Hepatic resection for breast cancer liver metastases: Impact of intrinsic subtypes

IntroductionThe role of surgery for breast cancer liver metastases (BCLM) remains controversial. This study aimed to analyze survival in patients treated with hepatectomy plus systemic therapy or systemic therapy alone for BCLM and to determine selection factors to guide surgical therapy.Materials and methodsPatients who underwent hepatectomy plus systemic therapy (n = 136) and systemic therapy alone for isolated BCLM (n = 763) were compared. Overall survival (OS) was analyzed after propensity score matching. Intrinsic subtypes were defined as: luminal A (estrogen receptor [ER]+ and/or progesterone receptor positive [PR]+, human epidermal growth factor receptor 2 [HER2]–), luminal B (ER and/or PR+, HER2+), HER2-enriched (ER and PR–, HER2+), and basal-like (ER, PR, HER2–).ResultsAfter hepatectomy, independent predictors of poor OS were number and size of liver metastases, and intrinsic subtype (hazard ratios, 1.11, 1.16, and 4.28, respectively). Median OS was 75 and 81 months among patients with luminal B and HER2-enriched subtypes, compared with 17 and 53 months among patients with basal-like and luminal A subtypes (P < .001). Median progression-free survival (PFS) was 60 months with the HER2-enriched subtype, compared with 17, 16, and 5 months with luminal A, luminal B, and basal-like subtypes, respectively (P < .001). After propensity score matching, 5-year OS rates were 56% vs. 40% in the surgery vs. systemic therapy alone groups (P = .018).ConclusionSurgical resection of BCLM yielded higher OS compared with systemic therapy alone and prolonged PFS among patients with the HER2-enriched subtype. These findings support the use of surgical therapy in appropriately selected patients, based on intrinsic subtypes.     

Optimal duration of first-line chemotherapy for advanced gastric cancer: data from the AGAMENON registry

Clinical and Translational Oncology - The optimal duration of first-line chemotherapy for patients with advanced gastric cancer is unknown. Diverse clinical trials have proposed different...     

Survival in patients with brain metastases from breast cancer: the importance of HER-2 status

BACKGROUND

Brain metastases (BM) are the most common intracranial tumors in adults. To the authors' knowledge, established prognostic factors for survival after the diagnosis of BM in breast cancer patients do not take into account HER–2 status, which may have increasing relevance in the trastuzumab therapy era.

METHODS

The authors identified 83 patients with breast cancer and new parenchymal BM diagnosed between January 1, 2001 and December 31, 2005 who were treated at Massachusetts General Hospital. Survival was estimated using the Kaplan‐Meier method and curves were compared using the log‐rank test. A Cox proportional hazards model was used to determine independent predictors of survival.

RESULTS

The median overall survival from the time of BM was 8.3 months. On univariate analysis, HER‐2‐positive patients were found to have prolonged survival after BM compared with HER‐2‐negative patients (17.1 months vs 5.2 months). Patients with triple negative disease had a median survival of 4.0 months, compared with 11.2 months for all other patients. Additional predictors of improved survival on univariate analysis included ≤3 BM, controlled or absent systemic disease, and controlled local disease. On multivariate analysis, only HER‐2 status, number of BM, and local disease status remained independent predictors of survival.

CONCLUSIONS

HER‐2 status is a strong predictor of survival after the diagnosis of BM. The survival of breast cancer patients with BM appears to be improving, but a better understanding of both the predictors of brain recurrence and the delayed effects of treatment is needed to properly counsel patients regarding the risk‐benefit ratio of various treatment modalities. Cancer 2008. © 2008 American Cancer Society.     

