HG) or grade 3 (G3) and 65.1% had T1 lesions. Aberrant biomarker expression was found in tumors of some cases. Most (40/46) metastases of mNMIBC occurred at a single site, mainly in lung, bone and lymph nodes. Apart from three cases of de novo mNMIBC, the mean metastasis-free survival (MFS) interval of metachronous mNMIBC was 42.5 months, which was obviously longer than conventional metastatic bladder cancer. Shortened MFS interval was associated with old age, T1 or HG/G3 primary tumors, and non-lung metastases. Systemic chemotherapy and metastasectomy or radiotherapy for oligometastatic lesion were main therapeutic approaches of mNMIBC, and immunotherapy was adopted for the case from our center. Lung and bone metastases correlated with relatively favorable and unfavorable survival outcomes, respectively. Compared with monotherapy, chemotherapy, or immunotherapy combined with local cytoreduction got more favorable outcomes.ConclusionAlthough rare, mNMIBC occurs more in tumors with high-risk features. Usually, mNMIBC metastasizes later than conventional metastatic bladder cancer and manifests as solitary lesion. Outcomes of mNMIBC would be influenced by metastatic site and post-metastatic treatment. Systemic treatment combined with local cytoreduction may render survival benefit in selected patients.

Matrix-assisted laser desorption ionization mass spectrometry profiling of plasma exosomes evaluates osteosarcoma metastasis

SummaryOsteosarcoma is the most common primary sarcoma of bone among adolescents, often characterized by early lung metastasis resulting in high mortality. Recently, exosomes have been used in liquid biopsy to monitor tumors. Herein, we used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to profile human plasma exosomes for the evaluation of osteosarcoma lung metastasis. Forty patients with osteosarcoma with (n = 20) or without (n = 20) lung metastasis as well as 12 heathy controls were recruited. Exosomes were isolated from human plasma for MALDI-TOF MS analysis. Multivariate statistical analyses were performed based on the MALDI-TOF mass spectra. The strategy can efficiently differentiate osteosarcomas from healthy controls and further discriminate osteosarcoma lung metastasis from non-lung metastasis. We identified seven exosomal proteins as potential biomarkers of osteosarcoma lung metastasis. The proposed method holds great promise to clinically diagnose osteosarcoma and monitor osteosarcoma lung metastasis.

Analysis of related risk factors of lung metastasis after laparoscopic radical hysterectomy of cervical cancer.

To explore the risk factors of lung metastasis in patients after laparoscopic radical hysterectomy (LRH) of cervical cancer (CC).The clinical data of CC patients with clinical stage of IA1–IIA2 diagnosed in our hospital from April 2007 to October 2015 were collected. According to the situation of metastasis, the patients were divided into lung metastasis (n = 73) and non-lung metastasis group (n = 2076). The clinical data were compared between 2 groups, and logistic stepwise regression model was used to analyze the risk factors of lung metastasis in patients with CC after LRH.The incidence of lung metastasis after LRH of CC was 3.39%, and 67.13% of patients with lung metastases had no obvious clinical symptoms. 15.06% patients had lung metastasis in the first year, 38.35% in the second year, 43.83% in the third year and later. The postoperative lung metastasis of CC was related to tumor diameter (P < .001), pathological type (P < .001), interstitial invasion depth (P < .001), pelvic lymph node metastasis (PLNM, P < .001), vascular tumor thrombus (P = .011), tumor uterine invasion (P = .002), and abnormal preoperative tumor markers (P = .015). However, it was not related to age, clinical stage, tumor growth pattern, tumor differentiation, and para-aortic lymph node metastasis (P > .05). Logistic regression analysis revealed non-squamous cell carcinoma (P = .022), tumor diameter ≥4 cm (P = .008), interstitial invasion depth >2/3 (P = .003), PLNM (P = .007), and tumor uterine invasion (P = .037) is an independent risk factor for lung metastasis after LRH of CC.Non-squamous cell carcinoma, tumor diameter ≥4 cm, tumor interstitial invasion depth >2/3, PLNM, and tumor uterine invasion are independent risk factors for lung metastasis after LRH of CC.

