Search

Combining antineoplastic analogues may increase efficacy by increasing the serum and intracellular concentration of the cytotoxic moiety shared by the analogues. Topotecan and irinotecan are two camptothecan analogues that are active in different human tumors (topotecan in ovary; irinotecan in colon) and in different experimental tumor systems. These data suggest that different mechanisms of drug resistance may be operative for the two agents, and if incomplete cross-resistance exists between analogues, concomitant administration may be advantageous. The objectives of this phase I study were 1) to determine in a phase trial design whether topotecan and irinotecan administered concomitantly on a weekly schedule can be delivered at the same dose intensity as that of single-agent topotecan or irinotecan delivery; and 2) to determine whether hematologic and/or nonhematologic toxicity is increased with topotecan and irinotecan administered together as a prelude to a possible phase II trial in responsive tumor categories. Irinotecan was administered for 30 to 45 minutes weekly X 4 at four dose levels: 50, 75, 100, and 125 mg/m 2 /wk. Topotecan was administered for 30 minutes (after irinotecan administration) at two dose levels within each of the irinotecan dose levels (1.0 and 1.5 mg/m 2 ). Concomitant single-dose granulocyte-macrophage colony-stimulating factor (G-CSF) was used for leukocyte counts between 1,000 cells/mm 3 and 3,500 cells/ mm 3 to maintain schedule. Maximum tolerated dosage (MTD) for the topotecan and irinotecan combination was defined as that which permitted 4 weeks of topotecan and irinotecan administration with G-CSF at or near the dose intensity reported for each single agent. Twenty-one patients received 32 4-week cycles. Dose-limiting toxicity was hematologic with grade IV leukopenia and neutropenia occurring at all dose levels. There was no apparent increase in the diarrhea syndrome associated with irinotecan. The MTD for irinotecan (at 125 mg/m 2 /wk) is the same MTD as with single-agent irinotecan use. The MTD for concomitant topotecan (1.5 mg/m 2 /wk) is 60% of the single-agent topotecan dose for the 5-day topotecan schedule (at 2.5 mg/m 2 /wk) but only 30% of the single-agent topotecan dose for the weekly schedule (5 mg/m 2 /wk). The topoisomerase I inhibitor dose is increased minimally when the analogues are administered concomitantly on a weekly schedule. Comparative trials of single-agent topotecan and irinotecan versus the combination of topotecan and irinotecan would be necessary to provide the proof of principle that combining analogues can increase therapeutic effectiveness.

The choice between cisplatin (cis) and carboplatin (carbo) as the platinum analogue to be used in combination chemotherapy regimens continues to be a point of controversy, and a new platinum analog...

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.