Surgery for gastric cancer: 10-year experience worldwide

To demonstrate recent experience of gastric cancer surgery worldwide and to evaluate modern strategies for the treatment of gastric cancer, we investigated the English-language literature of the past 10 years, based on papers published in well-known medical journals. In many countries, the increased detection of early gastric cancer, advanced operative procedures, and careful postoperative management have improved the surgical results of gastric cancer over the years. Although randomized controlled trials in Europe showed no survival benefit of D2 resection over D1 resection, the results must be interpreted with caution and cannot be extrapolated to Japanese patients, because the morbidity and mortality after D2 gastrectomy in Japan are much less than those after D1 gastrectomy in Europe. Recently, less invasive treatments, including endoscopic mucosal resection and laparoscopic gastrectomy, have become feasible for patients with early gastric cancer, but their risks and benefits compared with traditional gastrectomy are unclear. Received: February 28, 2001 / Accepted: August 3, 2001     

Intrathecal administration of anti-HER2 treatment for the treatment of meningeal carcinomatosis in breast cancer: A metanalysis with meta-regression

Leptomeningeal Metastases (LM) is a turning point in terms of prognosis and quality of life of patients with breast cancer (BC). Intrathecal therapy is largely used for the treatment of breast cancer LM. In this metanalysis with meta-regression, we gathered data on intrathecal (IT) trastuzumab administration in patients with HER2 positive breast cancer with LM. A total of 24 articles (58 patients) were included in the study and intrathecal trastuzumab was used in all patients. The mean age at IT administration was 50.7 years (SD 11.4, range 24–80) and the mean total dose of IT trastuzumab was 711.9 mg (SD 634.9, median 450). IT trastuzumab was used both alone (n = 20) and in combination with systemic pharmacotherapy (n = 37). No serious adverse events were reported in 87.9% of cases. In this selected population a significant clinical improvement was observed in 55.0% of cases while stabilization was reported in 14% of cases. CSF response was observed in 55.6% of the cases. MRI was improved or stable in 70.8% of the cases. Interestingly, the CNS-PFS was 5.2 months and the median OS was 13.2 months. A clinical improvement (HR 0.13, 95% CI 0.03–0.49) and CSF response (HR 0.13, 95% CI 0.03–0.58) were associated with a longer CNS-PFS. The association of longer CNS-PFS with radio- or neurosurgery prior to the administration of IT trastuzumab did not reach statistical significance. This metanalysis with meta-regression indicates that IT trastuzumab in patients with HER2 positive breast cancer LM might be a safe and effective treatment, but further prospective studies are needed to definitively prove such a point.     

The role of surgery for unusual sites of metastases from colorectal cancer: A review of the literature

Although systemic therapy represents the backbone of metastatic colorectal cancer management, surgical resection in selected patients may lead to improved survival, such as observed for hepatic, pulmonary or peritoneal metastases. In regards to surgery for less frequent sites of metastases, far less data are available. The purpose of this article is to review the literature regarding the role of surgery for unusual sites of metastases from colorectal cancer, specifically adrenal, ovarian, and retroperitoneal sites. There are no randomized data to strongly support surgical approach in these scenarios. Despite that, benefit following surgery was suggested in several retrospective studies, with some reports of long-term survival. A careful selection of patients is certainly the key to obtaining better outcomes. Potential characteristics suggesting greater benefit from metastasectomy are isolated site of metastasis, longer disease-free interval from previous treatment, complete resectability, and good performance status.     

Lapatinib versus lapatinib plus capecitabine as second-line treatment in human epidermal growth factor receptor 2-amplified metastatic gastro-oesophageal cancer: A randomised phase II trial of the Arbeitsgemeinschaft Internistische Onkologie