MALDI-TOF Mass Spectrometry Profiling of Plasma Exosomes Evaluates Osteosarcoma Metastasis

Osteosarcoma is the most common primary sarcoma of bone among adolescents, often characterized by early lung metastasis resulting in high mortality. Recently, exosomes have been used in liquid biopsy for monitoring tumors. Herein, we used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to profile human plasma exosomes for the evaluation of osteosarcoma lung metastasis. Forty osteosarcoma patients with (n = 20) or without (n = 20) lung metastasis as well as 12 heathy controls were recruited. Exosomes were isolated from human plasma for MALDI-TOF MS analysis. Multivariate statistical analyses were performed on the MALDI-TOF mass spectra. It was demonstrated that the strategy can differentiate osteosarcomas from healthy controls and further discriminate osteosarcoma lung metastasis from non-lung metastasis. Seven exosomal potential protein biomarkers of osteosarcoma lung metastasis were identified. The proposed method has a great clinical application prospect in the diagnosis of osteosarcoma and monitoring of osteosarcoma lung metastasis.

Metastasis-directed stereotactic body radiation therapy in the management of oligometastatic head and neck cancer.

Recently major efforts have been made to define the oligometastatic setting, but for head and neck cancer (HNC) limited data are available. We aimed to evaluate outcome of oligometastatic HNC treated with Stereotactic body radiotherapy (SBRT) as metastasis-directed therapy. We analyzed patients treated with SBRT on a maximum of five oligometastases from HNC, in up to two organs. Concomitant treatment was allowed. End points were toxicity, local control of treated metastases (LC), progression-free survival (PFS) and overall survival (OS). 48 consecutive patients and 71 lesions were treated. With a follow-up of 20.2months, most common primary tumors were larynx (29.2%) and salivary glands (29.2%), while common site of metastases was lung (59.1%). Median dose was 48Gy (21-75) in 3-8 fractions. Treatment was well tolerated, with two patients reporting mild pain and nausea. LC rates at 1 and 2years were 83.1% and 70.2%. Previous local therapy (HR 4.97; p = 0.002), oligoprogression (HR 4.07; p = 0.031) and untreated metastases (HR 4.19; p = 0.027) were associated with worse LC. PFS at 1 and 2years were 42.2% and 20.0%. Increasing age (HR 1.03; p = 0.010), non-adenoid cystic carcinoma (HR 2.57; p = 0.034) and non-lung metastases (HR 2.20; p = 0.025) were associated with worse PFS. One- and 2-years OS were 81.0% and 67.1%. Worse performance status (HR 2.91; p = 0.049), non-salivary primary (HR 19.9; p = 0.005), non-lung metastases (HR 2.96; p = 0.040) were correlated with inferior OS. SBRT can be considered a safe metastasis-directed therapy in oligometastatic HNC. Efficacy of the treatment seems to be higher when administered upfront in the management of metastatic disease; however, selection of patients need to be improved due to the relevant risk of appearance of new metastatic site after SBRT.

A Multi-Institutional Analysis of Outcomes following Stereotactic Body Radiation Therapy (SBRT) for Management of Metastases from Squamous Cell Carcinomas of the Head and Neck

