Michael A. Friedman

Retinoids in cancer therapy.

PURPOSE Recent reports of the dramatic antitumor effect of all-trans retinoic acid (RA) in patients with acute promyelocytic leukemia (APL) have generated renewed enthusiasm for clinical studies of retinoids for oncologic therapeutic indications. Here we provide an overview of relevant aspects of retinoid physiology and molecular biology, review preclinical studies indicating antitumor activity for retinoids, and summarize the current status of clinical investigations of retinoid use for the treatment of adult and pediatric tumors. DESIGN The published literature was reviewed with attention to areas of retinoid research that would shed insight into the oncologic uses of retinoids. RESULTS Retinoids play critical roles during normal fetal development and induce differentiation (and/or growth inhibition) in a variety of tumor-cell lines. Retinoid effects seem to result from changes in gene expression mediated via specific nuclear receptors (termed retinoic acid receptors, RAR-alpha, -beta, and -gamma), and a specific chromosomal translocation involving the RAR-alpha gene occurs in APL patients. In addition to the very high clinical response rate for RA in patients with APL, significant clinical responses have been observed for patients with cutaneous T-cell malignancies, juvenile chronic myelogenous leukemia, and dermatologic malignancies. Additionally, the combination of 13-cis-retinoic acid (cRA) with interferon alpha (IFN alpha) has produced high objective response rates for patients with squamous cell carcinomas of the head and neck and of the cervix. CONCLUSIONS The antitumor activity demonstrated for retinoids (especially RA) alone and in combination with other agents supports the need for targeted phase II trials to define the spectrum of responsive tumors and for laboratory studies to further delineate the biologic mechanisms associated with therapeutic responses. High priority should then be given to phase III trials to delineate optimal strategies for improving outcome by combining retinoid-based treatments with conventional chemotherapy and radiotherapy regimens.

A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California Oncology Group trial.

In 1983, the Northern California Oncology Group (NCOG) instituted a randomized trial of intravenous (IV) versus intraarterial (IA) floxuridine (FUDR) administered via an implantable pump for patients with colorectal cancer metastatic to the liver. The study objectives were to compare the hepatic response rate, time to hepatic progression, and toxicity for the two treatment arms. The study design, which allowed patients failing IV FUDR to crossover to the IA arm, prevents a meaningful comparative analysis of survival. Patients with liver-only metastases (N = 143) were randomized, 76 to the IV arm and 67 to the IA arm, and 115 patients (65 IV, 50 IA) were fully evaluable. Of the 65 patients in the IV arm, 28 crossed over to IA treatment after failing IV FUDR. The dose-limiting toxicity of IV FUDR was diarrhea, whereas biliary toxicity limited both the dose and duration of IA FUDR therapy. Of the first 25 patients treated with IA FUDR at a dose of .3 mg/kg/day, 10 developed radiographically evident biliary strictures, and three developed permanent jaundice. With reduction of the initial IA FUDR dose to .2 mg/kg/day, and adoption of a policy of early dosage reduction, treatment interruption, or termination of therapy for persistent elevations in alkaline phosphatase, only two further cases of serious biliary toxicity occurred. However, 26 of the 50 IA FUDR patients ultimately had therapy terminated because of drug toxicity rather than disease progression. When compared with systemic infusion, infusion into the hepatic artery greatly enhanced the antitumor activity of FUDR against colorectal liver metastases. Although biliary toxicity is the most serious limitation of this form of therapy, biliary stricture and jaundice usually can be averted through careful monitoring of liver enzymes and early dosage reduction.

A reevaluation of nonhormonal cytotoxic chemotherapy in the treatment of prostatic carcinoma.

The palliative role of nonhormonal cytotoxic chemotherapy in the treatment of endocrine-resistant prostatic carcinoma has not been established. Conventional means of quantifying tumor response are most frequently not applicable in this disease because of the lack of measurable objective parameters to allow for a reliable estimation of antitumor effects. While this problem is not unique to prostatic carcinoma, this review illustrates its magnitude in this disease. Only approximately 5% of patients studied fulfill the various criteria for complete response (CR), partial response (PR), or both, while the vast majority of patients reported as responders are actually in the stable disease category. Stable disease is highly questionable as an indicator of antitumor response and should not be used as a criterion for response in conventional phase II studies unless it is convincingly demonstrated that it occurs as a result of treatment. A study design that may allow a more reliable assessment of the value of the stable disease category is described in the text. More effective means for assessing tumor responses and better instruments to measure aspects of quality of life are needed. Review of several prospective randomized clinical trials showed that no treatment program tested during the last decade resulted in a survival advantage when compared with a concurrently treated control group. Furthermore, in two such trials, four different single chemotherapeutic agents widely used in the treatment of this disease (cyclophosphamide, 5-fluorouracil, estramustine phosphate, and streptozocin) either alone or in combination, did not produce any prolongation of survival when compared to a no chemotherapy (standard treatment) control arm. Survival curves for endocrine-resistant patients fall within a relatively narrow and possibly predictable range that may be used as an additional endpoint in conjunction with response (CRs and PRs only) in phase II trials. More definitive evidence of therapeutic efficacy in this disease should derive from phase III trials using survival as one of the major endpoints. Because of the poor results observed with chemotherapy thus far, we suggest that the appropriate control arm for phase III testing in endocrine-resistant patients continues to be a no chemotherapy control arm consisting of a best symptomatic care or a uniformly applied second-line endocrine manipulation.

Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: update of a Northern California Oncology Group randomized trial.

Between 1978 and 1984, the Northern California Oncology Group (NCOG) conducted a randomized trial to study the efficacy of combined radiotherapy (RT) and chemotherapy (CT) for stage III or IV inoperable head and neck cancer. One hundred four patients were randomized to receive: (1) RT alone, or (2) RT plus CT. RT consisted of 7,000 cGy to the involved areas and 5,000 cGy to uninvolved neck at 180 cGy/fraction, five fractions/wk. CT consisted of bleomycin, 5 U intravenously (IV), twice weekly during RT, followed by bleomycin, 15 U IV, and methotrexate, 25 mg/m2 IV weekly for 16 weeks after completion of RT. Fifty-one patients in the RT alone group and 45 in the combined treatment group were evaluable. The local-regional complete response (CR) rate was 45% v 67% (P = .056); the 2-year local-regional control rate, including salvage surgery, was 26% v 64% (P = .001); and the incidence of distant metastasis was 24% v 38% (P greater than .25), for the RT alone and RT plus CT groups, respectively. The relapse-free survival curves were significantly different (P = .041), favoring the combined treatment. However, the survival curves were not significantly different (P = .16). Patient compliance to maintenance CT was poor. Bleomycin significantly increased the acute radiation mucositis, although the difference in late normal tissue toxicity was not statistically significant. Thus, bleomycin and concurrent RT produced a more favorable CR rate, local-regional control rate, and relapse-free survival, but the difference in survival was not statistically significant.

A critical appraisal of low-dose cytosine arabinoside in patients with acute non-lymphocytic leukemia and myelodysplastic syndromes.

We reviewed 53 publications reporting 751 patients with hematologic malignancies treated with low doses (5 to 20 mg/m2/d) of cytosine arabinoside (LoDAC). Of 507 patients evaluable for response, complete remission (CR) rates varied from 32% for patients with primary acute non-lymphoblastic leukemia (1 degree ANLL) to 16% for patients with hematologic malignancies secondary to previous chemotherapy or following a myelodysplastic syndrome (MDS) (2 degrees ANLL), and 16% for MDS. Median duration of CR was 9.5 months for 1 degree ANLL, and 10.5 months for both 2 degrees ANLL and MDS. Based on limited available survival data, overall median survival for these groups was 9 months, 3 months, and 15 months, respectively. Only three CRs were reported of 31 evaluable patients treated for a variety of other hematologic malignancies. CR rates for patients with 1 degree ANLL greater than or equal to 50 years old was 56%, compared with 29% less than 50 years old (P = .10). While prior chemotherapy was more common in 1 degree ANLL patients less than 50 years of age (86% v 21%; P less than .001), it did not influence response rates in those greater than 50 years of age, suggesting other biases. Hematologic toxicity was mentioned in only 33 of 53 publications, affecting 254 of 289 patients (88%), with at least 15% treatment-related deaths. LoDAC hypothetically acts as a differentiating agent; however, correlative laboratory studies were rarely performed. Cytogenetic data were available for only 15%, and in vitro studies for 10% of all patients with marked discrepancies in the interpretation of results. LoDAC is clearly cytotoxic for both malignant and normal hematopoietic cells. While large numbers of patients have been reported, the lack of well-designed clinical trials prohibits definitive conclusions as to its role as a differentiating agent. Future LoDAC studies should determine optimal dose and schedule, with clinical laboratory correlates to assess differentiation. Trials in ANLL comparing LoDAC with conventional chemotherapy, and in MDS with supportive care alone, may help identify the role of LoDAC. Until appropriate indications can be identified, LoDAC should not be routinely used in clinical practice.

Clinical trials in primary hepatocellular carcinoma: current status and future directions

