John J. Kavanagh

Anticancer therapy targeting the apoptotic pathway

Apoptosis, or programmed cell death, has an essential role in controlling cell number in many developmental and physiological settings and in chemotherapy-induced tumour-cell killing. It is a genetically regulated biological process, guided by the ratio of proapoptotic and antiapoptotic proteins. Recently, inducers of apoptosis have been used in cancer therapy. Several studies have attempted to induce apoptosis by triggering the tumour-necrosis-factor-related apoptosis-inducing ligand receptor and the BCL2 family of proteins, and others have targeted the caspases, and proteins that inhibit apoptosis. Most of these therapies are still in preclinical development because of their low efficacy and susceptibility to drug resistance, but some of them have shown promising results. In this article, we review the development and clinical efficacy of proapoptotic drugs that have shown promise.

Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma.

PURPOSE To determine the efficacy and toxicity of topotecan administered as a 5-day intravenous infusion in patients with advanced ovarian cancer refractory to cisplatin-based chemotherapy. PATIENTS AND METHODS Thirty patients with advanced epithelial ovarian cancer refractory to cisplatin-based chemotherapy received intravenous infusions of topotecan 1.5 mg/m2 delivered over 30 minutes each day for 5 days. A course was repeated every 21 days. The patient eligibility requirements included age > or = 18 years, Zubrod score < or = 2, measurable disease, adequate hepatic and renal function, neutrophil count > or = 1,500/microL, platelet count > or = 100,000/microL, and anticipated survival > or = 3 months. RESULTS Twenty eight patients were assessable for response and toxicity. All patients were assessable for survival. The major toxicity from administration of topotecan at this dose schedule was myelosuppression; 21 patients required dose reductions. Four patients had neutropenic fever that required hospitalization, and seven patients required platelet transfusions. Maculopapular pruritic exanthema occurred in 20% of patients; gastrointestinal side effects were mild. No deaths were reported on the study. At dose levels of 1.5, 1.25, and 1.0 mg/m2, 61%, 31%, and 25% of patients, respectively, required dose reductions. Of 28 assessable patients, four (14%; 95% confidence interval [CI], 4% to 34%) achieved a partial response (PR) at a median of 1.4 months and lasting 8.9 months, and 17 had stable disease (SD). The overall median survival time was 10.0 months (95% CI, 8.1 to 13.5). CONCLUSION Topotecan shows modest clinical activity against cisplatin-refractory ovarian cancer, although the dose-intensity is compromised by the depth of the granulocyte nadir and the duration of granulocytopenia. Further studies of topotecan may necessitate a reevaluation of optimal dose schedule, with the possible incorporation of multilineage cytokines, and its activity in taxane-resistant tumors.

The taxoids: paclitaxel (Taxol®) and docetaxel (Taxotere®)☆

The taxoids, paclitaxel (Taxol) and docetaxel (Taxotere), represent a novel class of antineoplastic drugs. Paclitaxel and docetaxel share a similar mechanism of action: the promotion of microtubule assembly and inhibition of microtubule disassembly. The clinical development of paclitaxel was initially hampered by hypersensitivity reactions (HSRs). The use of premedications and prolongation of the infusion time to 24h has reduced these reactions and allowed this drugs clinical development. Although paclitaxels clinical activity has not been fully investigated, clinical trials have demonstrated its activity against ovarian, breast, and bronchial carcinomas. Because phase I studies of docetaxel noted occasional HSRs and these observations increased with further clinical experiences, those premedications employed with paclitaxel have now been instituted in many phase II studies of docetaxel. Docetaxel is currently being investigated in ovarian, breast, and bronchial carcinomas and has shown impressive clinical activity. The dose-limiting toxicity of both these agents is neutropenia; myalgias, mucositis, neuropathies, and alopecia have also been observed with both drugs. Additionally, a fluid retention syndrome and cutaneous toxicities have been noted in patients treated with docetaxel. Future studies of the taxoids will allow further comparisons of the toxicity and efficacy of these agents.

Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin.

Since 1984, we have treated 26 patients with malignant ovarian germ cell tumors with a combination of bleomycin, etoposide (VP-16), and cisplatin (BEP) at The University of Texas MD Anderson Cancer Center (UTMDACC). The median age of the patients was 19 years (range, 8 to 32). All patients underwent initial surgery (unilateral salpingo-oophorectomy in 14, unilateral salpingo-oophorectomy plus abdominal hysterectomy in one, and bilateral salpingo-oophorectomy with or without hysterectomy in 11 patients). Twenty patients had no residual disease, three had less than or equal to 2 cm (one each, dysgerminoma, mixed, and immature teratoma), and three had more than 2 cm lesions (two dysgerminomas, one endodermal sinus tumor). Fourteen patients had pure dysgerminoma (five, stage I; one, stage II; six, stage III; and two, recurrent), and 12 had nondysgerminomatous tumors (five, stage I; two, stage II; three, stage III; and two, recurrent). All four patients with clinically measurable disease had a complete response. All four patients who underwent second-look laparotomy had negative findings. Twenty-five patients (96%) remain in sustained remission 10.4 to 54.4 months from the start of chemotherapy. One patient died of progressive disease 14 months after beginning chemotherapy. We conclude that the BEP regimen has excellent activity and acceptable toxicity in patients with malignant ovarian germ cell tumors.