While increasing evidence supports the potential role of stereotactic body radiation therapy (SBRT) for oligometastatic disease, multi-institutional outcomes are limited for metastatic head and neck squamous cell carcinoma (mHNC). We screened a prospectively maintained international multi-institutional registry for mHNC patients treated with SBRT. Potential predictive factors of local control (LC), progression-free survival (PFS), and overall survival (OS) were evaluated with the Kaplan-Meier method and a Cox-proportional hazards model for multivariate analysis (MVA). Eighty-five patients with 102 lesions treated with SBRT were identified. Median patient age was 68 years, median KPS was 90%, and the median gross tumor volume (GTV) was 25cc. The median biologically effective dose (BED10) and dose/fraction were 82.75 Gy10 and 10 Gy, respectively. Commonly treated areas included the lung (51.8%), lymph node metastases (15.3%), and spine (14.1%), and common primary locations included the oral cavity (41.1%), larynx (24.7%), and oropharynx (23.5%). One- and 2-year OS rates were 62.7% and 40.7%, respectively. Patients with GTVs ≥ 25cc (77.4% vs. 58.2%; p = 0.02), those with non-lung metastases (67.5% vs. 58.2%; p = 0.07), lymph node metastases (43.3% vs. 66.6%; p = 0.10), spinal metastases (50% vs. 65.3%; p = 0.07), or KPS < 90% (42.2% vs.74.1%; p = 0.04) demonstrated inferior 1-year OS. On MVA, patients with spinal metastases (hazard ratio (HR) = 2.21 (95% CI: 1.07-4.60); p = 0.03)) were noted to have poorer OS in addition to those with GTVs ≥ 25cc (HR = 1.95 (95% CI: 0.93-4.09); p = 0.08). Utilizing KPS, GTV, and the presence of spinal metastases as potential prognostic indicators, 2-year OS rates were 81.2%, 32.6%, 38.2%, and not reached for patients with 0-3 of these factors, respectively (p = 0.0014). One-year and 2-year PFS rates were 72.5% and 60.6%, respectively, with superior 1-year PFS noted for patients of age < 70 (80.4% vs. 64.7%; p = 0.04) or with KPS ≥ 90% (78.3% vs. 61.5%; p = 0.03). One- and 2-year LC rates were 94.0% and 79.3%, respectively, with no prognostic or predictive factors relating to LC identified. Roughly 15% of patients reported toxicities, with no Grade 3 toxicities or association between dose and toxicities noted. To our knowledge, this represents the largest series of mHNC patients treated with SBRT. Patients with mHNC tolerated SBRT well without significant toxicities and encouraging LC. No significant dose-response for LC, PFS, OS, or toxicity was identified. When determining patient selection for aggressive local therapy in the setting of mHNC, KPS, GTV, and the presence of spinal metastases are potential prognostic factors to consider, particularly with regards to future clinical trial design.

1629P - Basket trial in advanced cancers: A clinical observation of apatinib in lung metastases and non-lung metastases

1629P - Basket trial in advanced cancers: A clinical observation of apatinib in lung metastases and non-lung metastases

The Values of Receptor Activator Nuclear Kappa-B Ligand Expression in Stage III Giant Cell Tumor of the Bone.

Background:Giant cell tumor (GCT) of bone is a benign locally aggressive primary bone tumor which is risky for local recurrences and pulmonary metastasis. Till date, there are still many uncertainties in predicting the aggressiveness of GCT. We aim to investigate whether receptor activator nuclear kappa-B ligand (RANKL) expression may determine the prognosis of the lesion.Materials and Methods:We examined RANKL expression in 39 patients (21 males, 18 females) by immunohistochemistry. Four patients (10%) were presented with tumor recurrence, eight patients (20%) were complicated with lung metastasis, and two patients (5%) were presented with both recurrence and lung metastasis. Positive RANKL expression was assessed according to a scoring system evaluating the percentage of the immunostained epithelial area and the staining intensity. The cumulative score was calculated to determine the final score value. Data were analyzed using PASW version 18.0 and independent t-test between nonrecurrence/recurrence groups, and nonlung metastasis/lung metastasis groups. Significance was set at P < 0.05.Results:Thirty-two patients (82%) scored 3 in RANKL-staining percentage from whole stromal cell population (>75%), 6 patients scored 2, and 1 patient scored 1. Nine patients (23%) scored 3 in RANKL-staining intensity (most intense), 19 patients (48%) scored 2, and 11 patients (29%) scored 1. Twenty six patients (67%) had strong RANKL expression (total score of 5–6), 12 patients (31%) showed moderate score (3–4) whereas only 1 patient (2%) showed weak RANKL expression. Together, the mean value of RANKL-staining percentage was 2.79, intensity 1.95 and the total score 4.77. The mean RANKL-staining percentage between recurrence and nonrecurrence groups was statistically significant (P = 0.009). There was no significant difference in the mean staining intensity and total score between nonrecurrence and recurrence groups, and staining percentage staining intensity and a total cumulative score of RANKL expression between lung metastasis and nonlung metastasis groups.Conclusion:RANKL expression is generally high in Stage III GCT and is a reliable prognostic marker in predicting the risk of local recurrence however not in lung metastasis.

