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BACKGROUND Paclitaxel (T), etoposide (E), and cisplatin (P) are each active in gastric carcinoma, either as single agents or as part of a multidrug regimen. To the authors' knowledge, the combination of these three agents in the treatment of patients with esophageal or gastroesophageal carcinoma has not been previously studied. METHODS Previously untreated patients with locally advanced carcinoma of the stomach, esophagus, or gastroesophageal (GE) junction received at least 2 cycles of TPE administered twice weekly for 3 weeks, with the cycle repeated every 28 days. Drug doses, administered over 3 hours on either Monday and Thursday or Tuesday and Friday, consisted of T 50 mg/m2/dose, P 15 mg/m2/dose, and E 40 mg/m2/dose. For patients with local disease only, subsequent therapy consisted of radiation with or without surgical resection. RESULTS Twenty-five patients with gastric (10) or gastroesophageal or GE junction (15) carcinoma were treated. Eighteen had locally advanced disease and 7 had liver metastases at presentation. Hematologic toxicity, namely, Grade 3 anemia and neutropenia, was experienced by all patients. The median number of treatment cycles was 4 (range, 2–6). Three patients were not evaluable for response. All 22 evaluable patients responded; 3 were complete responders and 19 were partial responders. Eleven patients received radiation therapy with (6) or without (5) concomitant 5-fluorouracil, and 8 patients subsequently underwent surgical resection. Three of 8 patients had no tumor at surgery, 4 had minimal microscopic tumor at the primary site, and 3 had microscopic lymph node involvement. Twenty-three patients are alive, of whom 14 are without evidence of disease. Two patients with metastatic disease at presentation died at 9 and 29 months, respectively. The median survival was 12.5 months (range, 6 to 30+ months). CONCLUSIONS Multifractionated TPE chemotherapy is a highly active regimen in gastric and gastroesophageal carcinoma. It could be evaluated in Phase III trials against other active regimens for the treatment of patients with this disease. The introduction of 5-fluorouracil could also be an interesting direction to explore because of its primary role in the treatment of patients with gastric and esophageal carcinoma. Cancer 1999;85:2347–51. © 1999 American Cancer Society.

Multifractionated dosing (MFD) schedules for chemotherapy administration such as weekly or twice weekly administration are intended to maximize dose intensity while minimizing toxicity, but the cumulative drug effect may result in neutropenia necessitating interruption of dose fractions and thereby compromising dose intensity. Intermittent granulocyte colony-stimulating factor (G-CSF, Neupogen, Amgen) was administered to patients receiving MFD on three paclitaxel-based chemotherapy regimens. Single-dose G-CSF was administered concomitant with the chemotherapy dose fraction when the white blood count was between 2000 and 3500 cells/microliter. A retrospective analysis of the concomitant administration of single-dose G-CSF with chemotherapy in these trials demonstrated that in most patients, G-CSF administration guided by the level or grade of leukopenia permitted maintenance of the chemotherapy dose intensity and completion of the treatment cycle. The common pattern in a six-dose, twice weekly, multifractionated cycle was for G-CSF to be administered with every other chemotherapy dose beginning with the third, fourth, or fifth dose, but some courses required G-CSF administration with each chemotherapy dose fraction. Guidelines for the concomitant use of G-CSF and paclitaxel-based MFD chemotherapy can be used to maintain chemotherapy dose intensity. A prospective study of guidelines for cytokine usage developed on the basis of this retrospective study will be necessary to determine the optimal cytokine dose and schedule for use simultaneously with chemotherapy.

BACKGROUND The cost of infusional administration of cancer chemotherapy has been assumed to be more expensive than the traditional bolus schedule related to the use of durable medical equipment and other components of the delivery system. The objective was to develop a model of projected charges as a basis for the cost estimate for selected common chemotherapy regimens comparing the cost based on charges for bolus and infusional chemotherapy schedules. METHODS Chemotherapy programs using either bolus or infusional delivery were selected representing standard or commonplace regimens for the treatment of patients with breast cancer (cyclophosphamide, methotrexate, fluorouracil [CMF] or CA); colon cancer (5-fluorouracil[5-FU] infusion vs. 5-FU bolus + leucovorin [LCV]) or lymphoma (cyclophosphamide, hydroxydaunomycin, Oncovin (vincristine), prednisone [CHOP] or CDE [cyclophosphamide, doxorubicin, etoposide]). Cost projections were estimated based on charges and were calculated in a model system using six charge (cost) centers including medical doctor [MD] and/or clinic visit; laboratory; drug cost based on average wholesale price (AWP); cost of disposables; and pump rental fee. Standard dosages were applied for each regimen using total mg/M2 for a 1.5 M2 person. RESULTS Projected charges for chemotherapy for colon cancer (5-FU infusion vs. 5-FU + LCV) are variable depending on the LCV dose and the infusion duration. The longer infusion duration or higher doses of LCV result in a 40 to 50% increment in monthly charges excluding cost related to toxicity. For breast cancer, the charges for bolus or infusion administration CMF are similar, but for CA bolus charges are higher than infusion charges related to higher drug doses. For lymphoma, CHOP chemotherapy dosage costs are approximately half of those for CDE infusion related to the specific drug regimen and drug dosage used. CONCLUSIONS The perception that infusional delivery of chemotherapeutic agents adds to the cost of cancer care is appropriate for some regimens but the absolute amount of cost increment is generally modest. The principle cost differences between bolus and infusional schedules relate to drug dosage and the toxicity profile. Generally, but not consistently, infusional schedules use lesser doses and are associated with lesser toxicity. Although the benefit of infusional delivery of chemotherapy in terms of response rates and survival are comparable to bolus schedules for 5-FU infusion and 5-FU + LCV in colon cancer, this has not been established for the regimens analyzed for breast cancer (CMF, CA) or lymphoma (CDE, CHOP). The misperception of cost advantages for bolus delivery should not preclude comparative trials of bolus versus infusional chemotherapy schedules and cost should be studied prospectively in clinical trials comparing different schedules of administration in addition to studies of quality of life and toxicity. Cancer 1996; 78:294-9.

