Resection Of Distant Metastases Research Articles

Efficacy and safety of "second adjuvant" therapy with BRAF/MEK inhibitors after resection of recurrent melanoma following adjuvant PD-1–based immunotherapy.

9575 Background: Both anti-PD-1 antibodies and BRAK/MEK inhibitors (BRAF/MEKi) reduce the risk of recurrence for patients with resected stage III melanoma. For patients with V600 BRAF-mutated melanoma who recur with resectable disease on or after adjuvant, many may be suitable for ‘second adjuvant' treatment after surgery. We sought to examine the efficacy and safety of ‘second adjuvant’ BRAF/MEKi in patients who recurred despite adjuvant PD-1 based immunotherapy. Methods: Patients with V600 BRAF-mutated melanoma treated with adjuvant PD-1 based immunotherapy for resected stage III/IV disease who recurred, underwent resection of recurrence and were then treated with adjuvant BRAF/MEKi were identified retrospectively from 13 centres. Demographics, disease characteristics, treatment details, and outcome data were examined. Results: 55 patients were included; median age at commencement of PD-1 was 53y, most were V600E (91%) and had IIIB (42%) or IIIC (44%) melanoma. PD-1 based adjuvant therapy included nivolumab (71%), nivolumab plus ipilimumab (14%), pembrolizumab (13%) and pembrolizumab plus mRNA-4157 vaccine (2%). Patients had initial recurrence after mean 8.4 months (95% CI 7.4-10.6), mainly while on treatment (65%), in regional nodes (42%), in-transit metastases (ITMs; 38%), both regional nodes and ITMs (7%) and distant metastases (13%). Surgical management included CLND (36%), selected nodal resection (11%), ITM resection (33%) and resection of distant metastasis (13%). A minority had adjuvant radiotherapy (17%). Stage at start of second adjuvant BRAF/MEKi included IIIB (29%), IIIC (53%) IIID (4%) and IV (15%). Patients received dabrafenib and trametinib (95%, N = 52) and encorafenib and binimetinib (5%, N = 3). After a median follow up of 21.4 months (19.7-25.4), 17 (31%) patients have recurred again. Mean duration of treatment was 9 months (95% CI 7.4-10.6); 20% ceased for toxicity, 7% for recurrence and 35% were on treatment at last follow up. The most common toxicity was pyrexia (43%) and 21% patients experienced a severe (G3-4) adverse event. Median RFS was 33.4 months (14.3.7-NR) and median DMFS was not reached. At 12 months, 72% (59-88) of patients were recurrence free and 90% (81-100) were free of distant recurrence. For those whose disease recurred again, most recurred after cessation of second adjuvant BRAF/MEKi (13/17, 76%). 7 (41%) recurred locally and 8 (47%) recurred with new metastatic disease but none had brain metastases. Conclusions: This is the first study examining outcomes of patients receiving second adjuvant targeted therapy for melanoma, after failure of adjuvant PD-1 based immunotherapy. While RFS appears shorter compared to first line trials, second adjuvant treatment with BRAF/MEKi appears safe and active in preventing further recurrence. Further data on sequencing adjuvant therapies are needed.

Clinical significance of brain metastases in patients with bronchopulmonary neuroendocrine tumors: A population-based analysis.

e21575 Background: The clinical significance of brain metastases in patients with bronchopulmonary neuroendocrine (NE) tumors is unknown; we therefore conducted a population based analysis to evaluate the implications of brain metastases in these patients. Methods: The NCDB database was queried to identify patients with stage IV bronchopulmonary NE tumors treated between the years of 2004-2012. Patients were split into two groups based on the presence of brain metastases at diagnosis and survival probabilities with multivariate models were performed. Results: A total of 7,725 patients with Stage IV bronchopulmonary NE tumors were identified. The histological subtypes studied in this cohort were NE carcinoma (65.4%), large cell NE carcinoma (30.5%), typical carcinoid (2.8%) and atypical carcinoid (1.3%) . The patients included in this study were mainly white (86.4%) men (56.8%) with a median age of 67 years who had liver (9.5%), bone (6.2%) and brain (5.9%) metastases at diagnosis. The median overall survival (OS) of the cohort was 5.59 (95% CI: 5.4-5.8) months, but when OS was stratified by histological subtype it was significantly better in patients with typical carcinoid (table). In the whole cohort, the median OS did not differ between patients with and without brain metastases (5.55 vs. 5.68; p = 0.24). However, a sensitivity analysis by histology showed that the presence of brain metastases worsen the median OS of patients with typical carcinoid only (15.1 vs 4.6, p = 0.04). An adjusted multivariate analysis restricted to patients with brain metastases showed that administration of systemic chemotherapy (HR:0.5; 95% CI:0.35-0.72, p < 0.001) and resection of distant metastases (HR:0.5; 95% CI:0.29-0.88, p = 0.017) were the two most powerful independent prognostic factors. Conclusions: The presence of brain metastases negatively impact survival of patients with typical carcinoids but not in those with the other histological subtypes included in this study. Staging MRI should be strongly considered at diagnosis in patients with bronchopulmonary NE tumors, due to the sizable proportion of these patients presenting with brain metastases and also due to its prognostic value in a subset of this population. [Table: see text]