BACKGROUND Paclitaxel, cisplatin, and vinorelbine are three important antineoplastic drugs with different mechanisms of cell kill. A combination of these three drugs potentially could have additive therapeutic effects. METHODS The three-drug combination (designated TPN) was administered on a twice-weekly (Monday/Thursday; Tuesday/Friday) schedule for 3 weeks, with cycles repeated every 28 days. The Phase I design utilized a dose de-escalation schema in which the maximum tolerated dose was defined by a patient's ability to complete 6 doses (a full cycle) without interruption for hematologic Grade 3 or 4 toxicity. RESULTS Twenty-seven patients received a total of 42 evaluable courses of the 3-drug regimen. The cisplatin dose was fixed at 15 mg/M2/fraction. The paclitaxel dose was first fixed at 50 mg/M2/fraction, and venorelbine was delivered at 3 dose levels per fraction: 10, 7.5, and 5 mg/M2. Paclitaxel then was de-escalated to 40 mg/M2/fraction, and the same 3 dose levels of vinorelbine were evaluated. The dose-limiting toxicity was neutropenia. Using fixed doses of paclitaxel at 40 mg/M2/fraction and cisplatin at 15 mg/M2, the optimal dose fraction for vinorelbine was 7.5 mg/M2, defined as the dose that allowed > 67% of patients to complete 3 weeks (6 consecutive doses) of therapy. Using paclitaxel at 50 mg/M2/fraction (cisplatin at 15 mg/M2/fraction), the optimal dose of vinorelbine was 5 mg/M2/fraction. Tumor responses were observed in 13 patients: 2 with unknown primary, 1 with esophageal carcinoma, 6 with nonsmall cell lung carcinoma, and 3 with breast carcinoma. Grade 2 neurologic (sensory) toxicity was observed in 5 patients. CONCLUSIONS TPN administered according to a twice-weekly dosing scheme can be delivered with acceptable toxicity. The dose intensity for paclitaxel (60–75 mg/M2/week), cisplatin (22 mg/M2/week), and vinorelbine (15 mg/M2/week) is > 50% of the single agent dose intensity for the component agent. Recommended Phase II or Phase III trials could utilize dose fractions of paclitaxel, cisplatin, and vinorelbine at either 50, 15, and 5 mg/M2/fraction or 40, 15, and 7.5 mg/M2/fraction in this twice-weekly, multifractionated dose schedule. Cancer 1999;85:499–503. © 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 costs of infusion versus bolus administration of chemotherapy has been a point of controversy as has been the method of quantitating the cost. The present study analyzes the reimbursement for chemotherapy administration by infusion compared with bolus delivery based on reimbursement and relates this to cost based on projected charges and actual charges in a private practice setting. METHODS Actual reimbursement records were retrieved for selected patients receiving infusion or bolus administration of specific chemotherapy regimens for three tumors: colon carcinoma, breast carcinoma, and lymphoma. All services were included except for radiology and hospitalization. Medicare reimbursement represented 90% of the treatment cycles analyzed. RESULTS Actual reimbursement per month for each infusion regimen was as follows: colon carcinoma, $528 (5-fluorouracil [5-FU]); breast carcinoma, $621 (doxorubicin and cyclophosphamide [AC]) and $685 (cyclophosphamide, methotrexate, and fluorouracil [CMF]); and lymphoma, $603 (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]). Actual reimbursement per month for a bolus regimen was colon carcinoma, $393 (5-FU + leucovorin); breast carcinoma, $991 (AC) or $453 (CMF); and lymphoma, $749 (CHOP). Actual reimbursement represents 21–36% of actual charges. Projected charges based on the model system are generally less than the actual charges. CONCLUSIONS The cost of chemotherapy as defined by reimbursement are substantially less than actual charges and are also less than projected costs based on charges. Data comparing bolus versus infusion reimbursement costs for colon carcinoma, breast carcinoma, and lymphoma indicate that differences between reimbursement for bolus and infusion administration are not substantial. Cancer 1996;78:300-3.

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.

BACKGROUND Ifosfamide and carboplatin are agents that have completed Phase I studies using a continuous infusion schedule for as long as 14 days. The in vitro compatibility of the two drugs allows for the simultaneous administration in an admixture, and a pilot study was undertaken to determine the feasibility and tolerability of the infusion schedule for the combination. METHODS Ifosfamide at 500 mg/M2/day and carboplatin at 15 or 20 mg/M2/day were administered for 14-day cycles repeated at 28 days in 29 patients, with a total of 60 courses administered. RESULTS Total cumulative dose per cycle was: ifosfamide 7.0 g/M2 and carboplatin 210-280 mg/M2. Hematuria developed in five patients, four of whom had prior urologic disease, severe thrombocytopenia, or pelvic radiation. In all patients, the hematuria was transient and inconsequential despite the absence of mesna. Grade 3 or 4 leukopenia was observed in eight patients with or without thrombocytopenia and delayed subsequent treatment cycles. Thrombocytopenia was less frequent (Grade 3, 2 patients: Grade 4, 1 patient). No significant episodes of sepsis or hemorrhage were noted. Anemia requiring transfusion developed in 12 of 29 patients. Twenty-one of the 29 patients had received prior chemotherapy. Five of seven previously untreated patients with non-small cell lung cancer achieved a complete (1) or partial (4) response. CONCLUSIONS A continuous 14-day infusion of ifosfamide admixed with carboplatin is feasible in an ambulatory setting with no need for adding mesna for urologic protection and full dosage administration for each agent. Phase 2 studies in non-small cell lung cancer would be reasonable at the optimal doses of ifosfamide 500 mg/M2/day and carboplatin 15 mg/M2/day, and the potential exists for the introduction of additional agents, such as etoposide.

