Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma.

This paper is a report of response rate (RR) and survival of 34 metastatic melanoma patients who received a dinitrophenyl (DNP)-modified autologous melanoma cell vaccine. In all, 27 patients started the vaccine as a primary treatment for metastatic melanoma and seven started it as an adjuvant, with no evidence of disease at the time, but had developed new metastases. Interleukin-2 (IL-2) was administered in 24 out of the 34 patients: 19 who progressed on vaccine alone and five who had the combination from start. Interleukin-2 was administered in the intravenous, bolus high-dose regimen (seven patients) or as subcutaneous (s.c.) low-dose treatment (17). Overall response for the entire group was 35% (12 patients out of 34), 12% having a complete response (CR) and 23% a partial response (PR). However, only two patients had tumour responses while on the vaccine alone, whereas the other 10 demonstrated objective tumour regression following the combination with IL-2 (two CR, eight PR), lasting for a median duration of 6 months (range 3-50 months). Of the 12 responding patients, 11 attained strong skin reactivity to the s.c. injection of irradiated, unmodified autologous melanoma cells. None of the patients with a negative reactivity experienced any tumour response. Patients with positive skin reactions survived longer (median survival - 54 months). The results suggest enhanced RRs to the combination of IL-2 and autologous melanoma vaccine. Skin reactivity to unmodified autologous melanoma cells may be a predictor of response and improved survival, and therefore a criterion for further pursuing of immunotherapeutic strategies.

A 68930 and dihydrexidine inhibit locomotor activity and d-amphetamine-induced hyperactivity in rats: a role of inhibitory dopamine D(1/5) receptors in the prefrontal cortex?

The behavioral and biochemical effects of the full dopamine D(1/5) receptor agonists, dihydrexidine and (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HCl (A 68930), were examined in rats. Both A 68930 (0-4.6 mg kg(-1), s.c.) and dihydrexidine (0-8.0 mg kg(-1), s.c.) caused a dose-dependent suppression of locomotor activity, as assessed in an open-field. This locomotor suppression was dose-dependently antagonized by the selective dopamine D(1/5) receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (SCH 23390; 0-5.0 microg kg(-1), s.c.), but not by the selective dopamine D(2/3) receptor antagonist raclopride (0-25.0 microg kg(-1), s.c.). Furthermore, A 68930 and dihydrexidine did not cause any locomotor activity in habituated rats that displayed a very low base-line activity. Neither did A 68930 nor dihydrexidine produce any excessive stereotypies that could possibly interfere with and mask ambulatory activity. In fact, both A 68930 and dihydrexidine potently blocked hyperactivity produced by d-amphetamine (0-4.0 mg kg(-1), s.c.). Such findings traditionally would be interpreted as a sign of potential antipsychotic properties of A 68930 and dihydrexidine. Examination of neuronal activation, as indexed by the immediate early gene c-fos, showed that A 68930 and dihydrexidine caused a highly significant expression of c-fos in the medial prefrontal cortex. This c-fos expression was sensitive to treatment with SCH 23390, but not with raclopride. The effects of A 68930 and dihydrexidine on c-fos expression in caudate putamen or nucleus accumbens were less marked, or undetectable. The results indicate that stimulation of dopamine D(1/5) receptors, possibly in the medial prefrontal cortex, is associated with inhibitory actions on locomotor activity and d-amphetamine-induced hyperactivity. Assuming an important role of prefrontal dopamine D(1/5) receptors in schizophrenia, such inhibitory actions of dopamine D(1/5) receptor stimulation on psychomotor activation may have interesting clinical implications in the treatment of schizophrenia.

Lack of efficacy of 'naked' small interfering RNA applied directly to rat brain.

