Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer.

BACKGROUND: The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood. METHODS: We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use. RESULTS: Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not. CONCLUSIONS: A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).

Is a Pathological Complete Response Following Neoadjuvant Chemoradiation Associated With Prolonged Survival in Patients With Pancreatic Cancer?

OBJECTIVES: To describe the survival outcome of patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) who have a pathologic complete response (pCR) following neoadjuvant chemoradiation. BACKGROUND: Patients with BR/LA-PDAC are often treated with neoadjuvant chemoradiation in an attempt to downstage the tumor. Uncommonly, a pCR may result. METHODS: A retrospective review of a prospectively maintained database was performed at a single institution. pCR was defined as no viable tumor identified in the pancreas or lymph nodes by pathology. A near complete response (nCR) was defined as a primary tumor less than 1 cm, without nodal metastasis. Overall survival (OS) and disease-free survival (DFS) were reported. RESULTS: One hundred eighty-six patients with BR/LA-PDAC underwent neoadjuvant chemoradiation and subsequent pancreatectomy. Nineteen patients (10%) had a pCR, 29 (16%) had an nCR, and the remaining 138 (74%) had a limited response. Median DFS was 26 months in patients with pCR, which was superior to nCR (12 months, P = 0.019) and limited response (12 months, P < 0.001). The median OS of nCR (27 months, P = 0.003) or limited response (26 months, P = 0.001) was less than that of pCR (more than 60 months). In multivariable analyses pCR was an independent prognostic factor for DFS (HR = 0.45; 0.22-0.93, P = 0.030) and OS (HR=0.41; 0.17-0.97, P = 0.044). Neoadjuvant FOLFIRINOX (HR=0.47; 0.26-0.87, P = 0.015) and negative lymph node status (HR=0.57; 0.36-0.90, P = 0.018) were also associated with improved survival. CONCLUSIONS: Patients with BR/LA-PDAC who had a pCR after neoadjuvant chemoradiation had a significantly prolonged survival compared with those who had nCR or a limited response.

Phase 2 study of erlotinib combined with adjuvant chemoradiation and chemotherapy in patients with resectable pancreatic cancer.

PURPOSE: Long-term survival rates for patients with resected pancreatic ductal adenocarcinoma (PDAC) have stagnated at 20% for more than a decade, demonstrating the need to develop novel adjuvant therapies. Gemcitabine-erlotinib therapy has demonstrated a survival benefit for patients with metastatic PDAC. Here we report the first phase 2 study of erlotinib in combination with adjuvant chemoradiation and chemotherapy for resected PDAC. METHODS AND MATERIALS: Forty-eight patients with resected PDAC received adjuvant erlotinib (100 mg daily) and capecitabine (800 mg/m(2) twice daily Monday-Friday) concurrently with intensity modulated radiation therapy (IMRT), 50.4 Gy over 28 fractions followed by 4 cycles of gemcitabine (1000 mg/m(2) on days 1, 8, and 15 every 28 days) and erlotinib (100 mg daily). The primary endpoint was recurrence-free survival (RFS). RESULTS: The median follow-up time was 18.2 months (interquartile range, 13.8-27.1). Lymph nodes were positive in 85% of patients, and margins were positive in 17%. The median RFS was 15.6 months (95% confidence interval [CI], 13.4-17.9), and the median overall survival (OS) was 24.4 months (95% CI, 18.9-29.7). Multivariate analysis with adjustment for known prognostic factors showed that tumor diameter >3 cm was predictive for inferior RFS (hazard ratio, 4.01; P=.001) and OS (HR, 4.98; P=.02), and the development of dermatitis was associated with improved RFS (HR, 0.27; P=.009). During CRT and post-CRT chemotherapy, the rates of grade 3/4 toxicity were 31%/2% and 35%/8%, respectively. CONCLUSION: Erlotinib can be safely administered with adjuvant IMRT-based CRT and chemotherapy. The efficacy of this regimen appears comparable to that of existing adjuvant regimens. Radiation Therapy Oncology Group 0848 will ultimately determine whether erlotinib produces a survival benefit in patients with resected pancreatic cancer.

Evaluation of adjuvant chemoradiation therapy for ampullary adenocarcinoma: the Johns Hopkins Hospital-Mayo Clinic collaborative study.

