Sensitivity to CPT-11 and platinum derivatives of stage I/II node-negative breast, lung, and gastric cancer with occult neoplastic cells in lymph node sinuses.

Tumor sensitivity to anticancer drugs such as CPT-11 and platinum derivatives was investigated by assessing Topo-1 and Bax/ERCC-1 expression in patients with stage I/II breast, lung, and gastric cancer who were positive for ONCs, and tumor sensitivity was compared between CPT-11 and platinum derivatives. In the recurrence group (RG) (n=5), immunohistochemistry revealed high expression of Topo-1 in 3 patients (60%) and low expression in 2 patients (40%), while the non-recurrence group (N-RG) (n=17) showed high Topo-1 expression in 3 patients (17.6%) and low expression in 14 patients (82.4%) (not significant; N.S.). High Bax expression combined with low ERCC-1 expression was observed in 2 patients (40%) from the RG and other patterns of expression were seen in 3 patients (60%), while high Bax/low ERCC-1 expression was observed in 3 patients (17.6%) from the N-RG and other patterns were found in 14 patients (82.4%) (N.S.). PCR analysis of Topo-1 expression in the RG (n=4) revealed high expression in 4 patients (100%), while the N-RG (n=5) showed high expression in 3 patients (60%) and low expression in 2 patients (40%) (N.S.). With respect to ERCC-1, PCR analysis of the RG (n=4) also revealed high expression in 4 patients (100%), while the N-RG (n=5) again showed high expression in 3 patients (60%) and low expression in 2 patients (40%) (N.S.). There were significant differences between the expression of high Topo-1 and low ERCC-1 in the RG (p<0.01). These results suggest that tumor sensitivity to CPT-11 may be higher than that for platinum derivatives in patients with node-negative stage I/II breast, lung, or gastric cancer who are positive for ONCs.

Sensitivity to CPT-11 and platinum derivatives of stage III/Dukes' C colorectal cancer with occult neoplastic cells in lymph node sinuses.

The sensitivity of LN metastases to anticancer drugs such as CPT-11 and platinum agents was investigated by assessing Topo-1 and Bax/ERCC-1 expression in patients who had stage III/Dukes' C colorectal cancer with ONCs. In the recurrence group (RG) (n=21), immunohistochemical expression of Topo-1 was high in 8 patients (38.1%), and low in 13 patients (61.9%), while the non-recurrence group (N-RG) (n=12) showed high expression in 1 patient (8.3%) and low expression in 11 patients (91.7%) (not significant; N.S.). Regarding the immunohistochemical expression of Bax/ERCC-1, high Bax/low ERCC-1 expression was observed in 6 patients (28.6%) from the RG and other patterns of expression were seen in 15 patients (71.4%), while high Bax/low ERCC-1 expression level was observed in 3 patients (25.0%) from the N-RG and other patterns were found in 9 patients (75.0%) (N.S.). PCR analysis of Topo-1 expression in the RG (n=13) revealed high expression in 10 patients (76.9%) and low expression in 3 patients (23.1%), while the N-RG (n=3) showed high expression in 3 patients (100%) and low expression in none (N.S.). With respect to ERCC-1, PCR analysis of the RG (n=13) revealed high expression in 6 patients (46.2%) and low expression in 7 patients (53.8%), while the N-RG (n=3) showed high expression in 2 patients (66.7%) and low expression in 1 patient (33.3%) (N.S.). These results suggest that tumor sensitivity to CPT-11 and platinum derivatives is similar in stage III colorectal cancer patients with ONCs.

Sensitivity to CPT-11 and platinum derivatives of stage II/Dukes' B colorectal cancer with occult neoplastic cells in lymph node sinuses.