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.

Thirty-five patients were entered in a Phase I trial of an admixture infusion of etoposide (VP-16) and carboplatin (CBDCA) administered continuously for 5 or 7 days. Because of the compatibility and solubility of the two agents, the treatment program could be administered on an outpatient basis. The dose rate of VP-16 was fixed at 30 mg/m2/day (total dose 150 mg/m2 for 5 days or 210 mg/m2 for seven days) for each cycle. Carboplatin was evaluated at three dose rates: 50, 60, and 75 mg/m2/day on the 5-day infusion and 40, 50, and 60 mg/m2/day on the 7-day infusion with cycles repeated at 28 to 42 days. The dose limiting toxicity was hematologic and followed a pattern typical for carboplatin, that is, delayed neutropenia and/or thrombocytopenia with a protracted leukocyte recovery. Renal toxicity was observed in three patients. The optimum total dose for the infusional carboplatin component was 300 mg/m2 (5-day) and 420 mg/m2 (7-day). The total etoposide dose was 150 mg/M2 and 210 mg/M2, which did not appear to contribute to the hematologic toxicity. Delivery of the admixture of VP-16 and CBDCA was feasible, although cumbersome, as a result of the portable delivery system. Extending the duration of infusion increases the total cumulative dose of carboplatin and etoposide that can be administered without increasing adverse effects.

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.

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.

Oral fluoropyrimidines are presumed to emulate a parenteral continuous low-dose infusion delivery of the drug and the commonly used schedule is a 14 day on, 7 day off cycle at a total daily dose of 2500 mg/m2 dose. There is a substantial incidence of diarrhea and hand/foot syndrome with this dose schedule.To retrospectively analyze a clinical experience with a fixed-unit daily dose of capecitabine employed continuously (open ended without cycling) as a single agent, in combination with other agents, or combined with radiation to determine the drug tolerability with regard to stomatitis, diarrhea, and hand/foot syndrome, compared with the "standard" dose schedule.Fifty patients received 58 courses of continuous fixed daily dose capecitabine as a single agent (19 courses), combination with weekly irinotecan (15 courses); combined with 24-hour 5-fluorouracil (5-FU) infusion weekly (5 courses), combined with radiation (3 courses), or with other chemotherapy (16 courses). A fixed divided daily dose of 1500 or 2000 mg was administered for an open-ended period of time designed to deliver 10 weeks of continuous administration. Incidence and time to adverse event (toxicity) was determined for each course.Capecitabine was administered continuously for 4 weeks to 8 months with a median of 3 months. Seven of 50 patients (14%) experienced grade 2 or 3 toxicity; hand/foot syndrome, 4 (8%); stomatitis plus diarrhea (grade 2), 1%; and diarrhea alone, 3 (6%). Four of the 7 patients developing toxicity received concomitant weekly 24-hour 5-FU and 3 patients received concomitant CPT 11 (1), doxil (1), or taxane (1). None of the patients on single-agent capecitabine (19) developed toxicity of any grade. The total daily dose of capecitabine was 830 to 1250 mg/m2. The maximum dose intensity of the continuous fixed-dose schedule is 8750 mg/m2/week compared with 11,666 mg/m2/week for the standard dose and schedule (2500 mg/m2/day for 14 days every 21 days).Capecitabine administered as a continuous daily fixed dose has a low toxicity profile and can be administered in conjunction with other therapies relatively easily. This schedule provides for convenience and simplicity, and therapeutic effects are demonstrated even at low doses. The dose intensity of the noncycling continuous regimen is approximately 20% less than the standard cycling 2 weeks on every 21-day schedule.