IntroductionHuman epidermal growth factor receptor 2 (HER2) amplification is present in a subgroup of gastroo-esophageal cancers (GCs). HER2 inhibition with trastuzumab has shown to improve outcomes in advanced disease. Lapatinib ditosylate (LAP), a dual anti-epidermal growth factor receptor (EGFR) and anti-HER2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in HER2-positive breast cancer. We aimed to study the activity of LAP in HER2-amplified GC.Materials and methodsPatients (pts) with HER2-positive (gene amplification or increased copy numbers based on predefined criteria) advanced GC were randomly allocated 1:1 to receive LAP 1250 mg per day 1–21 plus capecitabine (CAP) 2000 mg/m² on days 1–14 of a 21-day cycle or LAP 1500 mg monotherapy day 1–21 after having failed on a platinum-based first-line therapy. HER2 status was assessed centrally. The primary end-point was the objective response rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). We aimed to include 38 pts per arm to show an interesting response rate of ⩾20% in either of the two arms.Results37 pts were enrolled (18 to LAP + CAP, 19 to LAP). Pts had received a median of three prior treatment lines. 12 pts in the LAP + CAP group (67%) and 12 pts in the LAP group (63%) had received prior trastuzumab. Only two pts (11.1%; 95% confidence interval (CI): 1.37–34.7), both in the LAP + CAP arm, achieved an objective response. The study was closed prematurely for futility. Median time to progression was 42 (95% CI: 38–61) days in the LAP group and 83 (95% CI: 42–86) days in the LAP + CAP group. Other secondary efficacy end-points (progression-free and overall survival) were comparable in the two treatment groups. Rates of diarrhoea were higher with LAP + CAP (61%; 95% CI: 35–83) compared to 26% (95% CI 9–51) with LAP mono, whereas other adverse events were mostly similar between the groups (18 [100%] versus 17 [90%]).DiscussionLapatinib showed insufficient activity in HER2-amplified pretreated advanced GC. The safety profile of LAP or LAP + CAP was as expected with some more toxicity in the combination arm. (ClinicalTrials.gov Identifier, NCT01145404).     

Brain metastases in patients who receive trastuzumab-containing chemotherapy for HER2-overexpressing metastatic breast cancer

Background  Recently, a high rate of brain metastases has been reported among patients with human epidermal growth factor receptor (HER2)-overexpressing metastatic breast cancer who were treated with trastuzumab. The present study examined risk factors for the development of brain metastasis in patients with HER2-overexpressing breast cancer who were treated with trastuzumab. Methods  We retrospectively reviewed 204 patients with HER-2-overexpressing breast cancer who were treated with a trastuzumab-containing regimen between 1999 and 2006. Patients with clinical symptoms were diagnosed as having brain metastases when brain magnetic resonance imaging (MRI) or a computed tomography (CT) scan revealed positive findings for brain metastases. The median follow-up time of this cohort was 53.6 months. Results  Among the patients who received a trastuzumabcontaining regimen, 74 patients (36.3%) developed brain metastases. The median survival from the diagnosis of brain metastases was 13.5 months (95% confidence interval [CI], 12.2–14.7 months). The median time interval between the beginning of trastuzumab treatment and the diagnosis of brain metastases was 13.6 months (range, 0.0–45.8 months). Among patients with brain metastases, the median overall survival period was 39 months. A multivariate logistic regression analysis showed that age (≤50 years), recurrent breast cancer, and liver metastases were significant risk factors for the development of brain metastases. Conclusion  Patients with HER2-overexpressing breast cancer treated with trastuzumab had a high incidence of brain metastases (36.3%). Routine screening for brain metastases 1 year after the start of trastuzumab treatment, may be warranted in younger patients (≤50 years) who had recurrent breast cancer with liver metastases.     

Immunohistochemical profiles of brain metastases from breast cancer

The aim of present study is to explore the immunohistochemical profiles of brain metastases from breast cancer. We retrospectively performed immunohistochemical staining for estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor type 2 (HER2/neu), and cytokeratin (CK) 5/6 in 29 patients with resected tumor specimens of brain metastases. Immunohistochemical staining for ER, PgR and HER2/neu was performed in 24 patients with primary tumors. The positive frequency of immunohistochemical profiles of ER, PgR, HER2/neu, and CK5/6, in the brain metastases were 13.8%, 6.9%, 37.9%, and 24.1%, respectively. The immunohistochemical profiles including ER, PgR, and HER2/neu of the primary tumor and the brain metastasis differed in seven patients (29.2%, N = 7/24). Interestingly, the biological characteristics of brain metastasis sometimes changed which were represented by immunohistochemical staining. Therefore, the changes in the biological features of breast cancer should be taken into account when developing treatment strategies, including new molecular-targeted drugs, for brain metastases.     

