Node-positive Pts Research Articles

Validation of sentinel lymph node (SLN) mapping (M) in colon cancer (Cca) over three continents: An international experience

4047 Background: Lymph node (LN) status is the most important prognostic factor in colon cancer (Cca). In various trials, the average nodal positivity of conventional surgery in Cca is about 33%. Ultrastaging of SLNs results in higher and more accurate nodal staging of patients (pts) with Cca. However, some recent publications of SLNM in Cca have shown variable results with differing conclusions. Hence, prospective data from 3 continents were analyzed to study the international experience of SLNM in Cca. Methods: Only centers with experience of 40 or more cases of SLNM in Cca were included in the study. SLNM was performed by peri-tumoral injections of 1–3 ml of 1% lymphazurin. First 1–4 blue nodes marked as SLNs were ultrastaged by multilevel microsections for H&E and IHC. Data for calculating the success rate, accuracy, skip metastases (mets), sensitivity, negative predictive value; nodal positivity and upstaging were collected from each center. Results: Our study included a total of 1,216 Cca pts from 9 centers over 3 continents. SLNM was successful in 92.9% pts ( Table 1 ). The average number of LN/pt was 18.5 and the average number of SLN/pt was 2.7. The overall sensitivity, accuracy rate and negative predictive value were 78.3%, 89.4% and 82.8% respectively. Nodal mets were found in 52.9% pts. Of these, SLNs were the exclusive site for mets in 30.1% pts while 18.3% pts were upstaged by SLNM. Skip mets were seen in 21.7% pts (range 9.5% - 44.1%). Conclusions: SLNM is highly successful in Cca when performed by experienced surgeons worldwide. Nodal positivity was found to be much higher in pts undergoing SLNM compared to conventional surgery. Upstaged pts may benefit from adjuvant chemotherapy. Though the variation of skip mets was wide, the clinical impact of skip mets in Cca is negligible compared to that in melanoma and breast cancer, since all pts undergo standard lymphadenectomy and all node positive pts (true +ve & skip mets) are usually treated with adjuvant chemotherapy. [Table: see text] No significant financial relationships to disclose.

Internal Mammary Nodal Chain Drainage Is a Prognostic Indicator in Axillary Node-Positive Breast Cancer

Internal mammary (IM) nodes are a potential site of breast lymphatic drainage. We examined the relationship between lymphoscintigraphic evidence of IM drainage and survival in early-stage breast cancer patients (pts). From a prospective database of 855 consecutive sentinel node mapping procedures using peritumoral radiocolloid injection from 1996-2004, we analyzed the 604 cases with stage I-III breast cancer. Overall survival and recurrence-free survival (OS, RFS) rates were compared in pts with (IM+) and without (IM-) IM drainage on lymphoscintigraphy using Kaplan-Meier plots and Cox proportional hazards models. 100 of 604 pts (17%) showed IM drainage. Five-year OS and RFS were 92% vs 88% and 88% vs 85% in IM- vs IM+ pts. In the 186 pts with axillary metastases (node+), 5-year OS and RFS were 91% vs 71% and 84% vs 69% in IM- vs IM+ pts. Univariate analysis of node+ pts estimated increased mortality risk for IM+ (hazard ratio, HR 2.9, P = .04), >or=4 positive nodes (HR 3.2, P = .02), tumors that were ER-negative (HR 3.4, P = .02), or had high Ki-67 (HR 6.8, P = .01). Multivariate analysis estimated similar increased risks [>or=4 nodes (HR 4.0, P = .02), IM+ (HR 3.3, P = .06), and ER negativity (HR 2.6, P = .09)]. IM nodal drainage predicted a nearly 3-fold increased mortality risk in node+ pts. Peritumoral radiocolloid injection provides a clinically relevant assessment of IM drainage and should be prospectively tested for its value in tailoring treatment strategies for axillary node-positive pts.