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

Bilateral synchronous or metachronous germ cell tumors (GCT) of the testis are recognized in 2-3% of patients. Extragonadal GCT in the mediastinum or the retroperitoneum have been rarely reported in patients with primary GCT of the testes. Two patients were observed with two separate primary GCT; in 1 a retroperitoneal embryonal carcinoma was successfully treated with chemotherapy and surgery and a new primary developed 14 years later in the testicle as a seminoma. A second patient had a primary teratocarcinoma of the testes treated with surgery only; 4 years later he developed a mediastinal endodermal sinus tumor, which was fatal. These cases suggest that not only is the remaining testicle at risk for a second primary GCT, but also that extragonadal sites impose a similar risk and monitoring of patients should consider all potential sites for the development of GCT.

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.

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.

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.

Thirty patients with Stage III non-small cell lung cancer were entered on a trial to evaluate the feasibility of combined radiation and concomitant 5-fluorouracil infusion. Patients had received prior debulking surgery (nine), induction chemotherapy (16), or no therapy (five). Radiation employed standard fractionation (180-200 rad/day) administered to a median cumulative dose of 5500 rad (range, 4500-6200 rad). 5-Fluorouracil was infused 24 hours per day throughout the period of radiation at a dose of 300 mg/m2/day for a median of 42 days (range, 28-56 days). Radiation complications included pneumonitis three of 30 (10%) and esophagitis (27%). Chemotherapy complications included stomatitis, two of 27 (7%), and hand-foot syndrome, three of 30 (10%). Treatment interruptions were necessary in six of 30 (20%) and four of 30 required parenteral nutrition. At a median follow-up of 12 months 26/30 (87%) maintained local control and eight had distant metastases (three of whom presented with Stage IV disease). 5-Fluorouracil delivered continuously throughout standard fractionation radiation to high cumulative doses is feasible and practical. Comparative clinical trials of the various combined radiation and chemotherapy schedules employed are in order. One additional clinical observation was the identification of six of 30 (20%) with brain metastases at presentation or after 12 months, all of whom had adenocarcinoma histologic subtype.

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.

Twenty patients received 28 courses of 5FUDR (floxuridine) admixed with Cisplatin (CDDP) and administered as a continuous infusion for 24 hours for 14 consecutive days. Pharmaceutical studies of the admixture of 5FU with CDDP and 5FUDR with CDDP demonstrated that only 5FUDR was compatible with CDDP and that the admixture was stable for 7 days. This Phase I study established the optimal dose rate for the individual components of the admixture and demonstrated that CDDP decreases the maximum tolerated dose rate for 5FUDR. The optimal dose rate for 5FUDR is 0.075 mg/Kg/d, and for CDDP the optimal dose rate is 7.5 mg/M2/d. Dose rate limiting toxicity is an enteritis which is radiographically similar to regional enteritis and is related to the 5FUDR. An ancillary finding was a significant decrease in serum magnesium levels in 11 of 13 monitored courses presumably related to the platinum.

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.

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.

Forty-five patients received escalating dose rates of continuous infusion thio-triethylene thiophosphoramide (TEPA) for either five (26 patients) or 28 (19 patients) days. Dose rate limiting toxicity for the 5-day infusion was myelosuppression with leukocyte and platelet nadirs on days 21 and 28, respectively. The nadir was influenced by the presence and degree of liver disease. The optimal dose rate for 5-day infusion in the absence of liver disease was 12 mg/m2/d and was reduced to 8 mg/m2/d in patients with major liver disease. Dose rate limiting toxicity for the protracted 28-day infusion was leukopenia. The optimal dose rate for the 28-day infusion was 4 mg/m2/d. Pharmacologic studies included determination of plasma steady state concentrations (CSS) of thio-TEPA and TEPA. Dose rates up to 10 mg/m2/d produced thio-TEPA and TEPA CSS below the levels of detection of available analytical methodology, except in three patients infused at dose rates of 1, 2, and 4 mg/m2/d, respectively.

