Aurelio Matamoros

Carcinoma of unknown primary with a colon-cancer profile—changing paradigm and emerging definitions

Carcinoma of unknown primary (CUP), which accounts for about 3-5% of all new cancers, is a challenging heterogeneous entity with an unmet research need. Traditionally, CUP has been managed with broad-spectrum chemotherapy, but with the increasing availability of sophisticated diagnostic techniques and the emergence of new treatments that have been shown to be effective in specific cancers the one-treatment-fits-all approach to CUP might eventually no longer be valid. CUP in association with a colon-cancer profile (CCP-CUP) is an example of an emerging, specific CUP subset that seems to benefit from a tailored approach. CCP-CUP is identified by CK20 and CDX2-positive and CK7-negative immunohistochemistry and a clinical course consistent with that of patients known to have metastatic colon cancer. Our findings suggest that patients with CCP-CUP derive substantial benefit from the use of specific treatments developed for colon cancer and larger clinical trials are warranted to more definitely test this finding. In the era of molecular profiling, we expect that additional work with CCP-CUP and other CUP subsets will provide attractive tailored treatment alternatives, with efficacies that exceed the current one-treatment-fits-all approach.

Predictors of Survival in Patients with Resectable Gastric Cancer Treated with Preoperative Chemoradiation Therapy and Gastrectomy

BACKGROUND The purpose of this study was to determine the overall survival (OS) of patients with resectable gastric cancer treated with preoperative chemoradiation therapy and gastrectomy. STUDY DESIGN The medical records of patients with gastric adenocarcinoma presenting to our institution (January 1995 to August 2012) were reviewed to identify patients who underwent diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy. Associations between various clinicopathologic factors and OS were examined with Cox proportional hazards models. RESULTS Of 192 patients who met inclusion criteria, 103 (54%) required total gastrectomy. One hundred sixty-eight patients (88%) had an extended lymph node dissection, 26 (14%) had resection of adjacent organs, and 178 (93%) had an R0 resection. Median follow-up time for surviving patients was 4.2 years. Median OS for all patients was 5.8 years, and 5-year OS rate was 56%. Multivariable Cox regression model results identified variables associated with diminished OS including age ≥ 65 years (hazard ratio [HR] 1.62; 95% CI 1.05 to 2.51), male sex (HR 1.76; 95% CI 1.13 to 2.74), adjacent organ resection (HR 1.97; 95% CI 1.16 to 3.35), R1 status (HR 2.29; 95% CI 1.17 to 4.48), pathologic N1 stage (HR 1.92; 95% CI 1.24 to 2.98), N2 stage (HR 2.58; 95% CI 1.01 to 6.58), and N3 stage (HR 6.54; 95% CI 2.69 to 15.93). Five-year OS rates for patients with pathologic N0, N1, N2, and N3 disease were 67%, 42%, 43%, and 0%, respectively. CONCLUSIONS Patients with gastric cancer who undergo diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy have a high frequency of obtaining an R0 resection and excellent OS rates. Nodal status after surgery remains an important determinant of OS.

Long-term survival in patients with metastatic gastric and gastroesophageal cancer treated with surgery

The purpose of this study was to determine the survival of patients with metastatic gastric cancer treated with surgery.

Cancer of Unknown Primary in Adolescents and Young Adults: Clinicopathological Features, Prognostic Factors and Survival Outcomes.

