Otilia Dalesio

Effects of Concomitant Cisplatin and Radiotherapy on Inoperable Non-Small-Cell Lung Cancer

BACKGROUND AND METHODS Cisplatin (cis-diamminedichloroplatinum) has been reported to enhance the cell-killing effect of radiation, an effect whose intensity varies with the schedule of administration. We randomly assigned 331 patients with nonmetastatic inoperable non-small-cell lung cancer to one of three treatments: radiotherapy for two weeks (3 Gy given 10 times, in five fractions a week), followed by a three-week rest period and then radiotherapy for two more weeks (2.5 Gy given 10 times, five fractions a week); radiotherapy on the same schedule, combined with 30 mg of cisplatin per square meter of body-surface area, given on the first day of each treatment week; or radiotherapy on the same schedule, combined with 6 mg of cisplatin per square meter, given daily before radiotherapy. RESULTS Survival was significantly improved in the radiotherapy-daily-cisplatin group as compared with the radiotherapy group (P = 0.009): survival in the radiotherapy-daily-cisplatin group was 54 percent at one year, 26 percent at two years, and 16 percent at three years, as compared with 46 percent, 13 percent, and 2 percent, respectively, in the radiotherapy group. Survival in the radiotherapy-weekly-cisplatin group was intermediate (44 percent, 19 percent, and 13 percent) and not significantly different from survival in either of the other two groups. The survival benefit of daily combined treatment was due to improved control of local disease (P = 0.003). Survival without local recurrence was 59 percent at one year and 31 percent at two years in the radiotherapy-daily-cisplatin group; 42 percent and 30 percent, respectively, in the radiotherapy-weekly-cisplatin group; and 41 percent and 19 percent, respectively, in the radiotherapy group. Cisplatin induced nausea and vomiting in 86 percent of the patients given it weekly and in 78 percent of those given it daily; these effects were severe in 26 percent and 28 percent, respectively. CONCLUSIONS Cisplatin, given daily in combination with the radiotherapy described here to patients with nonmetastatic but inoperable non-small-cell lung cancer, improved rates of survival and control of local disease at the price of substantial side effects.

K-ras Oncogene Activation as a Prognostic Marker in Adenocarcinoma of the Lung

BACKGROUND The capability of activated oncogenes to induce malignant transformation of immortalized cells in vitro has suggested that they have a similar role in the pathogenesis of human tumors. We previously found that activation of the K-ras oncogene by a point mutation in codon 12 occurs in about one third of human lung adenocarcinomas. METHODS We studied the clinical importance of this oncogene-activation in 69 patients with lung adenocarcinoma in whom complete resection of the tumor was possible. The polymerase chain reaction was used to amplify ras-specific sequences of DNA isolated from frozen or paraffin-embedded tumor samples. Ras point mutations were subsequently detected and classified with the use of mutation-specific oligonucleotide probes. RESULTS Nineteen of the tumors harbored a point mutation in codon 12 of the K-ras oncogene. There was no association between the K-ras point mutation and the age at diagnosis, sex, or presence of previous or concurrent neoplasms. Tumors positive for K-ras point mutations tended to be smaller and less differentiated than those without mutations. The K-ras codon-12 point mutation was a strong (and unfavorable) prognostic factor: 12 of the 19 patients with K-ras point-mutation-positive tumors died during the follow-up period, as compared with 16 of the 50 patients with no mutation in the K-ras oncogene (P = 0.002). This difference in prognosis was also reflected in the duration of disease-free survival (P = 0.038) and in the number of deaths due to cancer (P less than 0.001). CONCLUSIONS The presence of K-ras point mutations defines a subgroup of patients with lung adenocarcinoma in whom the prognosis is very poor and disease-free survival is not usually long despite radical resection and a small tumor load.

