Naveenraj L. Solomon

Is surgical resection superior to transplantation in the treatment of hepatocellular carcinoma

Objective:To compare outcomes for patients with hepatocellular carcinoma (HCC) treated with either liver resection or transplantation. Methods:A retrospective, single-institution analysis of 413 HCC patients from 1999 to 2009. Results:A total of 413 patients with HCC underwent surgical resection (n = 106) and transplantation (n = 270) or were listed without receiving transplantation (n = 37). Excluding transplanted patients with incidental tumors (n = 50), 257 patients with suspected HCC were listed with the intent to transplant (ITT). The median diameter of the largest tumor by radiography was 6.0 cm in resected, 3.0 cm in transplanted, and 3.4 cm in the listed-but-not-transplanted patients. Median time to transplant was 48 days. Recurrence rates were 19.8% for resection and 12.1% for all ITT patients. Overall, patient survival for resection versus ITT patients was similar (5-year survival of 53.0% vs 52.0%, not significant). However, for HCC patients with model end-stage liver disease (MELD) scores less than 10 and who radiologically met Milan or UCSF (University of California, San Francisco) criteria, 1-year and 5-year survival rates were significantly improved in resected patients. For patients with MELD score less than 10 and who met Milan criteria, 1-year and 5-year survival were 92.0% and 63.0% for resection (n = 26) versus 83.0% and 41.0% for ITT (n = 73, P = 0.036). For those with MELD score less than 10 and met UCSF criteria, 1-year and 5-year survival was 94.0% and 62.0% for resection (n = 33) versus 81.0% and 40.0% for ITT (n = 78, P = 0.027). Conclusions:Among known HCC patients with preserved liver function, resection was associated with superior patient survival versus transplantation. These results suggest that surgical resection should remain the first line therapy for patients with HCC and compensated liver function who are candidates for resection.

A Phase II Study of Neoadjuvant and Adjuvant Chemotherapy with 5-Fluorodeoxyuridine, Leucovorin, Oxaliplatin and Docetaxel in the Treatment of Previously Untreated Advanced Esophageal Adenocarcinoma

OBJECTIVE A complete pathologic response to neoadjuvant chemotherapy, without the use of radiation, has infrequently been reported in operable chemo-naïve stage III esophageal adenocarcinoma patients. METHODS Twenty-nine eligible patients were enrolled in the study. Neoadjuvant therapy consisted of 5-fluorodeoxyuridine, leucovorin, oxaliplatin and docetaxel and was administered in two 4-week cycles. Following therapy, patients underwent surgical resection. Those patients having residual disease were offered adjuvant chemotherapy. Patients having a complete pathologic response were not offered any further chemotherapy. RESULTS Twenty-four out of 29 patients finished neoadjuvant therapy and underwent curative esophagectomy. Two patients were declared inoperable after treatment, and three patients died prior to surgery. The median follow-up on all patients was 20.2 months. Median progression-free survival and median overall survival were 13.6 and 21.4 months, respectively. Clinical response to neoadjuvant chemotherapy was seen in 21 out of 29 patients (72.4%). Complete pathologic response with neoadjuvant chemotherapy was seen in 4 out of 24 patients (16.7%). Those four patients have been alive and progression-free for 20-37 months. Grade 3-4 toxicities occurred in 16 of the 29 patients during neoadjuvant therapy. Grade 3-4 toxicities were seen in 6 out of 14 patients during adjuvant therapy. (18)F-fluorodeoxyglucose-positron emission tomography standardized uptake values of ≥8 correlated with better progression-free survival. CONCLUSION 5-Fluorodeoxyuridine, leucovorin, oxaliplatin and docetaxel regimen is active in patients with esophageal adenocarcinoma. Toxicity profiles are manageable. Neoadjuvant chemotherapy allowed achievement of complete pathologic response without radiation. (18)F-fluorodeoxyglucose-positron emission tomography standardized uptake values might be prognostic.