Multicenter phase II study of trastuzumab in combination with capecitabine and oxaliplatin for advanced gastric cancer

BackgroundTrastuzumab has been approved for use in combination with fluoropyrimidine plus cisplatin for the treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC). Although capecitabine plus oxaliplatin (XELOX) is a standard first-line regimen for AGC, combination trastuzumab plus XELOX has not been studied.MethodsPatients with metastatic or unresectable HER2-positive AGC were diagnosed by either HER2 immunohistochemistry (IHC) 3+ or IHC 2+/fluorescence in-situ hybridisation (FISH)+ received intravenous trastuzumab (8 mg/kg for first cycle and 6 mg/kg for subsequent cycles on day 1) plus oral capecitabine (1000 mg/m² twice daily on days 1–14) and intravenous oxaliplatin (130 mg/m² on day 1), every 3 weeks. The primary end-point was the objective response rate, and secondary end-points included progression-free survival (PFS), overall survival (OS) and toxicity profiles.ResultsFifty-five HER2-positive AGC patients were enrolled between August 2011 and February 2013. The median age was 57 years (range = 29–74). The confirmed objective response rate was 67% (95% confidence interval (CI) = 54–80%). After a median follow-up period of 13.8 months (range = 6.1–23.9), the median PFS and OS were 9.8 months (95% CI = 7.0–12.6) and 21.0 months (95% CI = 6.4–35.7), respectively. Frequently encountered grade 3–4 toxicities included neutropenia (18%), anaemia (11%), and peripheral neuropathy (11%). There was a treatment-related death caused by severe diarrhoea and complicated sepsis.ConclusionCombination of trastuzumab and XELOX is well tolerated and highly effective in patients with HER2-positive AGC.     

Lymph node dissection for gastric cancer: Establishment of D2 and the current position of splenectomy in Europe and Japan

Two European phase III trials comparing D1 and D2 demonstrated that D2 did not improve the overall survival and was associated with a high mortality related to splenectomy. However, a long-term follow-up study showed that the gastric cancer-related death rate was significantly higher in D1 than D2. Based on these findings, the standard surgery in Europe became D2 without pancreatico-splenectomy to prevent mortality. In contrast, the JCOG9501 phase III comparing D2 and D2 plus para-aortic nodal dissection did not showed a survival efficacy of extended lymphadenectomy, but the mortality rate was quite low in both surgeries. Subsequently, the JCOG0110 phase III study comparing D2 and spleen-preserving D2 for upper gastric cancer not invading the greater curvature clearly showed the non-inferiority of spleen preservation. Thus, spleen-preserving D2 was made the standard surgery for these tumors in Japan. However, splenectomy is often selected for complete dissection of the splenic-hilar nodes, a frequent metastatic site for upper gastric tumors invading the greater curvature. Recently, an approach involving splenic hilar nodal dissection without splenectomy has been developed.     

Prediction of outcomes for patients with brain parenchymal metastases from breast cancer (BC): a new BC-specific prognostic model and a nomogram