Thymomas: A review of 169 cases, with particular reference to results of surgical treatment

One hundred sixty‐five patients with surgically treated thymoma were followed over 28 years; 73% had myasthenia gravis at presentation. Invasiveness was based on macroscopic findings at operation. Post‐surgical radiotherapy or chemotherapy were not routinely used. Overall survival was 84%, 79%, and 65% at 3, 5, and 10 years, respectively. Patients with invasive thymoma survived for a shorter period than patients with noninvasive tumors (67% versus 85% at 5 years); when radical excision was possible, no difference was detectable between the two groups. Patients with subtotally resected or only biopsied invasive thymomas survived 59% and 42% at 5 years, respectively. Lymphoepithelial cases had the worst prognosis of the histologic types considered. Myasthenia gravis did not adversely affect survival. Surgery is the basic treatment of thymomas. Macroscopic invasiveness and degree of excision judged by the surgeon have prognostic value and are reliable criteria of malignancy. Radiotherapy and chemotherapy may be effective, but their use should be limited to controlled trials. Cancer 58:765‐776, 1986.

Prognostic factors in superficial bladder tumors. A study of the European organization for research on treatment of cancer: Genitourinary tract cancer cooperative group

A randomized clinical trial was performed on 308 patients with stage T1 carcinoma of the bladder to compare the efficacy of transurethral resection alone or followed by bladder instillations of thiotepa or VM-26 (teniposide) for 1 year. With the recurrence rate as the primary end point of interest the data from this trial were used to assess the prognostic importance of the following factors at entry into the study: number of tumors, prior recurrence rate, tumor size, grade, age, treatment group assigned and, finally, the interval between transurethral resection at entry into the study and the start of intravesical treatment. Using multivariate statistical techniques we found that the number of tumors at presentation was the most important prognostic factor followed by, in order of importance, the recurrence rate at entry and the size of the largest tumor. Of particular note was the discovery that patients with less than 1 recurrence per year at entry had a prognosis similar to patients with primary tumors, while those with a higher recurrence rate did uniformly poorly. These results show that patients with stage T1 carcinoma of the bladder form a heterogeneous group and that more aggressive therapy should be considered for patients with a poor prognosis.

Interim analysis of a phase III study on preoperative radiation therapy in resectable rectal carcinoma. Trial of the gastrointestinal tract cancer cooperative group of the European organization for research on treatment of cancer (EORTC)

To improve surgical results of potentially operable rectal cancer (T2, T3, T4, Mo), the European Organization for Research on Treatment of Cancer (EORTC) conducted a two‐arm randomized clinical trial to evaluate the effect of administering radiotherapy before radical surgery. Four hundred ten patients were allocated to be treated either by surgery alone or by 34.5 Gy of radiotherapy (in 19 days overall) followed by surgery. The tolerance of the adjuvant radiation therapy was fairly good. The 5‐year survival rate was 65% overall and showed no difference between both therapeutic regimens. Similarly, the metastases‐free rate was the same in both groups. In contrast, the preoperative radiation therapy showed a marked effect on local control of the disease, the comparison of the time to local recurrence being highly significant between the two treatment groups (P = 0.001). The proportion of patients free of local recurrence at 5 years was 85% in the combined treatment versus 65% in the group of patients treated by surgery alone.

Adjuvant Chemotherapy of Superficial Transitional Cell Bladder Carcinoma:Preliminary Results of a European Organization for Research onTreatment of Cancer Randomized Trial Comparing Doxorubicin Hydrochloride, Ethoglucid and Transurethral Resection Alone

Patients with superficial transitional cell carcinoma of the bladder were entered in a randomized clinical trial to compare the efficacies of transurethral resection alone or followed by bladder instillation of doxorubicin hydrochloride or ethoglucid (Epodyl) for 1 year. Results showed that adjuvant chemotherapy with the selected drugs prolonged the mean interval between recurrences. Mild systemic toxicity and chemical cystitis were observed in 3 and 3 per cent, respectively, of the patients given ethoglucid, and in 5 and 4 per cent, respectively, of those taking doxorubicin.