The treatment of advanced colorectal cancer has improved in recent years. Prospective randomized trials comparing innovative therapies with the "standard" bolus dose of 5-fluorouracil (5-FU) found increased response rates after biochemical modification of the drug, infusion administration of 5-FU, and direct intrahepatic arterial infusion. Although the impact on survival of these techniques has been minimal, it is possible that these innovative approaches provide an incremental survival advantage for certain subgroups of patients that may be the foundation for additional therapeutic improvements in the future.

A combination of oral etoposide, infusional cisplatin (24-hr) and infusional 5-fluorouracil (5-day) was used to treat 87 patients with non-small-cell lung cancer in a Phase II trial. Twenty-six patients were Stage IIIB, and 61 patients were Stage IV (new international classification). The regimen was well tolerated, with 49% grade 3 or 4 toxicities of all types. Response rates, partial and complete, were 40%, (95% confidence interval: 30%, 51%) for Stage IV patients and 20% (95% confidence interval: 10%, 32%), in Stage IIIB. An additional 68% of patients in Stage IIIB and 45% of patients in Stage IV achieved stable disease and had a median survival of 8.8 months, similar to that of patients in partial remission. Median survival was 5.6 months (95% confidence interval: 4.4 months, 10.8 months) for Stage IV patients and 11.0 months (95% confidence interval: 8.8 months, 12.4 months), for Stage IIIB. Of interest was the finding of a higher response rate in patients with a shorter duration of symptoms (less than 6 months versus greater than 6 months).

One hundred eighty-four 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 assess the value of weekly cisplatin (20 mg/m2) when added to a protracted schedule of 5-fluorouracil (5-FU) infusion (PIF) at 300 mg/m2/d for 10 weeks of every 12 weeks. The liver was the primary indicator lesion in approximately 75% of the study group. All tumor measurements required radiographic confirmation. The response rate in the PIF alone arm was 35% (29 of 83; 95% confidence interval [CI], 25% to 46%) compared with 33% (28 of 85; 95% CI, 23% to 44%) for the arm in which weekly cisplatin was added to PIF. The median survival times were 11.8 and 11.2 months in the two groups. Weekly cisplatin does not appear to add to the effectiveness of PIF in colorectal carcinoma.

Ten patients with hepatic metastases from islet cell tumors or carcinoid tumors had clinical symptoms from hormonal secretion and/or pain related to the mass effect of neoplastic liver involvement. Hepatic arterial embolization (HAE) using radiographically guided catheters to inject thrombogenic material was applied to the right and/or left hepatic arteries separately 5 to 7 days apart. All ten patients improved within days of the procedure as confirmed by a decrease in measurable hormone levels (gastrin, adrenocorticotropin, and 5-hydroxy indole acetic acid) or by a decrease in tumor size and improved symptoms. Three patients underwent repeated reembolization from two to four times over nine to 50-month intervals for symptom control. Complications of and indications for HAE in these patients are discussed. It appears to be an effective treatment for dealing with the hormonal syndromes and local symptoms related to the hepatic metastases of hormone-secreting tumors.

