Vainutis K. Vaitkevicius

Combined Chemotherapy and Radiotherapy Compared with Radiotherapy Alone in Patients with Cancer of the Esophagus

BACKGROUND The efficacy of conventional treatment with surgery and radiation for cancer of the esophagus is limited. The median survival is less than 10 months, and less than 10 percent of patients survive for 5 years. Recent studies have suggested that combined chemotherapy and radiation therapy may result in improved survival. METHODS This phase III prospective, randomized, and stratified trial was undertaken to evaluate the efficacy of four courses of combined fluorouracil (1000 mg per square meter of body-surface area daily for four days) and cisplatin (75 mg per square meter on the first day) plus 5000 cGy of radiation therapy, as compared with 6400 cGy of radiation therapy alone, in patients with squamous-cell carcinoma or adenocarcinoma of the thoracic esophagus. The trial was stopped after the accumulated results in 121 patients demonstrated a significant advantage for survival in the patients who received chemotherapy and radiation therapy. RESULTS The median survival was 8.9 months in the radiation-treated patients, as compared with 12.5 months in the patients treated with chemotherapy and radiation therapy. In the former group, the survival rates at 12 and 24 months were 33 percent and 10 percent, respectively, whereas they were 50 percent and 38 percent in the patients receiving combined therapy (P less than 0.001). Seven patients in the radiotherapy group and 25 in the combined-therapy group were alive at the time of the analysis. The patients who received combined treatment had fewer local (P less than 0.02) and fewer distant (P less than 0.01) recurrences. Severe and life-threatening side effects occurred in 44 percent and 20 percent, respectively, of the patients who received combined therapy, as compared with 25 percent and 3 percent of those treated with radiation alone. CONCLUSIONS Concurrent therapy with cisplatin and fluorouracil and radiation is superior to radiation therapy alone in patients with localized carcinoma of the esophagus, as measured by control of local tumors, distant metastases, and survival, but at the cost of increased side effects.

Comparison of continuously infused 5-fluorouracil with bolus injection in treatment of patients with colorectal adenocarcinoma.

In a randomized series of 70 patients with with colo rectal adenocarcinoma, a comparison of systemic 5‐fluorouracil chemotherapy administered as a continuous 120‐hours infusion vs. intravenous bolus injection daily for 5 days demonstrated superiority of prolonged intravenous infusion. The most striking advantage of prolonged infusion of 5‐FU was the absence of myelotoxicity. Fifteen of the 34 patients treated with infusion and 8 of the 36 patients treated by bolus injection developed objective tumor responses. The difference in response rate at least in part is explainable by unequal distribution of patients with different characteristics between the two treatment groups.

Malignant melanoma and central nervous system metastases. Incidence, diagnosis, treatment and survival

One hundred and twenty‐two patients with clinically advanced, histologically confirmed, cutaneous malignant melanoma, seen at Wayne State University over a 12 year period were reviewed. The incidence of central nervous system metastases (CNS) diagnosed clinically was 46% and at autopsy 75%. Meningeal involvement was suspected clinically in 10.6% and found at autopsy in 52%. Motor dysfunction, mental confusion, cranial nerve disturbance, as well as headache, were the most common manifestations. EEG was found to be extremely sensitive in predicting and confirming CNS metastases even before clinical manifestation. Accuracy increased by performing an EEG serially or combining it with a brain scan. Best therapeutic results were noted after surgery for solitary CNS metastases. Palliative radiotherapy was effective in 37% of patients. Mean survival after neurological diagnosis was 4.0 months, but it varied depending on the site of the initial primary and the presence or absence of other visceral involvement. Concomitant liver metastases carried the worst prognosis. Patients with head, neck or trunk primaries who develop lung or liver metastases should be examined carefully and tested periodically with EEG. Persistent EEG abnormalities should strengthen the clinical suspicion of an underlying CNS metastases and may be an indication for further studies and possible therapy.

Combined therapy for cancer of the anal canal

Nineteen patients with squamous-cell cancer of the anal canal have been treated with combined chemotherapy and radiation therapy, followed by appropriate surgery. The authors are convinced that the combined therapy is effective enough to avoid abdominoperineal resection if disappearance of the lesion is proven by adequate examination and biopsy. Although they believe cancers 5 cm or less in maximum diameter are generally adequately managed in this manner, experience is still too limited to justify, a recommendation, to change currently accepted management.

Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy

An analysis of preoperative multimodality adjuvant therapy with 5-fluorouracil, mitomycin-C, and radiation therapy revealed that 38 of 45 patients (84 percent) treated were rendered free of cancer after chemotherapy/radiation therapy. No recurrence of tumor has been noted in those patients rendered free of disease by the preoperative treatment. Seven patients (15 percent) with residual macroscopic or microscopic cancer after preoperative therapy have had recurrence, all in distant sites. These seven patients have died from the disease. The prognosis for patients in this series depended on the success of the preoperative therapy in eradicating all tumor prior to surgery. Mitomycin-C and 5-fluorouracil are cytotoxic for local disease and for microscopic distant disease as well. Abdomino-perineal resection is unnecessary for patients whose primary tumor is eradicated by the preoperative therapy. The role of the relatively low dose of radiation therapy needs to be further defined.

Phase II study of gemcitabine and cisplatin in the treatment of patients with advanced pancreatic carcinoma

Pancreatic carcinoma is considered among the most chemoresistant of human malignancies. The most commonly used cytotoxic single agents, 5‐fluorouracil and 2′‐deoxy‐2′,2′‐difluorocytidine (gemcitabine), have objective response rates of less than 10% in large studies. Hypothesizing noncross resistance and a synergistic interaction between gemcitabine and cisplatin, early clinical studies have demonstrated significant activity with this combination in patients with several types of malignant disease. A Phase II study was undertaken to determine the efficacy of gemcitabine in combination with cisplatin in patients with locally advanced and metastatic pancreatic carcinoma based on these considerations.