High Serum CA19-9 Concentration Predicts Poor Prognosis in Elderly Patients with Stage IV Colorectal Cancer

Background/Aim: The optimal treatment strategy for elderly patients with stage IV colorectal cancer (CRC) remains controversial due to limited research data. The purpose of this study was to evaluate treatment results and to clarify the prognostic factors, especially poor prognosis factors, in elderly patients with stage IV CRC. Methods: We retrospectively reviewed the data of 82 elderly patients (aged ≥75 years) with stage IV CRC who underwent surgical treatment at our hospital between April 2001 and March 2017. Factors that affected prognosis and the ability to undergo treatment were analyzed via multivariate analysis. Results: The median overall survival (OS) in the patients with high pretreatment serum carbohydrate antigen 19-9 (CA19-9) concentration (> 370 U/mL) was significantly worse than in those with lower serum CA19-9 concentration (0–370 U/mL) (8.5 vs. 19.2 months, p = 0.0059). In univariate analysis, age (≥80 years) (p = 0.014), performance status of 1–3 (p = 0.028), and high pretreatment serum CA19-9 concentration (p = 0.014) were significant prognostic factors for poor OS. By contrast, resection of the primary tumor (p = 0.024), chemotherapy (p < 0.0001), and resection of distant metastasis (p = 0.0005) were significant prognostic factors for favorable OS. Multivariate analysis showed that a high pretreatment serum CA19-9 concentration was an independent prognostic factor for poor OS (p = 0.01). Meanwhile, resection of the primary tumor (p = 0.033), chemotherapy (p < 0.0001), and resection of distant metastasis (p = 0.0008) were prognostic factors for favorable OS. Conclusions: A high pretreatment serum CA19-9 concentration (> 370 U/mL) was a reliable predictive factor for poor prognosis, and aggressive treatments should be performed carefully in these patients. Moreover, various treatments, including surgery and chemotherapy, might improve OS in elderly patients with stage IV CRC.

Outcome after resection of Adrenocortical Carcinoma liver metastases: a retrospective study

BackgroundMetastatic Adrenocortical Carcinoma (ACC) is a rare malignancy with a poor 5-year-survival rate (<15%). A surgical approach is recommended in selected patients if complete resection of distant metastasis can be achieved. To date there are only limited data on the outcome after surgical resection of hepatic metastases of ACC.MethodsA retrospective analysis of the German Adrenocortical Carcinoma Registry was conducted. Patients with liver metastases of ACC but without extrahepatic metastases or incomplete tumour resection were included.ResultsSeventy-seven patients fulfilled these criteria. Forty-three patients underwent resection of liver metastases of ACC. Complete tumour resection (R0) could be achieved in 30 (69.8%). Median overall survival after liver resection was 76.1 months in comparison to 10.1 months in the 34 remaining patients with unresected liver metastases (p < 0.001). However, disease free survival after liver resection was only 9.1 months. Neither resection status (R0/R1) nor extent of liver resection were significant predictive factors for overall survival. Patients with a time interval to the first metastasis/recurrence (TTFR) of greater than 12 months or solitary liver metastases showed significantly prolonged survival.ConclusionsLiver resection in the case of ACC liver metastases can achieve long term survival with a median overall survival of more than 5 years, but disease free survival is short despite metastasectomy. Time to recurrence and single versus multiple metastases are predictive factors for the outcome.

Differences in systemic and surgical therapy between right (R) and left (L) sided metastatic colorectal cancer (mCRC).

