Pulmonary resection for colorectal metastases is well accepted. However, the main cause of death after pulmonary resection is recurrence in the lung. The aim of this study was to clarify whether a ...repeat pulmonary resection was warranted in patients with recurrent lung metastases. The records of 76 patients undergoing initial pulmonary resection, including 14 patients undergoing a repeat operation for lung metastases, were reviewed for survival, operative morbidity, and mortality. Overall, pulmonary resection was performed 96 times in this group of patients. The operative mortality was 0%, morbidity involved only one case of major postoperative hemorrhage associated with the first operation. The cumulative 5‐year survival rate for the 76 patients was 32%. After the second pulmonary operation, recurrence was identified in 79% (11 of 14) of the patients. In 10 patients with isolated lung recurrence after a first pulmonary resection, who showed no extrapulmonary disease before or at the time of first thoracotomy, the 3‐year, and 5‐year‐survival rate after the second pulmonary resection was 67%, and 33%, respectively, comparing favorably with the survival rate in those who underwent primary pulmonary resection. In contrast, all 4 patients with extrapulmonary disease before or at the time of thoracotomy had poor prognosis. Repeat pulmonary operation for isolated recurrent colorectal metastases to the lung yielded results comparable to those after the first pulmonary resection in terms of operative mortality and survival in the absence of hilar/mediastinal lymph node or extrathoracic involvement.
Metaplastic breast cancers (MBCs) spindle cell carcinoma (SpCC), squamous cell carcinoma (SCC), and matrix-producing carcinoma (MPC) and invasive carcinomas with central acellular zones (CACs) were ...analyzed with respect to biological potential by immunohistochemical analyses. Specimens from 40 patients 20 with MBCs (7 with SCC, 6 with SpCC, 5 with MPC, and 2 with mixed type) and 20 with CACs were analyzed using antibodies to cytokeratin (CK) 8, 5/6, 14, AE1/AE3, 34αE12, involucrin, c-kit, vimentin (VIM), alpha-smooth muscle actin, p63, epidermal growth factor receptor, epithelial cell adhesion molecule, and estrogen receptor (ER)/progesterone receptor (PR)/HER2. Expression of CK5/6, 34βE12, VIM, nuclear p63, and cytoplasmic p63 was significantly higher with MBCs than CACs (38%/13%, 70%/43%, 85%/33%, 68%/40%, and 48%/18%, respectively). Other markers were expressed at various levels in these tumors, but the difference between them was not significant. Eighteen MBC and 8 CAC cases were triple (ER/PR/HER2) negative; 17 MBCs and 7 CACs were basal-like tumors. Several differences were seen in MBCs and CACs, but they were heterogeneous, differentiating multipotentially into mesenchymal, myoepithelial, basal-like phenotypes with “stem cell-like” features. Thus, CACs are related to MBCs by immunohistochemical analyses as well as according to morphological findings.
Introduction
This multicenter phase II study determined the efficacy and safety of new daily oral S-1 and weekly irinotecan (CPT-11) combination schedule in patients with previously untreated ...advanced or recurrent colorectal cancer.
Patients and Methods
Patients received first-line chemotherapy comprising S-1 80 mg/m2/day given on days 3 to 7, 10 to 14, and 17 to 21 and 60 mg/m2 CPT-11 administered intravenously on days 1, 8, and 15 of a 28-day cycle.
Results
A total of 45 eligible patients were enrolled in this study. The overall response rate was 48.9%. Median progression-free survival and median overall survival was 8.1 months and 20.9 months, respectively. The rates of grade 3 or 4 toxicity were as follows: neutropenia, 8.9%; anemia, 4.4%; anorexia, 6.7%; and diarrhea, 6.7%.
Conclusions
This new S-1 and irinotecan combination schedule appeared to be an effective, well-tolerated, and convenient regimen in patients with advanced colorectal cancer as compared with conventional regimens such as FOLFIRI and IRIS.
A phase II study was designed to evaluate the efficacy, safety and predictors for response of metronomic chemotherapy using weekly low-dosage CPT-11 and doxifluridine (5'-DFUR) in 45 patients with ...metastatic colorectal cancer.
Forty mg/m2 of CPT-11 was administered for 3 consecutive weeks in a 4-week treatment cycle, with 5'-DFUR (800 mg/day) given orally.
One or more adverse effects were seen in 42 patients. However, most of these were mild at grade 1 or 2, including only leucopenia in 2, neutropenia in 1, diarrhea in 1 and nausea in 1 as grade 3. The objective response rate was 36% with a median overall survival of 452 days. The response rate in patients with a high expression of thymidine phosphorylase (dThdPase) in tumor cells (47%) was higher (p=0.092) than that (19%) in patients with a low expression.