Differential expression of DNA topoisomerases in non-small cell lung cancer and normal lung

UNLABELLED DNA topoisomerases are ubiquitous nuclear enzymes, and important targets of cancer chemotherapy. Expression of topoisomerase genes is often correlated with in vitro chemosensitivity. We investigated the expression of the topoisomerase genes in normal lung and non-small cell lung cancer. Expression of topoisomerase II-alpha, topoisomerase II-beta, and topoisomerase I genes has been assessed in tumor samples of 60 patients who underwent operation for a non-small cell lung carcinoma, by RNase protection assay, and by immunohistochemistry. The expression of topoisomerase II-alpha gene was either undetectable or very low in normal lung, while most NSCLC expressed readily quantifiable levels of this gene. No alteration of the topoisomerase II-alpha gene was found by Southern blotting in the NSCLC samples. In contrast to topoisomerase II-alpha, topoisomerase II-beta was expressed in most normal as well as in tumor tissue samples, at a similar level. The levels of expression of both topoisomerase II isoforms was lower than that of human lung cancer cell lines. The results of the topoisomerase II mRNA expression were confirmed by immunohistochemistry. Whereas topoisomerase II-alpha staining was mainly limited to the nucleus, staining with topoisomerase II-beta antibody was exclusively observed in nucleoli. Topoisomerase I was localized in the nuclei and expression was mainly limited to tumor cells. By RNase protection, topoisomerase I expression in NSCLC samples was in the range of that of human lung cancer cell lines. The expression of the topoisomerase genes did not seem to be coordinated. In tumor cells, there was a positive association between expression of topoisomerase II-alpha and Ki-67, a marker of cell proliferation, as assessed by immunohistochemistry, but not with topoisomerase II-beta or topoisomerase I. Clinical characteristics of the patients, and their survival did not appear to be correlated to the level of expression of any of the topoisomerase genes, although a trend towards a shorter survival was observed in patients whose tumors expressed relatively high topoisomerase II-alpha mRNA levels. IN CONCLUSION (1) the two isoforms of topoisomerase II are differentially expressed in normal lung and NSCLC cells; (2) higher topoisomerase II-alpha expression is associated with higher cell proliferation in NSCLC; (3) the expression of topoisomerase II-alpha and topoisomerase I, but not of topoisomerase II-beta, was higher in tumor cells compared to normal lung. Given the differential expression of topoisomerases in normal lung and tumors, research of more potent and specific topoisomerase inhibitors might prove beneficial in non-small cell lung cancer. Immunohistochemistry may be indicated in prospectively investigating the correlation between expression of topoisomerases and results of chemotherapy treatment.

Cis-platinum as second-line chemotherapy in advanced gastric adenocarcinoma. A phase II study of the EORTC gastrointestinal tract cancer cooperative group☆

Thirty-four patients with measurable metastatic gastric adenocarcinoma refractory to prior chemotherapy were treated with cis-platinum 100 mg/m2 in a 6-hr infusion at 3-week intervals. Thirty-one patients were evaluable for response. There were three complete and three partial responses. Median duration of response was 4 months. Toxicity consisted mainly of nausea and vomiting and was severe in 12 patients. One patient had a severe but reversible renal failure. These results confirm other data reported in the literature. Cis-platinum has activity in gastric adenocarcinoma and should now be further investigated in first-line chemotherapy.

Palliative therapy of inoperable oesophageal carcinoma with radiotherapy and methotrexate: Final results of a controlled clinical trial☆

Between May 1976 and January 1982, 170 patients were entered in a randomized study comparing a combined treatment consisting of methotrexate followed by irradiation versus radiotherapy alone in patients with non metastatic inoperable oesophageal cancer. Methotrexate was administered subcutaneously in 4 days to a total dose of 24 mg/m2. Radiotherapy was performed, in both groups, at a dose of 56.25 Gy in 25 fractions (5 weeks). The administration of methotrexate did not lead to an increased intolerance to radiotherapy but severe hematological toxicities were observed in 7.8% of the cases. No difference in the duration of survival was detected. Initial performance status of the patients and their weight loss prior to entry on trial were the factors that were most predictive of the patients prognosis.

Phase II study of epirubicin in advanced adenocarcinoma of the pancreas

The EORTC Gastrointestinal Group has conducted a phase II trial in 41 patients with locally advanced or metastatic adenocarcinoma of the pancreas with epirubicin 90 mg/m2 intravenously every 4 weeks, with dose escalation if possible. Seven patients were not evaluable for response. In 34 evaluable patients there were two complete and six partial responses (response rate 24%). Nine patients had stable disease for at least 2 months, including one patient with a minor response. Median time to progression for responders was 7 months, for all patients 3 months. Median survival for responders was 9 months, for all patients 5 months. It is concluded that epirubicin is an active drug in pancreatic cancer.