The practicality of chronic hepatic artery infusion therapy of primary and metastatic hepatic malignancies: Ten‐year results of 124 patients in a prospective protocol

Ten‐year results are presented of 124 patients with malignancy apparently limited to the distribution of the hepatic artery, treated by prospective protocol with continuous infusion of 5‐FUdR through an hepatic artery catheter. Nearly all patients had moderate to massive hepatic replacement. Of 88 patients with colorectal carcinoma, 64 (73%) had clinically significant objective and subjective remission. Median survival for responders was 13 months; for the entire group, ten months. Of 13 patients with hepatoma, nine had clinically significant regression with a median survival of 11 months. Ten patients had carcinoma of the gall bladder or bile duct with seven obtaining clinically significant regression. Complications encountered are discussed and are similar to other series. Of the patients experiencing clinically significant remission, all but one reached the complete independence performance status, and 84% reached normal activity levels. Thus, for hepatic localized tumor, this therapy is worthwhile and practical.

Factors that affect response to chemotherapy and survival of patients with advanced head and neck cancer

A review of 164 patients with far advanced head and neck cancer, treated by a cytotoxic chemotherapy over a ten year period, at Wayne State University, Detroit, Michigan, was done in an attempt to determine factors that may influence the response to chemotherapy and subsequent survival. Response rate to methotrexate was 28%, 5‐FU 31%, and porfiromycin 13%. Improved responses were noted with combination chemotherapy. Patients who failed to first line therapy rarely responded to other single agent or combination chemotherapy. Those who did not have prior surgery and/or radiotherapy had better results from drug therapy. Patients with good performance status at the time of initial chemotherapy, had better response to treatment (32% vs. 13% PR & CR) and longer survival (28 weeks vs. 9 weeks, p = 0.01) when compared to those with poor status. Patients who responded to chemotherapy have better survival compared to nonresponders (29 weeks vs. 16 weeks, p = 0.002). This information may prove helpful in future planning of multidisciplinary approach in the treatment of patients with head and neck cancer.

HER-2/neu expression in pancreatic adenocarcinoma: Relation to tumor differentiation and survival

HER-2/neu expression in pancreatic adenocarcinoma has been inconsistently reported and has not been fully evaluated with respect to histologic grade and tumor grade heterogeneity. We studied HER-2/neu expression in a series of 79 primary pancreatic carcinomas using immunohistochemical methods, with expression scored for each histologic grade represented in each tumor. We found significantly lower expression of HER-2/neu in poorly differentiated (PD) portions of tumors—those areas lacking glandular differentiation—compared to well-differentiated (WD) and moderately differentiated (MD) portions of tumors. Forty-two of 68 (62%) invasive tumors with WD or MD glands showed moderate or strong expression of HER-2/neu in WD/MD areas; only 6 of 32 (19%) invasive tumors with PD areas showed similar expression in PD. In mutually exclusive patient sets, we also found a statistically different prevalence of HER-2/neu expression in patients with PD (6/32 cases; 19%) and without PD (29/47 cases; 62%) tumors (p < 0.001). Twenty-three cases had directly comparable areas of PD versus MD or WD. In 19 of 23 cases HER-2/neu expression was graded comparatively lower (or negative) in areas of PD than in MD or WD. Overall 46 of 79 cases (58%) showed moderate to strong HER-2/neu expression inclusive of all histologic grades, and 63 of 79 (80%) cases were HER-2/neu positive, if including weak or focal staining. There was no significant difference in the survival of patients with HER-2/neu-positive versus-negative tumors or in patients with versus without PD tumors. We have confirmed that although HER-2/neu gene expression is common to many pancreatic carcinomas, it is not common to tumors lacking glandular differentiation. HER-2/neu gene expression could not be related to survival differences—perhaps due to overall poor survival within adenocarcinomas of the pancreas—but the pattern of HER-2/neu expression suggests a relationship to glandular differentiation and early oncogenesis.

Primary liver cancer. A review of the clinical features, blood groups, serum enzymes, therapy, and survival of 65 cases

A review of 65 patients with primary liver cancer was made. Of these, 53 had hepatocarcinoma. Primary cancer of the liver was most frequently found in patients aged 50 to 80 years, and was observed in three times as many males as females. There was an increased incidence of hepatocarcinoma in Negroes, especially those with blood group B. The most common symptoms with primary liver cancer were upper abdominal pain, weakness, and weight loss, while the most commonly found signs were hepatomegaly or an abdominal mass. Jaundice and ascites were also commonly found. Serum alkaline phosphatase, SGOT, SGPT, and LDH were elevated in most of these patients. In patients with hepatocarcinoma, 66% had histologically confirmed liver cirrhosis at autopsy. Serial alphafetoprotein tests were performed on 19 patients with hepatoma, in 14 of whom (73.6%) AFP was detectable. No Australia antigen was detected in 12 patients with hepatoma. In this study, 9 out of 16 patients (56%) had subjective and objective tumor responses with continuous 5‐FUdR hepatic artery infusion. None of 18 patients treated with systemic cytotoxic agents responded. The difference in response between hepatic artery infusion and systemic therapy is statistically significant (P < .0002). There was a statistically significant lengthening in survival of patients who responded to intra‐hepatic artery infusion as compared to non‐responders and patients who received systemic chemotherapy. In reviewing the autopsy findings on 30 patients with hepatocarcinoma and 9 with cholangiocarcinoma, there were differences in the incidence of metastases to the lungs or bones between these two types of primary liver cancer.