Twenty-two of 53 (42%) patients developed subclavian vein thrombosis (SVT) while receiving chemotherapy for advanced malignancy by an ambulatory pump constant infusion delivery system. The median time to thrombosis was 30 days (range, 5-270 days). Seven patients (36%) were asymptomatic and received no specific anticoagulation. Twelve patients (50%) received heparin followed by coumadin for 2 to 3 months. None of the 19 patients developed complications of the SVT. In three patients (14%), acute SVT progressed to complete or partial superior vena cava syndrome. The use of fibrinolytic therapy was successful in all three patients, and was adequate to lead to complete clinical resolution. Predisposing factors in the patient population included: (1) decreased antithrombin III levels prior to catheter insertion; (2) intrathoracic tumor, possibly creating low flow rates; and (3) improper or suboptimal home management of the catheter. The development of SVT was not related to the chemotherapeutic agent infused or the duration of therapy. The frequency of SVT in this patient population necessitates consideration of prophylactic methods in high-risk patients.

Thirteen patients with esophageal or gastroesophageal tumors with regional disease only were treated with sequential combined therapy. Weeks 1 to 6 continuous (24 hours) infusion 5-fluorouracil (5-FU) 300 mg/m2/d; weeks 6 to 10 or 12 infusional 5-FU administered concomitantly with radiation to the primary tumor site using standard fractionation with a cumulative median dose of 5000 rad; range 4400 to 6900 rad. Surgery was performed in five patients. All patients were evaluable for assessing response to the initial 5-FU infusion and 11/13 patients demonstrated tumor regression. Of 12 evaluable patients subsequently receiving combined infusional 5-FU and concomitant radiation, all 12 achieved complete clinical (10) or pathologic (two) tumor regression. Two of five patients having surgical resection had no pathologic evidence of tumor. All patients had relief of dysphagia within 1 week of initiating chemotherapy. Acute complications of therapy included stomatitis (two patients); hand-foot syndrome (two patients), and subclavian vein thrombosis (two patients). Stricture requiring periodic dilation occurred in three patients, and one patient developed a tracheoesophageal fistula at 36 months. Local control was maintained in 12/13 evaluable patients. Four of 13 patients were alive and without disease at 12 to 46 months. Nine patients died of distant metastases at 6 to 40 months. Median survival for the whole group was 16 months. Ten of the 13 patients (77%) survived for more than 1 year and 3/13 (22%) survived more than 3 years. This pilot study demonstrates the activity of 5-FU administered on an infusion schedule in both squamous and adenocarcinoma of the esophagus and the capacity to deliver infusional 5-FU throughout standard fractionation radiation. The local control and survival data may provide a basis for expanded Phase II trials, and a comparative trial against surgery alone might also be justified.

Ten patients with colorectal cancer metastatic to the liver were treated with hepatic arterial infusion (HAI) chemotherapy as second-line treatment following relapse after systemic venous infusion (SVI) of 5-fluorouracil. The objective was to determine if direct regional drug infusion would obviate drug resistance as has been reported when first-line treatment with 5-Fu was delivered by bolus schedule. The response rate to SVI as first-line treatment was 60% (6/10 patients) and only two patients responded to HAI; both had achieved an ongoing response to SVI. A tenuous interpretation of this experience is that the constant infusion schedule is the essential component to HAI chemotherapy in that none of the eight patients with established resistance to the infusion schedule responded to arterial infusion. However, prospective comparative trials will be necessary to establish the point. The advantages of SVI in comparison to HAI include the ability to treat extrahepatic disease as well as patients with aberrant or anomalous hepatic vasculature. In addition, the cost and complications of SVI are substantially less than that of HAI. A major question is the issue of the contribution of either treatment to meaningful survival.

