Hemoglobin brigham (alpha2Abeta2100 Pro--Leu). Hemoglobin variant associated with familial erythrocytosis.

Erythrocytosis associated with the presence of a hemoglobin with increased oxygen affinity has been reported for 10 hemoglobin variants, most of which demonstrate altered electrophoretic mobility. Several members of a family were found to have erythrocytosis, and both the whole blood and the hemoglobin exhibited increased oxygen affinity. Phosphate-free hemoglobin solutions had a normal Bohr effect and reactivity to 2,3-diphosphoglycerate. The electrophoretic properties of the hemoglobin were normal, but on peptide mapping of a tryptic digest of the isolated beta-chains, a normal betaT11 peptide and an abnormal betaT11 with greater R(f) were seen. Analysis of the abnormal peptide showed the substitution of leucine for the normal proline at beta100 (helical residue G2).The hemoglobin variant, designated Hb Brigham, serves to emphasize the necessity for detailed evaluation of the structure and function of hemoglobin in familial erythrocytosis even with electrophoretically "normal" hemoglobin.

Transient carcinoembryonic antigen (CEA) elevations following resection of colorectal cancer: a limitation in the use of serial CEA levels as an indicator for second-look surgery.

In a previous study, other investigators recommended second-look surgery for colorectal cancer primarily on the basis of plasma carcinoembryonic antigen (CEA) rises and prepared a nomogram for ready recognition of these "significant" increases. We found 25 patients whose CEA levels met the recommended criteria for significance; however, in 9 of these patients the rises were transient. Eight had no clinical evidence of recurrent cancer and they might have had negative second-look surgery had this been done because of CEA rises alone. The use of the CEA nomogram merely eliminated laboratory variation as a cause of the CEA rise. It did not, however, rule out biologic causes of CEA rises, other than that of cancer, especially benign liver disease. We were unable to differentiate benign from malignant rises on the basis of CEA changes alone. Preoperative CEA values helped to separate the two rises. Transient rises usually began earlier. Malignant CEA rises were more likely to be exponential. The rate of rise alone did not discriminate between the two rises. Thus, although serial CEA levels were helpful in making the decision for reexploration, they did not substitute for complete clinical assessment.

Criteria for monitoring carcinoembryonic antigen: variability of sequential assays at elevated levels.

Fifty-five patients with advanced cancer and elevated plasma carcinoembryonic antigen (CEA) levels greater than 20 ng/mL (Roche assay) were monitored by clinical parameters for disease activity and a daily plasma specimen was obtained and stored frozen. In 45 patients with evaluable metastatic lesions, 35 were stable; five had progressive disease; and five had regressive disease. Plasma CEA in patients with stable disease showed an overall coefficient of variation of 13%. The CV did not differ according to various quantitative CEA levels from less than 100 ng/mL to greater than 1,000 ng/mL. The coefficient of variation in responding and progressive disease patients ranged from 13% to 63%. An analysis of CEA variability relative to the baseline CEA level was possible using the formula square root 2 times the variability about the mean; this yields a value of +/- 36% representing the range within which approximately 95% of sequential CEA levels would lie in the absence of a clinical change in disease. In 225 CEA determinations in stable disease patients, 6% demonstrated an increase beyond this level (36%) and none demonstrated a decrease of 36% or more from the baseline level. This study establishes guidelines for the boundaries of change in plasma CEA that may be applied as a criterion (in conjunction with standard objective disease parameters) for determination of tumor response to therapy.

Biliary tract obstruction secondary to cancer: management guidelines and selected literature review.

Malignant biliary tract obstruction (MBTO) due to either primary biliary tract cancer or metastasis to the porta hepatis is a common clinical problem. The most common metastatic tumors causing MBTO in order of frequency are gastric, colon, breast, and lung cancers. Radiographic diagnostic procedures should proceed in a cost-effective sequence from ultrasonography, computerized tomography (CT), percutaneous transhepatic cholangiography (PTHC), and endoscopic retrograde pancreatography with the goal of establishing the site of the biliary tract obstruction. The identification of the site of obstruction could be established by ultrasound 70% to 80%, CT scan 80% to 90%, PTHC 100%, and endoscopic retrograde cholangiography (ERCP) 85%. Therapeutic intervention by radiographic decompression (PTHC or endoscopic prosthesis), surgical bypass, or radiation therapy with or without chemotherapy may be selectively used based on (1) the site of obstruction; (2) the type of primary tumor; and (3) the presence of specific symptoms related to the obstruction. ("Prophylactic" biliary tract decompression to prevent ascending cholangitis is not supported by the literature in that the frequency of sepsis in the face of malignant obstruction is small (in contrast to sepsis associated with stone disease). Furthermore, PTHC with drainage as a long-term procedure is associated with a substantial frequency of sepsis and is unnecessary and possibly problematic as a preoperative procedure simply to reduce the bilirubin level. The use of radiation therapy in conjunction with chemotherapy for patients not deemed suitable for a surgical bypass because of the presence of proximal obstruction is an important alternative to PTHC.