Objectives: To determine if “same day” Pegfilgrastim (Pf) with CHOP chemotherapy for non-Hodgkin lymphoma impacts on nadir white blood count (WBC) levels or on the nadir day. Methods: Ten patients with non-Hodgkin lymphoma treated with CHOP-R; CHOP with liposomal Doxorubicin replacing H; or CVAD received ‘same day’ Pf in a minimum of one cycle of chemotherapy to a maximum of 6 cycles with 8 of 10 patients receiving same day Pf for some but not all cycles allowing for comparison of nadir WBC levels within patients. Results: A total of 43 cycles of chemotherapy were reviewed. Same day Pf was administered with 21 of 43 cycles in all 10 patients with 8 of 10 receiving 22 cycles without Pf as well. White blood count nadir level and nadir day were compared in 9 patients in whom same day Pf was or was not administered in selected cycles. One patient experienced febrile neutropenia in a single cycle. Median nadir count and nadir day for cycles delivered with same day Pf was 1500 cells/ml (range, 200–11,000) at 14 days (range, 7–14 days). Median nadir count and nadir day cycles not delivered with same day Pf was 1600 cells/m3 and day 14 (range, 7–14), respectively. Four of 21 cycles (19%) delivered with same day Pf were associated with grade 4 leukopenia compared with 2 of 23 cycles (9%) delivered without same day Pf. With regard to the total 10 patient population 4 patients had a grade 4 leukopenia experience with same day Pf and 2 patients had a grade 4 leukopenia experience without same day Pf. Grade 4 leukopenia had a median nadir day of 7. Conclusions: Same day Pf may accentuate neutropenia in some patients with non-Hodgkin lymphoma receiving standard CHOP or CHOP-R chemotherapy but expanded studies are necessary to establish this point definitively. The accentuated neutropenia may be related to the specific chemotherapy regimen or drug, eg, cyclophosphamate since same day Pf was safe with regimens in which a non alkylating agent (taxane, gemcitabine, navelbine, cisplatin) was used with a weekly chemotherapy dosing schema and did not generate accentuated neutropenia.

A patient with metastatic adamantinoma from the tibia is described, in whom the biologic behavior of the tumor and the clinical course that evolved was typical. Tumor regression was observed on two separate occasions to a combination chemotherapeutic regimen of etoposide plus cisplatin or carboplati

The development of low-density lesions in the liver of patients with known cirrhosis raises the question of the clinical pathway for the diagnostic workup. Primary hepatocellular carcinoma (HCC) an...

Chemotherapy for 5-fluorouracil (5-FU)-resistant colorectal cancer is largely ineffective with new and innovative therapeutic strategies needed to benefit patients developing progressive disease while receiving 5-FU or 5-FU-based programs. The tumor antibiotic mitomycin C is an alkylating agent with a broad range of clinical activity in a variety of gastrointestinal malignancies and is therefore a reasonable agent to test for clinical activity in the setting of 5-FU-resistant or -refractory colorectal cancer. The principal goal of this study is to investigate the logistical feasibility and clinical efficacy of a 7-day infusion of mitomycin C, delivering an equitoxic dose to the standard bolus delivery in patients with progressive disease while receiving 5-FU-based chemotherapy. Twenty-five patients with advanced measurable colorectal cancer, resistant or refractory to 5-FU-based chemotherapy, were treated with a 7-day intravenous infusion of mitomycin C. Doses ranged between 1.5 and 3.0 mg/M2/day for total cumulative mitomycin C, ranging between 10.5 and 21.0 mg/M2 per chemotherapy cycle. Forty-four courses of infusional mitomycin C were delivered to 25 patients via surgically implanted venous access devices. The median age of all patients was 63 years (range, 27-83); there were 11 men and 14 women. Eleven patients had received two or more prior chemotherapy combinations, with the average number of prior therapies before mitomycin C being 1.6. The median number of cycles of mitomycin C administered was two (range, one to six). Thirty-seven of 44 cycles were administered at the dose range of 2.0-3.0 mg/M2/day. Hematologic toxicity was mild, with only three courses associated with grade III thrombocytopenia and one course with grade III neutropenia. No extrahematologic toxicities were observed. No patient had a complete response; two patients (8%) showed partial responses that lasted for 145 and 190 days. One patient had stable disease for 180 days. Twenty-two of 25 patients (88%) developed progressive disease during mitomycin C administration. Infusional mitomycin C for 7 days, cycled every 42 days, is logistically feasible and associated with minimal clinical toxicity. Used on this schedule and with these doses in 5-FU-resistant/refractory colorectal cancer, however, there is no meaningful clinical activity for this agent, and it cannot be recommended as a salvage or second-line therapy in the treatment of metastatic colorectal cancer.

A patient who had carcinoid tumor of the ileum and liver and intraabdominal lymph-node metastases sustained a substantial (more than 50%) reduction of metastatic tumor burden when treated with accelerated-dosage octreotide.