Among 13 patients with recurrent colorectal cancer (recurrence group: RG), immunohistochemical expression of Topo-1 was high in 4 patients (30.8%) and low in 9 patients (69.2%), while the non-recurrence group (N-RG) (n=8) showed high expression in 1 patient (12.5%) and low expression in 7 patients (87.5%) (NS). Regarding immunohistochemical expression of Bax/ERCC-1, high Bax/low ERCC-1 expression was observed in 6 patients (46.2%) from the RG and other patterns of expression were seen in 7 patients (53.8%), while high Bax/low ERCC-1 expression was observed in 4 patients (50.0%) from the N-RG and other patterns were found in 4 patients (50.0%) (NS). PCR analysis of Topo-1 expression revealed high expression in 9 patients (75.0%) from the RG (n=12) and low expression in 3 patients (25.0%), while the N-RG (n=8) showed high expression in all 8 patients (100.0%) and low expression in none (NS). With respect to ERCC-1, PCR analysis revealed high expression in 7 patients (58.3%) from the RG (n=12) and low expression in 5 patients (41.7%), while the N-RG (n=8) showed high expression in 1 patient (12.5%) and low expression in 7 patients (87.5%) (p<0.05). These results suggest that tumor sensitivity to CPT-11 and platinum derivatives is similar in stage II colorectal cancer patients with ONCs.

Prospective study on the recurrence/metastasis of stage II/III colorectal cancer and gastric cancer associated with occult neoplastic cells in lymph node sinuses: three-year interim results.

This study was designed to prospectively examine whether the presence of occult neoplastic cells (ONCs) in lymph nodes or positive high-risk (HR) criteria were related to the survival of patients with stage II/III colorectal cancer or gastric cancer. The 3-year relapse-free survival (3Y-RFS) rate was calculated for 79 patients who were registered during a 2-year period. The 3Y-RFS rate was 80.5% in patients without ONCs (n=54) and 84.3% in patients with ONCs (n=25; p=0.9089). Among patients who had stage II/III colorectal cancer, it was 89.0% (n=47) and 76.2% (n=15), respectively (p=0.4131). For patients with stage III colorectal cancer alone, it was 80.8% (n=24) and 62.5% (n=9), respectively (p=0.4006). The 3Y-RFS rate was respectively 88.1% and 77.6% for the HR patients (n=31) and low-risk (LR) patients (n=48) with stage II/III colorectal cancer or gastric cancer (p=0.5545). It was respectively 92.3% and 84.3% for the HR patients (n=20) and LR patients (n=42) with stage II/III colorectal cancer (p=0.5073). Also, the rate was respectively 80% and 76.2% for the HR patients (n=7) and LR patients (n=26) with stage III colorectal cancer alone (p=0.9506). These results indicate that the 3Y-RFS rate is lower in ONC-positive patients with stage II/III colorectal cancer, suggesting that ONCs may have an influence on survival.

Long-term survival and tumor 5-FU sensitivity in patients with stage IV colorectal cancer and peritoneal dissemination.

Among 125 patients with peritoneal dissemination (P1-3) of colorectal cancer, including those with other synchronous metastases, the 5-year overall survival (OS) rate was 13.3% for P1 patients (n=30), 12.8% for P2 patients (n=39), and 1.8% for P3 patients (n=56) (P1 vs. P2, p=N.S.; P2 vs. P3, p=0.02; P1 vs. P3, p=0.001), while the median survival time (MST) was 12.0, 14.1, and 3.1 months, respectively. The 5-year OS rates for patients who had peritoneal dissemination without other metastases were 17.6% (n=17), 12.5% (n=19), and 3.4% (n=28) (P1 vs. P2, p=N.S.; P2 vs. P3, p=N.S.; P1 vs. P3, p=0.039), while the MST was 25.1, 15.1, and 12.5 months, respectively. In the P3 short survival group (SSG; n=13), TS expression was high in 7.7% (1/13) and low in 92.3% (12/13) of tumors, while DPD expression was high in 38.5% (5/13) and low in 61.5% (8/13) of tumors. In the P3 long survival group (LSG; n=15), the corresponding values were 80.0% (12/15), 20.0% (3/15), 33.3% (5/15), and 66.7% (10/15). High TS and low DPD expression was found in only 7.7% (1/13) of the SSG tumors vs. 46.7% (7/15) of the LSG tumors (p=0.028). These results suggest that the prognosis of stage IV colorectal cancer with P3 peritoneal dissemination is extremely poor. In addition, patients fitting the SSG criteria are unlikely to respond to treatment with 5-FU+LV, and may need combination chemotherapy using CPT-11 and/or L-OHP.