3602 Background: Patients (pts) with L sided primary tumors and mCRC have a significantly longer overall survival (mOS) than R sided tumors. Reasons for this remain unclear. The objective of this study was to compare systemic and surgical therapy received by tumor side and correlate this with mOS. Methods: Sequential pts with mCRC referred to the British Columbia Cancer Agency in 4 treatment eras were included. Pts with unresected primary tumors were excluded to ensure accurate ascertainment of tumor location. Receipt of systemic therapy includes Òall 3 drugsÓ (irinotecan, oxaliplatin, fluouracil), bevacizumab and epidermal growth factor receptor inhibitors (EGFRi). Cox-regression survival analysis for sidedness was performed controlling for age, sex, tumor grade, lymphovascular/perineural invasion, nodes removed and metastatectomy. Results: Among 3242 pts, a progressive improvement in mOS is documented in both L and R sided tumors since 1995. L and R tumors received Òall 3 drugsÓ, bevacizumab and EGFRi therapy with similar frequency which plateaued after the introduction of EGFRiÕs in 2009. Patients with L sided tumors were significantly more likely to have a hepatic or pulmonary resection. In Cox regression analysis, the mOS difference between L and R sided tumors was more pronounced in more recent eras. Conclusions: Patients with R sided tumors receive similar systemic therapy compared to L sided tumors, but are significantly less likely to undergo resection of distant disease. Resection of distant metastases may be an important consideration to understand the survival differences between R vs L mCRC. [Table: see text]

Which factors affect the long-term survival of patients with hepatocellular carcinoma UICC stage IV?

In the 7th edition of the TNM classification, not only HCC with distant metastases but also those with regional lymph node metastases are classified as stage IV. From our prospectively recorded tumor registry, 138 patients (17%) with HCC were in stage IV. Among those were 68 and 70, respectively, in stage IVA (regional lymph node metastases) and IVB (distant metastases). The tumors were less frequently treated with resection or local ablative treatment (chemoembolization, RFA, SIRT, percutaneous radiation) than patients in stage I-III. Ten HCCs were resected. Five of the resected patients were in stage IVA and five in stage IVB. After tumor resection, patients lived longer than those who underwent local or systemic treatment only (p=0.003 or p=0.001, respectively). In the univariate survival analysis, the stage IV patients' long-term survival was decreased statistically significantly through elevated bilirubin, low albumin, Okuda stage III and BCLC stage D. Patients' age and sex, pre-treatment AFP level, Child stage and the presence of venous invasion did not influence survival. In the multivariate analysis (Cox regression), tumor resection and BCLC stage were independent prognostic factors. Patients with HCC in TNM stage IV have a very poor prognosis. Only few patients are eligible for resection because of the extent of tumor growth, comorbidities and general condition. These, however, benefit markedly from tumor resection with lymph node dissection and possibly resection of distant metastases.

P0183 Resection of colorectal cancer metastases in routine practice

Background The optimal management of metastatic colorectal cancer (mCRC) involves a multimodality approach. Complete resection of limited metastatic disease is a critical, potentially curative, intervention for a minority of patients. Data for resection rates and outcomes in routine clinical practice are limited. Methods We analysed records of patients enroled in the Australian prospective mCRC registry TRACC (Treatment of Recurrent and Advanced Colorectal Cancer). Data collection commenced in July 2009, with 14 sites now contributing. Treatment intent was recorded at initial patient review as curative, potentially curative, or palliative. Findings Of 1012 patients, 213 (21%) underwent metastasectomy, 179 (84%) with R0 resections. Liver (55.4%) and lung (20.2%) were the most commonly resected disease sites. For 26 (12.2%) patients, the initial treatment intent had been palliative. Patients who had metastases resected were younger (median age 63 years versus 70 years, p p p p p p = 0.046) and a single disease site (61.3% versus 54.5%; p = 0.029) than had patients in public hospitals, but the median age of private patients was older (70 years versus 67 years; p = 0.041). Overall survival for resected patients was equivalent in both groups (median undefined, hazard ratio 0.96, 95% confidence interval 0.45–2.06; p = 0.919). Interpretation In routine practice, a substantial proportion of patients with mCRC undergo resection of distant metastases, including some patients initially considered incurable. Significant variation between sites has been noted, which might relate to differences in patient population or a more aggressive treatment approach. Multivariate analyses and review of individual centre data are planned to explore reasons for potential underuse of this critical intervention.

Resection of colorectal cancer (CRC) metastases in routine practice.