Background Cancer in adolescents and young adults (AYAs) (15–39 years) is increasingly recognized as a distinct clinical and biological entity. Cancer of unknown primary (CUP), a disease traditionally presenting in older adults with a median age of 65 years, poses several challenges when diagnosed in AYA patients. This study describes clinicopathological features, outcomes and challenges in caring for AYA-CUP patients. Methods A retrospective review of 47 AYAs diagnosed with CUP at MD Anderson Cancer Center (6/2006–6/2013) was performed. Patients with favorable CUP subsets treated as per site-specific recommendations were excluded. Demographics, imaging, pathology and treatment data was collected using a prospectively maintained CUP database. Kaplan-Meier product limit method and log-rank test were used to estimate and compare overall survival. The cox-proportional model was used for multivariate analyses. Results Median age was 35 years (range 19–39). All patients underwent comprehensive workup. Adenocarcinoma was the predominant histology (70%). A median of 9 immunostains (range 2–29) were performed. The most common putative primary was biliary tract based on clinicopathological parameters as well as gene profiling. Patients presented with a median of 2 metastatic sites [lymph node (60%), lung (47%), liver (38%) and bone (34%)]. Most commonly used systemic chemotherapies included gemcitabine, fluorouracil, taxanes and platinum agents. Median overall survival for the entire cohort was 10.0 (95% confidence interval (CI): 6.7–15.4) months. On multivariate analyses, elevated lactate dehydrogenase (Hazard ratio (HR) 3.66; 95%CI 1.52–8.82; P = 0.004), ≥3 metastatic sites (HR 5.34; 95%CI 1.19–23.9; P = 0.029), and tissue of origin not tested (HR 3.4; 95%CI 1.44–8.06; P = 0.005) were associated with poor overall survival. Culine’s CUP prognostic model (lactate dehydrogenase, performance status, liver metastases) was validated in this cohort (median overall survival: good-risk 25.2 months vs. poor-risk 6.1 months). Conclusions AYA-CUP is associated with a poor prognosis. In the current “-omics” era collaborative research efforts towards understanding tumor biology and therapeutic targets in AYA-CUP is an unmet need, necessary for improving outcomes in young CUP patients.

Metastatic Gastroesophageal Adenocarcinoma Patients Treated with Systemic Therapy Followed by Consolidative Local Therapy: A Nomogram Associated with Long-Term Survivors

Objective: Patients with metastatic gastroesophageal adenocarcinoma (MGEAC) have a poor but heterogeneous clinical course. Some patients have an unusually favorable outcome. We sought to identify clinical variables associated with more favorable outcomes. Methods: Of 246 patients with MGEAC, we identified 64 who received systemic therapy and eventually received local consolidation therapy. Univariate and multivariate Cox regression models were used, and a nomogram was developed. Results: Of these 64 patients, 61% had received consolidation chemoradiation (CRT) with doses of 50-55 Gy and 78% did not undergo surgery. The median follow-up time of survivors was 3.9 years, and the median overall survival (OS) from CRT start was 1.5 years (95% CI, 1.2-2.2). Surgery (as local consolidation) was an independent prognosticator for longer OS in the multivariate analysis (p = 0.02). The 5-year OS rate was 25% (SE = 6%). The contributors to the nomogram were longer duration of systemic therapy before CRT and the type of local therapy. Conclusions: Our data suggest that a subset of patients with MGEAC have an excellent prognosis (OS >5 years). However, these patients need to be identified during their clinical course so that local consolidation (CRT, surgery, or both) may be offered.

Continuation of trastuzumab beyond disease progression in HER2-positive metastatic gastric cancer: the MD Anderson experience

BACKGROUND Despite the wide spread use of trastuzumab in human epidermal growth factor receptor 2 (HER2) overexpressing metastatic gastric cancer patients, its optimal duration of administration beyond first-line disease progression is unknown. In HER2 overexpressing metastatic breast cancer, trastuzumab continuation beyond first-line disease progression has shown improvement in time to progression (TTP) without an increased risk of treatment related toxicity. METHODS HER2-overexpressing metastatic gastric cancer patients were identified from our database between January 2010 and December 2014. We retrospectively reviewed the medical records of 43 patients who received trastuzumab in combination with chemotherapy as first-line and continued trastuzumab beyond disease progression. RESULTS Forty-three cases were identified, 27 males (62.8%), median age of the patients was 58 years. Thirty-five (81.4%) presented with stage 4 as their initial presentation. Eighty one percent had 3+ HER2 overexpression by immunohistochemistry (IHC) and 18% had 2+ HER2 overexpression confirmed by fluorescence in situ hybridization (FISH). Thirteen (52%) were moderately differentiated, 16 (37.1%) were poorly differentiated. The most common sites of metastasis were liver 35 (81.4%) and lung 14 (32.5%). The most commonly used first-line regimen was oxaliplatin, 5-fluorouracil (5-FU), and trastuzumab in 22 (51.1%) patients. Twenty-five (58.1%) patients received irinotecan, 5-FU and trastuzumab in the second-line. Progression-free survival (PFS) was 5 months (95% CI: 4.01-5.99 months). Five patients are still alive and excluded from calculating the median overall survival (OS) which was 11 months (range, 5-53 months) for the remaining 20 subjects of this second-line group. Trastuzumab was not discontinued due to side effects in any of the study population. CONCLUSIONS In conclusion, this retrospective analysis suggests that continuation of trastuzumab beyond disease progression in patients with HER2-overexpressing metastatic gastric cancer is feasible and safe. Randomized studies are warranted.