Summary Background Advanced pancreatic cancer is a rapidly fatal disease whose course has been little influenced by chemotherapy. Earlier studies have shown some modest promise for the combination of protracted infusional 5-fluorouracil (PIF) and cisplatin. We sought to evaluate a regimen of possibly lesser toxicity, PIF plus weekly carboplatin. Patients and Methods Fifty-four patients with advanced adenocarcinoma of the pancreas were treated with a regimen of protracted infusional fluorouracil 300 mg/m2/day for 70 days and carboplatin 100 mg/m2/weekly on weeks 1 through 10 of a 12-week cycle. After a two-week rest, cycles were repeated until progression. Results Median duration on treatment was 82 days (range 4–490 days). Toxicity was mild. Grade 3–4 toxicities were anemia 11%, leukopenia 6%, thrombocytopenia 2%, nausea/vomiting 7%, diarrhea 9%, mucositis 9%, and renal 2%. Response was evaluable in 47 patients. There were two complete and seven partial responses (17% overall objective response rate among all patients). Stable disease for greater than 12 weeks was seen in 19 patients (40%) and progression in 19 (40%). The median overall survival was 22 weeks (1–99), with 61 weeks median survival in responders (22–99). One-year survival was 13%. Conclusions Response and survival results with this regimen are at least equal to the best combination regimens reported, and were obtained with a low overall rate of serious toxicity.

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.

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.

The combination of dichloromethotrexate, cisplatin, and infusional 5-fluorouracil was evaluated as treatment for non-small-cell lung cancer in a phase II trial using 43 evaluable patients. Grade III or IV toxicity included thrombocytopenia (21%), leukopenia (14%), nausea/vomiting (14%), mucositis (9%), infection (5%), and other (16%). There were six responders (14%), with a 95% confidence interval of [5%, 28%]. Two additional patients achieved a 50% reduction in cross-sectional tumor size that was not documented twice. Median survival time was 6.5 months. This combination is not considered sufficiently active for further evaluation in this disease.

The application of multiple drugs or combination chemotherapy for the treatment of cancer has become standard practice since its introduction in the 1960s for the treatment of first testicular cancer and subsequently leukemias and Hodgkin’s disease. Today chemotherapy for malignancies virtually always entails the application of multiple agents, either simultaneously or in some planned sequence. The rationale for combination chemotherapy is based upon the concept of affecting multiple metabolic sites within the tumor cell or multiple points during the tumor cell cycle. At a practical level, the use of non-cross-resistant agents without overlapping toxicity maximizes the effectiveness of such combinations. Recent conceptual advances in the application of cancer chemotherapy have introduced the concept of alternating non-cross-resistant agents applied intensively on a weekly basis. Another conceptual development has been the application of biochemical modulation utilizing a noncytotoxic enhancing agent in conjunction with a primary cytotoxic drug.

Chemotherapy delivered by infusion has developed in the last decade, primarily as a consequence of advances in technology but perhaps also because of increasing scientific understanding of pharmacology and tumor cell kinetics. Although few prospective, randomized trials have compared infusion-delivery with bolus-delivery schedules, those that have been performed have found that the infusion schedule provides at least a comparable response rate while improving drug toxicity.

Metastatic breast cancer is thought never to be cured, although anecdotal cases of prolonged survival have been reported. A review of 1581 cases treated with combination chemotherapy at the M.D. Anderson Cancer Center in Houston identified 49 complete responders (3.1%) who remained in complete response (CR) for more than 5 years (1). Another report, from the Eastern Comparative Oncology Group (ECOG), identified 10-year survival in 10% of 147 patients receiving chemotherapy in two trials for metastatic breast cancer (2). In the presence of metastasis, the potential for cure is not a recognized goal or even considered to be a possibility in breast cancer, although isolated instances of long-term survivors with and without disease may contribute to a different definition of cure.

OBJECTIVE To determine whether very low doses of warfarin are useful in thrombosis prophylaxis in patients with central venous catheters. DESIGN Patients at risk for thrombosis associated with chronic indwelling central venous catheters were prospectively and randomly assigned to receive or not to receive 1 mg of warfarin, beginning 3 days before catheter insertion and continuing for 90 days. Subclavian, innominate, and superior vena cava venograms were done at onset of thrombosis symptoms or after 90 days in the study. RESULTS One hundred twenty-one patients entered the study, and 82 patients completed the study. Of 42 patients completing the study while receiving warfarin, 4 had venogram-proven thrombosis. All 4 had symptoms from thrombosis. Of 40 patients completing the study while not receiving warfarin, 15 had venogram-proven thrombosis, and 10 had symptoms from thrombosis (P less than 0.001). There were no measurable changes in the coagulation values assayed due to this warfarin dose, except in occasional patients who had become anorectic because of their disease or chemotherapy. CONCLUSIONS Very low doses of warfarin can protect against thrombosis without inducing a hemorrhagic state. This approach may be applicable to other groups of patients.

