Serum p53 antibodies in correlation to other biological parameters of breast cancer.

Breast cancer is the second most frequent cancer of Thai women. Mutation of p53 is a common event in breast cancer. This alteration can result in cellular accumulation of p53 and may also found in serum p53 antibodies (p53-Abs). To clarify prognostic significance of these antibodies, we evaluated p53-Abs in 158 sera of patients with breast cancer. Thirty (19%) patients were found to have p53-Abs. The incidence of p53-Abs tended to be higher in patients with advanced disease group (stages III and IV) than patients with early disease group (stages I and II) (P=0.055). Strong correlations were found between the presence of p53-Abs and p53 protein expression (P<0.001) and lymph node status (P=0.021). The presence of p53-Abs was associated with lack of estrogen (ER) receptor expression (P=0.035) but was not related to progesterone receptor (PR) (P=0.567). In addition, there was a statistically significant correlation between p53-Abs and proliferation associated antigen Ki-67 (P=0.006), but no relation between c-erbB2 oncoprotein and p53-Abs was observed (P=0.112). Additionally, no correlation was noted between the presence of p53-Abs and serum carcinoembryonic antigen (CEA) or carbohydrate antigen (CA15-3). Our findings indicate that p53-Abs appears to be a promising new parameter to evaluate the cellular biology and prognosis of breast cancer.

Phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non-small-cell lung cancer.

We conducted a phase II trial to investigate the efficacy of concurrent chemoradiation in patients with stage III non-small-cell lung cancer (NSCLC). Thirty patients with inoperable NSCLC were enrolled onto a multicenter phase II trial of concurrent chemoradiation therapy. Patients received six weekly cycles of paclitaxel 45 mg/m(2) over 1 h; carboplatin at (area under the curve) AUC 2; and radiation therapy of 60 Gy. Radiation was administered to the primary tumor and regional lymph nodes (40 Gy over 4 weeks) followed by a boost to the primary tumor (20 Gy in 2 weeks). After the initial phase of concurrent chemoradiation, patients received an additional four cycles of paclitaxel 175 mg/m(2) over 3 h and carboplatin at AUC 6 every 3 weeks. The overall objective response rate of 30 assessable patients was 76.7%. At the median follow-up time of 13.1 months, the median survival time was 14.5 months (95% CI, 10.59-18.48). The median progression-free survival was 10.5 months (95% CI, 7.72-13.28). The major toxicity was hematologic. The incidence of grade 3 esophagitis was 10%. In conclusion, this chemoradiation regimen is well tolerated and shows significant clinical results for locally advanced NSCLC. Locoregional failure rate remains an important issue with this newer chemotherapeutic regimen. A novel chemotherapy and radiation therapy is clearly needed.

Phase II study of concurrent chemoradiotherapy for inoperable (bulky) stage III (A/B) non-small cell lung cancer (NSCLC): a preliminary report.

We designed a phase II study to determine the feasibility and toxicity of concomitant radiotherapy and Paclitaxel/Carboplatin followed by adjuvant chemotherapy of the same regimen in patients with newly diagnosed inoperable stage III A/B non-small cell lung cancer. Patients were irradiated with a total dose of 66 Gy. Weekly courses of Paclitaxel 45 mg/m2 and Carboplatin AUC 2 were administered intravenously during the irradiation period. After completion of concurrent chemoradiotherapy, adjuvant chemotherapy with Paclitaxel 175 mg/m2 and Carboplatin AUC 6 intravenously every 3 weeks for 4 cycles were given. Since March 1998, 15 patients have been enrolled. All patients were assessable for efficacy and toxicity after concurrent chemoradiotherapy. Eleven patients were assessable for efficacy and toxicity after adjuvant chemotherapy. After concomitant chemoradiotherapy, complete response (CR) was documented in 2 of 15 (13%). Partial response (PR) was documented in 9 of 15 (60%). After completion of adjuvant chemotherapy in 11 patients, the overall response rate was 91 per cent. (18% CR, 73% PR). There were 8 per cent gr. 3-4 neutropenia which occurred during adjuvant chemotherapy. Concomitant Paclitaxel/Carboplatin and radiotherapy are promising modalities in the treatment of inoperable stage III A/B non-small cell lung cancer.