Localized Gastric Cancer Treated with Chemoradation without Surgery: UTMD Anderson Cancer Center Experience

Background: In patients with localized gastric cancer (LGC) who are unfit for surgery, decline surgery, or have unresectable cancer, chemoradiotherapy may provide palliation; however, data in the literature are sparse. Methods: We identified 66 LGC patients who had definitive chemoradiation but no surgery. All patients had baseline and postchemoradiation staging including an endoscopic biopsy. Multiple statistical methods were used to analyze outcomes. Results: Most patients were men and most had stage III or IV cancer. Five patients were surgery eligible but declined to have surgery. The median follow-up time was 33.9 months (95% CI 18.3–49.6). The median survival time (MST) for 66 patients was only 14.5 months (95% CI 10.8–19.7) and the median relapse-free survival (RFS) was 5.03 months (95% CI 4.67–6.40). The estimated overall survival (OS) and RFS rates at 3 years were 22.6% (95% CI 13.7–37.3) and 7.7% (95% CI 3.2–18.6), respectively. Twenty-three (35%) patients who achieved a clinical complete response (cCR; negative postchemoradiation biopsy and no progression by imaging) fared better than those who achieved less than cCR (<cCR) [cCR: MST 30.7 months (95% CI 20.4–NA); <cCR: MST 10.6 months (95% CI 8.43–14.9); p < 001]. In multivariate analysis, cCR was the only independent prognosticator for OS [hazard ratio (HR) = 0.32, p < 0.0012] and RFS (HR = 0.12, p < 0.0001). Conclusion: Our data demonstrate that in the absence of surgery, outcomes with definitive chemoradiation are only modest. A third of the patients achieved cCR and had a longer OS and RFS than those who achieved <cCR.

Preoperative accuracy of gastric cancer staging in patient selection for preoperative therapy: Race may affect accuracy of endoscopic ultrasonography

Background Over the last 15 years, large randomized controlled studies have validated the benefit of preoperative therapy for patients with resectable gastric cancer. Computed tomography (CT) and endoscopic ultrasonography (EUS) are commonly used to select patients for preoperative treatment, but studies of preoperative staging accuracy that focus on patient selection for preoperative therapy are rare; therefore, whether CT or EUS can reliably identify patients eligible for preoperative therapy is still unclear. Our purpose was to determine the accuracy of EUS and CT for preoperative staging of gastric cancer and to identify factors that may affect their usefulness in selecting patients for preoperative therapy. Methods We reviewed the medical records of 8,260 patients with gastric or gastroesophageal adenocarcinoma treated at our institution from 1995 to 2013, identifying those who underwent gastrectomy without preoperative treatment. We compared T stage and N status from preoperative EUS and CT reports with those drawn from surgical pathology reports. Clinicopathologic and demographic variables associated with incorrect preoperative staging were investigated using univariate and multivariate analyses. Results We identified 187 patients who underwent preoperative staging by EUS (n=145) and/or CT (n=134) before gastrectomy. The accuracy, sensitivity, and specificity of EUS in distinguishing stage T1 from more advanced tumors were 82%, 78%, and 85%, respectively. Variables associated with underestimation of EUS T stage were lymphovascular invasion [odds ratio (OR), 7.51; 95% confidence interval (CI), 1.91-29.50; P<0.01] and white race (OR, 3.75; 95% CI, 1.31-10.75; P=0.01). The accuracies, sensitivities, and specificities for determining N status were, respectively, 65%, 49%, and 79% with CT and 66%, 29%, and 95% with EUS. Lymphovascular invasion was associated with a false negative result (OR, 3.79; 95% CI, 1.34-10.70; P=0.01), and well- or moderately differentiated histology was associated with a false positive result for CT N status (OR, 7.14; 95% CI, 2.00-25.44; P<0.01). Conclusions EUS is accurate in distinguishing T1 from T2-T4 lesions; both CT and EUS have low sensitivities and high specificities in determining N status. These accuracies and variables associated with inaccurate staging, including race, should be considered when selecting gastric cancer patients for preoperative therapy.

