Adjuvant Therapy For High-risk Stage Research Articles

High-Risk Features Are Prognostic in dMMR/MSI-H Stage II Colon Cancer.

BackgroundHigh-risk features, such as T4 disease, bowel obstruction, poorly/undifferentiated histology, lymphovascular, perineural invasion, and <12 lymph nodes sampled, indicate poor prognosis and define high-risk stage II disease in proficient mismatch repair stage II colon cancer (CC). The prognostic role of high-risk features in dMMR/MSI-H stage II CC is unknown. Similarly, the role of adjuvant therapy in high-risk stage II CC with dMMR/MSI-H (≥1 high-risk feature) has not been studied in prospective trials. The aim of this analysis of the National Cancer Database is to evaluate the prognostic value of high-risk features in stage II dMMR/MSI-H CC.MethodsUnivariate (UVA) and multivariate (MVA) Cox proportional hazards (Cox-PH) models were built to assess the association between clinical and demographic characteristics and overall survival. Kaplan–Meier survival curves were generated with log-rank tests to evaluate the association between adjuvant chemotherapy in high-risk and low-risk cohorts separately.ResultsA total of 2,293 stage II CC patients have dMMR/MSI-H; of those, 29.5% (n = 676) had high-risk features. The high-risk dMMR/MSI-H patients had worse overall survival [5-year survival and 95%CI, 73.2% (67.3–78.1%) vs. 80.3% (76.7–83.5%), p = 0.0001]. In patients with stage II dMMR/MSI-H CC, the high-risk features were associated with shorter overall survival (OS) along with male sex, positive carcinoembryonic antigen, Charlson–Deyo score >1, and older age. Adjuvant chemotherapy administration was associated with better OS, regardless of the high-risk features in dMMR/MSI-H (log-rank test, p = 0.001) or not (p = 0.0006). When stratified by age, the benefit of chemotherapy was evident only in patients age ≥65 with high-risk features.ConclusionHigh-risk features are prognostic in the setting of dMMR/MSI-H stage II CC. Adjuvant chemotherapy may improve survival specifically in patients ≥65 years and with high-risk features.

Adjuvant Therapy for High-Risk Stage II or III Colon Adenocarcinoma: A Propensity Score-Matched, Nationwide, Population-Based Cohort Study.

Purpose: To determine the optimal adjuvant chemotherapy regimen for patients with high-risk stage II or III colon adenocarcinoma, we conducted this propensity score-matched, nationwide, population-based cohort study to estimate the effects of adjuvant treatments in high-risk stage II or III colon adenocarcinoma. Patients and Methods: Using propensity score matching, we minimized the confounding effects of sex, age, pathologic stage, tumor location, total chemotherapy cycles, and Charlson comorbidity index scores on adjuvant treatment outcomes in patients with high-risk stage II or III resectable colon adenocarcinoma. We selected the patients from the Taiwan Cancer Registry database and divided them into four groups: Group 1, comprising patients who received surgery alone; group 2, comprising those who received adjuvant fluoropyrimidine alone; group 3, comprising those who received adjuvant oxaliplatin-fluoropyrimidine-leucovorin (FOLFOX); and group 4, comprising those who received adjuvant folinic acid-fluorouracil-irinotecan (FOLFIRI). Results: In both univariate and multivariate Cox regression analyses, the adjusted hazard ratios (aHRs, as well as the 95% confidence intervals (Cis)) for mortality observed for groups 1, 2, and 4 relative to group 3 were 1.55 (1.32 to 1.82), 1.22 (1.05 to 1.43), and 2.97 (2.43 to 3.63), respectively. After a stratified subgroup analysis for high-risk stage II colon adenocarcinoma, we noted that the aHR (95% CI) for mortality for group 2 relative to group 3 was 0.52 (0.30 to 0.89). Conclusions: Adjuvant fluoropyrimidine alone is the most optimal regimen for patients with high-risk stage II colon adenocarcinoma compared with the other adjuvant chemotherapy regimens. Adjuvant FOLFOX can serve as an optimal regimen for patients with pathologic stage III colon adenocarcinoma, regardless of age, sex, or tumor location.