Phase II study of paclitaxel and carboplatin for advanced non-small-cell lung cancer.

A prospective phase II study was conducted to determine the response, toxicity and survival rate of lung cancer patients treated with combination paclitaxel and carboplatin in stage IIIB and IV NSCLC. Eligible patients required measurable and/or evaluable diseases; performance status (ECOG) 0-2; no previous chemotherapy; adequate hepatic, renal and bone marrow function. Paclitaxel was administered at a dose of 200 mg/m2, 3 h infusion, followed by carboplatin at an AUC of 6. Treatment was repeated every 3 weeks for six courses. G-CSF 5 microgram/kg was subcutaneously injected during subsequent courses if there was grade 3-4 leucopenia or granulocytopenia in the previous course. From April 1996 through July 1997, 53 patients were enrolled; all are assessable for toxicity and response. The median age was 56 years (range, 20-77 years). Sixty four percent were male, 64% had adenocarcinoma and 62% had stage IV disease. Two hundred and seventy two courses were administered; 36 patients (68%) completed all six cycles. Two patients achieved a complete response (4%) and 27 patients achieved a partial response (51%), for an overall response rate of 55%. Sixteen patients had stable disease (30%) and 8 patients had progressive disease (15%). The median progression free survival time for all patients, stage IIIB and stage IV patients was 28 weeks (range, 18-37 weeks), 31 weeks (range 21-41 weeks) and 22 weeks (range 16-29 weeks), respectively. The median survival time and 1 year survival rate for all patients was 55 weeks (range, 51-59 weeks) and 55%, respectively. Stage IIIB patients had better median survival time and 1-year survival rate than stage IV patients (75 vs. 46 weeks, P = 0.007; 80% vs. 42%, P = 0.003). Grade 3 and 4 granulocytopenia, anemia and thrombocytopenia were observed in 25, 3, and 1%, respectively, of the 272 courses administered. G-CSF was required in 28% of the 272 courses. There were four episodes of febrile neutropenia (1.5%), three episodes of angina pectoris (1%) and one episode of anaphylaxis (0.4%). Other common toxicities, generally mild, included myalgia, arthralgia, peripheral neuropathy and asthenia. Most toxicities showed cumulative effect. Paclitaxel plus carboplatin is a moderately active regimen in advanced NSCLC. Toxicities of this regimen are well tolerated.

Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Asian-Oceanian Clinical Oncology Association Nasopharynx Cancer Study Group.

BACKGROUND: The aim of this trial was to compare the outcome achieved with neoadjuvant chemotherapy followed by radiotherapy to that achieved with radiotherapy alone for patients with locoregionally advanced undifferentiated or poorly differentiated nasopharyngeal carcinoma (NPC) meeting one of the following criteria: Ho's T3 disease, Ho's N2-N3 disease, or lymph node size > or =3 cm. METHODS: Between September 1989 and August 1993, 334 patients were enrolled in the study, with equal numbers of patients randomized to the neoadjuvant chemotherapy arm (CT arm) and the radiotherapy arm (RT arm). Neoadjuvant chemotherapy consisting of 2-3 cycles of cisplatin (60 mg/m2 on Day 1) and epirubicin (110 mg/m2 on Day 1) followed by radiotherapy was given to the CT arm. For radiotherapy, a dose of 66-74 gray (Gy) (median, 71 Gy) was delivered to the primary tumor and 60-76 Gy (median, 66 Gy) to the neck. Two hundred eighty-six eligible patients completed the treatment and were evaluable for treatment response (134 in the CT arm, 152 in the RT arm). All patients were included in the survival analysis based on the intention to treat. The median follow-up was 30 months for the whole cohort and 41 months for the surviving patients. RESULTS: Analysis of the 334 patients based on the intention to treat showed no significant difference in relapse free survival (RFS) or overall survival (OS) between the 2 treatment arms (3-year RFS rate: 48% in the CT arm vs. 42% in the RT arm, P = 0.45; 3-year OS rate: 78% vs. 71%, P = 0.57). In an efficacy analysis based on only the 286 evaluable patients, a trend of improved RFS favoring the CT arm was observed (3-year RFS rate: 58% vs. 46%, P = 0.053), with again no significant difference in OS (3-year OS rate: 80% vs. 72%, P = 0.21). In the subgroup of 49 patients with bulky neck lymph nodes >6 cm, improved RFS (3-year RFS rate: 63% vs. 28%, P = 0.026) and OS (3-year OS rate: 73% vs. 37%, P = 0.057) were observed, favoring the CT arm. CONCLUSIONS: This multicenter randomized study did not demonstrate any benefit with the addition of cisplatin-epirubicin neoadjuvant chemotherapy for patients with locoregionally advanced nasopharyngeal carcinoma; therefore routine administration of neoadjuvant chemotherapy to this target group cannot be recommended. Although the overall incidence of recurrence was reduced with the addition of chemotherapy in the efficacy analysis, the overall survival was not affected. A more effective chemotherapy regimen, the selection of an appropriate target group, and the use of an alternative strategy for combining chemoradiotherapy should be explored in future trials.

