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A number of new therapeutic approaches are showing a high degree of activity against advanced colorectal cancer, according to investigators speaking at the annual meeting of the American Society of Clinical Oncology (ASCO) in May. The new therapies included both new single-agent treatment modalities and novel chemotherapeutic combinations.
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TRIMETREXATE ENHANCES CONVENTIONAL THERAPY |
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 Top Trimetrexate Enhances... Irinotecan and Sequential 5-FU...Tomudex Offers Advantages Over...Interferon Prolongs Survival for...Increased Survival of Non-Small...Growth Factor Increases...ASCO President Calls for... |
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While the standard therapeutic approach for advanced colorectal cancer of 5-FU with leucovorin modulation usually results in an overall response rate of around 23%, the addition of trimetrexate to this regimen produced a major response rate of 48% in patients with unresectable or metastatic colorectal cancer, Blanke said. Furthermore, the combination therapy was generally well manageable, with little hematologic toxicity, gastrointestinal adverse effects being the major difficulty.
These conclusions were reached from a study of 36 previously untreated patients with unresectable or metastatic colorectal cancer who received trimetrexate 110 mg/m2 on day 1 as a 60 min i.v. infusion; leucovorin 200 mg/m2 on day 2 as a 60 min i.v. bolus 24 h after the start of the trimetrexate; 5-FU 500 mg/m2 as an i.v. bolus on day 2 immediately following leucovorin; and then oral leucovorin 15 mg every 6 h times seven doses starting 6 h after 5-FU. A cycle was defined as eight weeks, to include six weeks of chemotherapy and two weeks off. Cycles were repeated until disease progression or other reasons for patient withdrawal.
In 29 evaluable patients, there were two complete responses (7%) and 12 partial responses (41%). An additional 12 persons (41%) had stabilization of disease. With a median follow-up of 51.8 weeks, the median time to progression of disease was 25.7 weeks, while the median survival, although not yet reached, was an estimated 53.4 weeks. 
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IRINOTECAN AND SEQUENTIAL 5-FU PROVING ACTIVE |
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TopTrimetrexate Enhances...Irinotecan and Sequential 5-FU...Tomudex Offers Advantages Over...Interferon Prolongs Survival for...Increased Survival of Non-Small...Growth Factor Increases...ASCO President Calls for... |
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Since simultaneous administration of irinotecan and 5-FU in patients with metastatic colorectal cancer resulted in an unexpectedly low response rate (11.1%; 4 PR/36 pts.), a study was set up to administer irinotecan with 5-FU as a sequential administration in previously untreated patients with measurable metastatic colorectal cancer, Yamao said.
Irinotecan was administered on a dose escalation schedule at 100 mg/m2, 125 mg/m2, 150 mg/m2, and 175 mg/m2 intravenously over 90 min on days 1 and 15. A fixed dose of 5-FU (600 mg/m2 daily) was given as a continuous infusion from day 3 for five consecutive days. Six patients were entered into each dose level, and treatment was repeated every four to five weeks.
At present, 20 persons have been entered into the study and 19 individuals were evaluable for toxicity and response at irinotecan doses of 100 mg/m2 to 150 mg/m2, Yamao said. The maximum tolerated dose has not yet been reached. Partial responses were obtained in five patients for a preliminary response rate of 26.3%. Toxicities were relatively well managed, with one grade 4 neutropenia at irinotecan 125 mg/m2 and one grade 3 diarrhea at the same dosage level.
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TOMUDEX OFFERS ADVANTAGES OVER CONVENTIONAL THERAPY |
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TopTrimetrexate Enhances...Irinotecan and Sequential 5-FU...Tomudex Offers Advantages Over...Interferon Prolongs Survival for...Increased Survival of Non-Small...Growth Factor Increases...ASCO President Calls for... |
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The trial included 439 patients with previously untreated colorectal cancer randomized to Tomudex 3.0 mg/m2 intravenously as a single dose once every three weeks (222 pts.) or 5-FU 425 mg/m2 and leucovorin 20 mg/m2 as an i.v. bolus daily for five days, given every four to six weeks (212 pts.). Five randomized patients did not receive therapy, but all individuals who received trial treatments whether or not they were eligible or evaluable were included in the analysis.