Hepatoma, or primary hepatocellular carcinoma (HCC), occurs infrequently in the United States, with fewer than 10,000 new patients annually accounting for less than 2% of all malignancies (150). The age-standardized annual incidence in males is 2.9 per 100,000 of the population, while that of females is 1.2 per 100,000. A similarly low incidence is found in Northern Europe, the United Kingdom, and South America. In areas ofAfrica and the Orient, however, it is the most common malignant tumor. Singapore men of Chinese descent have an annual age adjusted incidence of 34.2 per 100,000, while in Bulawayo, Zimbabwe, men have a rate of almost 65 per 100,000 (51). Kew reviewed the spectrum of disease occurrence in southern Africa and noted that Shengaan males in Mozambique had a particularly high rate of this tumor, representing more than 50% of all male cancers (87). Worldwide, the disease occurs predominantly in men in their fourth to seventh decade (51), with a median survival after diagnosis of less than four months. HCC is an important health problem throughout the world being responsible for between 250,000 and 1,250,OOO deaths a year. A detailed discussion of the etiology of HCC is beyond the scope of this review. However, there is an association of chronic hepatic injury with the development of HCC. In North and South America, the two coexist in from 22% to over 60% of HCC patients (35, 46, 77, 97, 103, 112), despite the fact that only a minority of patients have a clinical history of antecedent acute hepatitis or jaundice (35, 97). In Asia and Africa, the rate of cirrhosis is even higher, being pathologically documented in from 60% to almost 90% of patients (7, 11, 14, 66, 68, 88, 91, 95, 98, 102, 116, 126, 154). These patients also had subclinical liver disease (98, 102, 116, 126). The hepatitis B virus has been closely linked with the development ofHCC. The cirrhosis seen in HCC patients appears to be overwhelmingly the macronodular or postnecrotic type (7, 11,66,68,91,95, 103, 154), which is the chronic sequela of hepatitis B infection. In addition, HBsAg, an indicator of persistent viral infection, is found in sera from 3290% of HCC patients from widely disparate geographical locations (11, 14, 35, 68, 81, 91, 95, 97, 98, 102, 116, 126), a rate far in excess of the carrier rate of the asymptomatic

5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (dtic, Dic, nsc- -45388)-a new antitumor agent with activity against malignant melanoma.

Abstract 5 -( 3,3 -dimethyl- 1 -triazeno)-imidazole- 4 -carboxamide (DTIC, DIC, NSC- 45388 ) is a new synthetic chemical antitumor agent developed by the Chemotherapy Program of the National Cancer Institute. It was chosen for clinical trial because of activity against mouse leukemia L 1210 . Its mechanism of action is not definitely established but it has been postulated to be both a deranger of de novo purine synthesis and an alkylating agent. Clinical trials have shown the drug to be significantly active against malignant melanoma with an overall response rate of 20·6% ( 88 426 ). This response rate is remarkable for its consistency among various clinical trials. Marginal antitumor activity has been seen against other solid tumors and slightly better activity against sarcomatous disease. Toxicity is mainly to bone marrow and gastrointestinal tract and is reversible in almost all cases.

Hepatomas: Hormone receptors and therapy

Prompted by studies that suggested a causal relationship between sex steroids and human liver cancer, we assayed specimens of hepatoma from five patients and adjacent liver tissue from three of the same patients for estrogen receptors. After finding that the assay material contained specific cytosolic receptor proteins for estradiol, we treated a second group of five patients who had hepatomas with progestin. This therapy resulted in tumor regression in two of these patients.

Determination of liver, kidney, and spleen volumes by computed tomography: an experimental study in dogs.

Abstract: The volume of the dogs liver, kidneys, and spleen were measured by computed tomography (CT) and a water displacement method. Organ volume determination by CT is a rapid, simple procedure that is accurate to ±5% of the organ volume measured by water displacement. Individual measurements were reproducible to within ±3%. Determination of organ volume has potential importance in a variety of clinical situations.

The National Cancer Institute Audit of the National Surgical Adjuvant Breast and Bowel Project Protocol B-06

BACKGROUND The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-06, a clinical trial sponsored by the National Cancer Institute (NCI), has provided evidence of the value of lumpectomy and breast irradiation for treating women with breast cancer in an early stage. Publicity generated by the discovery that the study included fraudulent data on patients enrolled by St. Luc Hospital in Montreal aroused concern about the overall accuracy of the data and conclusions. To address this concern, the NCI conducted an audit of other participating institutions. METHODS In 1994, data on 1554 of the 1809 randomized patients (85.9 percent) enrolled by centers other than St. Luc Hospital were audited at 37 clinical sites in North America. The audit included data on eligibility, survival, disease-free survival, the length of time to a recurrence of cancer in the ipsilateral breast, and documentation of signed informed consent. RESULTS End points were assessed for all 1554 patients, and eligibility was assessed for 1507 patients; 47 patients were excluded because their forms were not complete or not returned. A total of 1429 patients had their eligibility status verified. Of a total of 7770 data points examined with respect to the number of positive nodes at base line, treatment characteristics, first events (excluding death), recurrence of cancer in the ipsilateral breast, and survival, 7577 (97.5 percent) were verified, 123 (1.6 percent) could not be verified, and 70 (0.9 percent) were discrepant with the NSABP file. Of the 1554 patients, 1340 (86.2 percent) had all audited items (including eligibility) verified, 69 (4.4 percent) had at least one discrepant item, and 113 (7.3 percent) had at least one unverified item (as a result of missing or incomplete data); 32 (2.1 percent) were not assessed for eligibility but had no other discrepant or unverifiable items. Written informed consent was documented for 1098 patients before surgery and 210 after surgery; no date appeared on the signed form for 137. The informed-consent status was not verified for 71 patients and could not be determined for 38. The rates of verification of end-point data and documentation of written informed consent were similar among the total-mastectomy group, the lumpectomy group, and the group treated by lumpectomy and breast irradiation. CONCLUSIONS The audit confirms the adequacy of the data on which the reanalysis of Protocol B-06 and the results after 12 years of follow-up are based.