The purpose of this study is to validate the recently published Breast-Graded Prognostic Assessment (GPA) and propose a new prognostic model and nomogram for patients with brain parenchymal metastases (BM) from breast cancer (BC). We retrospectively investigated 171 consecutive patients who received a diagnosis of BM from BC during 2000-2008. We appraised the recently proposed Sperduto's BC-specific GPA in training cohort through Kaplan-Meier survival curve using log-rank test and area under the curve for the BC-GPA predicting overall survival at 1 year and developed a new nomogram to predict outcomes using multivariate Cox-regression analysis. By putting the Sperduto's Breast-GPA together with our nomogram, we developed a new prognostic model. We validated our new prognostic model with an independent external patient cohort from 2 institutes for the same period. On the basis of our Cox-regression analysis, therapeutic effect of trastuzumab and status of extracranial systemic disease control were incorporated into our new prognostic model in addition to Karnofsky performance status, age, and hormonal status. Our new prognostic model showed significant discrimination in median survival time, with 3.7 months for class I (n = 15), 7.8 months for class II (n = 82), 10.7 months for class III (n = 42), and 19.2 months for class IV (n = 32; P < .0001). The new prognostic model accurately predicted survival among patients with BC from BM in an external validation cohort (P < .0001). We propose a new prognostic model and a nomogram reflecting the different biological features of BC, including treatment effect and status of extracranial disease control, which was excellently validated in an independent external cohort.     

Solitary metastasis to the left axillary lymph node after curative gastrectomy in gastric cancer

Regional lymph node metastasis in advanced gastric cancer is common, whereas axillary lymph node metastasis (ALNM) is rare. We experienced a patient with a solitary ALNM in gastric cancer. A 48-year-old woman underwent curative distal gastrectomy for advanced gastric cancer (P0H0T3N3M0CY0, stage IV). Twenty-one months after the surgery, she complained of an asymptomatic left axillary tumor. Mammography and computed tomography (CT) scans showed the presence of tumors in neither breast nor lung. Fine-needle aspiration of the axillary tumor demonstrated poorly differentiated adenocarcinoma cells, which coincided with the cells of the resected gastric carcinoma. We diagnosed ALNM from gastric cancer and operated on the patient with radical left axillary lymph node dissection. One year after the reoperation, she has had no recurrence. We conclude that gastric cancer can metastasize to unusual sites. A re-radical resection is recommended if curative resection is feasible. Received: March 6, 2002 / Accepted: April 23, 2002 Offprint request to: O. Kobayashi     

Oligometastatic gastric cancer: An emerging clinical entity with distinct therapeutic implications

Gastric cancer (GC) remains responsible for a high burden worldwide being the third leading cause of cancer-related mortality. Most of patients present at an advanced stage at diagnosis and are thus candidates to standard chemotherapy resulting in median survival of less than 1 year. Oligometastatic gastric cancer is an increasingly recognized clinical entity characterized by limited metastatic spread that has been showing to benefit from aggressive multimodality strategies encompassing chemotherapy and surgery. The ongoing RENAISSANCE/AIO-FLOT5 (NCT02578368) phase III trial is aimed at evaluating if perioperative chemotherapy with FLOT in combination with surgical resection of the primary tumour and metastases could become the new standard of care for oligometastatic GC. In the meantime, in addition to currently available clinical parameters, the emerging predictive/prognostic role of biomarkers such mismatch repair deficiency/microsatellite instability high status needs to be specifically addressed also in this subgroup of GC to assist in patient selection.     

A case of lung cancer metastasized to the gastrointestinal anastomosis site where the primary gastric cancer was resected 17 years ago

Metastasis from lung cancer, often found in the adrenal glands, bone, liver, brain, and kidneys, have been thought to be rare in the digestive system. When a metastatic tumor is found in the intestine, it is most commonly metastatic melanoma or carcinoma of the cervix uteri, ovary, or breast. Yet, intestinal metastases have been described in 11% of lung cancers at autopsy. These metastases may induce gastrointestinal perforation, obstruction, or bleeding. Patients with bleeding from small intestinal metastases secondary to lung cancer almost uniformly have poor prognoses. The lung cancer metastasized to the gastrointestinal site or location where a first primary cancer was once resected is never reported in the literature. We report the case of a 76-year-old man with a history of gastric adenocarcinoma treated by subtotal gastrectomy seventeen years ago who presented with lung cancer metastatic to the bone. One month later, he developed persistent melena due to duodenal metastases. Upper gastrointestinal endoscopy showed an ulcerative duodenal mass with bleeding. The pathohistological and immunohistochemical examinations of tissue from the pathologic fracture and the endoscopic biopsy specimen revealed metastatic poorly differentiated adenocarcinoma consistent with lung origin. The diagnosis of metastatic lung cancer can be rendered based on pathologic examination and immunohistochemical analysis, even without access to the primary lung tumor. In this case, the anastomosis site where a gastrectomy for gastric cancer was once performed might be a good niche or microenvironment for cancer cells or tumor stem cells to metastasize to.     