91P - Adjuvant therapy for high-risk stage II or stage III colon adenocarcinoma: A propensity score-matched, nationwide, population-based cohort study

BackgroundTo estimate the optimal adjuvant chemotherapy in patients with high-risk stage II and III colon adenocarcinoma, we use a propensity score-matched (PSM), nationwide, population-based cohort study to estimate different adjuvant treatments in high-risk stage II or stage III colon adenocarcinoma. MethodsWe minimized the confounding effects with PSM of sex, age, pathologic stages, tumor locations, total cycles of chemotherapy, and Charlson comorbidity index in various adjuvant treatments outcomes in patients with high-risk stage II and III resctable colon adenocarcinoma from the Taiwan Cancer Registry database by dividing them as follows: group 1, those undergoing surgery alone; group 2, those undergoing adjuvant fluoropyrimidine alone; group 3, those receiving adjuvant oxaliplatin, fluoropyrimidine, and leucovorin (FOLFOX) and group 4 those receiving adjuvant folinic acid, fluorouracil, irinotecan (FOFIRIL). ResultsIn both univariate and multivariate Cox regression analyses, adjusted HRs (aHRs) derived for mortality and 95% confidence intervals (CIs), reported as aHR (95% CI), derived for surgery alone, adjuvant fluoropyrimidine alone, and adjuvant FOLFIRI groups compared with the adjuvant FOLFOX group were 1.55 (1.32-1.82), 1.22 (1.05-1.43), and 2.97 (2.43-3.63), respectively. After stratified subgroup analysis, at high-risk stage II, the aHR (95% CI) derived for mortality was 0.52 (0.30-0.89) for the adjuvant fluoropyrimidine alone group compared with the group 3. ConclusionsAdjuvant fluoropyrimidine alone were more suitable for patients with high-risk stage II colon adenocarcinoma rather than other adjuvant chemotherapy regimens. Adjuvant FOLFOX could be the optimal regimen for patients with pathologic stage III colon adenocarcinoma whatever elderly, sex, or tumor locations. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma

BackgroundThe programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma.MethodsPatients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.ResultsAt a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1–positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group.ConclusionsAs adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594; EudraCT number, 2014-004944-37.)

Advances in the Management of Melanoma

Stage IV melanoma is an aggressive malignancy with the median survival historically being less than 1 year. Approximately 50% of melanomas contain an activating mutation in a targetable component of the mitogen-activated protein kinase (MAPK) pathway called BRAF. Melanoma growth is modulated by activating and inhibitory immune checkpoints. Advances in the management of distantly metastatic and stage III melanoma are reviewed. Targeting BRAF signaling in patients with metastatic V600 BRAF mutated melanoma and modulation of immune checkpoints confer survival benefit to patients with distantly metastatic melanoma. CTLA-4 blockade confers survival benefit as adjuvant therapy in patients with stage III melanoma. The efficacy of systemic therapy to treat stage IV melanoma is improving. Advances are being made to improve efficacy of adjuvant therapy for high-risk stage III melanoma patients and to determine optimal surgical management of patients with sentinel lymph node-positive melanoma.

Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy

BackgroundOn the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma.MethodsAfter patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis–free survival, and safety.ResultsAt a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis–free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events.ConclusionsAs adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis–free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168, and EudraCT number, 2007-001974-10.)

Recurrence risk and prognostic parameters in stage I rectal cancers.

The standard therapy for stage I rectum cancer is surgical resection. Currently, there is no strong evidence to suggest that any type of adjuvant therapy is beneficial. The risks of local relapse and distant metastasis are higher in rectal tumors. Therefore, while there is no clearly defined absolute indication for adjuvant therapy in lymph node negative colon cancers, rectum tumors that are T3N0 and higher require adjuvant treatment. Due to the more aggressive nature of rectal cancers, we explored the clinical and pathologic factors that could predict the risk of relapse in Stage I (T1-T2) disease and whether there was any progression-free survival benefit to adjuvant therapy. This multicenter study was carried out by the Anatolian Society of Medical Oncology. A total of 178 patients with rectal cancers who underwent curative surgery between January 1994 and August 2012 in 13 centers were included in the study. Patient demographics, including survival data and tumor characteristics were obtained from medical charts. The median age was 58 years (range 26-85 years). Most tumors were well or moderately differentiated. For adjuvant treatment, 13 patients (7.3%) received radiotherapy alone, 12 patients (6.7%) received chemotherapy alone and 15 patients (8.4%) were given chemoradiotherapy. Median follow up was 29 months (3-225 months). Some 42 patients (23.6%) had relapse during follow up; 30 with local recurrence (71.4%) whereas 12 (28.6%) were distant metastases. Among the patients, 5-year DFS was 64% and OS was 82%. Mucinous histology and receiving adjuvant therapy were found to have statistically insignificant correlations with relapse and survival. In our retrospective analysis, approximately one quarter of patients exhibited either local or systemic relapse. The rates of relapse were slightly higher in the patients who had no adjuvant therapy. There may thus be a role for adjuvant therapy in high-risk stage I rectal tumors.