Serial carcinoembryonic antigen (CEA) titers were measured in 38 patients receiving chemotherapy for metastatic carcinoma of the colon, pancreas, and stomach. CEA levels were initially elevated (over 2.5 ng/ml) in 26 patients (12/20 colonic, 8/10 pancreatic, 6/8 gastric). Seventeen patients had rising serial CEA values during therapy; 13 had evidence of tumor progression, 3 had stable disease, and 1 had no measurable disease. Nineteen patients had stable CEA levels which were either persistently elevated (11 patients) or normal (8 patients). Ten of 11 patients with elevated CEA levels developed tumor progression. In 8 patients with consistently normal CEA levels, 6 (colon) had no evidence of progressive tumor, and 2 (1 pancreatic and 1 gastric) eventually died of metastatic disease. CEA levels decreased in 2 patients with colon carcinoma during remission from chemotherapy. A rising CEA titer often presages clinical deterioration, although elevated CEA levels may remain stable despite progressive disease. Persistently normal CEA, however, is a favorable prognostic sign. The limited effectiveness of chemotherapy for gastrointestinal cancer in this series precludes any definitive conclusion regarding the effect of chemother-apeutically induced tumor regression on CEA levels, although there is suggestive evidence that CEA correlates with remission.

A patient with metastatic islet cell carcinoma demonstrated multiple clinical syndromes simultaneously with secretion of ACTH, gastrin, glucagon, and serotonin. Hepatic arterial embolization resulted in an initial decrease in all secretory products, which was sustained for glucagon and serotonin. Recrudescence of the Cushings and Zollinger-Ellison syndrome was managed by surgical extirpation of the primary tumor and regional metastases as well as bilateral adrenalectomy. Electron microscopy and immunocytochemistry of the primary tumor and the metastatic lesions revealed the presence of multiple types of granules within single cells and, different patterns of secretory profiles in different tumor sites.

A three-drug regimen composed of adriamycin, 50 mg/m2 and cyclophosphamide, 500 mg/m2 administered on day 1; and VP-16-213, 50 mg/m2 days 1-5, with courses repeated at 3-week intervals, was studied in 24 consecutive patients with extensive-stage small cell lung cancer (SCLC). Twelve of 33 patients (36%) evaluable for toxicity developed life-threatening marrow suppression and 12% died of septicemia following the first course of treatment. Eleven of 24 patients (46%) with extensive disease achieved an objective response and only one was classified as a complete response. Survival was related to performance status and metastatic site but was not influenced by tumor response. The present study is distinctive from that of previous reports of the same or similar three-drug regimen in that the response rate is lower and toxicity is substantial. Nonetheless, survival as measured by median duration (7.9 months) and proportion alive at 1 year (35%) is comparable to that of previous reports.

Fifty-two patients with advanced colorectal cancer were treated with a combination of 5-Fluorouracil (FU) plus methyl-1,3-cis (2-chlorethyl)-1-nitrosourea (MeCCNU). The treatment schedule program consisted of 5-FU, 300 mg/m2 i.v. bolus, daily for 5 days, repeated at 5-week cycles. MeCCNU was administered at a dose of 150 mg/m2 orally on day 1 of the initial 5-day course of FU and repeated at 10-week intervals. Eighty-four percent (44/52) of the patients with advanced measurable disease developed progressive disease by 4 months or one and a half cycles of therapy. Only two patients had definite partial regression of tumor over the period of observation. The median survival of all patients measured from the onset of treatment was 9 months and is comparable to literature reports of untreated advanced colorectal cancer. This therapeutic trial of combined FU and MeCCNU, employing a dose-schedule distinct from but comparable to previous studies has failed to confirm the substantial response rate reported by other investigators and reinforces the need for exploring new drugs and combinations of drugs in advanced colorectal cancer. The use of sequential plasma CEA determinations as a primary monitor of therapy is discussed in relationship to clinical trials and guidelines for determining significant quantitative changes in plasma CEA levels are recommended.

A randomized trial of Adriamycin (A) in combination with melphalan (M), (MA therapy), and in combination with M plus cyclophosphamide (C) (MAC therapy), was initiated in 40 evaluable patients with metastatic breast cancer. Twenty-two patients demonstrated an objective response to therapy: 9/20 to the MA regimen, and 13/20 to the MAC regimen. For the 22 responders, median duration of response is not yet achieved for either complete or partial responders, at 10 and 9 months, respectively. The addition of the two alkylating agents to Adriamycin was superior to the single alkylating agent addition, both in total response rate and in completeness of response. Maintenance therapy, after achieving the maximum cumulative dose of Adriamycin, was provided by cyclophosphamide plus methotrexate and 5-fluorouracil (CMF). In 19 patients completing induction and entering maintenance therapy, only one relapse has developed with maximun follow-up at 15 months.

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.

Twenty-eight cases of alpha cell tumors of the pancreatic islets have been reported. The clinical features include typical skin rash (termed migratory necrolytic erythema) and stomatitis with anemia, abnormal glucose tolerance, and weight loss. The time course of the disease is variable but the clinical syndrome may be present for up to 15 years (median five years) before discovery of the tumor. In 3 patients, cure was achieved by surgical resection, and in 17 patients in whom metastatic sites were evaluable, 16 involved the liver. Six patients have received chemotherapy: 4 with streptozotocin (STZ); 1 with dimethyl triazeno imidazole carboxamide (DTIC); and 2 with 5-fluorouracil. All 4 patients receiving STZ responded to therapy with objective regression of the tumor and in 3 the dermatitis syndrome receded as well. The selectivity of the STZ for beta cells observed in animals is contrasted with the specific antitumor activity of STZ for alpha as well as beta and delta cell tumors in man.