The early response of renal cell carcinoma to tyrosine kinase inhibitors evaluated by FDG PET/CT was not influenced by metastatic organ.

BackgroundTyrosine kinase inhibitors (TKIs) have become the mainstay of treatment for advanced renal cell carcinoma (RCC), but it has been unclear whether the antitumor effect of TKIs depends on the organ where the RCC metastasis is located. We previously reported that the FDG accumulation assessed by FDG PET/CT, was a powerful index for evaluating the biological response to TKI. In this study we investigated the differences in FDG accumulation and the response to TKI as assessed by FDG PET/CT among various organs where RCC were located.MethodsA total of 48 patients with advanced RCC treated with a TKI (25 with sunitinib and 23 with sorafenib) were evaluated by FDG PET/CT before and at 1 month after a TKI treatment initiation. The maximum standardized uptake value (SUVmax) of all RCC lesions were measured and analyzed.ResultsWe evaluated 190 RCC lesions. The pretreatment SUVmax values (mean ± SD) were as follows: in the 49 lung metastases, 4.1 ± 3.3; in the 40 bone metastases, 5.4 ± 1.6; in the 37 lymph node metastases, 6.7 ± 2.7; in the 29 abdominal parenchymal organ metastases, 6.6 ± 2.7; in the 26 muscle or soft tissue metastases, 4.4 ± 2.6; and in the nine primary lesions, 8.9 ± 3.9. Significant differences in the SUVmax were revealed between metastases and primary lesions (p = 0.006) and between lung metastases and non-lung metastases (p < 0.001). The SUVmax change ratios at 1 month after TKI treatment started were -14.2 ± 48.4% in the lung metastases, -10.4 ± 23.3% in the bone metastases, -9.3 ± 47.4% in the lymph node metastases, -24.5 ± 41.7% in the abdominal parenchymal organ metastases, -10.6 ± 47.4% in the muscle or soft tissue metastases, and -24.2 ± 18.3% in the primary lesions. There was no significant difference among the organs (p = 0.531).ConclusionsThe decrease ratio of FDG accumulation of RCC lesions evaluated by PET/CT at 1 month after TKI treatment initiation was not influenced by the organs where the RCC metastasis was located. This result suggests that TKIs can be used to treat patients with advanced RCC regardless of the metastatic site.

Colorectal Cancer Survival: An Analysis of Patients With Metastatic Disease Synchronous and Metachronous With the Primary Tumor

BackgroundWhether metastatic colorectal cancer (mCRC) that presents synchronously with the primary lesion behaves differently from mCRC that appears metachronously to the primary disease is not clear. Patients and MethodsThe South Australian Clinical Registry for mCRC collects data for patients diagnosed after February 2006. Data from 2502 patients, available on October 22, 2012, were analyzed according to stage at initial diagnosis (SAID) to compare outcomes between metachronous tumors (MTs) (stages I, II, III) and synchronous tumors (STs) (stage IV). Overall survival (OS) was calculated from the date of mCRC diagnosis. ResultsPatients with ST had more liver-only metastases, and patients with MT had more lung-only, non-lung and non-liver, and non-lung metastases. The median time to recurrence differed significantly according to SAID: stage I, 49.3 mo (n = 29), stage II, 25.2 mo (n = 346) and stage III, 18.4 mo (n = 497). The median OS was longer for patients with MT than for those with ST (19.0 vs.14.9 mo, P = .003). For patients who received any treatment for mCRC, the OS was longer for patients with MT than for those with ST (19.2 vs. 15.3 mo, P = .005). In patients who received only chemotherapy for mCRC, the median OS was longer for patients with MT than for those with ST (15.2 vs. 9.9 mo, P < .0001). No difference in OS between the MT and ST groups for patients who did not receive treatment for mCRC (1.6 vs. 2.6 mo; P = .95). ConclusionPatients with MT have a longer OS than those with ST, independent of treatment. Classification of patients according to whether they have metachronous or synchronous presentation of mCRC is prognostic. These results may add further support for population screening with the aim to reduce de novo metastatic disease.