UNLABELLED: The intrastriatal infusions of 'naked' small interfering RNA (siRNA) targeted to dopamine D1 receptors (1.0-10.0 nmol over 3 days) did not reduce dopamine D1 receptor messenger RNA levels or receptor protein, assessed by [125I] SCH 23982 binding in intact rats. This was in contrast to results in vitro where a 76% reduction in dopamine D1 receptor ligand binding could be observed. CONCLUSION: The results suggest that synthetic siRNA, when applied directly to rat brain, is not capable of inducing RNA interference.

Cancer patient expectations of and communication with oncologists and oncology nurses: the experience of an integrated oncology and palliative care service.

The purpose of this study was to evaluate ambulatory cancer patients' knowledge of their diagnosis and stage, their expectations of medical and nursing staff, and issues related to communication with the professional staff. A structured interview was conducted with each of 103 consecutive cancer patients attending the Oncology Day Hospital of the Shaare Zedek Medical Center. There were 77 women and 26 men, and their median age was 56 (18-86) years. Their religious status was elicited: 48% described themselves as religious, 25% as traditional, and 27% as secular. According to their physicians, 41 were in remission, 11 had stable disease, 47 had progressive disease and in 4 the disease status was unknown. Patients tended to underestimate the status of their disease: among those with progressive disease, 36% stated that their disease was stable or in remission. Overwhelmingly, patients expected that their oncologists should be patient and skilled in diagnostic procedures (98%), tactful, considerate and therapeutically skilled (90-95%), and skilled in the management of pain and the psychosocial consequences of cancer (75-85%). When there is bad news to be transmitted, 92% of patients indicated that they would want disclosure, while 6% indicated that they would want the news withheld from them but passed on to their family members. Most patients were very satisfied with the clarity of the information they received about their disease (85%) and the sensitivity with which it was transmitted (90%). Although 88% of patients reported that they relied on their oncologist for therapeutic decision making, 45% indicated that they had sought a second opinion and 32% reported seeking the opinion of a rabbinical medical broker. Almost all, 97%, of patients indicated that they felt comfortable seeking advice from their oncologist, and the oncologist was the staff member most often sought out for both information (69%) and support (66%). The data indicate high patient expectations of nursing and medical oncology staff members' skills and behaviors. Despite expressing a high level of satisfaction, a substantial percentage of patients had an inaccurate understanding of their disease status.

Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors.

PURPOSE: Fluorouracil (5-FU) continuous infusion is superior to 5-FU bolus in patients with advanced colorectal cancer, but the survival difference between the two treatments is small and, therefore, the difference in toxicity profile is crucial in choosing a treatment for individual patients. MATERIALS AND METHODS: We conducted a meta-analysis of all randomized trials that compared 5-FU bolus with 5-FU CI, based on individual data from 1,219 patients, to compare the toxicity of the two schedules of 5-FU administration and to identify predictive factors for toxicity. The toxicities considered were World Health Organization (WHO) grade 3 to 4 anemia, thrombopenia, leukopenia, neutropenia, nausea/vomiting, diarrhea, mucositis, and hand-foot syndrome. RESULTS: Hematologic toxicity, mainly neutropenia, was more frequent with 5-FU bolus than with 5-FU CI (31% and 4%, respectively; P < .0001). Hand-foot syndrome was less frequent with 5-FU bolus than with 5-FU CI (13% and 34%, respectively; P < .0001). There was no difference between the two treatment groups in terms of other nonhematologic toxicities. Independent prognostic factors were age, sex, and performance status for nonhematologic toxicities, performance status, and treatment for hematologic toxicities, and age, sex, and treatment for hand-foot syndrome. CONCLUSION: Based on a large data set, this study confirmed and quantified the toxicity profile of the two schedules of administration of 5-FU and allowed the identification of clinical predictors of toxicity.

Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer.