Does neoadjuvant chemotherapy improve outcomes for patients with gastric cancer

BACKGROUND The role of neoadjuvant and adjuvant therapy for gastric cancer remains undefined. We compared the outcomes for patients treated with surgery alone or with the addition of adjuvant or neaodjuvant treatment. METHODS A single-institution, retrospective evaluation of a prospective database of gastric cancer patients treated from 2000 to 2008 was performed. RESULTS Overall, 173 patients with gastric cancer underwent surgical extirpation. Of the 173 patients, 43% had early-stage disease (less than stage 2) and 57% had late-stage disease (stage 2 or greater; American Joint Committee on Cancer, 2010). The median survival from the date of diagnosis for those treated with neoadjuvant chemotherapy (NAC) (n = 35), adjuvant chemotherapy (n = 21), adjuvant chemoradiotherapy (n = 18), both NAC and adjuvant chemotherapy (n = 11), or surgery alone (n = 88) was 26.3, 17.3, greater than 60, greater than 60, and 50.3 months, respectively. The addition of NAC to surgery was detrimental to survival in those with early-stage disease (P = 0.002) and did not improve survival in those with late-stage disease (P = 0.687). For those with late-stage disease, surgery with adjuvant chemoradiotherapy exhibited the best overall survival compared with surgery alone (P = 0.021) or surgery with adjuvant chemotherapy (P = 0.01). Patients treated with NAC had a greater rate of R0 resection compared with surgery alone (P = 0.049). CONCLUSIONS NAC for patients with gastric cancer does not significantly improve the overall outcomes for those with late-stage disease and could be detrimental to survival for those with early-stage disease. However, treatment with NAC resulted in an improved rate of R0 resection.

Factors Associated With Underestimation of Invasive Cancer in Patients With Ductal Carcinoma In Situ: Precautions for Active Surveillance

Importance Recent recognition of the overdiagnosis and overtreatment of ductal carcinoma in situ (DCIS) detected by mammography has led to the development of clinical trials randomizing women with non–high-grade DCIS to active surveillance, defined as imaging surveillance with or without endocrine therapy, vs standard surgical care. Objective To determine the factors associated with underestimation of invasive cancer in patients with a clinical diagnosis of non–high-grade DCIS that would preclude active surveillance. Design, Setting, and Participants A retrospective cohort study was conducted using records from the National Cancer Database from January 1, 1998, to December 31, 2012, of female patients 40 to 99 years of age with a clinical diagnosis of non–high-grade DCIS who underwent definitive surgical treatment. Data analysis was conducted from November 1, 2015, to February 4, 2017. Exposures Patients with an upgraded diagnosis of invasive carcinoma vs those with a diagnosis of DCIS based on final surgical pathologic findings. Main Outcomes and Measures The proportions of cases with an upgraded diagnosis of invasive carcinoma from final surgical pathologic findings were compared by tumor, host, and system characteristics. Results Of 37 544 women (mean [SD] age, 59.3 [12.4] years) presenting with a clinical diagnosis of non–high-grade DCIS, 8320 (22.2%) had invasive carcinoma based on final pathologic findings. Invasive carcinomas were more likely to be smaller (>0.5 to ⩽1.0 cm vs ⩽0.5 cm: odds ratio [OR], 0.73; 95% CI, 0.67-0.79; >1.0 to ⩽2.0 cm vs ⩽0.5 cm: OR, 0.42; 95% CI, 0.39-0.46; >2.0 to ⩽5.0 cm vs ⩽0.5 cm: OR, 0.19; 95% CI, 0.17-0.22; and >5.0 cm vs ⩽0.5 cm: OR, 0.11; 95% CI, 0.08-0.15) and lower grade (intermediate vs low: OR, 0.75; 95% CI, 0.69-0.80). Multivariate logistic regression analysis demonstrated that younger age (60-79 vs 40-49 years: OR, 0.84; 95% CI, 0.77-0.92; and ≥80 vs 40 to 49 years: OR, 0.76; 95% CI, 0.64-0.91), negative estrogen receptor status (positive vs negative: OR, 0.39; 95% CI, 0.34-0.43), treatment at an academic facility (academic vs community: OR, 2.08; 95% CI, 1.82-2.38), and higher annual income (>

Role of lymph node ratio in selection of adjuvant treatment (chemotherapy vs . chemoradiation) in patients with resected gastric cancer

63 000 vs <

Comparison of perioperative chemotherapy with adjuvant chemoradiotherapy for resectable gastric cancer: findings from a population-based study

38 000: OR, 1.14; 95% CI, 1.02-1.28) were significantly associated with an upgraded diagnosis of invasive carcinoma based on final pathologic findings. Conclusions and Relevance When selecting patients for active surveillance of DCIS, factors other than tumor biology associated with invasive carcinoma based on final pathologic findings may need to be considered. At the time of randomization to active surveillance, a significant proportion of patients with non–high-grade DCIS will harbor invasive carcinoma.