BACKGROUND: The role of adjuvant chemoradiation therapy for ampullary carcinoma is unknown. Previous literature suggests that certain populations with high risk factors for recurrence may benefit from adjuvant chemoradiation. We combined the experience of two institutions to better delineate which patients may benefit from adjuvant chemoradiation. METHODS: Patients who underwent curative surgery for ampullary carcinoma at the Johns Hopkins Hospital (n=290; 1992-2007) and at the Mayo Clinic (n=130; 1977-2005) were reviewed. Patients with <60 days of follow-up, metastatic disease at surgery, or insufficient pathologic data were excluded. The final combined study consisted of 186 patients (n=104 Johns Hopkins, n=82 Mayo). Most patients received 5-FU based chemoradiation with conformal radiation. Cox proportional hazards models were used for survival analysis. RESULTS: Median overall-survival was 39.9 months with 2- and 5-year survival rates of 62.4% and 39.1%. On univariate analysis, adverse prognostic factors for overall survival included T3/T4 stage disease (RR=1.86, p=0.002), node positive status (RR=3.18, p<0.001), and poor histological grade (RR=1.69, p=0.011). Patients who received adjuvant chemoradiation (n=66) vs. surgery alone (n=120) showed a higher rate of T3/T4 stage disease (57.6% vs. 30.8%, P<0.001), lymph node involvement (72.7% vs. 30.0%, P<0.001), and close or positive margins (4.6% vs. 0.0%, P=0.019). Five year survival rates among node negative and node positive patients were 58.7% and 18.4% respectively. When compared with surgery alone, use of adjuvant chemoradiation improved survival among node positive patients (mOS 32.1 vs. 15.7 mos, 5 yr OS: 27.5% vs. 5.9%; RR=0.47, P=0.004). After adjusting for adverse prognostic factors on multivariate analysis, patients treated with adjuvant chemoradiation demonstrated a significant survival benefit (RR=0.40, P<0.001). Disease relapse occurred in 37.1% of all patients, most commonly metastatic disease in the liver or peritoneum. CONCLUSIONS: Node-positive patients with resected ampullary adenocarcinoma may benefit from 5-FU based adjuvant chemoradiation. Since a significant proportion of patients develop metastatic disease, there is a need for more effective systemic treatment.

Adjuvant chemoradiation therapy for adenocarcinoma of the distal pancreas.

BACKGROUND: This study was designed to examine the effect of adjuvant 5-FU-based chemoradiation therapy (CRT) after distal pancreatectomy for adenocarcinoma of the distal pancreas. METHODS: All patients underwent curative resection for adenocarcinoma of the distal pancreas between December 1985 and June 2006. Patients who received adjuvant CRT were compared with those who underwent surgery alone. A Kaplan-Meier estimate of the survival curve was used to determine estimates of the median survival and proportion alive at 1 and 2 years; log-rank tests were used to make comparisons between groups. RESULTS: A total of 123 patients underwent distal pancreatectomy; 29 patients were excluded for distant metastases at the time of surgery (n = 12, 10%) or before adjuvant therapy (n = 11, 9%), death within 2 months of surgery (n = 2, 2%), or if CRT treatment status was unknown (n = 4, 3%). Of the remaining 94 patients, 72% received adjuvant 5-FU-based CRT and 28% underwent surgery alone. Overall median survival was 16.2 (95% confidence interval (CI), 13.1-18.9) months. The groups were similar with respect to tumor size, nodal status, and margin status. There was no significant difference in overall survival between patients treated with adjuvant CRT versus surgery alone (p = 0.23). An exploratory subgroup analysis suggested a potential survival benefit of adjuvant CRT in patients with lymph node metastases (16.7 vs. 12.1 months, p < 0.01). CONCLUSIONS: Adjuvant CRT did not increase survival compared with surgery alone; however, patients with node-positive disease appear to benefit from adjuvant CRT.

Adjuvant chemoradiotherapy after pancreatic resection for invasive carcinoma associated with intraductal papillary mucinous neoplasm of the pancreas.