PURPOSE: The administration of fluorouracil (5-FU) by continuous intravenous infusion (CI) is an alternative to the bolus administration of 5-FU in patients with advanced colorectal cancer. Although more than 1,200 patients have been enrolled onto randomized trials that compared these two treatment modalities, there is still no definitive evidence of an advantage of 5-FU CI, and the magnitude of this advantage, if any, is also controversial. A meta-analysis was performed to assess this benefit in terms of tumor response and survival, and to compare the toxicity profiles of these two modalities of administration of 5-FU. DESIGN: Individual data of 1,219 patients included in six randomized trials served as the basis for this meta-analysis, which was conducted by an independent secretariat in close collaboration with the investigators. RESULTS: Tumor response rate was significantly higher in patients assigned to 5-FU CI than in patients assigned to 5-FU bolus (22% v 14%; overall response odds ratio, 0.55; 95% confidence interval [95% CI], 0.41 to 0.75; P = .0002). Overall survival was also significantly higher in patients assigned to 5-FU CI (overall hazards ratio [HR], 0.88; 95% CI, 0.78 to 0.99; P = .04), although the median survival times were close. Multivariate analyses showed that randomized treatment and performance status were the only two significant predictors of tumor response, whereas the same plus primary tumor site were independent significant predictors of survival (patients with rectal cancer did somewhat better). Grade 3 or 4 hematologic toxicity was more frequent in patients assigned to 5-FU bolus (31% v 4%; P < 10(-16)), whereas hand-foot syndrome was more frequent in the 5-FU CI group (34% v 13%; P < 10(-7)). CONCLUSION: 5-FU CI is superior to 5-FU bolus in terms of tumor response and achieves a slight increase of overall survival. The hematologic toxicity is much less important in patients who receive 5-FU CI, but hand-foot syndrome is frequent in this group of patients.

Acute promyelocytic leukaemia with t(15;17) following treatment of Hodgkin's disease--a report of 4 cases.

BACKGROUND: Therapy-related acute myeloid leukemia (t-AML) is a recognized entity complicating successful therapy for Hodgkin's disease (HD) and other neoplasias after many years. This risk appears to be related to cumulative exposure to alkylating agents and procarbazine, while drugs affecting DNA--topoisomerase II, such as epipodophyllotoxins and anthracyclines, are also associated with t-AML developing after a much shorter latent period. PATIENTS AND METHODS: Of 56 patients with t-AML or myelodysplasia seen in our institutes during the period 1980-1994 we encountered 5 patients with acute promyelocytic leukemia (APL) all of whom had t(15;17). Four of these had been treated for HD with both chemotherapy and radiotherapy, and one with radiotherapy alone. RESULTS: To the best of our knowledge these appear to be the first cases of t-AML in HD with cytogenetically proven t(15;17). Similarly to other cases of t-APL reported after therapy for neoplasias other than HD, these patients also have a relatively favorable prognosis as seen in de-novo APL. CONCLUSIONS: Although rare, t-APL should be added to the list of late complications of therapy for HD.

Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies.

PURPOSE: The purpose of our studies was to define the maximal-tolerated dose of liposomal doxorubicin (DOX-SL; Liposome Technology Inc, Menlo Park, CA), a doxorubicin formulation of polyethyleneglycol-coated liposomes, characterize the toxicities associated with this formulation, and evaluate any indication of antitumor activity within a phase I setting. PATIENTS AND METHODS: Two separate phase I studies were conducted following the initial human pharmacokinetic testing at one of the sites (Hadassah). The starting dose of 20 mg/m2 at the University of Southern California was just below the dose without toxicity in the pharmacokinetic study. At Hadassah, the phase I starting dose was just above their earlier safe single doses, 60 mg/m2. Both studies involved cohorts of at least three patients and redosing every 3 to 4 weeks. To determine the recommended dose for phase II trials, an additional level of 50 mg/m2 every 3 weeks was explored, and the level of 60 mg/m2 every 4 weeks was expanded. RESULTS: A total of 56 patients receiving 281 courses of DOX-SL was accrued and evaluated for toxicity. Hand-foot (H-F) syndrome and stomatitis are the two main dose-limiting factors of DOX-SL. Stomatitis was dose-limiting for high single doses of DOX-SL greater than 70 mg/m2. Skin toxicity manifested primarily as H-F syndrome was dose-limiting for repetitive dosing, but acceptable at either 50 mg/m2 every 3 weeks or 60 mg/m2 every 4 weeks. Attenuation of acute subjective symptoms and lack of alopecia were generally observed. Patients with carcinomas of the breast, ovary, prostate, and head and neck were among those showing objective antitumor responses or improvement based, in part, on blood levels of tumor markers. CONCLUSION: The toxicity profile of DOX-SL differs prominently from that of the free drug administered by bolus or rapid infusion and with some differences, resembles that of prolonged continuous infusion. This finding, as well as the antitumor activity observed, supports wide phase II testing of DOX-SL in solid tumors.