A pilot study of protracted venous infusion of 5-fluorouracil and concomitant radiation therapy.

A method to potentially increase the effectiveness of combination 5-fluorouracil (5-FU) and radiation therapy (XRT) using protracted (more than 30 days) venous infusion (PVI) of 5-FU with conventionally fractionated XRT (180 to 200 cGy per day) (100 cGy = 100 rad) is described. Forty-one patients were treated with this combination with acceptable acute toxicity. In 95% of patients, the toxicity was mild or moderate and symptom control was achieved with medications or a short treatment interruption. In two patients (5%), severe gastrointestinal side effects resulted in cessation of all therapy. This method of administration of 5-FU is feasible, and we have demonstrated that it can be safely used with a course of conventionally fractionated, high-dose (approximately to 6,500 cGy) radiation therapy.

Complications and management of implanted venous access catheters.

A totally implanted subclavian venous access system composed of a reservoir and silastic catheter was employed in 92 patients receiving infusion chemotherapy and/or hyperalimentation. The major catheter complication was subclavian or jugular vein thrombosis observed in 15 patients (16%). Thrombosis was observed in the ipsilateral subclavian or jugular vein surrounding the catheter without restricting function, except in two patients with thrombosis in the vein at the end of the catheter. Prophylaxis with low-dose Coumadin was effective in preventing thrombosis in high-risk patients as defined by a history of prior thrombosis. Streptokinase and/or heparin relieved the signs and symptoms of thrombosis, but clot dissolution or reversal of collateral flow was not observed. Explantation of the catheter was not necessary in all patients in that embolic complications of the thrombosis were not observed, and the system was retained and functioned in five patients in spite of the presence of thrombosis around the catheter. Other complications of the implanted system include "pocket" infection, catheter migration, and occlusion. Most complications may be managed without obligate catheter removal.

A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study.

One hundred seventy-nine patients with advanced measurable colorectal cancer not previously treated with chemotherapy were entered into a prospective randomized clinical trial by the Mid-Atlantic Oncology Program (MAOP) to compare two schedules of delivery for single-agent fluorouracil (5-FU). The "standard" treatment was a schedule commonly employed in clinical practice, namely, a daily bolus dose administered intravenously (IV) for five consecutive days and repeated at 5-week intervals. The investigational treatment was a continuous infusion of 5-FU administered 24 hours a day for a protracted time (10 weeks or more). Both treatments were continued until the development of disease progression or unless interrupted for toxicity. Using stringent objective criteria requiring independent confirmation of x-ray or scan-documented response, the tumor response rate reached 7% (six of 87) for the bolus arm and 30% (26 of 87) for the infusion arms (P less than .001). Toxicity was substantially different for the two arms with major leukopenia observed only on the bolus arm, 22% developing grade 3 (severe) or grade 4 (life-threatening) leukopenia with four sepsis-related deaths. Hand-foot syndrome was observed only in the infusional arm, requiring treatment interruptions and dose reductions in 24% of patients, but with little impact on quality of life. In spite of the major difference in objective response rate, overall survival for the two groups was comparable. Administration of 5-FU as a continuous infusion for protracted periods clearly improves the therapeutic index for this agent in patients with advanced colon cancer with respect to response rate and reduced toxicity. This schedule appears workable in the community setting and yields response rates similar to those reported for 5-FU with high-dose leucovorin, but without the gastroin testinal toxicity profile of the latter combination.

Hormonal palliation of chemoresistant ovarian cancer: three consecutive phase II trials of the Mid-Atlantic Oncology Program.