The efficacy of metronomic chemotherapy using low-dosage weekly CPT-1 and 5'-DFUR is worthy of further clinical study, especially in patients with a high expression of dThdPase in primary tumor cells.
We have pathologically evaluated the tumor spread in low rectal cancer treated with abdominoperineal resection to clarify the potential indication of intersphincteric resection and other ...anus-preserving operations with external sphincter muscle resection.
A total of 197 patients received abdominoperineal resection between 1982 and 2001. We determined histopathologically any invasion or metastasis into the anal canal structures.
When the lowest edge of a tumor was located above the dentate line, the invasion was rarely beyond the internal sphincter muscle, in particular, where the distance between the tumor and the dentate line was longer than 2 cm. When the lowest edge was located at or below the dentate line (Pb-cancer), invasion tended to extend into the external sphincter muscle and into the intermuscular groove. A logistic regression analysis showed that the Pb-cancer, any distant metastasis, and the tumor histology of mucinous carcinoma were each an independent significant risk factor to invasion beyond the internal sphincter muscle, whereas the Pb-cancer, the poorly differentiated adenocarcinoma, and the mucinous carcinoma were each an independent significant risk factor to invasion into the intermuscular groove.
The anus-preserving operation with sphincter muscle resection was theoretically possible for low rectal cancer in patients who underwent abdominoperineal resection. However, the procedure cannot be indicated for a tumor where the lowest edge is below the dentate line and where a preoperative biopsy shows a poorly differentiated adenocarcinoma or mucinous carcinoma, even if the intermuscular groove is macroscopically unaffected by the tumor.
We evaluated the relationship between biological behavior and microsatellite instability (MSI) status, with or without p53 status, in sporadic colorectal carcinoma.
MSI was analyzed with regard to ...biological features such as cellular proliferation and apoptotic cell death, in addition to clinicopathological features, in 87 patients with sporadic colorectal carcinoma.
Fourteen (16.1%) of 87 tumors showed instability at two or more of the five loci examined (high-frequency MSI MSI-H). Four demonstrated instability at one locus (low-frequency MSI MSI-L), and 69 showed no instability (microsatellite-stable MSS). The MSI-H tumors tended to be located in the proximal colon and more often were mucinous carcinoma. The MSI-H tumors also tended to be in patients with multiple colorectal carcinomas and to demonstrate, rarely, an infiltrating growth pattern or venous invasion. The incidence of p53 protein overexpression in the MSI-H tumors was significantly lower than that in the MSI-L/MSS tumors (21% vs 54%). There was no significant difference in the proliferating-cell nuclear antigen (PCNA) labeling index (PI) or apoptotic index (AI) between the MSI-H and MSI-L/MSS tumors. The AI in the MSI-H tumors with p53 overexpression was significantly lower than that in the MSI-H tumors without p53 overexpression, and was also significantly lower than that in the MSI-L/MSS tumors with p53 overexpression. In the MSI-H tumors with p53 overexpression, no expression of BAX protein was found, and there was high expression of bcl-2 protein, resulting in a low BAX/bcl-2 ratio.
In sporadic colorectal carcinoma, an MSI-H tumor with p53 protein overexpression may display aggressive biological features.
Purpose
This multicenter phase II study was designed to determine the efficacy and tolerability of oxaliplatin, levoforinate, and infusional 5-fluorouracil (FOLFOX4) as a second-line therapy for ...Japanese patients with unresectable advanced or metastatic colorectal cancer.
Methods
A total of 53 patients with progressive disease after first-line chemotherapy were enrolled in the study. The treatment was repeated every 2 weeks until disease progression or unacceptable toxicity occurred, or the patient chose to discontinue the treatment.
Results
Four patients were ineligible and one did not receive the protocol therapy. Therefore, the response rate, overall survival (OS), and progression-free survival (PFS) were evaluated in 48 patients; toxicity was evaluated in 52 patients, excluding the patient who had not received the protocol therapy. A partial response was observed in 10 patients. The overall response rate was 20.8% (95% confidence interval CI, 10.5%–35.0%). The median PFS was 5.6 months (95% CI, 4.1–7.0 months) and the median OS was 19.6 months (95% CI, 11.4–24.3 months). The most frequently encountered grade 3/4 hematological symptom was neutropenia (43.1%). The toxicity profile was generally predictable and manageable.