Responses of 3-dimensional arch wires to vertical v-bends: comparisons with existing 2-dimensional data in the lateral view.

The mechanics of V-bends in orthodontic arch wires have been described almost exclusively in terms of bending forces in two-dimensional (2-D) single plane terms. When a rectangular arch wire enters a third dimension, a more complex wire deformation pattern develops from both torsion and bending during the activation of the V-bends. The necessity for a rectangular three-dimensional (3-D) arch wire to undergo torsion during activation results in a greater resistance to deformation at those points in the wire where the torsion is greatest. This is especially apparent with 2 x 2 long span arch wires. This study used finite element analysis to model the force systems produced by activation of V-bends in 3-D arch wires. In both 2-D and 3-D data, greater moments are present as any V-bend is moved toward either adjacent bracket. In 3-D systems, however, a V-bend at the molar produces significantly less moment and associated equilibrium forces than the same V-bend located the same distance from the incisor. Moreover, the reversal of the direction of the moments at either bracket does not occur when the V-bend location is two thirds of the distance toward that tooth as reported with 2-D studies.

Megestrol acetate in advanced breast carcinoma after failure to tamoxifen and/or aminoglutethimide.

Seventy-three patients with metastatic breast cancer, whose disease progressed on hormonal therapy with tamoxifen or aminoglutethimide, were treated with megestrol acetate, 160 mg/day. No complete responses were observed. Partial response was achieved in 3 patients (4%), for a median of 9 months (range 5-13). Thirty-five patients (48%) remained stable, for a median of 8 months (3-26). The remaining 35 patients (48%) had clear progression of their metastatic disease on therapy. Response to megestrol acetate was achieved in patients with metastases in bone and pleura only. There was no correlation between response to megestrol acetate and response to prior chemotherapy, prior tamoxifen therapy, previous treatment with aminoglutethimide, or hormone receptor status. The actuarial 24-month survival for all patients was 37%. The main side effects of megestrol acetate included weight gain (20% or over), pruritus, elevation of blood pressure, weakness, and vaginal bleeding; they were only occasionally observed. The objective improvement observed during this trial is disappointing; the only reasons to justify the use of megestrol acetate as second- or third-line hormonal therapy in patients with metastatic breast cancer, would be the relatively long duration of disease stabilization in a large proportion of patients, and the low toxicity observed with the drug.

Clinical studies of liposome-encapsulated doxorubicin.

Initial clinical studies with doxorubicin entrapped in the bilayer of phosphatidylglycerol-rich liposomes were hindered by the avid reticuloendothelial system (RES) uptake and by drug leakage from circulating liposomes. In contrast, recent tests of a doxorubicin formulation of polyethyleneglycol-coated liposomes (Doxil) in cancer patients indicate that the drug pharmacokinetic properties are significantly altered, with a prolonged distribution half-life of approximately 2 days. Plasma fractionation studies show that nearly all the drug measured in plasma is in liposome-encapsulated form. The dose of Doxil has been escalated from 25 to 60 mg/m2. Stomatitis is the most significant toxicity, and skin toxicity, in the form of hand-foot syndrome, may complicate the repeated administration of Doxil. A number of objective antitumor responses in a variety of malignancies have been observed, indicating that Doxil is an active antitumor compound. Polyethyleneglycol-coated liposomes show a distinct advantage over previous liposome formulations directed at the RES and appear to be a promising drug delivery system for doxorubicin.

