Is it time for oncologists to modify their laissez-faire attitude toward alternative/complementary 'drug therapy'?
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Attitude of Health Personnel↗
Biomedical subjects
Maurie Markman
Publications and source records attributed to Maurie Markman.
Phase 2 trial of carboplatin, paclitaxel, and irinotecan in ovarian, fallopian tube, and primary peritoneal cancers.
OBJECTIVE: Our goal in this nonrandomized phase 2 trial was to evaluate the toxicity and obtain preliminary data on the potential efficacy of a novel three-drug combination regimen (carboplatin-paclitaxel-irinotecan) when employed as initial therapy of advanced ovarian cancer or as second-line treatment in the setting of a prolonged (>or=12 months) treatment-free interval. METHODS: Patients with a histologically confirmed diagnosis of advanced ovarian cancer, primary adenocarcinoma of the peritoneum, or fallopian tube cancer were enrolled in the study. Patients received carboplatin (AUC 5), paclitaxel (150 mg/m(2) over 3 h), and irinotecan (100 mg/m(2) over 90 min). The three-drug combination was initially administered on an every 21-day schedule, but due to toxicity was subsequently changed to a 28-day program. RESULTS: A total of 30 patients were enrolled into this phase 2 trial. Twenty-three patients were chemotherapy naive, while 7 had received prior chemotherapy. Seventeen patients completed all six cycles of treatment. Eight patients (27%) were removed from the study after a median of three cycles due to toxicities. Seventeen patients (57%) experienced grade 4 neutropenia, with three individuals requiring hospitalization for neutropenic fever and dehydration. Grades 3 and 4 thrombocytopenia were experienced by three patients each. The principal nonhematologic toxicities were diarrhea (grade 3: three patients) and fatigue. The overall objective clinical response rate was 83%. CONCLUSIONS: The combination of carboplatin-paclitaxel-irinotecan can be administered to women with advanced ovarian cancer with significant, but overall acceptable toxicity. Modification of the regimen from a 3-week to a 4-week schedule permits a greater percentage of patients to complete the program without experiencing excessive toxicity. The overall objective response rate observed in this trial is comparable to other combination regimens employed in this setting. Defining a place for this three-drug program in the standard management of ovarian cancer will require the conduct of an appropriately designed randomized trial.
Adult↗
Activity of weekly paclitaxel in patients with advanced endometrial cancer previously treated with both a platinum agent and paclitaxel.
PURPOSE: The aim of this report is to describe the potential clinical utility of the weekly administration of paclitaxel in patients with endometrial cancer previously treated with a platinum agent and paclitaxel (delivered on an every 3-week schedule). METHODS: We briefly describe the clinical courses of three women with recurrent endometrial cancer who had prior exposure to platinum and paclitaxel, and who were subsequently treated with weekly paclitaxel in an effort to relieve significant cancer-related symptoms. RESULTS: In these individuals, the weekly administration of paclitaxel was reasonably well tolerated. There was evidence of both objective and subjective improvement in the status of the malignant process. CONCLUSION: The weekly administration of paclitaxel is a rational management approach in women with metastatic or recurrent endometrial cancer who have previously received treatment with both a platinum agent and paclitaxel. This delivery strategy should be further explored through the conduct of well-designed clinical trials, both in the primary and secondary chemotherapeutic management of this malignancy.
Aged↗
Experience with the management of neutropenia in gynecologic cancer patients receiving carboplatin-based chemotherapy.
Objective. There exists limited information in the medical literature regarding the incidence and severity of carboplatin-associated neutropenia, outside the setting of a clinical trial. We wished to examine this issue in a large single institution experience involving patients receiving both single agent and combination carboplatin-based chemotherapy for management of a female pelvic malignancy. Patients and methods. The medical records of women with gynecologic cancers treated with carboplatin-based chemotherapy at the Cleveland Clinic from January 1, 1998 through December 31, 2002 were retrospectively reviewed to determine the incidence and severity of neutropenia. Results. During the time period encompassed by this analysis, a total of 323 patients received 2145 cycles of carboplatin-based chemotherapy (total of 441 courses; median cycles/patient: 6 [range 1-27]). The total number of each program utilized, and the incidence of grades 3 and 4 neutropenia observed (lowest nadir/regimen), were as follows: single agent carboplatin (178 courses; 5% grade 3, and <1% grade 4), carboplatin/paclitaxel (198; 23% and 6%), carboplatin/docetaxel (42; 17% and 73%) and carboplatin/paclitaxel/irinotecan (23; 39% and 61%). Febrile neutropenia was uncommon, and there was only a single neutropenic-related death. Conclusion. Both single-agent carboplatin and carboplatin/paclitaxel result in a very low incidence of grade 4 neutropenia. While combining docetaxel with carboplatin or adding a "third drug" to carboplatin/paclitaxel substantially increases the incidence of severe neutropenia, neutropenic fever, and required hospitalizations for septic episodes are uncommon. The prophylactic oral administration of a broad-spectrum antibiotic (e.g., ciprofloxicin) in the presence of grade 4 neutropenia appears to be an effective strategy to minimize the risk of subsequent febrile events.