599 Background: The optimal management of metastatic colorectal cancer (mCRC) involves a multimodality approach. Complete resection of limited metastatic disease is a critical, potentially curative intervention for a minority of patients (pts). Data on resection rates and outcomes in routine clinical practice are limited. Methods: Analysis of pts prospectively entered onto the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) database, a multisite Australian mCRC registry. Data collection commenced in July 2009 and is ongoing at 14 centres. Treatment intent was recorded at initial pt review as curative, potentially curative or palliative. Results: At median follow-up of 20.9 months, 213 (21%) of 1,012 pts have undergone metastasectomy, including 179 (84%) R0 resections. Liver (55.4%) and lung (20.2%) were the commonest resected disease sites. For 26 (12.2%) pts the initial treatment intent had been palliative. Pts who had metastases resected were younger (median age 63 vs. 70 years, p&lt;0.0001), of better performance status (PS0-1: 97.7 vs. 75.5%, p&lt;0.0001), had fewer comorbidities (Charlson Index ≤3: 75.1 vs. 55.9%, p&lt;0.0001) and fewer sites of disease (single site: 79.8% vs. 52.5%, p&lt;0.0001). A significantly higher proportion of pts treated in private than public hospitals underwent resections: 143/548 (26.1%) vs. 70/459 (15.3%), p&lt;0.0001. At initial presentation, more private pts had PS0-1 (82.8% vs. 77.8%, p=0.0459) and single disease site (61.3% vs. 54.5%, p=0.0291) than public pts, but the median age of private pts was higher (70 vs. 67 years, p=0.041). Overall survival was equivalent for resected pts in both groups (median not reached, HR 0.96, 95% CI 0.45-2.06, p=0.9189). Conclusions: A substantial proportion of mCRC pts in routine practice undergo resection of distant metastases, including some pts initially considered incurable. Significant variation between sites has been noted, which may relate to differences in pt population and/or a more aggressive treatment approach. Multivariate analyses and review of individual centre data are planned to explore reasons for potential underutilization of this critical intervention.

Impact of stereotactic body radiotherapy on colorectal cancer with distant metastases

Stereotactic radiotherapy is a minimally invasive technique for delivering highly focused ionizing radiation with extreme precision. This technique was initially developed in neurosurgical practice and applied to extracranial lesions in the 1990s, and was termed stereotactic body radiotherapy (SBRT). Studies have reported that the resection of distant metastases from colorectal cancer (CRC) contributes to relatively long-term survival. However, the resection of pulmonary and liver metastases is not possible for various reasons. SBRT offers a therapeutic alternative to unresectable metastatic lesions. The present study describes three cases of distant metastasis from CRC that exhibited a complete response (CR) to SBRT. Case 1 is a 70-year-old man with recurrent liver metastases after surgery for rectal cancer with liver metastasis (S3: diameter 1.8 cm and volume 3.0 ml; S6: diameter 1.3 cm and volume 1.2 ml). Cases 2 and 3 were 65-year-old and 70-year-old men, respectively. Both patients had pulmonary metastasis after surgery for rectal and cecum cancer (Case 2: diameter 1.2 cm and volume 0.9 ml; Case 3: diameter 0.8 cm and volume 0.27 ml). All cases were moderately differentiated adenocarcinomas. No serious adverse side-effects were observed during the therapy. CR was obtained in all patients on the basis of computed tomography 15-33 months after radiotherapy. Our experience supports that SBRT is a safe and alternative technique for resection in patients with distant metastasis from CRC who have small metastatic tumor volume.

FOLFOX as adjuvant chemotherapy after curative resection of distant metastatic lesions in patients with colorectal cancer.