Predicting recurrence and metastasis of primary esophageal cancer with or without lymph node metastasis.

We studied 42 patients, consisting of 11 stage I/II patients who were node-negative (LN-) and 31 stage II/III patients who were node-positive (LN+). In the LN- patients, detection of occult neoplastic cells (ONCs) in lymph nodes had a sensitivity of 0.0% (0/5), a false-positive (FP) rate of 33.3% (2/6), a specificity of 66.7% (4/6), a false-negative (FN) rate of 100% (5/5), a positive predictive value (PPV) of 0.0% (0/2), and a negative predictive value (NPV) of 44.4% (4/9). In the LN+ patients, the sensitivity of ONCs was 25.0% (5/20), FP rate was 36.4% (4/11), specificity was 63.6% (7/11), FN rate was 75.0% (15/20), PPV was 55.6% (5/9), and NPV was 31.8% (7/22). In LN- patients, positivity for at least 2 of the 3 high-risk criteria had a sensitivity of 20.0% (1/5), FP rate of 16.7% (1/6), specificity of 83.3% (5/6), FN rate of 80.0% (4/5), PPV of 50.0% (1/2), and NPV of 55.6% (5/9). In LN+ patients, these criteria had a sensitivity of 75.0% (15/20), FP rate of 9.1% (1/11), specificity of 90.9% (10/11), FN rate of 25.0% (5/20), PPV of 93.8% (15/16), and NPV of 66.7% (10/15). These results suggest that the high-risk criteria may be useful for predicting recurrence or metastasis in stage II/III lymph node-positive patients with esophageal cancer.

Recurrence and 5-FU sensitivity of stage I/II node-negative breast, lung, or gastric cancer with occult neoplastic cells in lymph node sinuses.

This study was designed to examine the relationship between the presence of occult neoplastic cells (ONCs) in lymph nodes (LNs) and survival in 238 patients with stage I/II LN-negative cancer of the breast, lung, or stomach. In addition, immunohistochemistry for TS and DPD was used to compare the 5-FU sensitivity of the primary tumor in ONC (+) patients. The 5-year relapse-free survival (RFS) rate of 215 ONC (-) patients and 23 ONC (+) patients was 95.2 and 82.6%, respectively (p=0.0107). The 5-year overall survival (OS) rate of the ONC (-) and (+) patients was 97.4 and 77.4%, respectively (p=0.0000). The 6 ONC (+) patients with recurrence showed high and low TS expression in 33.3% (2/6) and 66.7% (4/6), respectively, while high and low DPD expression was observed in 16.7% (1/6) and 83.3% (5/6), respectively. In the 17 ONC (+) patients without recurrence, the corresponding values were 64.7% (11/17), 35.3% (6/17), 29.4% (5/17), and 70.6% (12/17). Patients with a combination of high TS and low DPD expression accounted for 33.3% (2/6) of the ONC (+) patients with recurrence and 52.9% (9/17) of those without recurrence, showing no significant difference between the two groups. These results suggest that ONCs are associated with a lower survival rate and that ONC (+) patients are unlikely to respond to 5-FU+LV therapy.

Recurrence and 5-FU sensitivity of stage II/III node-positive gastric cancer with occult neoplastic cells in lymph node sinuses.