Objective tumor regression in response to therapy invariably results in prolonged patient survival and often improves the quality of remaining life. The author describes criteria for determining, and clinical guidelines for predicting, tumor response. Further, he reviews tactics of cancer chemotherapy with regard to dose-response relationships and kinetics of tumor response.

Eighty-four patients with small cell carcinoma of the lung were reviewed with respect to the frequency and biologic behavior of patients with a demonstrated ectopic hormone syndrome. This subgroup of 12 patients (14%) was compared with regard to stage of disease, distribution of metastases, response rate, and survival to those patients not demonstrating a clinical syndrome. Stage, distribution, and response rates are comparable in the two groups but differences were observed with regard to sites of metastases and survival. The ectopic hormone syndrome patients had an increased likelihood of liver metastasis and CNS metastasis. The frequency of CNS metastasis in patients without the ectopic hormone syndrome was 11/72 (15%) of which four of the 11 were present at initial presentation. In contrast, 5/12 (42%) of the patients with ectopic hormone syndromes developed CNS metastasis, and all five had clinically demonstrated SIADH. Survival was consistently inferior in those patients with the ectopic hormone syndrome.

Plasma carcinoembryonic antigen (CEA) and serum enzyme levels of phosphohexose isomerase (PHI), gamma-glutamyl transpeptidase (psi-GTP), and lactate dehydrogenase (LDH) were measured in 147 patients with malignancy. Levels were higher in patients (particularly with G.I., breast and lung cancers) than in normals or in patients with cancer in clinical remission. Elevations of CEA and of all three enzymes in blood were most frequent in patients with hepatic metastases. CEA elevations correlated directly with PHI levels. Seventy-eight percent of patients with metastatic G.I. cancer could be identified by CEA (greater than 5 ng/ml) alone, as well as 38% with breast cancer and 85% with lung cancer; but only 17% of other cancers could be identified by CEA alone. CEA or one or more enzymes was elevated in 64% of metastatic breast cancer patients, 92% of lung cancer and 41% of other cancers, but enzyme measurement did not increase identification of G.I. cancer over that achieved by CEA alone. These findings suggest that circulating levels of CEA, PHI, psi-GTP and LDH may reflect a direct contribution from the malignant tissue and/or liver malfunction secondary to liver replacement.

Twenty-six patients received vinblastine by ambulatory pump infusion via the subclavian vein for a median duration of 30 days of continuous therapy at an average dose rate of 0.5 mg/m2/day. Drug toxicity was minimal compared to the standard bolus schedule but bone marrow suppression was dose-limiting. There was no gastrointestinal or neurologic toxicity. The maximum duration of continuous therapy was 89 days (at 0.5 mg/m2/day) with the duration of therapy specifically related to the daily dose rate. Nondrug-related toxicity included subclavian vein thrombosis in two patients. Two of 11 patients with malignant melanoma had transient objective responses and 1/3 patients with soft tissue sarcoma had a partial response. Expanded phase II studies are ongoing at the dose of 0.5 mg/m2/day for a minimum duration of 30 days.

Hypoglycemia secondary to malignant tumors is rare. Mesenchymal tumors of nonpancreatic origin are the most common tumors associated with the hypoglycemia syndrome, and the clinical features of 115 reported cases are reviewed. The major anatomic distributions of the tumors are thoracic (30%), abdominal (65%), and uncommon locations (

B-DOPA (Bleomycin (B), D-imidazole carboxamide (D), Oncovin (O), Prednisone (P), Adriamycin (A) is a program developed for the treatment of Hodgkin's disease resistant to MOPP therapy. Twenty unselected patients were treated by the following dose schedule: B, 4 mg/m2 days 2 and 5; D, 150 mg/m2 days 1 to 5; O (vincristine), 1.5 mg/m2 days 1 and 5; P, 40 mg/m2 days 1 to 6; A, 60 mg/m2 day 1. Each course, was repeated at 3 to 4 week intervals to maximum adriamycin dose of 450 mg/m2. All patients had received prior MOPP therapy and six had received prior radiotherapy. Fifteen of the 20 patients entered into the study were evaluable for response. There were nine (60%) complete responders and three (20%) partial responders. The median duration of complete remission was 14+ months with six of nine patients remaining in remission to a maximum of 21 months. The median survival of the nonresponders was 3 months. B-DOPA is an effective combination chemotherapy regimen for advanced Hodgkin's disease in patients who have previously received MOPP treatment, including patients who are refractory to MOPP therapy. The B-DOPA program or modifications thereof, may be integrated into primary treatment programs for advanced Hodgkin's disease.