PURPOSE: To evaluate the efficacy of three hormonal manipulations in the palliation of chemoresistant ovarian cancer, and to analyze the results in the light of other clinical trials. PATIENTS AND METHODS: Three sequential phase II trials were performed in patients with refractory epithelial ovarian carcinoma, using high-dose megestrol acetate (800 mg/d for 30 days, then 400 mg/d), high-dose tamoxifen (80 mg/d for 30 days, then 40 mg/d), and aminoglutethimide (1 g/d plus tapering doses of hydrocortisone). Results were compared with those described in the world literature from trials of the same or similar agents. RESULTS: No responses were seen among 30 assessable patients treated with megestrol acetate, and most (but not all) similar trials have reported low response rates. Five responses (17%) were seen among 29 patients treated with tamoxifen. Two responses exceeded 5 years in duration. No responses were seen among 15 patients treated with aminoglutethimide. CONCLUSION: Antiestrogen therapy may offer the possibility of useful and, occasionally, long-term palliation of refractory epithelial ovarian carcinoma, with little toxicity. There may be a trend toward a dose-response effect, which represents a suitable topic for a future prospective trial.

A study of infusional cisplatin and infusional fluorouracil for locally advanced or metastatic non-small-cell lung cancer: a Mid-Atlantic Oncology Program study.

A combination of cisplatin administered as a 24-hour infusion and fluorouracil administered as a 5-day infusion was used to treat 97 patients with non-small-cell lung (NSCLC) cancer in a phase II trial. Thirty patients had stage IIIB disease; 67 patients, stage IV disease (new international classification). Patients with stage IIIB disease also received thoracic radiation after chemotherapy. The regimen was well tolerated, with 24% or less grade 3 or greater toxicities of all types. One toxic death was attributed to fluid overload. The response rate, partial and complete, was 43% (95% confidence interval, 27% to 63%), and median survival was 13.8 months for patients with stage IIIB disease. Response rates refer to the chemotherapy response. For patients with stage IV disease, the response rate was 34% (95% confidence interval, 24% to 47%), and median survival was 6.2 months. On this regimen, stable-disease patients with stage IV disease had survivals at least equal to responders.

1.3 Bis-(2 chloroethyl)-1-nitrosourea and streptozotocin chemotherapy.

Streptozotocin (STZ) was combined with 1,3 bis-(2 chloroethyl)-1-nitrosourea (BCNU) and with BCNU and 5-fluorouracil (FU) in a 2- and 3-drug clinical chemotherapeutic trail. The premise that STZ and BCNU are qualitatively different with regard to marrow suppression was the primary rationale of the study. The 2- and 3-drug regimes were associated with a higher incidence of severe leukopenia and thrombopenia (47% and 100%, respectively) and a lower mean nadir for each (1,700/mm3 and 15,000/mm3) than the reported experience with single drug BCNU therapy. However, this synergism did not apply to therapeutic effects. The reasons for potentiation of marrow toxicity may be related to specific aspects of direct drug interaction as well as alterations in pharmacologic reactions.

5-fluorouracil with cytosine arabinoside in metastatic gastrointestinal cancer.

A 2-drug combination chemotherapy regimen of 5-fluorouracil (FU) and cytosine arabinoside (ara-C) was used in 23 patients with gastrointestinal cancer. The drugs were administered as a mixture by daily continuous infusion for 5 days at 4-wk intervals. Dosages for each drug were: FU, 1.1 gm/m2/day and ara-C, 50 mg/m2/day. The incidence of leukopenia (WBC, less than 3,500/mm3) was 36% and of thrombocytopenia (platelets, less than 125,000/mm3), 18% during 33 courses administered at full doses. No clinical antitumor effects were observed in 18 patients evaluable for therapeutic response. The addition of ara-C to a nonmyelosuppressive dose schedule of FU results in potentiated marrow suppression, and the antitumor effect for the combination is less than would have been predicted for either drug alone.

Determination of response in treatment of hepatic neoplasia.