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.

Patients with multiple discrete metastatic pulmonary nodules were serially monitored and tumor growth and regression rates were determined for selected measurable lesions. Tumor volume doubling time (TDT) in growing tumors or tumor volume halving time (THT) in regressing tumors was measured for multiple lesions. The objective of the study was to correlate tumor growth and/or regression rates with initial tumor size. A total of eight patients with 29 nodules of varying sizes was studied over observation periods the nodules regressed in response to specific chemotherapy. This study suggests that metastatic pulmonary nodules grow or regress at a relatively constant rate that is independent of pretreatment size. Growth and regression rates do not generally fluctuate, although tumor nodules may remain stationary or arrested for variable time periods. The study of tumor kinetics by clinical techniques is relevant to understanding tumor biology and to developing approaches to therapy.

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.

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.

The oral cavity is a common site of the origin of malignancy. It is also commonly affected by secondary infection and therapeutic modalities, such as radiation and chemotherapy. The symptom complex resulting from oral pathology includes pain and the inability to swallow. The secondary effects of compromised deglutition or swallowing are a decrease in food intake and an impoverished nutritional state which contributes to the inability of the local ulcerations to heal. The management of mouth care is therefore an extremely important aspect of cancer care, not only for patients with cancer of the head and neck, but also for patients on therapy programs which may cause secondary oral irritation. This chapter will focus on the diagnosis and treatment of oral ulcerations primarily induced by chemotherapy and on prophylaxis programs for oral hygiene to prevent or minimize local mucositis.

Marrow suppression and immune suppression commonly accompany cancer. They are most frequently observed in the leukemias and other diseases associated with replacement of the marrow and in primary malignant diseases of the immune system. In addition “solid” tumors or non-hematologic malignancy may metastasize to the bone marrow replacing normal elements. Finally, treatment directed at the tumor may incidentally affect production of cells. Bone marrow suppression is associated with the secondary development of anemia, leukopenia, or thrombocytopenia. Peripheral and central depletion of the “formed elements” of the blood—that is, the red blood cells, white blood cells, and platelets—leads to anemia, and can bring about infection and/or bleeding. Immune suppression may be distinguished from marrow suppression in that the cells involved in the immune system are lymphocytes and plasma cells. Furthermore, the depletion of these elements may only be evaluated by specific tests, such as immunoglobulin analysis and the lymphocyte function tests. The management of marrow suppression and immune suppression is one of the most delicate clinical issues because the common causes of mortality in cancer result from secondary sepsis or hemorrhage. This chapter will focus on the management of anemia, leukopenia, and thrombocytopenia in the patient with neoplastic disease and also on the management of chemotherapy in patients with secondary marrow and immune suppression.

Cancer therapy spans the disciplines of surgery, radiation therapy, chemotherapy, and immunotherapy. To these tumor-specific therapies may be added the general modalities of support therapy, including rehabilitation, and psychological therapy, and the multiplicity of non-specific therapies, such as pain management and transfusion. In more general terms, cancer therapy may be subdivided into two broad categories: curative therapy and palliative therapy. The former therapy usually consists of surgically excising the malignant lesion with the expectation of achieving cure. Radiotherapy has become recognized as another curative measure, particularly in treating Hodgkin’s disease and carcinoma of the cervix. Chemotherapy may have a role in curative therapy but is more properly applied in adjuvant therapy in connection with either radiation or surgery.