Adult↗
Use of tamoxifen in asymptomatic patients with recurrent small-volume ovarian cancer.
OBJECTIVES: Tamoxifen, a well-tolerated oral hormonal agent with biological activity in ovarian cancer, is a potentially attractive option in asymptomatic patients with recurrent disease. Unfortunately, the clinical utility of the drug in this specific setting has not been well documented. PATIENTS AND METHODS: A retrospective review was conducted of patients with cancers of the ovary, fallopian tube, and primary cancer of the peritoneum at the Cleveland Clinic who experienced recurrence of the malignancy, in the absence of large volume disease (by physical exam and radiographic evaluation) or any cancer-related symptoms, and who received tamoxifen (20 mg [most patients] or 40 mg/day) before re-initiation of cytotoxic chemotherapy. RESULTS: Fifty-six patients (45 after primary chemotherapy; 12 after second-line treatment) satisfied the criteria noted above. The median duration of treatment was 3 months (range 1-30 months), with 42% and 19% of patients remaining on tamoxifen for >/=6 and >/=12 months, respectively. Reasons for discontinuation were equally divided between three causes: (a) continued rise in CA-125 antigen level without symptoms or other objective signs of cancer; (b) evidence of progressive disease by physical exam or radiographic evaluation in the absence of symptoms; and (c) development of cancer-related symptoms. CONCLUSION: In the absence of data from a randomized controlled trial which defines optimal management of the asymptomatic ovarian cancer patient with documented recurrent disease, tamoxifen is a rational management option, although it remains unknown if the delay in subsequent administration of chemotherapy in some individuals for periods greater than 6-12 months results from a direct effect of this agent or simply reflects the natural history of disease in a subset of patients in this clinical setting.
Adult↗
Examples of the marked variability in the relationship between the serum CA-125 antigen level and cancer-related symptoms in ovarian cancer.
OBJECTIVE: While the clinical utility of the serum CA-125 antigen level in demonstrating objective evidence of regression or progression of disease in women with ovarian cancer is well-established, the relationship between both the absolute value of this tumor maker, or its rate of change over time, and the short-term clinical course (e.g., development of cancer-related symptoms) in individual patients remains poorly defined. CASE REPORTS: Five women currently under the care of physicians in the Gynecologic Cancer program of the Cleveland Clinic demonstrate the marked variability in the correlation between the serum CA-125 antigen and the natural history of disease for individual patients with ovarian or primary peritoneal cancers. In these cases, persistent elevations (>100 units/ml for >2 years), rapid changes (<200 units/ml to >2000 units/ml over < or = 2 months), or extremely high CA-125 values (>5000 units/ml) failed to accurately predict the presence, time to development, or severity of symptoms. CONCLUSION: In the second-line and palliative management of ovarian or primary peritoneal cancers, it is important to emphasize the critical need for clinical judgement in the decision to initiate or alter therapy in individual patients based solely on changes in the serum level of the CA-125 antigen.
Aged↗
Survival following the documentation of platinum and taxane resistance in ovarian cancer: a single institution experience involving multiple phase 2 clinical trials.
OBJECTIVES: There are very limited data in the oncology literature regarding the survival of women with both platinum and taxane-refractory ovarian cancer. METHODS: To examine this issue, we retrospectively reviewed the survival of patients treated on one (or more) of four previously reported nonrandomized single-agent phase 2 trials (topotecan, liposomal doxorubicin, gemcitabine, docetaxel), involving women with well-characterized platinum/taxane-resistant ovarian, fallopian tube, and primary peritoneal cancers. Following their most recent treatment with both classes of agents, patients must have either not responded to therapy or experienced a treatment-free interval of <3 months before documented disease progression. RESULTS: The median survival of the 111 patients (median age 61) included in this analysis was 6 months (range 1-37 months). Whereas 36 patients (32%) survived for <4 months, 30 patients (27%) lived for > or =12 months following documentation of resistance to both platinum and taxane therapy. CONCLUSION: With currently available antineoplastic drug therapy of platinum/taxane-resistant ovarian cancer, overall survival is relatively short, but a substantial minority of patients can be anticipated to live for periods in excess of 1 year. It remains uncertain whether such unexpectedly prolonged survival results from a biological response to chemotherapy or simply reflects the natural history of disease in a subset of patients with this malignancy.