Dose-dense sequential chemotherapy with epirubicin(E), paclitaxel (T) and cyclophosphamide (C) (ETC) is superior to conventional dosed chemotherapy in high-risk breast cancer patients (≥ 4 +LN). First results of an AGO-trial

513 Background: Dose-dense chemotherapy will become a new treatment option in breast cancer patients (pts) (INT C9741). Here we report the initial results of a second prospective randomized trial that compares dose-dense vs. conventionally scheduled sequential chemotherapy in high-risk node positive pts. Methods: A multi-center phase-III trial of the German “Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO)” recruited 1284 pts from 12/98 until 4/03. Pts below 65 years of age were eligible if they had at least 4 involved axillary lymph nodes. In the experimental arm, pts were assigned to receive three courses each of epirubicin(150 mg/m2), paclitaxel (225 mg/m2) and cyclophosphamide (2500 mg/m2) at 2 weeks interval (q2wks) (ETC) with G-CSF support (5μg/kg/SC day 3–10). A second randomization ± Epoetin-alpha was performed (150 IU/kg/SC three times weekly). In the standard arm 4 courses of conventional dosed epirubicin/cyclophosphamide (90/600 mg/m2) followed by 4 courses of paclitaxel (175 mg/m2) (q3wks) were given. Results: Median patient age was 50 years. Risk factors were well balanced in both arms. 59% and 41% of the pts had 4–9 and ≥10 infiltrated nodes. The median number of positive nodes was 8. In this second interim analysis 1169 pts were fully evaluable. No unusual toxicities were seen, especially no severe cardiotoxicity. Hematological toxicity (anemia, neutropenia and thrombopenia) was more frequent in the ETC arm (p<0,0001) and varied distinctly between drugs. The incidence was highest during treatment with cyclophosphamide and lowest during treatment with paclitaxel. 7% of pts in the ETC arm vs. 2% in the standard arm were hospitalized for febrile neutropenia (p<0,0001). There were no treatment-related deaths during therapy. 82% of pts in the ETC arm vs. 90% in the standard arm received the planned number of cycles. The number of dose reductions was relatively small, ranging from 6,5% on the ETC arm to 2% on the standard arm. At a median follow-up of 28 months 94 pts in the ETC arm vs. 127 pts in the standard arm had relapsed. This difference was highly significant in the two-sided log-rank test (p=0,0009) with a HR of 0,64 (95% CI: 0,49–0,83). Estimated 3-year RFS is 80% in the ETC arm vs. 70% in the standard arm. 103 pts have died (43 events vs. 60 events) favoring again the ETC arm (two-sided log-rank test: p=0,030; HR: 0,65 (95% CI: 0,44–0,96). Estimated 3-year OAS is 90% in the ETC arm vs. 87% in the standard arm. There was a highly significant difference in anemia grade 1–4 as well as in the number of RBC's transfusions between ETC ± Epoetin alpha (p<0,0001). No difference in DFS (p=0,84) or OAS (p=0,98) was found between ETC ± Epoetin alpha. Conclusions: Evidence to date indicates that the dose-dense ETC-regimen as adjuvant therapy in high-risk breast cancer pts is well tolerated and significantly improves DFS and OAS. Confirming the results of INT C9741, dose-dense sequential regimens may become a future standard option in the adjuvant treatment of node positive breast cancer pts. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb; Amgen; Pharmacia; Ortho-Biotech

Dose-dense sequential chemotherapy with epirubicin(E), paclitaxel (T) and cyclophosphamide (C) (ETC) is superior to conventional dosed chemotherapy in high-risk breast cancer patients (≥ 4 +LN). First results of an AGO-trial