A preliminary report of a pilot randomized trial comparing cyclophosphamide, methotrexate and 5-fluorouracil with cyclophosphamide, mitoxantrone and 5-fluorouracil in the adjuvant therapy of stage II breast cancer with four or more positive axillary nodes.

Thirty-eight patients with stage II breast cancer with four or more positive axillary lymph nodes were randomized to receive CMF (cyclophosphamide, methotrexate and 5-fluorouracil, every 3 weeks) or CXF (cyclophosphamide, mitoxantrone and 5-fluorouracil, every 3 weeks). Pretreatment characteristics were similar for both groups. The actuarial 5 year disease-free survival (DFS) was 36% for the CMF group and 23% for the CXF group. The actuarial 5 year survival was 60% for the CMF arm and 66% for the CXF arm. These differences were not statistically significant. Partial alopecia was observed in 42% of patients in the CMF arm and in 100% of those receiving CXF (p = 0.0002). No episodes of leucopenic fever were observed in patients receiving CMF, while they were present in 53% of patients treated with CXF (p = 0.0006). No stomatitis occurred in the CMF group, but it was observed in 90% of patients who received CXF (p < 0.0001). Treatment with CXF had to be discontinued in two patients because of toxicity. In this small group of patients with poor prognosis, it seems that CXF at the doses given here is more toxic but not more effective than CMF, as represented by a similar DFS and survival.

Recurrence-associated mortality in patients with differentiated thyroid carcinoma.

Differentiated thyroid carcinoma (DTC) is associated with prolonged natural history, and even recurrent tumor is not necessarily followed by increased mortality. Prognostic factors and different treatment strategies, therefore, are difficult to assess. One hundred and fifty-seven patients were followed in our clinic. In an attempt to predict mortality from this tumor, we evaluated the risk factors in 36 patients who presented with recurrent disease. Ten of these patients died. Age above 40 years at initial diagnosis was the predominant risk factor associated with 44% mortality after recurrence. Male sex, lack of radioiodine treatment, and distant site of initial recurrence were all associated with a trend towards increased mortality. Tumor histology and local invasion or extent of initial surgical treatment failed to affect mortality. In conclusion, this approach may be used to identify those patients who will die from their disease, despite currently available treatment. It remains to be seen, however, if new treatment protocols can be developed to improve the prognosis of these patients.

Chemo-immunotherapy in patients with metastatic melanoma using sequential treatment with dacarbazine and recombinant human interleukin-2: evaluation of hematologic and immunologic parameters and correlation with clinical response.

We have treated 18 patients with metastatic malignant melanoma (MM) with high-dose IL-2 administered by continuous iv infusion in combination with dacarbazine (DTIC), and correlated the clinical response with various hematologic and immunologic parameters. Two regimens differing in the sequence of treatment were employed, and 1-6 treatment cycles were given, depending on patient response. Two patients had a complete response (CR, 46+m, 14m), two patients a partial response (PR, 16m,6m), one a minimal response and four had a stable disease lasting 2-7 months, thus the response rate (CR+PR) was 22%. None of the following parameters, tested prior to initiation of the therapy and 1-2 days after termination of each course of IL-2, correlated with the clinical response: WBC counts (total and differential), levels of blood CD4 and CD8 T cells, NK cells, monocytes and B cells, production of IL-1 and IL-1 inhibitor by monocytes, responsiveness to 3 mitogens, NK/LAK cell activity, and serum levels of IL-1 alpha, IL-2, soluble IL-2 receptor, and TNF alpha. The only prognostic parameter was the greater increase in the level of IL-2 receptor (Tac)-bearing lymphocytes in the responding patients after 1-3 cycles of IL-2. The data suggests that non-specific immune parameters have no prognostic value for patients undergoing IL-2-based immunotherapy.