PURPOSE: Intraductal papillary mucinous neoplasms are mucin-producing cystic neoplasms of the pancreas. One-third are associated with invasive carcinoma. We examined the benefit of adjuvant chemoradiotherapy (CRT) for this cohort. METHODS AND MATERIALS: Patients who had undergone pancreatic resection at Johns Hopkins Hospital between 1999 and 2004 were reviewed. Of these patients, 83 with a resected pancreatic mass were found to have an intraductal papillary mucinous neoplasm with invasive carcinoma, 70 of whom met inclusion criteria for the present analysis. RESULTS: The median age at surgery was 68 years. The median tumor size was 3.3 cm, and invasive carcinoma was present at the margin in 16% of the patients. Of the 70 patients, 50% had metastases to the lymph nodes and 64% had Stage II disease. The median survival was 28.0 months, and 2- and 5-year survival rate was 57% and 45%, respectively. Of the 70 patients, 40 had undergone adjuvant CRT. Those receiving CRT were more likely to have lymph node metastases, perineural invasion, and Stage II-III disease. The 2-year survival rate after surgery with vs. without CRT was 55.8% vs. 59.3%, respectively (p = NS). Patients with lymph node metastases or positive surgical margins benefited significantly from CRT (p = .047 and p = .042, respectively). On multivariate analysis, adjuvant CRT was associated with improved survival, with a relative risk of 0.43 (95% confidence interval, 0.19-0.95; p = .044) after adjusting for major confounders. CONCLUSION: Adjuvant CRT conferred a 57% decrease in the relative risk of mortality after pancreaticoduodenectomy for intraductal papillary mucinous neoplasms with an associated invasive component after adjusting for major confounders. Patients with lymph node metastases or positive margins appeared to particularly benefit from CRT after definitive surgery.

Outcomes of adjuvant chemoradiation after pancreaticoduodenectomy with mesenterico-portal vein resection for adenocarcinoma of the pancreas.

PURPOSE: Surgery followed by chemotherapy and radiation (CRT) offers patients with pancreatic adenocarcinoma a chance for extended survival. In some patients, however, resection is difficult because of vascular involvement by the carcinoma, necessitating resection and grafting of the mesenterico-portal vessels. The purpose of this study was to compare outcomes between pancreaticoduodenectomy (PD) with and without mesenterico-portal vein resection (VR) in patients receiving adjuvant CRT for pancreatic adenocarcinoma. METHODS AND MATERIALS: Between 1993 and 2005, 160 patients underwent PD with 5-FU-based adjuvant CRT followed by maintenance chemotherapy at the Johns Hopkins Hospital; 20 (12.5%) of the 160 underwent VR. Clinical outcomes, including median survival, overall survival, and complication rates were assessed for both groups. RESULTS: Patients who underwent VR had significantly longer operative times (p = 0.009), greater intraoperative blood loss (p = 0.01), and longer postoperative lengths of stay (p = 0.03). However, postoperative morbidity, median survival, and overall survival rates were similar between the two groups. Most patients (70%) from both groups were able to complete CRT, and a subgroup analysis demonstrated no appreciable differences in terms of complications. None of the VR patients who received adjuvant CRT developed veno-oclusive disease or graft failure/leakage. CONCLUSION: In a cohort of patients treated with adjuvant 5-FU-based CRT at the Johns Hopkins Hospital, having a VR at the time of PD resulted in similar complication rates and survival. These data support the feasibility and safety of adjuvant CRT in patients undergoing VR at the time of PD.

Analysis of fluorouracil-based adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected database at the Johns Hopkins Hospital.

PURPOSE: To examine the efficacy of adjuvant chemoradiotherapy after pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PC) in patients undergoing resection at Johns Hopkins Hospital (JHH; Baltimore, MD). PATIENTS AND METHODS: Between August 30, 1993, and February 28, 2005, a total of 908 patients underwent PD for PC at JHH. A prospective database was reviewed to determine which patients received fluorouracil (FU) -based CRT. Excluded patients had metastatic disease, died 60 or fewer days after PD, received preoperative therapy, an experimental vaccine, adjuvant chemotherapy or radiation alone. The final cohort includes 616 patients. RESULTS: The median follow-up was 17.8 months (interquartile range, 9.7 to 33.5 months). Overall median survival was 17.9 months (95% CI, 16.3 to 19.5 months). Groups were similar with respect to tumor size, nodal status, and margin status, but the CRT group was younger (P < .001), and less likely to present with a severe comorbid disease (P = .001). Patients with carcinomas larger than 3 cm (P = .001), grade 3 and 4 (P < .001), margin-positive resection (P = .001), and complications after surgery (P = .017) had poor long-term survival. Patients receiving CRT experienced an improved median (21.2 v 14.4 months; P < .001), 2-year (43.9% v 31.9%), and 5-year (20.1% v 15.4%) survival compared with no CRT. After controlling for high-risk features, CRT was still associated with improved survival (relative risk = 0.74; 95% CI, 0.62 to 0.89). CONCLUSION: These data suggest that adjuvant concurrent FU-based CRT significantly improves survival after PD for PC when compared with patients not receiving CRT. These data support the use of combined adjuvant CRT for PC.

Adjuvant concurrent chemoradiation for node-positive adenocarcinoma of the duodenum.