Enhanced recovery after surgery (ERAS) versus standard recovery for gastric cancer patients: The evidences and the issues

The significant advances that have been reached, in the last decades, in the treatment of gastric cancer, contributed to the concept of enhanced recovery after surgery (ERAS) with the aim to reduce the surgical stress, accelerate postoperative recovery, and reduce the length of hospital stay. The most important items included in the ERAS protocols are the pre-operative patient education, early mobilization and immediate oral intake from the first postoperative day. The aim of this narrative review is to focus the attention on the possible advantages of ERAS program on perioperative functional recovery outcomes after gastrectomy for gastric cancer.     

Hepatic resection for metastatic breast cancer: a systematic review

Background

Systemic chemotherapy is the mainstay of treatment for metastatic breast cancer with the role of surgery being strictly limited for palliation of metastatic complications or locoregional relapse. An increasing number of studies examining the role of therapeutic hepatic metastasectomy show encouraging survival results. A systematic review was undertaken to define its safety, efficacy and to identify prognostic factors associated with survival.

Methods

Electronic search of the MEDLINE and PubMed databases (January 2000–January 2011) to identify studies reporting outcomes of hepatectomy for breast cancer liver metastases (BCLM) with hepatectomy was undertaken. Two reviewers independently appraised each study using a predetermined protocol. Safety and clinical efficacy was synthesised through a narrative review with full tabulation of results of all included studies.

Results

Nineteen studies were examined. This comprised of 553 patients. Hepatectomy for BCLM was performed at a rate of 1.8 (range, 0.7–7.7) cases per year in reported series. The median time to liver metastases occurred at a median of 40 (range, 23–77) months. The median mortality and complication rate were 0% (range, 0–6%) and 21% (range, 0–44%), respectively. The median overall survival was 40 (range, 15–74) months and median 5-year survival rate was 40% (range, 21–80%). Potential prognostic factors associated with a poorer overall survival include a positive liver surgical margin and hormone refractory disease.

Conclusion

Hepatectomy is rarely performed for BCLM but the studies described in this review indicate consistent results with superior 5-year survival for selected patients with isolated liver metastases and in those with well controlled minimal extrahepatic disease. To evaluate its efficacy and control for selection bias, a randomised trial of standard chemotherapy with or without hepatectomy for BCLM is warranted.     

Breast cancer clinical practice recommendations from Saint-Paul-de-Vence: excerpts concerning targeted therapies

This article presents excerpts of the conclusions obtained by a working group applying ANAES (Agence nationale d’accréditation et d’évaluation en santé, France) methodology to the following: Treatment of overexpressed HER2 breast cancers.Excerpts translated and reprinted with permission from Oncologie (2005) 7: 342-379.     

A case of small bowel obstruction due to intraluminal metastases from metastatic renal cell cancer

A 71-year-old man, with a history of metastatic renal cell cancer (RCC), presented with symptoms of a small bowel obstruction with nausea, vomiting, cramps, and diarrhea. He underwent surgery and was found to have intraluminal metastases from his metastatic RCC. Intraluminal metastases are rare and usually present with obstruction, bleeding, or perforation. The mainstay of treatment remains complete surgical excision, even in the face of widely metastatic disease. Surgery not only palliates symptoms, but may also extend survival because metastatic RCC can be a very indolent and unpredictable disease. Furthermore, these patients can now be treated with a new class of antiangiogenic agents that are showing impressive response rates, which may also translate into improved overall survival.