Eight-four patients with renal cell carcinoma were analyzed retrospectively in order to 1) determine the effectiveness of systemic chemotherapy—hormonal and non-hormonal, 2) identify the clinical features of renal cell carcinoma that may be important in prognosis and 3) characterize the paraneoplastic features of renal cell carcinoma. Metastatic disease was present at diagnosis in 57 per cent of the cases and developed within 1 year in an additional 19 per cent. Multiple sites of metastasis were paradoxically associated with a longer survival (20 months median) compared to single-organ metastasis (5 to 11 months median). Paraneoplastic syndromes occurred in up to 40 per cent of patients with variable survival. Metastatic disease was unresponsive objectively to either primary nephrectomy or to a variety of chemotherapy trials.

One hundred patients with malignant disease were screened for leukocyte alkaline phosphate (LAP) activity. The new observation made was that patients with malignant disease demonstrate significantly lower levels of LAP than in normal controls. The low LAP activity is present irrespective of primary tumor category, "activity" of disease, or type of therapy. The pattern of metastases may influence LAP activity, in that patients with liver metastases tended to have higher LAP levels. In spite of low baseline LAP levels in patients with malignant disease, the development of secondary infection is associated with elevated LAP levels.

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.

Plasma CEA levels were determined in 61 patients with small cell lung cancer entering chemotherapy protocols between 1976 and 1980. Five quantitative categories were determined: less than 2.5 ng/ml (the standard normal for Hansen assay); 2.6-5.0 ng/ml (the extended normal for smokers); 5.1-20.0 ml; (the intermediate elevation and the transition for the indirect to the direct assay); 20-100 ng/ml; and greater than 100 ng/ml. Forty-seven percent of patients had levels less than 5 ng/ml and only ten of 61 or 16% had levels greater than 20 ng/ml. There was no clearcut relationship of plasma CEA level to stage of disease, in that 40% of patients with extensive disease (32 patients) had levels less than 5 ng/ml and 45% of patients with limited disease (29 patients) had levels greater than 5 ng/ml. Similarly, there was no relationship of CEA level to site of metastases, although levels greater than 100 ng/ml were always associated with liver metastases. The median survival for each quantitative category was similar, ranging from seven to nine months. The use of sequential determinations of CEA to correlate with tumor response was studied in only eight patients with levels greater than 20 ng/ml and a measurable parameter of disease. The qualitative direction of change of CEA was appropriate in those patients responding to treatment but in three nonresponding patients the direction of CEA change paradoxically decreased. In five patients who developed progressive disease, the plasma CEA level predicted the clinical relapse. CEA as a tumor marker for oat cell carcinoma must be applied in conjunction with other tumor parameters and is meaningful in only a small proportion of the total small cell patient population.

A case of a 26-year-old woman with metastatic choriocarcinoma and clinical and biochemical thyrotoxicosis is described. This represents the eighth reported case of the association of choriocarcinoma and thyrotoxicosis. Serial monitoring of serum thyroxine (T4) and thyroid stimulating hormone (TSH) levels correlated precisely with the beta sub-unit human chorionic gonadotropin (hCG) level and the quantitation of host tumor burden. The development of a hypermetabolic syndrome in patients with choriocarcinoma may be due to secondary thyrotoxicosis from either the TSH-like activity of hCG or from the concomitant production of molar thyrotropin by the tumor.

Fifteen patients were studied during short-term (5 days at 10-15 mg/m2/day) or long-term (5-104 days at 3 mg/m2/day) doxorubicin infusion. Levels of doxorubicin and metabolites in serum and 24-h timed urine collections were determined by high-performance liquid chromatography. Quantifiable anthracycline levels were identified in serum of 5 of 6 patients (6 courses) receiving drug at 10 mg/m2/day. In 5 courses, total anthracycline levels were 10-80 ng/ml, whereas levels as high as 370 ng/ml were observed in a patient with hepatorenal failure. No detectable serum levels of anthracycline were seen in patients receiving long-term doxorubicin therapy. Although analysis of 24-h timed urine collections revealed that doxorubicin was the predominant anthracycline, the extent of urinary elimination showed considerable interpatient variation (1.0-52.5% of the infused dose/24-h period on the short-term protocol and 5.3-57.2%/24-h period on the long-term protocol). Metabolic processing of doxorubicin administered by continuous infusion was found to be similar to that of drug given by bolus administration and showed no change in pattern with time. However, a greater variability in serum and urinary anthracycline levels was seen among patients on infusion schedules than has been noted with bolus drug treatment.