Response to the Letter “Importance of Tumor Burden in the Survival Analyses of Stage IV Colorectal Cancer Patients”

Background Recent randomized controlled trials have failed to show a survival difference between adjuvant chemotherapy (CT) and adjuvant chemoradiotherapy (CRT) in patients with resected gastric cancer (GC). However, a subset of patients with lymph node (LN) positive disease may still benefit from CRT. Additional evidence is needed to help guide physicians in identifying patients in whom CRT should be considered. Our objective was then to compare survival outcomes based on lymph node ratio (LNR) (ratio of metastatic to harvested LNs) for patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma treated with surgery and either CT or CRT. Methods This retrospective population-based study used California Cancer Registry (CCR) data from 2004 to 2013. It included 1,493 patients diagnosed with stage IB-III gastric/GEJ adenocarcinoma and treated with CT or CRT following total or partial gastrectomy. Overall survival (OS) was the primary outcome and GC-specific survival was secondary. Mortality hazards ratios (HR) for these outcomes were computed using propensity score weighted Cox regression models, stratified by LNR strata categories as 0%, 1-9%, 10-25% and >25%. Results Out of 1,493 patients that met inclusion criteria, 462 were treated with CT while 1,031 received CRT. Median follow-up for all subjects was 76 months and median survival was 54 months for CRT and 35 for the CT cohort, P<0.001. Compared to CT, CRT was associated with improved survival among patients with LNR of 10-25% [HR =0.62 (95% CI, 0.46-0.83)] and >25% [HR =0.67 (95% CI, 0.56-0.80)]. Similar findings were observed for GC-specific survival and for analyses limited to patients that had at least 15 LNs evaluated. Conclusions LNR appears to be a simple and readily available measure that could be used in treatment planning for resected GC. CRT offers significant survival advantage over CT among patients with high LN disease burden (LNR of ≥10%).

Should Chemoradiotherapy Be Used in Node-Negative Esophageal or Gastric Adenocarcinoma?

Background Both perioperative chemotherapy (PC) and adjuvant chemoradiotherapy (CRT) improve survival in resectable gastric cancer; however, these treatments have never been formally compared. Our objective was to evaluate treatment trends and compare survival outcomes for gastric cancer patients treated with surgery and either PC or CRT. Methods We performed a retrospective population-based cohort study between 2007 through 2013 using California Cancer Registry data. Patients diagnosed with stage IB-III gastric adenocarcinoma and treated with total or partial gastrectomy were eligible for this study. Based on the type of treatment received, patients were grouped into surgery-only, PC, or CRT. Primary and secondary outcomes were overall survival (OS) and gastric cancer-specific survival (GCCS) respectively. Mortality hazards ratios (HRs) for each of these outcomes were computed using propensity score weighted and covariate-adjusted Cox regression models, stratified by clinical node status. Results Of 2,146 patients who underwent surgical resection, 1,067 had surgery-only, while 771 and 308 received PC or CRT, respectively. Median OS was 25, 33, and 52 months for surgery-only, PC, and CRT, respectively; P<0.001. Overall, patients treated with PC had significantly poorer survival compared to CRT (HR =1.45; 95% CI: 1.22-1.73). PC was also associated with higher mortality in patients with signet ring histology (HR =1.66; 95% CI: 1.21-2.28) and clinical node negative cancer (HR =1.85; 95% CI: 1.32-2.60). Survival was not different between PC vs. CRT in clinical node positive patients (HR =1.29; 95% CI: 0.84-2.08). Of note, the percentage of patients receiving PC increased from 17.5% in 2007-2008, to 41.5% in 2013-2014; P<0.001. Conclusions Despite the rapid adoption of PC, overall, CRT is associated with better survival than PC. Specifically, clinical node negative and signet ring histology patients had better survival when treated with CRT compared to PC. Based on these findings, we recommend against indiscriminate adoption of PC and consideration for CRT over PC in clinical node negative patients.