HYPOTHESIS: Adjuvant chemoradiation improves local control and survival in patients with node-positive duodenal adenocarcinoma treated with pancreaticoduodenectomy. DESIGN: A retrospective review of outcomes, with a planned comparison with historical controls. SETTING: A single, high-volume academic referral center. PATIENTS: All patients with periampullary carcinoma treated with pancreaticoduodenectomy and adjuvant chemoradiotherapy at The Johns Hopkins Hospital between 1994 and 2003. Fourteen cases of node-positive duodenal adenocarcinoma were identified. Median radiation dose was 5000 cGy (range, 4000-5760 cGy). Concurrent fluorouracil-based chemotherapy was given with radiation therapy, followed by maintenance chemotherapy. RESULTS: The median follow-up was 12 months for patients who died and 42 months for those who lived. Death occurred in 7 of 14 patients (50%) during the follow-up period. Median survival for all patients was 41 months, and the 5-year survival rate was 44%. Of the 7 patients who experienced disease recurrence, 6 experienced distant metastasis as first recurrence. One of these 7 patients experienced both local recurrence and distant metastasis. Local control for all patients in the study was 93%, which compares favorably with local control reported in a series of patients treated with surgery alone (67%). Compared with historical controls treated with surgery alone, patients who received adjuvant chemoradiation therapy had an improved median survival (21 months vs 41 months, respectively). Overall 5-year survival, however, was not improved (44% vs 43%, respectively). CONCLUSION: Adjuvant chemoradiation therapy after pancreaticoduodenectomy for node-positive duodenal adenocarcinoma may improve local control and median survival but does not impact 5-year overall survival.

Adjuvant concurrent chemoradiation for adenocarcinoma of the distal common bile duct.

PURPOSE: To examine the effect of adjuvant chemoradiation for adenocarcinoma of the distal common bile duct (DCBD) after pancreaticoduodenectomy (PD) on local control and survival. METHODS AND MATERIALS: A total of 34 cases of adenocarcinoma of the DCBD were treated with PD and adjuvant chemoradiation at Johns Hopkins Hospital between 1994 and 2003. Median radiation dose was 5,040 cGy (range, 4,000-5,400 cGy). Concurrent 5-fluorouracil-based chemotherapy was given with radiation therapy, followed by maintenance chemotherapy. RESULTS: The median follow-up of patients alive at the time of analysis was 41 months. Death occurred in 21 of 34 patients (62%) during the follow-up period, all from progressive, distant metastatic disease. Median overall survival was 36.9 months, with a 5-year survival of 35%. On multivariate analysis, only nodal status significantly predicted survival (p < 0.02). For patients with negative and positive lymph nodes, 5-year survival was 100% and 24%, respectively. Actuarial 5-year local control was 70%. Compared with historical controls who underwent PD alone, patients who underwent surgery and adjuvant chemoradiation had significantly longer survival (36.9 months vs. 22 months; p < 0.05). Overall survival was significantly longer for both lymph node negative and lymph node positive patients (p < 0.05). CONCLUSIONS: Adjuvant chemoradiation after PD for adenocarcinoma of the DCBD may improve local control and overall survival. The predominant mode of failure is distant metastatic disease, highlighting the need for improved systemic therapy.

Spiritual issues of family members in a pancreatic cancer chat room.

PURPOSE/OBJECTIVES: To describe spiritual issues addressed by users of a pancreatic cancer informational Web site. DESIGN: Qualitative, descriptive. SETTING: The patient and family chat room of Johns Hopkins Hospital's pancreatic cancer Web site. SAMPLE: 600 postings on the pancreatic cancer Web site. METHODS: Identification of categories and themes in Web postings using the constant comparison method of content analysis. MAIN RESEARCH VARIABLES: Spirituality, relationship of the person posting a message (poster) to the person with cancer. FINDINGS: Relationship of the poster to the person with pancreatic cancer was explicit in 68% (n = 410) of the 600 postings, and 83% of those 410 postings indicated that the poster was a family member. Issues of spirituality appeared in 19% (n = 114) of the 600 postings and addressed four themes: spiritual convergence, reframing suffering, hope, and acceptance of the power of God and eternal life. Six percent of postings were by family members reporting on the death of their loved ones, suggesting that the site also served a bereavement function. CONCLUSIONS: Family members of patients with pancreatic cancer sought and received spiritual comfort in a variety of forms in an Internet-based cancer chat room. IMPLICATIONS FOR NURSING: Nurse developers of cancer information Web sites should periodically assess how the sites are being used and apply the information to the refinement of the sites to better meet user needs. Further study is needed to develop and evaluate cancer Web sites as an evolving medium for providing spiritual support to family members of patients with life-threatening forms of cancer.