Scintigraphic evaluation of patients with thyroid carcinoma--therapeutic approaches.

The therapeutic approach to patients with differentiated thyroid carcinoma has become a major issue of controversy in the last decade. The major aspects are the surgical resection and adjuvant therapy, particularly the need for thyroid ablation following surgery. According to the risk group definition suggested by Cady in 1979, low risk patients may be subjected to lobectomy only, then placed on thyroxine treatment and followed clinically with thyroglobulin determination. High risk patients should undergo total thyroidectomy and 131I ablation. Follow-up should include thyroxine treatment and an annual whole body 131I scan. In the event of residual thyroid tissue or functional metastases, 131I treatment is to be given.

Hodgkin's Lymphoma: Results of ABVD Chemotherapy in 40 Patients with Advanced or Bulky Disease.

During 1980-1986, 40 patients with advanced Hodgkin's disease or bulky disease were treated with six cycles of ABVD chemotherapy, and adjuvant radiotherapy was added to sites of bulky disease when required. Twenty-seven of the 40 patients (67.5%) were treated with ABVD as primary therapy and 13 (32.5%) received it as salvage therapy after initial failure. Twenty-seven patients (67.5%) had advanced stages 3 or 4 disease, while 13 (32.5%) had stage 2 with bulky mediastinal disease (more than 30% chest diameter). Only 7.5 % of the patients had no response to ABVD while 75% achieved CR and 17.5% PR. Seventy-four per cent of the patients with advanced stages 3 and 4 achieved CR and 15% reached PR, with only two failures to ABVD. The median survival for the entire group is currently more than 41 months, with a median disease-free interval (DFI) of 27.5 months for all treated patients. The results compare favorably with those reported from other major centers dealing with larger series of patients. New approaches for future treatment employing alternating shorter courses of MOPP/ABV are discussed, and the importance of radiotherapy for bulky disease is emphasized.

Cisplatin, bleomycin, and methotrexate (PBM) chemotherapy in locally advanced and metastatic head and neck cancer.

Twenty-two patients with locally advanced or metastatic head and neck tumors received a total of 84 courses of a combination of cisplatin, bleomycin, and Methotrexate (PBM) for a median of four courses per patient (range, 1-7). Among these 22 patients there were four patients (18%) who achieved complete remission (CR) and 13 patients (60%) who had a partial remission (PR). The overall remission rate (CR + PR) thus reached 78%; five patients (22%) progressed while on therapy. The mean duration of objective response (CR + PR) was 8 months; CR lasted a median of 18 months (range, 2-48). Survival was not influenced by tumor histology or by previous surgery. The presence of locoregional disease did adversely affect survival from the onset of chemotherapy (P = 0.1). The rate of survival was also affected by primary tumor site; patients with nasopharyngeal primaries survived longer than all other patients (22 vs. 11 months, P = 0.06). Toxicity to chemotherapy consisted mainly of nausea and vomiting and stomatitis. Three patients developed fever while leukopenic. One patient experienced irreversible renal damage, and another suffered from bleomycin-induced pulmonary fibrosis. The high response rate obtained in our group of patients did not have a substantial impact on overall survival. Aggressive, multimodality approaches should be considered in the treatment of these patients when possible.

Diffuse large cell non-Hodgkin's lymphoma: results of M-BACOD combination chemotherapy.