The Proportion of Signet Ring Cell Component in Patients with Localized Gastric Adenocarcinoma Correlates with the Degree of Response to Pre-Operative Chemoradiation

Background: Patients with localized gastric adenocarcinoma (LGAC), who get pre-operative therapy, have heterogeneous/unpredictable outcomes. Predictive clinical variables/biomarkers are not established. Methods: We analyzed 107 LGAC patients who had chemoradiation and surgery. LGACs were grouped for (1) presence/absence of signet ring cell histology (SRC) and (2) histologic grade: G2 or G3. %SRC was assessed (0, 1-10, 11-49, and 50-100%) and correlated with pathologic complete response (pathCR) or <pathCR in the resected specimens. Results: Most patients were men (60%), had stage cIII LGAC (50%), and received chemotherapy before chemoradiation (93%). Most had G3 tumors (78%) and SRC (58%). Presence of SRC was associated with a lower rate of pathCR (11 vs. 36%, p = 0.004), and the association remained significant even with a low percentage of SRC (1-10%; p = 0.014). The higher the fraction of SRC, the lower was the probability of pathCR (p = 0.03). G3 and SRC led to a shorter overall survival (OS) (p = 0.046 and p = 0.038, respectively). yp stage independently prognosticated OS and recurrence-free survival (p < 0.001). Conclusion: Our novel findings suggest that LGACs with SRC are relatively chemoradiation resistant compared to LGACs without SRC. A higher fraction of SRC is associated with higher resistance. Upon validation/biomarker(s) evaluation, reporting of the fraction of SRC may be warranted.

101 Long-Term Survivors Who Had Metastatic Gastroesophageal Cancer and Received Local Consolidative Therapy

Background: Through a multidisciplinary decision-making process, we developed a strategy of systemic therapy followed by local consolidative therapy (chemoradiation with/without surgery) in selected patients with metastatic gastroesophageal carcinoma (mGEAC). Only after a consensus during multidisciplinary discussions, local therapy was initiated. Methods: We identified 101 patients with mGEAC who had local consolidation. We evaluated the association between various clinical variables (location of the primary, location of metastases, duration of initial chemotherapy, histologic grade, and radiation dose) and overall survival (OS). Results: Of 101 patients, 71 had a proximal primary (esophageal, Siewert type I or II), and 30 patients had a distal primary (Siewert type III or distal). The median OS was 25.7 months (95% confidence interval [CI] 22.3-32.8). The OS rates at 2 and 5 years were 53.8% (95% CI 44.7-64.8) and 20.7% (95% CI 13.4-31.9), respectively. OS was highly associated with the location of the primary (median of 22.8 months for Siewert I/II vs. 41.5 months for Siewert III or distal, p = 0.03). The duration of initial chemotherapy was highly associated with OS (median of 21.8 months for <3 months vs. 32.5 months for ≥3 months, p = 0.004). Conclusion: Some mGEAC patients with a favorable clinical course can achieve a ∼20% 5-year survival rate with an approach that uses initial chemotherapy followed by multidisciplinary discussion to proceed with consolidation with local therapy. Patients with distal GEAC and those who receive initial chemotherapy for ≥3 months are the maximum beneficiaries.