The overall objective response rates were 20% in the Tomudex-treated patients and 16.5% for those on conventional therapy, Seitz said. Median time to disease progression was 4.9 months and 3.5 months, respectively, and median survival was 10.3 months and 10.5 months, respectively. There were no statistically significant differences between the two treatments in any of the efficacy endpoints.
Patients treated with Tomudex had much lower rates of potentially life-threatening toxicities than did patients treated with 5-FU and leucovorin, Seitz said. Toxicities included higher levels of grades 3 and 4 leucopenia (30% versus 14%) and mucositis (22% versus 2%) on 5-FU plus leucovorin. Also, patients on Tomudex had a significantly lower incidence of alopecia.
In a related presentation, J.R. Zaleberg of Heidelberg Repatriation Hospital, Melbourne, Victoria, Australia, and a spokesman for the Tomudex Colorectal Cancer Study Group, pointed out that a more comprehensive analysis of the safety profiles of the two treatment approaches used in the comparison trial confirmed an association of increasing age and female gender with grades 3 and 4 toxicities of leucopenia and mucositis in patients receiving modulated 5-FU.
On multivariate analysis, Zaleberg said, for 5-FU plus leucovorin patients only, female gender predicted for increased grades 3/4 leucopenia, while increasing age (60-69, over 70) was associated with both increased grades 3/4 leucopenia and increased grades 3/4 mucositis. For Tomudex, the only association noted was an increase in transaminase with female gender, which appeared to be of limited clinical significance.
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INTERFERON PROLONGS SURVIVAL FOR RENAL CELL CANCER PATIENTS |
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In a phase III clinical trial, patients volunteered for a one-year course of treatment and were randomized to receive either interferon alfa-2a injected s.c. three times every week at a dose of 18 million international units (IUs) and vinblastine given i.v. once every three weeks at 0.1 mg/kg, or vinblastine alone.
Of the 160 individuals with advanced renal cell carcinoma who took part in the trial, 79 received the combination treatment and 81 received vinblastine chemotherapy alone. Treatment was continued for one year unless disease progression or intolerable side effects occurred. The main endpoint of the study was survival.
Some of the patients in the study needed to reduce the interferon alfa-2a dose from 18 million IUs three times weekly to 9.0 million IUs three times weekly to manage the typical side effects seen with interferon (fever, muscle pain, and fatigue). Not only were the side effects easily reversible, but results of the study demonstrated that these patients lived as long as the patients who continued at the higher dose, Pyrhönen said. This means that these persons can adjust the dose to control side effects and still benefit from treatment.
Median survival in the combination vinblastine and interferon alfa-2a arm was 15.8 months, versus 8.8 months in the vinblastine-only arm, a statistically significant increase of 80%, Pyrhönen said. Median time to disease progression in the combination arm was 3 months versus 2.1 months in those on vinblastine alone. The overall objective response rate for interferon alfa-2a and vinblastine-treated individuals was 16.5% with seven complete responses (8.9%) and six partial responses (7.6%), versus two partial responses (2.5%) in those on chemotherapy alone. Pyrhönen said several patients on the combination regimen can be considered long-term survivors. Fifty persons are still alive and two individuals have survived more than five years.
"In comparison with conventional chemotherapy regimens, this study shows that combination therapy with interferon prolongs survival by seven months and delays disease progression," commented Lynn Mara Schuchter, University of Pennsylvania Cancer Center. "While there was an increased incidence of side effects in the combination therapy group, the addition of interferon can be considered an important advance in prolonging the overall survival of patients with advanced renal cancer," Schuchter said.