The Roles of Neoadjuvant Radiotherapy and Lymphadenectomy in the Treatment of Esophageal Adenocarcinoma

To the Editor, We appreciate the comments from authors Drs. Goffredo, Utria, and Hassan in regard to our manuscript investigating resection of the primary tumor in patients with unresectable colorectal liver metastases and thank them for bringing up important issues in utilizing large databases. The National Cancer Database (NCDB), as with many other large databases, has several limitations that can affect outcome analysis. The article we present clearly acknowledges the limitations of performing analysis in the NCDB. We also stated that these large administrative databases have multiple variables that are not accounted for, and despite the most advanced statistical methods employed, there will always be bias not accounted for. We agree with the authors that tumor burden can play a part in which patients will receive surgical resection of the primary tumor which may contribute to selection bias in who undergoes surgery. However, as mentioned in the response, there is no data available to quantify the amount of tumor burden. Even with the use of advanced survival statistical methods, we understand that these databases were not designed and not randomized for this purpose, and its use would impact the final result. In our conclusions, we stated that surgical resection is associated with a significant survival benefit, and with the use of propensity scores, we attempted to account for selection bias by reducing the probability of the treatment using the available variables in the analysis. More sophisticated methods to account for survival time bias have been used and showed no significance in survival benefit for primary tumor resection, but again, as stated in that study, there remains potential for instrument outcome confounding because the patients could have also received other treatments. In our study, compared to the paper by Alawadi et al., by including patients through 2012, the patients treated with newer regimens of systemic therapy including biologic agents shown to improve overall survival would be included in our analysis. The NCDB only shows if patients received singleor multi-agent chemotherapy. Over 80% of the patients in our study in both the surgical and non-surgical arm received multi-agent chemotherapy. As mentioned by the authors, multi-agent chemotherapy regimens and targeted therapy in the form of biologic agents would impact prognosis. Our data does show that the use of multi-agent chemotherapy regimens along with surgical resection of the primary tumor confers a survival advantage compared to no surgical resection. Improved systemic regimens showing benefit in survival in treated patients with metastatic disease likely help reduce tumor burden and along with surgery may confer improved survival. Resection of the primary tumor in unresectable colorectal liver metastases continues to be an area that requires further investigation, taking into account all the various factors including tumor burden. However, the answer to this question relies on ongoing randomized studies that will account for these factors as mentioned in our conclusion, specifically the GRECCAR 8, SYNCHRONOUS, and CAIRO4 trials. The future results of these studies will clarify our questions and will help to determine which subsets of stage IV patients will benefit the most from surgical intervention. We again thank the authors for providing great discussion on this controversial issue.

Screening criteria for breast cancer

We agree with Drs. Hotenrott and Ziogas that the role and timing of chemotherapy and radiation for patients with advanced disease in the esophagus and stomach needs further clarification. Our retrospective study attempted to answer this question by analyzing 3378 patients treated in the state of Florida between 1998 and 2002. This data set is complete and allows for patient comorbidities. We demonstrated a significant benefit for neoadjuvant or adjuvant therapy for patients with regional (node positive) disease. Similar analysis of node-negative disease, however, did not reveal a benefit. Although our data do not demonstrate a benefit for nodenegative disease, such a benefit is certainly possible; however, our study was underpowered to detect this. In addition, the possibility of downstaging among node-negative patients after neoadjuvant chemotherapy may be an additional confounder. We look forward to the completion and reporting of the CRITICS trial. Yet the possibility of insufficient power for detecting node-negative disease may result in this question remaining unanswered. We nonetheless agree that patients with node-positive adenocarcinoma of the esophagus or stomach benefit from chemotherapy. We also think that the potential benefit in node-negative patients is smaller, if any. Patients should be counseled about these points in the management of these diseases.