International trial of adjuvant therapy in high risk stage I non-squamous cell carcinoma identified by a 14-gene prognostic signature.

There is widespread agreement amongst clinical oncologists that more refined risk-stratification in early-stage lung cancer patients beyond conventional TNM staging is needed. Over the past decade, a number of molecular prognostic signatures have been designed to meet this need by correlating patterns in the differences in gene expression or modification to patient prognosis. Unfortunately, the majority of proposed signatures are not amenable to practical widespread implementation or have not yet undergone large-scale, rigorous clinical validation. A practical 14-gene prognostic signature that has undergone large-scale blinded independent validation is now ready for widespread clinical use. An international clinical trial is underway that has been designed to document the precise degree of benefit derived from adjuvant therapy in high-risk stage I patients identified by the 14-gene prognostic assay.

Retrospective analysis of 178 patients with stage I rectum cancer.

e14662 Background: There is no strong evidence to suggest that type of adjuvant therapy has any role in the management of stage I rectum cancer. The risks of local relapse and distant metastasis are higher in rectal cancer than colon cancer. Due to the more aggressive nature of rectal cancers, we explored the clinical and pathologic factors that could predict the risk of relapse in stage I disease. Methods: This multicenter study was carried out by Anatolian Society of Medical Oncology. 178 patients with rectal cancers who underwent curative surgery between 1994 and 2012 were included. Retrospective analyses were made using data collected from medical records. Results: The median age was 58 years (26-85). Low anterior resection (LAR) was the most preferred surgical method. Most tumors were well or moderately differentiated. After surgery, 13 patients (7.3%) received radiotherapy alone, 12 patients (6.7%) received chemotherapy alone and 15 patients (8.4%) were given chemoradiotherapy. Median follow-up was 29 months (3-225). 41 patients (23%) had relapse; relapses were local in 18 patients (10.1%) and distant in 12 patients (6.7%). 11 patients (6.2%) who had no relapse data were considered to be disease free. The 3-year disease free survival (DFS) was 74% and the overall survival (OS) was 94%. Mucinous histology and adjuvant therapy were found to have statistically insignificant correlations with relapse and survival. Conclusions: There is no strong evidence to support the role of any type of adjuvant therapy after resection in stage I rectal cancer. Approximately ¼ of patients had local or systemic relapse. This is a high rate for stage I tumors. The rates of relapse were slightly higher in the patients who had no adjuvant therapy and those who had mucinous tumors. There may be a role for adjuvant therapy in high-risk stage I rectal tumors. However, there is still a need for prospective studies in this regard. [Table: see text]

Report of the long-term efficacy of two cycles of adjuvant bleomycin/etoposide/cisplatin in patients with stage I testicular nonseminomatous germ-cell tumors (NSGCT): A risk adapted protocol of the Hellenic Cooperative Oncology Group

Objectives Stage I testicular nonseminomatous germ-cell tumors (NSGCT) are highly curable. Following orchidectomy surveillance, adjuvant chemotherapy and retroperitoneal lymph node dissection can be applied. Certain factors are used to select patients in high-risk for relapse. We report the outcome and safety of a risk-adapted strategy by the Hellenic Cooperative Oncology Group. Methods Between 1994 and 2004, 142 patients with stage I NSGCT and 1 of the following risk factors: lymphovascular invasion (LVI), invasion of tunica vaginalis, spermatic cord, rete testis or scrotal wall, embryonal component >50% of the total tumor, were prospectively included in a protocol of adjuvant chemotherapy consisting of two 3-week courses of bleomycin 15 IU, etoposide 120 mg/m 2, and cisplatin 40 mg/m 2 for 3 consecutive days with G-CSF support. Results Median follow-up was 79 months and 138 patients have been followed for at least 2 years. Seventy-seven patients (54%) had LVI and 74 (52%) had >50% embryonal component. There was 1 relapse, which was cured with chemotherapy and surgery. Another patient died due to disease-unrelated causes and 1 patient developed a new primary of the remaining testicle, which was cured with surgery. Conclusion Two cycles of bleomycin/etoposide/cisplatin is an effective and safe form of adjuvant therapy in high-risk stage I NSGCT.