Prognostic importance of p53 and c-erbB-2 oncoproteins overexpression in patients with breast cancer.

Using immunohistochemistry, 119 breast cancer tissues were examined for overexpression of p53 and c-erbB-2 oncogene proteins. In 46 (38.7%) of the cases p53 was overexpressed, while 35 (29.4%) demonstrated positive c-erbB-2 immunostaining. Expression of these two oncogene products was closely correlated (p < 0.01). There was no significant association between p53 protein expression and age of the patients, clinical stage, tumor size, number of involved nodes or estrogen receptor status. However, we found significant correlation between p53 protein expression and 5-year disease-free survival (p = 0.0113). In addition, the findings in this study clearly indicated that the co-overexpression of p53 and c-erbB-2 proteins was a powerful predictor for early recurrence in the patients with breast cancer.

Immunohistochemical detection of c-erbB-2 oncoprotein in patients with breast cancer.

Using a polyclonal antibody against the c-erbB-2 gene product, an immunohistochemical study on the expression of c-erbB-2 oncoprotein was performed in routine formalin-fixed, paraffin-embedded tissue sections from 119 patients with primary breast cancer. Overexpression of c-erbB-2 protein was detected in 35 cases (29%). There was a strongly negative association between c-erbB-2 protein overexpression and estrogen receptor status (p < 0.001). Expression of c-erbB-2 protein was found to be related to clinical stage and tumor size (p < 0.05) but not to the number of involved nodes or age of patients at diagnosis. In addition, this study demonstrated that the c-erbB-2 protein over-expression was an effective independent prognostic indicator in patients with breast cancer.

Randomized trial of epirubicin and cisplatin chemotherapy followed by pelvic radiation in locally advanced cervical cancer. Cervical Cancer Study Group of the Asian Oceanian Clinical Oncology Association.

PURPOSE: Pelvic radiation is standard treatment for women with stage IIb to IVa cervical cancer, but treatment results are disappointing, particularly for women with bulky tumors. We investigated the role of primary chemotherapy followed by pelvic radiotherapy in a randomized trial. PATIENTS AND METHODS: Two hundred sixty patients with stage IIb and IVa cervical cancer received either standard pelvic radiotherapy or primary chemotherapy with cisplatin 60 mg/m2 and epirubicin 110 mg/m2 administered at 3-week intervals for three cycles, followed by pelvic radiotherapy. RESULTS: Ninety-nine patients have relapsed with a median follow-up duration of 1.3 years; in 62 patients, the first site of progressive disease was the pelvis. Patients who received primary chemotherapy had a significantly higher pelvic failure rate than those who received radiotherapy alone (P < .003). Seventy-six patients have died, and those who received primary chemotherapy had significantly inferior survival compared with those who received radiotherapy alone (P = .02). Tumor response following chemotherapy was observed in 63%. After radiotherapy, tumor response occurred in 72% of those who received combined modality treatment, compared with 92% of those who received radiotherapy alone. CONCLUSION: Primary chemotherapy with epirubicin and cisplatin, although resulting in tumor response in a significant proportion of patients, is accompanied by an inferior local control rate and survival compared with standard pelvic radiotherapy alone.

Ondansetron: prevention of nausea & vomiting in cisplatin based chemotherapy.