513 Background: Dose-dense chemotherapy will become a new treatment option in breast cancer patients (pts) (INT C9741). Here we report the initial results of a second prospective randomized trial that compares dose-dense vs. conventionally scheduled sequential chemotherapy in high-risk node positive pts. Methods: A multi-center phase-III trial of the German “Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO)” recruited 1284 pts from 12/98 until 4/03. Pts below 65 years of age were eligible if they had at least 4 involved axillary lymph nodes. In the experimental arm, pts were assigned to receive three courses each of epirubicin(150 mg/m2), paclitaxel (225 mg/m2) and cyclophosphamide (2500 mg/m2) at 2 weeks interval (q2wks) (ETC) with G-CSF support (5μg/kg/SC day 3–10). A second randomization ± Epoetin-alpha was performed (150 IU/kg/SC three times weekly). In the standard arm 4 courses of conventional dosed epirubicin/cyclophosphamide (90/600 mg/m2) followed by 4 courses of paclitaxel (175 mg/m2) (q3wks) were given. Results: Median patient age was 50 years. Risk factors were well balanced in both arms. 59% and 41% of the pts had 4–9 and ≥10 infiltrated nodes. The median number of positive nodes was 8. In this second interim analysis 1169 pts were fully evaluable. No unusual toxicities were seen, especially no severe cardiotoxicity. Hematological toxicity (anemia, neutropenia and thrombopenia) was more frequent in the ETC arm (p<0,0001) and varied distinctly between drugs. The incidence was highest during treatment with cyclophosphamide and lowest during treatment with paclitaxel. 7% of pts in the ETC arm vs. 2% in the standard arm were hospitalized for febrile neutropenia (p<0,0001). There were no treatment-related deaths during therapy. 82% of pts in the ETC arm vs. 90% in the standard arm received the planned number of cycles. The number of dose reductions was relatively small, ranging from 6,5% on the ETC arm to 2% on the standard arm. At a median follow-up of 28 months 94 pts in the ETC arm vs. 127 pts in the standard arm had relapsed. This difference was highly significant in the two-sided log-rank test (p=0,0009) with a HR of 0,64 (95% CI: 0,49–0,83). Estimated 3-year RFS is 80% in the ETC arm vs. 70% in the standard arm. 103 pts have died (43 events vs. 60 events) favoring again the ETC arm (two-sided log-rank test: p=0,030; HR: 0,65 (95% CI: 0,44–0,96). Estimated 3-year OAS is 90% in the ETC arm vs. 87% in the standard arm. There was a highly significant difference in anemia grade 1–4 as well as in the number of RBC's transfusions between ETC ± Epoetin alpha (p<0,0001). No difference in DFS (p=0,84) or OAS (p=0,98) was found between ETC ± Epoetin alpha. Conclusions: Evidence to date indicates that the dose-dense ETC-regimen as adjuvant therapy in high-risk breast cancer pts is well tolerated and significantly improves DFS and OAS. Confirming the results of INT C9741, dose-dense sequential regimens may become a future standard option in the adjuvant treatment of node positive breast cancer pts. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb; Amgen; Pharmacia; Ortho-Biotech

Risk factors for brain metastases in patients with a metastatic relapse of breast cancer

837 Background: Brain metastases are a more and more frequent, difficult clinical problem in advanced breast cancer (BC) patients (pts). We searched for risk factors of brain metastasis (BM) among pts diagnosed with a metastatic relapse of BC. Methods: A total of 557 premenopausal BC pts receiving systematic adjuvant chemotherapy were accrued at Institut Gustave-Roussy in a randomized trial of ovarian suppression [Arriagada et al, ASCO 03]. After a median follow-up of 9.5 years, 215 developed a first metastasis at a site other than brain alone. Of these 215 metastatic patients, 31 developed BM. The risk of BM in these 215 patients was analyzed as a function of patient, tumor and treatment characteristics by Cox models. Risk factors identified in the multivariate analysis were re-evaluated in a confirmatory series of 199 patients with metastatic relapse registered at Institut Gustave-Roussy in two randomized adjuvant chemotherapy trials (691 postmenopausal node-positive pts [Arriagada et al, Ann Oncol 2002] and 247 premenopausal node-negative pts [Arriagada et al, submitted]). Of these 199 pts, 19 developed BM. Results: In the first series, risk factors for BM in univariate analyses were lung metastasis as first site (yes/no): 2-year incidence rates of BM 24% vs 7% (p<0.001), negative hormone receptor (HR- vs HR+): 2-year BM rates 34% vs 5% (p<0.001) and short interval between BC and metastatic relapse (≤ vs >24 months): 18% vs 6% (p<0.008). In the multivariate analysis, only lung metastases remained prognostic (RR 5.3, 95% confidence interval (95%CI): 2.6–11, p<0.001). This was confirmed in the second series where the 2-year rates of BM were respectively 44% [95% CI: 26%–64%] and 3% [95%CI: 1–7%] in pts with or without lung metastases (RR 10 [95%CI: 3.8–27], p< 0.0001). Conclusions: This study shows that lung metastasis is a strong risk factor for the occurrence of brain metastases among BC patients. The occurrence of brain and lung metastases could be due to a common, albeit unknown, biological determinant. We suggest that prophylaxis of brain metastases may be evaluated in BC patients with lung metastases. No significant financial relationships to disclose.