Twenty-seven adult patients with diffuse large cell lymphoma were treated with the M-BACOD regimen during the period 1980-86. Of these, 24 (89%) had advanced Stage III-IV disease by clinical staging and only 3 (11%) had limited disease. CR was achieved in 14 patients (52%), all of whom had advanced disease prior to therapy. The remaining 13 patients (48%) achieved only PR. Of the entire group of 27 patients, 11 (41%) died, 12 (44%) are still in CR, and 4 (15%) have relapsed and are still alive with PR. Of the 14 patients who achieved CR, 1 relapsed, but is currently in PR, showing minimal disease. All of these 14 patients are alive (11 months to 6 years post therapy), and 13 (93%) still remain in CR with a median time of CR of 45 months. Of the 13 patients who only achieved PR, 11 (85%) relapsed and died within a median time of 3.6 months, and 2 patients remain in PR. The above results are similar to those obtained in larger series recorded from other centers. In the light of improved results obtained with new regimens and ABMT, we have now adopted the MACOP-B regimen for treating aggressive lymphoma and have entered an ABMT program for patients with predictable poor prognostic features.

Treatment of primary and metastatic liver cancer using an implantable chemoinfusion pump.

Twenty evaluable patients with primary or secondary neoplastic liver involvement received FUDR (0.2 to 0.3 mg/kg per day) by continuous infusion to the hepatic artery for 14 days, every 4 weeks, through a surgically implanted Infusaid (USA) pump. In addition to FUDR, MMC (15 mg/m2 every 6 to 8 weeks) was given to 14 patients with colorectal cancer and one patient with breast cancer, and ADR, (40 mg/m2 every 4 to 6 weeks) was given to 5 patients with hepatocellular carcinoma. MMC and ADR were given as a bolus injection, through the pump sideport. Radiation therapy to the liver (2,000 rads in fractions of 180 to 200 rads each) was given to eight patients with colorectal carcinoma. In total, the 20 patients received 218 months of treatment and 580 injections. The overall remission rate (complete, partial and minor response) was 55%; one patient with a colorectal carcinoma achieved a CR and seven patients (35%) a PR; three patients (15%) had a MR, and in eight patients (40%) stabilization of disease was observed. Overall median survival was 12 months: 15.5 months for colorectal cancer patients and 7.5 months for patients with hepatocellular carcinoma. Toxicity consisted mainly of chemical hepatitis, mild to severe peptic disease and sclerosing cholangitis. Hematological toxicity was not observed. These data suggest that chemotherapy through the hepatic artery, while still experimental, may be considered for selected patients with tumor confined to the liver.

Combination chemotherapy in metastatic tumors of unknown origin. 5-Fluorouracil, adriamycin and mitomycin C for adenocarcinomas and adriamycin, vinblastine and mitomycin C for anaplastic carcinomas.

Twenty-nine evaluable patients with metastatic carcinomatosis in whom initial workup failed to reveal the primary site were entered into this trial. Patients with histological evidence of adenocarcinoma (n = 15) received FAM, while patients with anaplastic carcinomas (n = 14) were given AVM. Pretreatment characteristics were similar for the FAM- and AVM-treated patients with regard to age and sex, but 47% of patients on FAM had liver metastases as compared with 36% for the AVM group. Of the 14 patients on AVM, 1 (7%) achieved a complete response lasting 16 months, and 3 patients (22%) achieved a partial response for 10, 12 and 20 months, respectively. No patient on FAM reached a complete response, and only two patients (13%) showed a partial remission for 7+ and 24 months, respectively. The median survival for the AVM patients was 8.5 months, not significantly different from a median of 5 months for the FAM-treated group. AVM caused substantial myelotoxicity, resulting in five hospitalizations for leukopenia and fever; the FAM regimen was better tolerated with no episodes of leukopenic fever. AVM appears to be more effective than FAM in the treatment of carcinomas of unknown origin. A higher response rate was achieved with AVM, despite the fact that patients on this combination had undifferentiated carcinomas and a larger proportion of three or more metastatic sites (36 vs. 13% on FAM), and received a lower percent of the planned dose than did the FAM patients. Further clinical trials to fully establish the role of vinblastine in the treatment of metastatic carcinomatosis of unknown origin seem warranted.