Conclusion
The results showed good tolerability and efficacy for second-line FOLFOX4 in patients with advanced colorectal cancer, thus indicating the promise of this regimen as an effective second-line therapy for advanced colorectal cancer in the Japanese population.
To clarify the clinical significance of the expression of vascular endothelial growth factor (VEGF) in squamous cell carcinoma in the thoracic esophagus, particularly as a prognostic factor, we have ...investigated the correlation between VEGF expression in tumor cells and microvessel density (MVD), pathologic factors, and survival. A total of 92 specimens, each from a thoracic esophageal squamous cell cancer patient who underwent transthoracic curative R0 esophagectomy between 1991 and 1994, were examined immunohistochemically using anti‐human VEGF and anti‐human von Willebrand factor antibodies. The incidence of VEGF expression in the tumor cells was relatively low, at 23.9% of all specimens. There was no significant correlation between VEGF expression and histopathologic factors. The MVD at the tumor margin in patients with VEGF‐positive tumor cells was significantly greater than that in VEGF‐negative cases (35.2 ± 8.9 vs. 22.7 ± 8.2). The survival rate for patients with VEGF expression was significantly lower than that of those without VEGF expression; the same situation was found in node‐positive patients but not in node‐negative patients. In addition, multivariate analysis revealed that VEGF expression was an independent prognostic factor in node‐positive patients. VEGF may be implicated in the definition of the malignant phenotype of squamous cell esophageal cancer via tumor angiogenesis. Accordingly, VEGF expression in the tumor cells could be a useful prognostic factor for esophageal cancer, particularly in node‐positive patients.
The anti-angiogenic efficacy of chemotherapy would seem to be optimized by administering comparatively lower doses of drugs on a more frequent (daily, several times a week, or weekly) or continuous ...schedule, with no extended interruptions – sometimes referred to as ‘metronomic’ chemotherapy. This phase I study was performed to determine the recommended dosage (RD) of metronomic chemotherapy using oral fluoropyrimidine S-1 plus weekly irinotecan (CPT-11) in patients with previously untreated advanced or recurrent colorectal cancer. Patients received first-line chemotherapy consisting of 80 mg/m2 of S-1 given on days 3 to 7, 10 to 14, and 17 to 21 with escalating dosages of CPT-11 (from 40 mg/m2) administered intravenously on day 1, 8, and 15 of a 28-day cycle. Standard patient eligibility criteria were used. Based on the concept of metronomic chemotherapy, dose limiting toxicity (DLT) was defined any toxicity that resulted in skipping of CPT-11 administration, or more than 5 days suspension in S-1 administration, in addition to the conventional criteria. If the maximum tolerated dosage (MTD) was defined as the maximum dosage at which no suspension of CPT-11 or S-1 administration occurred, the RD was considered to be the dosage one rank lower than the MTD. On the other hand, in the present study the MTD was defined as the dosage at which at least one suspension of CPT-11 or S-1 administration occurred, the MTD was considered to be the RD. Two of the first 3 patients at level 4 received 60 mg/m2 of CPT-11 and 80 mg/m2 of S-1 experienced a suspension in CPT-11 administration, thus level 4 was defined as the MTD and RD. Sixty mg/m2 of CPT-11 and 80 mg/m2 of S-1 were the indicated RD for the following phase II study of metronomic chemotherapy.
The aim of this study was to determine any correlation between the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines and the matrix metalloproteinase 9 (MMP-9) expression ...in primary colorectal cancer tissues.
The data on 307 patients with colorectal cancer at stage II or III, who underwent potentially curative resection with lymphadenectomy, were reviewed. Of these, 188 received postoperative administration of oral fluoropyrimidines such as UFT and 5'-DFUR (chemotherapy group), while the other 119 patients underwent surgery alone (surgery-alone group). Immunostaining for MMP-9 was performed using surgical specimens of all 307 primary tumors and 18 recurrent tumors.
Overall, MMP-9 was positively expressed in the primary tumor in 44% of patients. Multivariate analysis revealed that the MMP-9 expression was a worse prognostic factor with a second highest hazard ratio for recurrence. The disease-free survival rate in the chemotherapy group was significantly higher than that in the surgery-alone group. However, no significant difference in disease-free survival rate between the two groups was found in patients with a tumor positive for MMP-9. There was a strong positive correlation of MMP-9 expression between the primary tumors and the recurrent liver or lung tumors.
The efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines such as UFT and 5'-DFUR may not be as great for patients with a tumor positive for MMP-9 having a greater risk to postoperative recurrence.
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