The determination of objective antitumor response by therapeutic modalities is a complex process limited by the resolution of available tools. Nonetheless, within these limitations objective measurements are critical to the identification of effective therapies. The determination of complete regression of hepatic metastases should not be difficult clinically, but such an event occurs only rarely. More commonly, there is no clinically measurable response, although some degree of tumor cell kill may be achieved. The recognition of such effects is limited by the inadequacy of clinical assessment tools, and the concomitant application of multiple parameters is necessary if not essential. Of the presently employed methods to measure objective antitumor response as outlined in Table 1, only the monitoring of hepatomegaly and the quantitative criteria indicated in Fig. 7 has met the critical requirement of correlation with survival. Nonetheless, the method is a relatively gross estimate and subject to major interobserver variation. Radiologic studies have similar limitations and resolution power precludes adequate assessment of small lesions. The biochemical parameters are indirect tumor effects and may modulate as a consequence of therapy on normal tissue without tumor effects. Tumor antigens and particularly sequential monitoring of plasma CEA is theoretically the most optimal means of measuring tumor growth or regression. Practical clinical application is preliminarily encouraging, but precise quantitative guidelines must be established and meet the standards of a cost-benefit analysis. The high tumor response rate in hepatic artery infusion programs offers the opportunity to determine the usefulness of plasma CEA as a specific determinant of tumor activity, and such studies are ongoing.

The effect of cancer chemotherapeutic agents on the liver-spleen scan.

The effects of short-term cancer chemotherapy on the liver-spleen scintiscans of 15 patients were assessed. Half of these exhibited minimal and transient changes in the pattern of radiocolloid distribution and/or chemical liver-function tests. No examples of new focal defects were seen. The data suggest that cytotoxic drugs are capable of inducing minor scan changes that might be attributed erroneously to intrinsic hepatic disease.

Randomized clinical trial of mitomycin-C with or without pretreatment with WR-2721 in patients with advanced colorectal cancer.

The use of mitomycin for metastatic colorectal cancer has been limited by mitomycin's myelosuppressive potential. The objective of this randomized study was to determine whether WR-2721 would decrease the hematologic toxicity of mitomycin in patients with colorectal cancer resistant to fluorouracil-based therapy. Ninety-seven patients with refractory colorectal cancer were randomized to receive either mitomycin 20 mg/m2 only or the same dose of mitomycin after pretreatment with WR-2721, 910 mg/m2. The principal toxicity in both groups was thrombocytopenia. The platelet nadirs were lower in patients receiving single-agent mitomycin (P = 0.026). Surprisingly, no clinical complete or partial responses were noted in either group, and survival was not different between the two groups. Thus, while WR-2721 decreased the thrombocytopenia associated with mitomycin therapy, mitomycin was ineffective in the treatment of refractory colorectal carcinoma.

Systemic infusional chemotherapy for liver metastasis: an improved schedule for 5-fluorouracil.

The clinical studies of infusion schedules for cancer chemotherapy have established that this schedule substantially alters the pattern of drug toxicity without necessarily compromising therapeutic effectiveness. Although increased tumor cell killing has not been definitively established, in at least two prospective comparative trials of 5-FU the infusion schedule was superior to bolus delivery in terms of response rate. It is possible that the infusion schedule may be the primary determinant of the effectiveness of hepatic arterial chemotherapy, and preliminary reports of prospective trials comparing systemic infusion with hepatic infusion do suggest that response rates for both routes are similar. An important consideration with regard to infusion schedules is establishing whether or not tumor cell resistance is augmented by the continuous exposure. Almost all chronic disease therapy necessitates maintaining adequate drug levels to ensure disease control including infections, seizure disorders, arthritis, and cardiovascular diseases. For cancer, the intermittent schedule of drug delivery has been dictated by the concept of the primacy of dose and the substantial toxicity associated with these agents. With the technological capability of providing an ambulatory setting for infusion chemotherapy and the substantial modification of toxicity, therapeutic regimens may be more cost effective with the constant infusion schedule.

Management of malignant ascites with peritoneovenous shunting.

The onset of intractable ascites secondary to malignant disease is a harbinger of a short life span (less than 8 weeks) in most patients. Repeated paracentesis is a preferable form of management unless a longer life span is anticipated. In patients with ovarian or breast carcinoma, peritoneovenous shunting is an effective means of controlling malignant ascites. In addition, long-term symptomatic relief can be achieved for the balance of the patient's life. Postoperative coagulation defects are minimal if most of the ascites is removed at the time of shunt placement. Circulating fibrin split products universally appear postoperatively in the peripheral circulation of patients with patent shunts. Pulmonary metastasis is not a clinically significant problem secondary to placement of the peritoneovenous shunt for malignant ascites.