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INCREASED SURVIVAL OF NON-SMALL CELL LUNG CANCER WITH TAXOL-CISPLATIN COMBINATION |
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"The Taxol combination produced superior response rates and a trend toward longer survival for these patients than the standard treatment," said David Johnson, Cornelius A. Craig Professor of Medicine and Director of Medical Oncology at Vanderbilt University Medical Center, Nashville, TN. "Lung cancer is extremely difficult to treat and any survival advantage, even the two to three months found in this study, is clinically meaningful to the patient," he said. "Taxol is the most active agent we have seen for the treatment of NSCLC, and we are just beginning to see its full potential in combination therapy."
The multi-centered ECOG trial involved 599 patients from across the United States. Three groups of patients received one of the following regimens: a standard dose of Taxol plus Platinol; a high dose of Taxol plus Platinol with G-CSF; or etoposide plus Platinol. The response rates and median survival times and one-year survival rates for patients receiving the Taxol/Platinol combinations were higher than for those receiving the standard treatment of Platinol plus etoposide. In addition, researchers reported that the Taxol/Platinol combination was well tolerated by patients.
The Taxol/Platinol combinations extended median survival time by two to three months, compared to the standard chemotherapy of etoposide/Platinol. The Taxol/Platinol combinations extended median survival to approximately 10 months, as compared to survival with the standard treatment. Response rates were also higher for the Taxol combination therapy. The Taxol/Platinol combination showed a 26.5% response rate, compared to the 12% response rate with standard treatment. The high-dose Taxol combination, given with G-CSF, showed a 31.2% response rate. "This is consistent with the findings of other studies in which Taxol is used as a first-line therapy in combination with a platinum," said Johnson.
A study reported earlier this year by the Gynecologic Oncology Group demonstrated that Taxol plus Platinol used first-line in treatment of women with advanced ovarian cancer improved median survival by 50% or approximately 13 months. "Taxol in combination with a platinum is now considered standard therapy for ovarian cancer in the United States and, based upon these findings, this combination is now considered ECOG’s standard first-line treatment in future lung cancer trials as well," Johnson said. He noted that while the higher dose of Taxol with G-CSF had a statistically superior response rate over a lower dose of Taxol, toxicity levels were increased at the higher dose level. The most common side effects from the therapy included alopecia (hair loss), and neutropenia (low white blood cell count) with and without fever.
A European Organization for Research and Treatment of Cancer randomized study of 264 advanced NSCLC patients showed a response rate of 47% for patients who received the Taxol/Platinol combination, as compared to 29% for the standard tiniposide/cisplatin combination. Median survival was more than nine months.
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GROWTH FACTOR INCREASES PLATELETS IN THROMBOCYTOPENIA, STUDY FINDS |
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The patients then received the same dose of rHuTPO after chemotherapy for either advanced malignancies (thiotepa 65 mg/m2 every 28 days in two cycles) or soft tissue sarcoma (doxorubicin mg/m2 and ifosfamide 10 g/m2 every 21 days). To date, Vadhan-Raj noted, 14 patients have been treated in the two studies. In all patients, rHuTPO was well tolerated and there were no serious adverse effects.
Although the two phase I studies were not designed to demonstrate definitive efficacy of the investigational drug, and while the early results represent only a small number of patients, the fact that rHuTPO caused the blood platelet counts to increase in all 14 patients was encouraging, Vadhan-Raj said.
The increase began early after administration of the single dose of rHuTPO and peaked on day 12 before beginning to drop back toward baseline. At day 20, however, the platelet count still was higher than baseline. At the highest dose level tested (1.2 mcg/kg) the median platelet count increase was 158%.
Morphologically, the platelets appear normal, Vadhan-Raj said. In addition, with the administration of rHuTPO, there was a fourfold increase in bone marrow megakaryocytes observed, as well as a significant increase in the CD34+ cell count and a number of other hematopoietic progenitors. There were no changes in white blood cell counts or in hemoglobin values following the single dose rHuTPO administration.
"Single-dose treatment with thrombopoietin was well tolerated and effective in raising platelet counts," Vadhan-Raj said. "Also, rHuTPO appears to be a potent stimulator of megakaryocytopoiesis in vivo."
In a related presentation, Michael Fanucchi, Emory University, pointed out that another platelet growth factor – pegylated recombinant human megakaryocyte growth and development factor (MGDF) – was able to stimulate the production of more blood platelets in lung cancer patients undergoing intensive chemotherapy.