Age as a prognostic factor in osteosarcoma: Survival analysis.

10074 Background: Studies comparing survival between adult and paediatric population with osteosarcoma are scarce and contradictory. Generally adults were excluded from analysis in historical series. End Point: evaluate age as prognostic factor in ostosarcomas IIb treated exclusively by a multidisciplinary group in a single institution. Methods: 132/278 patients with histological diagnosis of osteosarcoma IIb were selected. All were treated exclusively in our hospital from July 1988 until December 2010. Patients 17 years old or younger were considered paediatric. They all received presurgical chemotherapy with the same scheme: ifosfamide + doxorrubicin + high dose methotrexate. Univariate analysis was made (Fischer exact test). Survival was calculated wih Kaplan-Meier actuarial method. Curves were compared with log rank test. Multivariate Cox analysis was made. Results: Median age was 19.6 years (std: 9,1; range 5-58). Adults: 77, children: 55. No differences were detected between the two age groups regarding: elevated alkaline phosphatase, kind of surgery (amputation vs. limb sparing), relapse site (lung, local, other), necrosis greater than 90% or number of lung resections. There was a tendency towards axial localization in adults (p=0.05). No paediatric patient had inadequate medical intervention, but it was present in 14.3% of adults (p=0.002). 5 year Overall survival (5y OS) in children was 85,2% compared with 61,8% in adults (p=0.005); Disease free survival (DFS) had a non significant tendency to be better in children (69.6% vs. 51,3%). Variables associated with worse OS were: axial location (p=0.01), elevated alkaline phosphatase (0.003), amputation (p=0.008), local relapse or systemic non-lung metastasis (p= 0.001), necrosis less than 90% (0.001). Multivariate Cox analysis showed association between OS and paediatric population (p=0.01) and necrosis greater than 90% (p=0.001), while DFS was associated with necrosis greater than 90% (p=0.01) and elevated alkaline phosphatase (p=0.05). Conclusions: Paediatric population presents better survival compared to adults in our institution. Differences in tumour biology and in the mode of presentation related to age may be the explanation.

Survival after recurrent osteosarcoma: Data from 3 European Osteosarcoma Intergroup (EOI) randomized controlled trials

BackgroundRecurrence after osteosarcoma usually leads to death; thus prognostic factors for survival are of great importance. MethodsBetween 1983 and 2002, the European Osteosarcoma Intergroup accrued 1067 patients to 3 randomized controlled trials of pre- and post-operative chemotherapy for patients with resectable non-metastatic high-grade osteosarcoma of the extremity. Control treatment in all trials was doxorubicin 75mg/m2 and cisplatin 100mg/m2. The comparators were additional high-dose methotrexate (BO02), T10-based multi-drug regimen (BO03) and G-CSF intensified-DC (BO06). Post-recurrence survival (PRS) was investigated on combined data with standard survival analysis methods. ResultsMedian recurrence-free survival was 31months; 8 recurrences were reported more than 5years after the diagnosis. In 564 patients with a recurrence (median 13months post-randomisation), there was no difference in post-relapse survival between treatment arms. Patients whose disease recurred within 2years after randomization had a worse prognosis than those recurring after 2years. Patients with good initial histological response to pre-operative chemotherapy had a better overall survival after recurrence than poor responders. Local relapse was more often reported after limb-saving procedures (2 versus 8%; amputation versus limb-saving), independent of the primary tumour site. Site of first recurrence (local 20%, lung 62%, “other” 19%) affected survival, as patients recurring with non-lung distant metastases only or any combination of local relapse, lung metastases and non-lung metastases (=group “other”) had significantly worse overall survival (local 39%, lung 19%, “other” 9% at 5years). ConclusionsThese data describing a large series of patients with recurrent extremity osteosarcoma confirm the relationship between early recurrence and poor survival. There was better PRS in patients after good histological response to pre-operative chemotherapy, or with local-only recurrence.