Is adjuvant chemotherapy beneficial to high risk stage II colon cancer? Analysis in a single institute

Colorectal carcinoma is the most common malignancy of the gastrointestinal tract. It remains controversial for adjuvant chemotherapy in patients with stage II colon cancer. This study was designed to identify the risk factors of tumor recurrence in stage II colon cancer. Furthermore, the benefit of adjuvant chemotherapy for high-risk stage II colorectal cancer will be investigated. From May 1998 until August 2004, 375 patients with stage II (T3N0M0, T4N0M0) colon cancer received curative operation in a single hospital. The clinical data were extracted from the prospectively collected colorectal cancer database. The disease-free survival curves were calculated with Kaplan-Meier's analysis, and the survival difference was determined by log-rank test. The p value less than 0.05 was considered to be significant. Of 375 stage II colon cancer, 66 patients received 5-FU-based adjuvant chemotherapy, either oral or intravenous (IV) form. Within the median of 48.5 months of follow-up, recurrence developed in 35 patients (9.3%). T4 lesion (p=0.024), lymphovascular invasion (p=0.022), obstruction at presentation (p=0.008), and mucinous component more than 50% (p=0.032) were associated with significantly decreased disease-free survival. High-risk patients (n=102), but not other patients with stage II colon cancer, benefited from adjuvant therapy (3-year disease-free survival: 96.4% vs. 84.7%, p=0.045; 5-year overall survival: 100% vs. 86.4%, p=0.015). Adjuvant therapy for high-risk stage II colon cancer may be beneficial, and we suggest adjuvant therapy should be considered in high-risk stage II colon cancer patients.

Randomized Trial of High Dose Chemotherapy With Autologous Bone Marrow Support as Adjuvant Therapy for High-Risk, Multi-Node Positive Malignant Melanoma

Chemotherapy adjuvant to surgery in metastatic melanoma has been evaluated in only a few prospective randomized trials. In the treatment of metastatic melanoma, dacarbazine has response rates of 15%-25% and in several studies, when combined with other alkylating agents, has yielded even higher response rates. Among the highest response rates are those achieved by using high-dose chemotherapy regimens combined with autologous bone marrow support (transplantation). We conducted a prospective randomized clinical trial to test the efficacy of high-dose alkylating agents in combination with autologous bone marrow support given as adjuvant therapy for high-risk stage II (World Health Organization) melanoma. Thirty-nine patients with metastases involving five or more lymph nodes were randomly assigned to one of two treatment arms within 8 weeks of lymphadenectomy: immediate treatment or observation only. The immediate-treatment arm consisted of 19 patients who, immediately after random assignment, received high-dose chemotherapy with alkylating agents, followed 3 days later by reinfusion of autologous bone marrow. The observation arm consisted of 20 patients who were observed until relapse (confirmed by biopsy) and were then treated with the identical high-dose alkylating agent chemotherapy followed by reinfusion of autologous bone marrow. Bone marrow was harvested from the patients under general anesthesia 1-2 weeks prior to chemotherapy and was cryopreserved. Chemotherapy consisted of intravenous administration of cyclophosphamide (1875 mg/m2 as a 1-hour infusion daily for 3 days), cisplatin (55 mg/m2 per day by continuous infusion over the same 72-hour period), and carmustine (BCNU) (600 mg/m2) given immediately after cisplatin on the 4th day as a 2-hour infusion. The total doses of the three drugs were 5625, 165, and 600 mg/m2, respectively. All patients received medical evaluations every 6-12 weeks over the study period. Kaplan-Meier estimates were used to determine the time to disease progression on the basis of intent to treat. There was no statistically significant difference in overall survival or in time to disease progression between the two treatment arms. However, the median time to progression was 16 weeks in the observation arm and 35 weeks in the immediate-treatment arm. Immediate adjuvant high-dose chemotherapy with alkylating agents followed by autologous bone marrow support more than doubled the time to disease progression compared with observation alone, though the difference was not statistically significant. No differences in overall survival were noted.