In a multicenter phase I/II study, 50 chemotherapy-naive patients with NSCLC, stage III or IV, were treated for 10 days before (cycle 0) and up to 17 days after (cycle 1) chemotherapy with either escalating doses of MGDF 0.03, 0.1, 0.3, 1.0, 3.0, or 5.0 mg/kg/day as a daily s.c. injection, or placebo.
In cycle 1, these individuals were treated with carboplatin at the area under the curve equal to 9 mg/m2/min by Calvert, with measured Crcl, and paclitaxel 175 mg/m2 in a 3-h i.v. infusion. The study showed that MGDF was generally well tolerated, with no systemic toxicities, and that MGDF decreased the duration and severity of thrombocytopenia, Fanucchi said. There was a rapid return to baseline platelet count and a higher platelet nadir in the patients who received MGDF. After chemotherapy, the median return to baseline platelet count in the MGDF-treated individuals was 13 days, while persons on placebo did not recover to baseline before the next cycle of themotherapy.
"The genes that control red and white blood cell production have already been cloned which give rise to drugs that counteract the effects of chemotherapy on those cells," Fanucchi stated. "Platelets were the missing link."
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ASCO PRESIDENT CALLS FOR NEW COALITION TO REPRESENT CLINICAL ONCOLOGY |
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"The rapidity of change in health care delivery, cost containment, and managed care all threaten the practice of oncology," John Glick, Director of the University of Pennsylvania Cancer Center, said at the ASCO annual meeting in Philadelphia on May 20, 1996. Glick completed his term as ASCO President later that day.
The new coalition, which Glick proposed to call the American Federation of Clinical Oncology Societies, would consist of representatives of various clinical societies representing oncology professionals. Cancer patient organizations also would be invited to become members, Glick said.
Glick’s proposal coincided with the society’s decision to withdraw from the National Coalition for Cancer Research (NCCR), which has represented the interests of several large oncology socieities and cancer patient advocacy groups for the past 10 years. ASCO and another organization, the National Coalition for Cancer Survivorship, recently withdrew from NCCR. Both groups cited unresolved differences over governance of NCCR as their reasons for leaving the coalition.
In his remarks, Glick characterized ASCO as an organization undergoing major changes and growth. The society’s annual meeting attracted nearly 14,000 participants this year, the largest in the group’s 32 years. The society has 10,700 members, about 1,000 more than last year.
Over the past year, Glick said, ASCO has:
Endorsed a new set of goals for the society. Fully implemented the recommendations of a 1993 strategic plan, which called for ASCO to hire an executive vice president and establish a headquarters in the Washington, DC, area. Developed a set of priorities for the next one to three years. Established a partnership with patient advocacy organizations. Expanded its health services research program. Improved its scientific and educational programs. Developed ASCO Online, which will make ASCO information available over the Internet. Broadened its active membership category and created an associate membership category for residents and trainees. Improved ASCO’s relationships with other oncology societies. Published several position papers on policy issues. Lobbied successfully for increased funding from the NCI for patient-oriented research. Developed a course on methods in clinical cancer research. "It is a time of transition, growth and maturity for ASCO," Glick said. "We must be prepared to realistically assess our strengths and meet new challenges in a time of unprecedented scientific and educational opportunities. Revolutionary new knowledge from laboratory research has raised public expectations for the prevention and cure of cancer to a higher level than before...At the same time, we are confronted by major changes and challenges in our everyday practice of medicine and in the conduct of both laboratory and patient-oriented research.
"The practice of oncology and the delivery of high quality cancer care are threatened by major changes in health care delivery and financing, as well as by frequent changes in public policy. ASCO is dedicated to improving the health and well-being of people with cancer through research, education and the practice of medicine. I believe ASCO’s credo should be ‘Do what’s right for and in the best interest of people with cancer." If we can remember to do what’s right for our patients and their families, and make that the guiding principle that motivates our actions and policies, then we will do what’s right for our profession."
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FOOTNOTES |
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