Adult↗
Cardiac safety profile of prolonged (>or=6 cycles) pegylated liposomal doxorubicin administration in patients with gynecologic malignancies.
OBJECTIVE: Pegylated liposomal doxorubicin (PLD) is currently utilized in the management of several solid tumors. While PLD has been shown to be less cardiotoxic than doxorubicin, the safety of prolonged administration (e.g., >or=6 cycles) of the agent remains undefined. METHODS: A retrospective chart review was performed of the Cleveland Clinic experience from 1997 to 2003 with the prolonged (>or=6 cycles) use of PLD in individuals with gynecologic malignancies. PLD was administered at doses ranging from 20 to 40 mg/m(2) (infused over 1-2 h) with treatment repeated every 4-6 weeks. While on therapy, patients underwent routine evaluation for toxicity, including the performance of multigated acquisition (MUGA) scans for determination of left ventricular ejection fraction (LVEF). RESULTS: Twenty-two patients (18 ovarian cancer; 3 primary peritoneal cancer, 1 endometrial cancer) met the criteria for inclusion in this analysis. This population had received a median of 4 (range 1-8) chemotherapy regimens before initiation of PLD. No patient had previously received doxorubicin. The median number of PLD cycles and cumulative dose of LD delivered were 8 (range 6-26) and 483 mg/m(2) (256-1699 mg/m(2)), respectively. One or more MUGA scans were obtained in 14 (64%) patients. No patient experienced clinical evidence (physical findings, symptoms) of heart failure. There were no dose reductions due to cardiac dysfunction, and no patient experienced a decline in LVEF to <50%, or a >or=10% reduction compared to a baseline value. CONCLUSIONS: Prolonged therapy with PLD is possible in appropriately selected patients with advanced gynecologic malignancies. In this clinical setting, cardiac dysfunction does not appear to be a toxicity, which limits the duration of treatment. The development of evidence-based guidelines for monitoring cardiac function in this patient population would be quite useful.
Aged↗
Grade 3 liposomal-doxorubicin-induced skin toxicity in a patient following complete resolution of moderately severe sunburn.
PURPOSE: Palmar-plantar erythrodysesthesia (PPE) is a potentially serious toxicity of a number of cytotoxic chemotherapeutic agents, including liposomal doxorubicin. Activities that may increase the risk of this toxicity should be avoided. CASE REPORT: A patient with platinum-resistant ovarian cancer, responded to, and tolerated (including no skin rash) an initial cycle of liposomal doxorubicin (40 mg/m(2)). Unfortunately, several days before her next scheduled cycle, she developed significant sunburn (intense erythema without blistering). Despite an additional 1-week delay (total of 5 weeks from the prior liposomal doxorubicin), and complete visual recovery from the effects of the sunburn, the patient developed severe (grade 3) PPE involving both hands (pain, pronounced erythema, blistering, without ulceration), and a slightly less extensive reaction of both feet, following subsequent treatment with a 25% reduced dose of the agent (30 mg/m(2)). CONCLUSION: Caution is advised when considering the administration of liposomal doxorubicin following a major sunburn, despite total resolution of the visible effects on the skin. A delay of several weeks may be appropriate to avoid exacerbation by the chemotherapeutic agent of persistent subclinical damage to normal epithelial cells.
Doxorubicin↗
Phase 2 trial of carboplatin plus tamoxifen in platinum-resistant ovarian cancer and primary carcinoma of the peritoneum.
OBJECTIVES: A previously reported phase 2 trial suggested substantial clinical activity associated with the combination of a platinum agent and tamoxifen in the treatment of platinum-resistant ovarian cancer. We wished to confirm or refute this observation in a patient population with well-characterized platinum-resistant disease. METHODS: Patients with ovarian or fallopian tube cancers or primary carcinoma of the peritoneum whose disease had either failed to respond to a platinum-based regimen or had responded but experienced a "treatment-free interval (TFI)" of < or =3 months, or if the TFI was >3 months they had been retreated and failed a platinum-based program, were eligible for entry into this phase 2 single institution protocol. Carboplatin (AUC 5) was delivered on a q-21 day cycle. Tamoxifen was administered at a dose of 80 mg/day for the first cycle, and then reduced to 40 mg/day. Treatment was to be continued until evidence of disease progression or unacceptable toxicity. RESULTS: Fourteen patients were treated on this phase 2 trial. In addition to being platinum-resistant, 10 patients had cancers that were also documented to be taxane-resistant (similar criteria to that defined above for platinum). While treatment was generally well tolerated, there were no objective (measurable disease or CA-125 response criteria) or subjective responses to this treatment program. CONCLUSION: In this phase 2 trial, we have been unable to confirm a meaningful level of clinical activity for the combination of carboplatin plus tamoxifen in a patient population with well-characterized platinum-resistant ovarian cancer.