There are approximately 80 anti-tumor drugs employed to treat cancer patients today. Many of these drugs were discovered by virtue of animal tumor screening programs, some by rational chemical design, and others by astute clinical observation. An example of a drug developed by rational design is 5-Fluorouracil. Heidelberger created this drug after analyzing many human and animal tumors and discovering that malignant cell growth (in contrast to normal cell growth) was heavily dependent upon uracil as an essential component of DNA. He reasoned that distorting the uracil molecule by attaching a halogen, fluorine, may result in a DNA which is incompatible with tumor cell viability. Methotrexate is an example of a drug discovered by clinical observation. Dr. Sidney Farber was the first to detect that leukemic children developed progressive disease when placed on vitamins which included folic acid. The folic acid antagonist Methotrexate (see Figure 4.1) was just then in the process of development and Farber demonstrated in 1948 that an analogue drug of Methotrexate could induce remission in acute leukemia. The great majority of agents, however, have been incorporated into clinical use because of empiric drug screening. The plant alkaloid derivatives, for example, were identified as active anti-tumor agents in the process of screening any and all plant components of all species for such activity.

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.

The chemotherapy of primary and secondary neoplasms of the liver has evolved over the past decades passing through phases of single-agent systemic treatment; regional infusion chemotherapy; combination or multidrug chemotherapy; and finally, the present resurgence of regional delivery systems with single or multiple agents. The chemotherapeutic agents employed as a common denominator throughout the chronology of liver tumor therapy have been the fluoropyrimidines which exist as the inadequate “standard” for the palliative treatment of gastrointestinal malignancies. It would be fair to state at the outset that the systemic chemotherapy for primary and secondary tumors of the liver is woefully inadequate, and existing regimens do not consistently yield objective tumor responses of more than 20% or demonstrate a meaningful impact on survival. The exceptions to this perspective are the clinical circumstances in which the liver is occupied by responsive tumors such as breast cancer or lymphoma.

One hundred twenty-four patients with metastatic malignancy were treated with four different single agent infusion programs by constant intravenous infusion for 30 or more days. Drug was administered via a tunneled subclavian line by a battery-driven peristaltic pump (Cormed model ML6) on an ambulatory basis. This schedule allowed for increased cumulative drug dose for 5-Fu, decreased tolerated dose for vinblastine, and comparable doses for adriamycin and mitomycin-C relative to that delivered with the standard intermittent bolus schedule. Therapeutic effects were observed for three of four drugs studied: 5-Fu 13/31 colorectal cancer; adriamycin 7/29; and vinblastine 4/12, including 2/4 melanoma. Adverse effects were significantly reduced, particularly with regard to gastrointestinal toxicity, but also in adriamycin-associated cardiac effects and hair loss. Phase III comparative trials of intermittent bolus therapy with protracted infusion therapy are in progress for 5-Fu in advanced colorectal cancer and for adriamycin in specific tumors. Ambulatory pump infusion (API) chemotherapy is technically feasible and has improved patient tolerance to chemotherapy while demonstrating similar, if not comparable, antitumor effects.

Fifty-two patients received one of two doxorubicin (DOX)-based admixtures; DOX plus cyclophosphamide (CTX) or DOX plus vinblastine (VBL) administered as a continuous 24-hour infusion for protracted periods. Compatibility and stability of the two-drug admixture was established for a minimum of 7 days. Twenty patients on the DOX/CTX admixture were infused for a median of 20 days (range, 7-56 days). DOX/VLB was infused in 32 patients for a median of 18 days (range, 5-48 days). Dose limiting toxicity was leukopenia observed in 14/52 patients; 4/20 on DOX/CTX and 10/32 on DOX/VLB. Additional toxicities observed included stomatitis (15%) and subclavian vein thrombosis (23%). Tumor responses were observed in 11 patients, including 6/13 breast cancer; 2/2 hepatoma; 2/4 sarcoma and 1/1 ovarian cancer. Responses were relatively short-lived and no responses were noted in known anthracycline resistant tumors. Admixtures of chemotherapeutic agents represents a novel, but feasible, mechanism for delivery of multiple drugs with an infusion schedule and can be considered for Phase III comparative clinical trials.