e14142 Background: Although FOLFOX regimen is shown to be effective to suppress the recurrence of stage III colorectal cancer (CRC) who received curative resection, the prophylactic effect of has not fully been investigated in adjuvant setting of stage IV CRC cases, namely, after curative resection of distant metastases. Methods: This is a retrospective study including 116 CRC patients with synchronous metastases and 91 with metachronous metastases who received curative resection in our hospital between 2000 and 2009. Pathological parameters of primary CRC, postoperative chemotherapeutic regimen, relapse-free survival (RFS) were analyzed retrospectively. Results: After resection of CRC and synchronous metastases, 53 (84%) out of 63 patients without chemotherapy, and 38 (83%) out of 46 that received oral or intravenous 5-fluorouracil (5-FU) alone or with leucovorin (LV) developed recurrent tumors. By contrast, only single patient (17%) among 6 who underwent FOLFOX showed recurrence. With a median follow-up period of 775 days, the FOLFOX group exhibited a significantly improved RFS as compared to the 5-FU(+LV) or surgery alone group (p=0.03, p=0.007, respectively). The 5-year OS rates of the surgery alone, 5-FU(+LV), and FOLFOX group were 67%, 75%, and 100%. In CRC cases with metachronous metastases, on the other hand, the recurrence rate of the group without chemotherapy was 63%, and that of the 5-FU (+LV) group 55%. In 7 patients who underwent FOLFOX chemotherapy (5 cases of FOLFOX4 and 2 cases of mFOLFOX6, no antibody therapy) after metastasectomy, 71% (5 patients) relapsed afterward. Thus, the tumor-relapse rate after metastasectomy was similar among patients who received no postoperative chemotherapy. The median RFSs of the surgery alone, 5-FU(+LV), and FOLFOX groups were 323, 917, and 322 days, respectively. Conclusions: Adjuvant FOLFOX is certainly beneficial for stage IV CRC patients with synchronous metastasis who received curative resection. In contrast, the prophylactic effect of FOLFOX is not superior to other follow-up strategies in patients who received complete resection of metachronous metastases.

Treatment of rectal cancer with synchronous metastasis at diagnosis: 65 consecutive Italian cases of the Bologna Multidisciplinary Rectal Cancer Group.

676 Background: Twenty per cent of middle/low rectal cancer pts have synchronous distant metastasis (M1) at diagnosis. At present, the treatment strategy in this pt setting is not well defined. This mono-institutional retrospective analysis evaluates the treatment strategy and clinical outcome of three different pt group. Methods: Between January 2000-July 2011 the Bologna Multidisciplinary Rectal Group of S. Orsola-Malpighi Hospital evaluated 65 pts with rectal cancer M1 disease. Three different groups were defined: rectal cancer with resectable metastatic disease (Group A); rectal cancer with potentially resectable metastatic disease (Group B); and rectal cancer with unresectable metastatic disease (Group C). Treatment strategy in the different groups entailed an individualized approach. Results: The distribution per group was: Group A 11 (17%) pts, Group B 28 (43%), and Group C 26 (40%). The pt characteristics were: M 42 (64.6%), F 23 (35.4%); median age 62 years (35-83); median ECOG PS 0 (0-2); cT3 45(69.2%), cT4 20 (30.8%); cN- 10 (15.4%), cN+ 55 (84.6%); M1 sites: liver 32 (49.2%), lung 8 (12.3%), liver + lung 11 (16.9%), ovary/peritoneal carcinosis/abdominal lymph nodes 7 (10.8%), liver + bone 2 (3.1%), &gt;2 sites 5 (7.7%). Forty-three (66.2%) pts underwent to surgery for primary rectal tumor, and 30 (46.2%) pts for metastasis resection (23 liver, 5 lung, 2 liver + lung). Treatments for different groups are shown (Table). Median OS according to the three different groups was: Group A not reached, Group B 32 months (95% CI 24-40), and Group C 16 months (95% CI 7-26). Patients undergoing metastasis resection have higher median OS than those not resected: 44 months (95%CI 12-76) vs 15 months (95% CI 8-23) (p=0.0006). Conclusions: Treatment strategy in synchronous metastatic rectal cancer must consider the possibility of distant metastasis resection. Long-term survival can be achieved using an integrated approach. [Table: see text]

Malignes Melanom

Malignant melanomas have one of the highest increases in incidence among malignancies. There are four histological types: superficial spreading melanoma, nodular melanoma, acrolentiginous melanoma and lentigo maligna melanoma. The TNM classification considers depth of infiltration (Clark's level), vertical tumor thickness (Breslow's thickness), ulceration of the primary tumor, satellites and in-transit metastases as well as regional lymph node and distant metastases. An adequate margin of clearance is important in primary resection. Sentinel lymph node biopsy is relevant in all melanomas with a Breslow tumor thickness >1 mm without clinically suspicious lymph nodes. In the case of lymph node metastases therapeutic dissection is recommended, in patients with in-transit metastases of the extremities hyperthermic isolated limb perfusion with cytostatic agents may be indicated. Resection of distant metastases can be useful if only one site is affected or a R0 resection is expected to be achieved. Adjuvant, neoadjuvant and palliative procedures, such as radiotherapy, chemotherapy and immunotherapy are additional treatment options.