Adult↗
Recombinant human erythropoietin as an adjunct to radiation therapy and cisplatin for stage IIB-IVA carcinoma of the cervix: a Southwest Oncology Group study.
OBJECTIVE: The survival of cervix cancer patients is associated with their hemoglobin (Hgb) level during radiotherapy. The Southwest Oncology Group (SWOG) conducted a phase II trial to determine whether recombinant human erythropoietin (rHuEPO) safely corrects anemia during chemoradiotherapy for cervix cancer. METHODS: Patients had stage IIB-IVA cervix cancer and a Hgb between 8.0 and 12.5 g/dl. All patients received rHuEPO thrice weekly and oral iron starting 10-15 days before their 5-week course of whole pelvic irradiation and weekly cisplatin followed by intracavitary brachytherapy. RESULTS: Fifty-three patients from 26 institutions received the protocol treatment. The mean Hgb was 10.4 +/- 1.3 g/dl on the first day of rHuEPO administration (baseline), 11.0 +/- 1.6 g/dl on the first day of chemoradiotherapy, 11.6 +/- 1.9 g/dl at the midpoint of chemoradiotherapy, and 11.8 +/- 2.2 g/dl at the end of chemoradiotherapy. The target Hgb level of 12.5 g/dl was achieved in 40% of patients (95% CI 26-56%) by the midpoint of Chemoradiotheraphy. Change in Hgb was associated with baseline serum iron (P = 0.008) and transferrin saturation (P = 0.05) levels, but not with baseline Hgb or serum ferritin, or patient age. Seven patients developed deep vein thrombosis. Two-year progression-free survival (PFS) was 43% and overall survival (OS) was 51%. Survival was significantly associated with Hgb level at the end of chemoradiotherapy, but not with the baseline Hgb level. CONCLUSIONS: rHuEPO and iron gradually increased Hgb levels in anemic women with local advanced cervix cancer during chemoradiotherapy. There was a higher than expected incidence of deep vein thrombosis. The progression-free and overall survival rates were lower than reported for women with normal Hgb levels.
Adult↗
Phase 2 trial of prolonged administration of oral topotecan in platinum/taxane-refractory ovarian, fallopian tube, and primary peritoneal cancers.
OBJECTIVES: Preclinical and clinical data have demonstrated the importance of schedule in optimizing the cytotoxic potential of topotecan, one of the most active agents in ovarian cancer. The availability of oral topotecan permits the exploration of the clinical utility of prolonged treatment programs employing this drug. METHODS: Patients with platinum/taxane resistant ovarian and primary peritoneal cancers were treated with oral topotecan at an initial fixed dose of 1.5 mg/day for 5 days, followed by a 2-day break, with treatment continued on this schedule until disease progression or unacceptable toxicities. RESULTS: Seven patients (median age 61) were entered into this phase 2 trial before further enrollment was discontinued due to the development of excessive side effects (grade 3: fatigue (n = 3); emesis (n = 1), thrombocytopenia with bleeding (n = 1). Two additional patients noted grade 2 fatigue. Four patients experienced reductions in hemoglobin concentrations >4.0 g/dl from baseline during treatment, with two patients requiring red cell transfusions and two receiving recombinant erythropoietin. Three patients developed grade 3 neutropenia, while there were no episodes of > or =grade 2 diarrhea. Three patients exhibited biological evidence of an anti-neoplastic effect of therapy (>50% declines in serum CA-125 levels). CONCLUSION: Despite the strong theoretical appeal (as well as limited biological evidence of activity in platinum/taxane-refractory disease) associated with prolonging exposure of cycling ovarian cancer cells to topotecan, the specific oral regimen employed in this trial was associated with excessive bone marrow suppression, especially treatment-induced anemia, resulting in an unacceptable incidence of severe fatigue.
Aged↗
Phase II trial of vinorelbine for relapsed ovarian cancer: a Southwest Oncology Group study.