Risk factors for brain metastases in patients with a metastatic relapse of breast cancer

837 Background: Brain metastases are a more and more frequent, difficult clinical problem in advanced breast cancer (BC) patients (pts). We searched for risk factors of brain metastasis (BM) among pts diagnosed with a metastatic relapse of BC. Methods: A total of 557 premenopausal BC pts receiving systematic adjuvant chemotherapy were accrued at Institut Gustave-Roussy in a randomized trial of ovarian suppression [Arriagada et al, ASCO 03]. After a median follow-up of 9.5 years, 215 developed a first metastasis at a site other than brain alone. Of these 215 metastatic patients, 31 developed BM. The risk of BM in these 215 patients was analyzed as a function of patient, tumor and treatment characteristics by Cox models. Risk factors identified in the multivariate analysis were re-evaluated in a confirmatory series of 199 patients with metastatic relapse registered at Institut Gustave-Roussy in two randomized adjuvant chemotherapy trials (691 postmenopausal node-positive pts [Arriagada et al, Ann Oncol 2002] and 247 premenopausal node-negative pts [Arriagada et al, submitted]). Of these 199 pts, 19 developed BM. Results: In the first series, risk factors for BM in univariate analyses were lung metastasis as first site (yes/no): 2-year incidence rates of BM 24% vs 7% (p<0.001), negative hormone receptor (HR- vs HR+): 2-year BM rates 34% vs 5% (p<0.001) and short interval between BC and metastatic relapse (≤ vs >24 months): 18% vs 6% (p<0.008). In the multivariate analysis, only lung metastases remained prognostic (RR 5.3, 95% confidence interval (95%CI): 2.6–11, p<0.001). This was confirmed in the second series where the 2-year rates of BM were respectively 44% [95% CI: 26%–64%] and 3% [95%CI: 1–7%] in pts with or without lung metastases (RR 10 [95%CI: 3.8–27], p< 0.0001). Conclusions: This study shows that lung metastasis is a strong risk factor for the occurrence of brain metastases among BC patients. The occurrence of brain and lung metastases could be due to a common, albeit unknown, biological determinant. We suggest that prophylaxis of brain metastases may be evaluated in BC patients with lung metastases. No significant financial relationships to disclose.

Lymphatic mapping and sentinel lymphadenectomy (LM/SL) in thin (pT1≤1mm) and thick (pT4 > 4mm) primary cutaneous melanoma (CM) patients (pts)

7539 Background: The benefit of LM/SL in thin (≤1 mm pT1) and thick (>4 mm - pT4) CM pts is controversial. We analyzed the results of LM/SL in these pts at one institution. Methods: We analyzed a group of consecutive pts with CM thickness ≤ 1 mm (A, 176 pts, range: 0.5mm to 1mm) and > 4mm (B, 223 pts, range: 4.1 - 58.0mm) selected from database of 832 pts who underwent LM/SL using the technetium radiocolloid combined with blue dye technique from 06/1996 to 04/2003. The median follow-up time was 30 months. Results: The sentinel node(s) (SLN) were successfully identified in 98.3% of pts in A and in 96.9% in B. SLN metastases in A were found in significantly (p<0.0001) lower number of 14 pts (7.9%, the thickness for positive SLN ranged from 0.75 mm to 1.0 mm and only 2 pts had evidence of ulceration) as compared with 79 pts (35.4%) in B (thickness for positive SLN ranged from 4.2 mm to 35.0 mm and 69 pts with ulceration). The false-negative LM/SL rate was 1.9% (3/162) in A and 6.2% (9/144) in B (p=0.048). All node-positive pts underwent radical lymph node dissection. Lymph nodes other than SLNs were found to contain metastases in 21.4% (3/14) in group A and in 45.6% (36/79) in group B (p=0.09). The estimated 5-year overall survival (OS) rate was 94% for A and 58% for B (p<0.0001). In A we did not detect statistically significant differences for OS between SLN-positive and negative pts (5-year OS rate 95% and 93%, respectively), however SLN positive pts had significantly lower disease free survival - DFS (5-year ratio: 94%% and 85%, respectively, p=0.01). In B 5-year OS rate was 75% for SLN negative pts and 31% for SLN positive pts (p=0.00001) and 5-year DFS ratio was 63% and 33% (p=0.00002). SLN status was an independent prognostic factor for both OS and DFS by univariate and multivariate analyses in B, but not in A. Conclusions: LM/SL should be offered to all pts with thick (pT4 > 4 mm) CM, as well as to pts with pT1 CM thicker than 0.75 mm. In thick CM the regional lymph node status is the strongest predictor for survival. LM/SL in thick CM is connected with a higher false negative results rate when compare with thin CM, what can be explained by wider excision of advanced primaries. No significant financial relationships to disclose.