Eighteen of 78 patients (23%) with metastatic colorectal cancer developed clinically significant metastases to the central nervous system (CNR). The patients developing CNS metastases had a decreased likelihood of associated liver metastases compared to the patients without CNS metastases (22% versus 80%). Pulmonary metastases were present in 55% of patients with CNS lesions and in 25% of those without CNS lesions. Overall survival from diagnosis of the primary tumor was comparable (median, 28 months) for patients with or without CNS lesions. The incidence of CNS metastases was comparable irrespective of Duke stage at presentation. For early lesions (Duke B or C), CNS metastases were associated with a shorter survival (31 versus 42 months). For advanced disease (Duke D lesions) at presentation, the overall survival of the group with CNS metastases was longer (24 versus nine months). Therefore, the longer survivorship of patients with advanced disease may contribute to a greater likelihood of CNS metastases.

Medical, radiation, and surgical oncologists have been stymied in their efforts to produce meaningful changes in the natural histories of most cancers of the gastrointestinal tract. But new clinical strategies used in the treatment of squamous cell cancers at opposite ends of the g.i. tract have caused these tumors to yield to efforts. This chapter will outline the clinical data that have evolved from protocols developed at Wayne State University combining preoperative infusion chemotherapy and external beam radiation for epidermoid malignancies of the anal canal and esophagus. These data allow us to conclude that the natural histories of these malignant diseases have indeed changed. Furthermore, there is now reason to question the role of the time-honored method of treatment for these tumors-surgery-in terms of adding to the survival and comfort of patients with these cancers.

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.

2 patients with metastatic cancer (Ewing's sarcoma and breast cancer) developed pleural effusions while undergoing systemic therapy for pulmonary metastases. Thoracenteses failed to reveal malignant cells and in both instances the characteristics of the fluids were those of transudates. The effusions developed in association with dissolution of pulmonary lesions and presumably represent a reactive process to tumor regression.

Five patients with breast cancer and malignant melanoma are reported. Two patients had a third primary malignancy. In 4 out of 5 patients the breast tumor was the initial tumor discovered, and in 4 out of 5 the second tumor evolved metachronously. No specific carcinogenic factor could be established. The low malignancy potential of the melanoma by pathologic criteria may explain the lack of previous reports of this association.

The cost of health care in the United States is an enormous political and social issue. The health care industry, second only to the military in annual budget needs, is being subjected to extraordinary regulation in an attempt to restrain growth and limit costs. In 1980, the overall medical costs for patients with cancer was $10.8 billion. At the established rate of rise of 20% per year, that cost by 1985 had doubled. The major portion (two-thirds) is spent for hospital care and approximately one-fourth for physicians’ fees.

A total of 14 patients with advanced visceral carcinoma which produced carcinoembryonic antigen (CEA) were treated in a Phase I study with IV infusion of affinity purified baboon anti-CEA antibody (dosage range from 0.1 to 2 mg/kg body weight). In all 14 patients, the antibody infusion caused a decrease (26% to 97%) in the plasma level of CEA. The degree of decrease depended upon the patients initial CEA level and the amount of antibody given. In 12 of the 14 patients "free" circulating antibody was observed. The plasma half-life of the antibody ranged from 0.7 to 21 h and the duration of detectable free antibody ranged from 3 to 216 h postinfusion. No toxicity was observed for the dosage range of antibody tested. In 9 of the 14 patients a low titer anti-baboon antibody response occurred between 14 and 28 days postinfusion. No clinical regression of carcinoma was documented. In 7 of the 14 patients disease remained stable during the 28-day study period. By the end of the 28-day study period plasma CEA levels had returned to at least the preinfusion level in 11 of the 14 patients.

Gastrointestinal symptoms are among the most common and the most distressing for patients with cancer. Symptoms may be secondary to inflammatory lesions from the esophagus to the anus and may range from anorexia with nausea and vom­iting to diarrhea, constipation, obstipation, and tenesmus. The broad range of gastrointestinal symptomatology may be a di­rect consequence of the tumor or a secondary effect due to treatment of the tumor. In some instances the gastrointestinal symptoms may be secondary to an unrelated clinical disease such as infection, hepatitis, peptic ulceration, or diverticulitis.

Serial measurements of plasma carcinoembryonic antigen (CEA) levels were analyzed in 42 patients with advanced breast cancer undergoing systemic chemotherapy. Pretreatment CEA levels exceeded 5 ng/ml in 22 patients, and 19 of 22 serial assays uniformly heralded tumor regression as well as subsequent tumor relapse. A significant quantitative alteration in CEA levels was established as a minimum change of 20% within 8 weeks of therapy. In 13 of 15 patients responding to chemotherapy and in all patients with CEA levels higher than 35 ng/ml, this criterion was not abrogated, and there were no discordant observations. Rising CEA levels were correlated with subsequent progression of disease in all patients with elevated baseline levels at a minimum of 8 weeks before the progression was clinically evident. In advanced breast cancer the effectiveness of therapy and the development of tumor resistance may be monitored by serial plasma CEA levels, and specific quantitative criteria should be applied.