The 5-year overall survival (OS) rates for patients without occult neoplastic cells (ONCs) were 43.0% in stage II (n=15), 52.2% in stage III (n=23), and 48.5% for stages II and III combined (n=38). For ONC-positive patients, the 5-year OS rates were 44.4% in stage II (n=7; p=0.88322), 11.3% in stage III (n=30; p=0.0006), and 17.5% for stages II and III combined (n=37; p=0.0019). Among the ONC(+) recurrence group (75.7%, 28/37), 42.9% (12/28) showed high TS expression in metastatic lymph nodes and 57.1% (16/28) showed low TS expression. In the case of DPD expression, 32.1% (9/28) showed high expression and 67.9% (19/28) showed low expression. Among the ONC(+) non-recurrence group (24.3%, 9/37), 66.7% (6/9) showed high TS expression and 33.3% (3/9) showed low TS expression, while high and low DPD expression was seen in 22.2% (2/9) and 77.8% (7/9), respectively. A combination of high TS and low DPD expression was found in 32.1% (9/28) of the recurrence group vs. 66.7% (6/9) of the non-recurrence group (p=0.070). These results suggest that ONCs are associated with OS. Unlike the non-recurrence group, the ONC(+) patients with recurrence of stage II/III node-positive gastric cancer are unlikely to respond to treatment with 5-FU + LV and may need combination chemotherapy based on L-OHP and/or CPT-11.

Recurrence and 5-FU sensitivity of stage III/Dukes' C colorectal cancer with occult neoplastic cells in lymph node sinuses.

In 72 patients without occult neoplastic cells (ONCs) in their lymph node sinuses, the 5-year relapse-free survival (RFS) rate and overall survival (OS) rate were 71.3% and 69.2%, respectively. In 33 patients with ONCs, the 5-year RFS rate and OS rate were 33.9% and 31.3%, respectively. There was a marked difference of survival between the two groups (p=0.0001 and p=0.0003). The metastatic lymph nodes of the 33 ONC-positive patients had high and low levels of thymidilate synthase (TS) expression in 38.1% (8/21) and 61.9% (13/21) of the recurrence group (n=21), respectively, while high and low levels of dihydropyrimidine dehydrogenase (DPD) expression were found in 38.1% (8/21) and 61.9% (13/21), respectively. In the non-recurrence group (n=12), high and low levels of TS or DPD expression were detected in 58.3% (7/12) and 41.7% (5/12) versus 16.7% (2/12) and 83.3% (10/12), respectively. Patients with high TS and low DPD expression accounted for 9.5% (2/21) of the recurrence group and 50.0% (6/12) of the non-recurrence group (p<0.01). These results suggest that ONCs are clearly associated with the 5-year RFS and OS rates. Unlike the non-recurrence group, the recurrence group of ONC-positive patients with Dukes' C colorectal cancer is unlikely to respond well to treatment with 5-FU plus LV and require combination chemotherapy based on CPT-11 and/or L-OHP.

Recurrence and 5-FU sensitivity of stage II/Dukes' B colorectal cancer with occult neoplastic cells in lymph node sinuses.

In 103 patients without occult neoplastic cells (ONCs) in the lymph node sinuses, the 5-year relapse-free survival (RFS) rate and overall survival (OS) rate were 90.2% and 91.8%, respectively. In 21 patients with ONCs, the 5-year RFS and OS rates were 34.9% and 62.3%, respectively. There were marked differences of survival between the two groups (p=0.0000 and p=0.0003). In the primary tumors of the 21 ONC-positive patients, high and low TS levels were found in 46.2% (6/13) and 53.8% (7/13) of the recurrence group (n=13), respectively. High and low DPD levels were found in 23.1% (3/13) and 76.9% (10/13), respectively. In the non-recurrence group (n=8), high and low TS or DPD levels were found in 75.0% (6/8) and 25.0% (2/8) versus 12.5% (1/8) and 87.5% (7/8), respectively. The percentage of patients with high TS and low DPD levels was 23.1% (3/13) in the recurrence group and 62.5% (5/8) in the non-recurrence group (p=0.07). These results suggest that the presence of ONCs had a clear association with the 5-year RFS and OS rates. The recurrence group of ONC-positive patients with stage II/Dukes' B colorectal cancer was unlikely to be highly responsive to 5-FU-based treatment, thus requiring multi-combination chemotherapy using CPT-11 and/or L-OHP.