OBJECTIVES: To assess the activity of vinorelbine in women with recurrent or resistant epithelial ovarian cancer following treatment with platinum and paclitaxel in terms of survival rate at 6 months, objective response rate (in the subset of patients with bidimensionally measurable disease), and health-related quality of life. METHODS: Seventy-nine evaluable patients with progressive ovarian cancer following platinum and taxane therapy received vinorelbine 30 mg/m(2) days 1 and 8 of a 21-day treatment cycle. RESULTS: Six-month survival rate for the entire group was 65% (95% CI: 54-75%) and median survival was 10.1 months (95% CI: 7.7-13.6 months). In the 71 women with measurable disease, 0 complete and 2 partial responses were observed (RR = 3%) (95% CI: 0.3-10%). Patients reported substantial symptom-related distress at baseline, which persisted, but did not worsen, during treatment. Patients also had impaired physical functioning at baseline and this continued to decline during treatment. CONCLUSIONS: The 6-month survival rate achieved with salvage vinorelbine is comparable to the results obtained with other salvage therapies in patients with relapsed ovarian cancer. During the initial 10 weeks of treatment, vinorelbine did not appear to be effective in alleviating the symptom-related distress or progressive impairment of physical functioning associated with this disease.
Adult↗
Liposomal anthracycline treatment for ovarian cancer.
Platinum/taxane regimens induce high response rates and prolong survival in women with ovarian cancer. After recurrence, however, response to second-line chemotherapy is limited. Pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), is the only liposomal anthracycline indicated for second-line treatment of platinum- and paclitaxel-refractory ovarian cancer. Response rates ranged from 14% to 20% in nonrandomized trials of this patient population. In a large phase 3 randomized trial, single-agent PLD and topotecan had similar efficacy overall in response rates, but PLD-treated patients had significantly improved overall survival compared with topotecan with a pronounced advantage in platinum-sensitive patients. Another randomized trial reported that PLD and paclitaxel were comparable with regards to response rate, progression-free survival, and overall survival, regardless of the degree of platinum sensitivity. Additional nonrandomized trials of PLD in combination with other active agents resulted in response rates ranging from 20% to 76%. PLD is generally well tolerated and its side-effect profile compares favorably with other commonly used chemotherapeutic agents in this clinical setting. Proper dosing and monitoring may further enhance tolerability while preserving the efficacy of this versatile agent for ovarian cancer.
Antibiotics, Antineoplastic↗
Can we do a better job preventing clinically-relevant peripheral neuropathy resulting from carboplatin/paclitaxel chemotherapy?
Minor modifications in the standard "dose reduction" strategy commonly employed in the presence of developing carboplatin/paclitaxel-induced peripheral neuropathy may favorably impact the quality-of-life associated with use of this important combination chemotherapy regimen.
Antineoplastic Combined Chemotherapy Protocols↗
Phase 2 trial of interferon-beta as second-line treatment of ovarian cancer, fallopian tube cancer, or primary carcinoma of the peritoneum.
OBJECTIVE: The protocol was designed to examine the biological effects and clinical activity of interferon-beta in patients with platinum/taxane-resistant ovarian cancer. METHODS: Patients with resistant ovarian and fallopian tube cancers and primary peritoneal carcinoma were treated with recombinant human interferon-beta (Rebif, Serono International) at doses ranging from 6 to 24 million international units (MIU)/day, based on their tolerance to therapy. Levels of IP-10, an interferon-inducible protein, were measured in the serum to evaluate the biological effects of the drug. Also, the peripheral blood mononuclear cells and serum were examined for the induction of previously described novel regulators of interferon-induced death. RESULTS: Eighteen patients were treated, of whom 9 (50%) could be treated at the highest dose level (24 MIU). The major toxicities were fever, chills and fatigue. The median duration of therapy was 6 weeks (range 1-22). No objective responses were observed. IP-10 levels were significantly increased, compared with baseline, at 2, 4, and 6 weeks after initiation of therapy (p < 0.01). CONCLUSIONS: Recombinant human interferon-beta produced a definite biological effect in the serum of treated patients, but this outcome was not translated into any clinically observable or meaningful impact on the disease process.
Aged↗
Ethical conflict in providing informed consent for clinical trials: a problematic example from the gynecologic cancer research community.
The principle of respect for patient autonomy and the importance of informed consent are well established in the conduct of clinical research. However, in actual clinical practice, how one applies this concept is not always clear. The provocative results of a randomized trial examining "consolidation/maintenance" therapy in women with advanced ovarian cancer who achieved a clinically defined complete response to primary chemotherapy have raised difficult issues for clinicians and clinical investigators regarding their obligations to provide patients with information that may interfere with the conduct of ongoing or future research studies.
Antineoplastic Agents, Phytogenic↗
Genetic discrimination arising from cancer risk assessments: a societal dilemma.
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Breast Neoplasms↗