Ondansetron in the prophylaxis of Cisplatin-induced emesis and nausea. The 5-HT3 antagonist ondansetron clearly offers a new approach to the control of Cisplatin-induced emesis and has been evaluated in Thailand. To evaluate anti-emetic efficacy of ondansetron in the prevention of nausea and vomiting induced by Cisplatin containing cancer chemotherapy regimen, we carried out an open multicentre study from January 1991 to December 1992. In this study, patients receiving Cisplatin based chemotherapy received ondansetron 32 mg as a single intravenous dose over 15 minutes prior to the administration of Cisplatin. This was followed by oral ondansetron 8 mg three times a day, preferably one hour before each meal for 5 days. All patients were chemotherapy naive in-patients and were at least 18 years or older with Karnofsky performance status of at least 60 per cent. The number of emetic episodes, nausea and food intake were recorded during the 24 hours following Cisplatin administration. A total of 103 patients were recruited with 84 (81.6%) evaluable patients (48 men and 36 women) scheduled to receive cisplatin chemotherapy at dose 60 mg/m2 or more (60-100 mg/m2), either as single agent or combination therapy. Complete response (complete control of emesis) was achieved in 60 per cent; major response (1-2 emetic episodes) was 13 per cent; minor response (3-5 emetic episodes) was 13 per cent; and failure (5+ emetic episodes) was 10 per cent. Side effects were very mild and not significant. We conclude that ondansetron is efficacious in protecting patients from Cisplatin induced emesis and nausea.

Primary chemotherapy for locally advanced uterine cervical carcinoma.

From September 1985 to May 1991, thirty consecutive patients with locally advanced cervical carcinoma stage IB-II (FIGO) with high risk factors of local treatment failure were treated with Epirubicin and Cisplatinum combination as primary chemotherapy. Twenty-five patients were evaluated for response, operability and survival. This combination chemotherapy could induce remarkable clinical complete response of 68% (17/25) and partial response of 28% (7/25), but only 18 patients were permitted for surgery, therefore operability rate was 72% (18/25). Pathological examination revealed complete response at 24% (6/25) and partial response was 48% (12/25) due to the presence of residual tumor at the cervix and dissected lymph nodes. The average number of lymph node dissected was II (range 0-26), which have been usually found in stage IIB-III patients. This combination chemotherapy did not allow to complicate surgery in these circumstances. Toxicities were mild except only leukopenia which was moderate to severe degree (WHO, grading). No death related to treatment has been found. The median time of follow up was 19 months (range 4-72), 24 patients still living, 22 without disease and 2 with diseases at the cervix and bone. The result of pilot study has suggested a beneficial role of primary chemotherapy in this type of malignancy. However, these data require further confirmation and longer follow up before a definite conclusion can be made regarding cure rate and prolong disease free-survival in locally-advanced uterine cervical carcinoma.

High-dose mitomycin C: activity in hepatocellular carcinoma.

Hepatocellular carcinoma is the most common cause of cancer death in Thai males. It is usually found to be inoperable, and the reported median survival for Thai patients is only 4.3 months. From October 1984 to December 1986, 30 cases of nonresectable hepatocellular carcinoma were treated at the National Cancer Institute, Bangkok, Thailand, with high-dose mitomycin C. Patients were given 20-25 m/m2 (median, 40 mg) by i.v. injection, followed by 10-12.5 mg/m2 (median, 20 mg) at 6-week intervals in responding patients until the disease progressed or toxicity was detected. In all, 23 patients were evaluable by WHO criteria. A partial response was achieved in 11 of 23 cases (48%); the median duration of this response was 7 months (range, 3-11 months). The median cumulative dose of mitomycin C was 80 mg (range, 40-120 mg). Toxicity was relatively well tolerated; only one patient developed an unusual erythematous, reticular skin rash that spontaneously disappeared within 1 month of injection of the drug. The median survival of responders was 12 months, and the longest survival was 18+ months. We conclude that high-dose mitomycin C given according to the present dose and schedule has antitumor activity in hepatocellular carcinoma in Thai patients. Although its response rate is as high as that produced by doxorubicin, with less toxicity, no complete response was achieved in this study.