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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...

The recent introduction of three oral fluoropyrimidine preparations to the antineoplastic armamentarium has been welcomed as a major step forward in providing a patient-convenient delivery system f...

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.

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.

Three patients with hydrocephalus secondary to central nervous system (CNS) metastases from lung or breast cancer are reviewed representing less than 5% of patients with CNS metastases seen at The Cancer Center of Boston over a 10-year period. The clinical picture is characterized by ataxia and mental confusion with dilated ventriculi on computed tomography (CT) scan of the brain. Computerized tomography of the brain and microscopic analysis of the cerebrospinal fluid are complementary in establishing the diagnosis of meningeal carcinomatosis. Surgical management by ventricular peritoneal shunt is an important component to multimodality therapy. The clinical course and extended survival in three patients provides a basis for recommending palliative surgical bypass as a therapeutic intervention with or without intrathecal chemotherapy, radiation, or both.

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.

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.

Clinical studies of infusional chemotherapy at The Cancer Center of Boston began in 1980 at the New England Deaconess Hospital and from 1986 to the present have continued under the auspices of a network of free-standing ambulatory cancer treatment centers in Massachusetts. Over 50 peer-reviewed articles on infusional chemotherapy and 3 textbooks on the topic have been published by clinical investigators associated with The Center, including phase I, II, and III trials, multidrug infusion programs, and combined chemo/radiotherapy programs. Bringing together the total experience in this review provides a perspective to address those areas that have been inadequately explored and a framework for future development in the field. This paper represents a comprehensive synthesis and analysis of clinical infusional studies carried out at The Center to the present with the goal of achieving those objectives.

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.

It is important that the stability of reconstituted parenteral antineoplastic agents be established, particularly in the context of ambulatory infusion systems for delivery. The stability of selected agents within each of the five classes of compounds (antimetabolites, alkylating agents, antibiotics, alkaloids and glycosides, and metals) is reviewed from the literature together with additional data from studies carried out using high-performance liquid chromatographic (HPLC) technology in clinically applicable volumes and concentrations for ambulatory infusion. The stability of reconstituted drugs varies from a few minutes (mecloethamine) to many months (FU). Compatibility data on two- and three-drug admixtures of cytotoxic agents are reported for a number of common multidrug regimens. Tabular presentation of the drug-drug compatibilities and incompatibilities is included along with a discussion of the mechanisms for drug-drug interaction. The use of a broad spectrum of compatible cytotoxic drugs is possible, including fluoropyrimidine-, anthracycline-, and platinum-based combinations, providing the capability of carrying out multidrug infusions for 4–7 days in an ambulatory delivery system.

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.

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.

This is a distinctly British textbook that will provide little competition to the three leading textbooks in the field of clinical oncology available in the United States. Although it is presented as a comprehensive and up-to-date text with the intent of providing authoritative help on how best to manage an individual patient, it is in fact neither comprehensive nor authoritative but provides instead superficial information that is frequently outdated or incomplete, and the treatment orientation is extraordinarily unbalanced in the direction of radiation therapy. The book is divided into three sections: "Principles," "Clinical Practice," and "Common Problems." Four of the 13 chapters in the first section are devoted to radiation therapy, reflecting the orientation of the whole text. The second section includes 25 chapters that are unbalanced with regard to comprehensive detail. For example, 20 pages are devoted to breast cancer, a common condition, and 42 pages are devoted to

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.

Fine-needle aspiration biopsy for cytologic diagnosis was performed on seven patients suspected of having pancreatic tumors. A 23-gauge biopsy needle was accurately placed in the suspicious lesion under ultrasonic guidance. Six patients had tumors; of these, five had a definite cytologic diagnosis, and the sixth was suspicious of tumor. There was no morbidity associated with the procedure in these patients. Although fine-needle biopsy is not expected to prolong life in patients with pancreatic tumors, it does eliminate the need for more complicated, expensive, uncomfortable and hazardous diagnostic procedures. In many cases exploratory surgery may be obviated.

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.

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

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.

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.

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.