Implantable central venous access system.

Prolonged central venous access for outpatient chemotherapy was achieved in 74 patients utilizing a totally implantable access disc system. The system consists of a stainless steel drug reservoir implanted in the subcutaneous tissue of the anterior chest wall. The reservoir is attached to a Silastic catheter which is then tunneled to a central vein and positioned in the superior vena cava. In 6,762 patient days of observation, there was a high degree of patient acceptance and a low incidence of complications. There were four instances of thrombosis and two of catheter-related sepsis among 17 complications. Seven access discs required removal. The implantable nature of this system offers an attractive alternative to other available methods of prolonged central venous access.

Cancer chemotherapy and infusional scheduling.

The practice of infusional cancer chemotherapy has evolved over the past decade as our increased understanding of tumor cell kinetics and drug pharmacology has brought into focus the concentration x time formulation and its importance in tumor cell killing and host tolerance. Technologic advances have contributed substantially to the practical capability of infusional drug delivery, with improved vascular access and ambulatory infusion pumps. In the past 10 years, infusional schedules have been used for virtually every class of antineoplastic agent and have demonstrated an improved therapeutic index by reduced or altered toxicity (doxorubicin, fluorouracil, ifosfamide, platinum analogs) or increased tumor cell killing (fluorouracil, etoposide, cladribine). Although there are few phase III trials comparing infusion and bolus administration, the evidence is clear that toxicity is altered and therapeutic benefit is not diminished by infusional schedules of drug administration.

Secondary uncommon solid neoplasms in cured Hodgkin's disease and follow-up of the original B-DOPA chemotherapy patient group.

Three patients with Stage III or IVB Hodgkin's disease were cured with MOPP (regimen of nitrogen mustard, Oncovin, prednisone, and procarbazine) and/or B-DOPA (regimen of bleomycin, dacarbazine, Oncovin, prednisone, and Adriamycin). One had also received prior mantle radiation. After 13, 15 and 18 years in complete remission, three unusual solid tumors were diagnosed. One patient presented with a T3N2M0 epidermoid carcinoma of the soft palate; the second patient developed a T2N1M0 epidermoid carcinoma of the anus. The third patient developed a meningeal sarcoma that was metastatic to the lungs. Two additional patients, both of whom received MOPP and B-DOPA, died with more common tumors (esophageal and renal cell) at 7 and 10 years in association with recurrent Hodgkin's disease. Uncommon tumors may develop after long intervals following treatment for Hodgkin's disease and early detection requires diligent and persistent follow-up. The retrospective review of long-term survivors of the original B-DOPA regimen is of particular interest in that four of seven such patients developed solid tumors at 7, 10, 13, and 15 years. These patients had all received MOPP chemotherapy and six of seven had received radiation as well. The possibility of delayed solid tumors developing, particularly in patients having received both MOPP and B-DOPA or the related ABVD (regimen of Adriamycin, bleomycin, vinblastine, and dacarbazine) program, is of some concern.

Optimal schedule for 5-fluorouracil chemotherapy. Intermittent bolus or continuous infusion?

5-Fluorouracil (5-FU) remains the standard chemotherapy for gastrointestinal cancer, particularly colorectal cancer, with response rates of 8% to 33% and median survivals of 24 to 44 weeks. The schedule of delivery for 5-FU has been addressed in a number of clinical trials over the past two decades, but the optimal schedule based upon more recent studies is not clear. The prospective comparative trial by Ansfield et al., investigated bolus delivery in four schedules and the daily X 5 loading regimen was superior to the less intensive regimens. However, two randomized trials of bolus 5-day vs. continuous 5-day infusions have indicated that the infusion schedule is superior: in colorectal cancer, the study by Seifert et al. demonstrated a response rate of 42% for infusion vs. 21% for bolus; and in head and neck cancers 5-FU administered in conjunction with cisplatin achieved a response rate of 76% for infusion vs. 20% for bolus delivery. Further support for the superiority of the infusion schedule is provided by the comparative trials of hepatic arterial infusion (HAI) and systemic venous infusion, in which response rates are equivalent regardless of the route of delivery. In order to definitively establish an improved therapeutic effect for the infusion schedule, additional prospective trials comparing standard bolus schedules to infusion schedules are necessary, and should address other issues, such as the optimal duration of infusion and relative cost-effectiveness.