Uterine papillary serous carcinoma (UPSC) treated with cisplatin, doxorubicin, and cyclophosphamide (PAC)

Uterine papillary serous carcinoma (UPSC) is an aggressive malignancy that accounts for a disproportionate number of intraabdominal failures among endometrial carcinoma patients. The histologic appearance and tendency toward intraabdominal spread resemble those of papillary serous adenocarcinoma of the ovary. Because approximately 70% of untreated ovarian carcinoma patients respond to platinum-based chemotherapy, it has been suggested that UPSC patients might respond to similar treatment regimens. Twenty patients with UPSC were treated with cisplatin, doxorubicin (Adriamycin), cyclophosphamide (PAC) chemotherapy between January 1982 and December 1989. They included 9 patients with advanced primary disease, 5 with recurrence, and 6 who received PAC as adjuvant therapy. Patients received a mean of five cycles of PAC. Only 2 of 11 patients with measurable disease greater than 2 cm achieved complete clinical responses of 12 and 31 months duration; there were no partial responses. Actuarial 5-year survival for all patients was 23%. The mean progression-free interval was 9 months. Patients with clinical stages I or II disease had a higher survival rate than those with stage III or IV disease (P = 0.003). Survival did not correlate with depth of myometrial invasion (P = 0.81) or size of residual tumor following initial surgery (P = 0.16). Estrogen or progesterone receptors were detected in 10 of 11 tumors tested. Seven of 9 patients tested had elevated serum levels of CA-125 (greater than 35 U/ml). Correlation between CA-125 value and clinical course was demonstrated in 3 of 5 patients who had serial measurements. Of all patients, 3 are currently alive; 1 has documented disease. Moderate to severe toxicity was seen in 14 patients (70%). There was one possible treatment-related death from cardiomyopathy. UPSC, despite its histologic and clinical similarities to ovarian carcinoma, was relatively resistant to PAC chemotherapy in this mixed group of patients.

Recombinant human thrombopoietin attenuates carboplatin-induced severe Thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer

Myelosuppression is a serious complication in patients who are receiving chemotherapy for cancer. The use of myeloid growth factors has reduced the incidence of febrile neutropenia (1, 2). However, thrombocytopenia has been managed predominantly by platelet transfusion and modification of the chemotherapy dose. Although platelet transfusion can reduce hemorrhagic complications, repeated transfusions increase the risk for transfusion reactions, alloimmunization, and transmission of infectious agents and increase health care costs (3). Recently, thrombopoietin was identified and cloned and became available for clinical investigations (4-7). In early clinical trials, therapy with thrombopoietin increased platelet counts before chemotherapy and enhanced platelet recovery after moderately myelosuppressive regimens (8-11). However, the value of this agent in preventing severe thrombocytopenia and averting the need for platelet transfusions has not been established. Carboplatin has a broad spectrum of antitumor activity and is highly effective in the treatment of gynecologic cancer; however, cumulative thrombocytopenia is frequently dose-limiting (12, 13). We therefore initiated a phase I/II trial of recombinant human thrombopoietin (rhTPO, a full-length glycosylated molecule) to evaluate the clinical safety and activity of this agent in patients with gynecologic cancer who are at high risk for chemotherapy-induced severe thrombocytopenia. Methods Patients Patients with platinum-sensitive, recurrent, or advanced gynecologic cancer were referred from multiple sources to our comprehensive cancer center. Patients were eligible if they had adequate Karnofsky performance status ( 80%); adequate bone marrow, renal, cardiac, and hepatic function; and life expectancy of at least 3 months. Patients with a history of rapidly progressive disease (marked increase in tumor size [>50%], ascites, or symptoms related to underlying cancer in the preceding 4-week period), pelvic irradiation, surgery within the previous 2 weeks, chemotherapy or radiotherapy within the previous 4 weeks, or thromboembolic or bleeding disorders were excluded. Design The study had two phases: a cohort dose-escalation (safety) phase and a dose-expansion (activity) phase. During the dose-escalation phase, a single dose of rhTPO was administered to assess clinical tolerance and hematopoietic effects. Three weeks later, patients entered cycle 1, in which they received carboplatin at a dose calculated to provide an area under the curve (AUC) of 11 by using the Calvert formula (carboplatin dose=target AUC [glomerular filtration rate + 25]). Three weeks later, upon recovery (absolute neutrophil count 1.5 109 cells/L and platelet count 100 109 cells/L), patients entered cycle 2, in which they received carboplatin (AUC, 11) followed by rhTPO every other day for four doses (on days 2, 4, 6, and 8). Cycle 1 served as an internal control for cycle 2. At least three patients were enrolled for each dose level of rhTPO (0.6, 1.2, 2.4, and 3.6 g/kg of body weight per day). The optimal biological dose was defined as the lowest active dose at which platelet count response reached a plateau. Once the optimal biological dose was established, prechemotherapy treatment with rhTPO was eliminated and 12 patients received carboplatin alone until thrombocytopenia (platelet count nadir<30 109 cells/L) was observed. In subsequent cycles, the optimal biological dose of rhTPO was given as secondary prophylaxis on the same schedule (days 2, 4, 6, and 8 [n=6]) or a modified schedule (days 1, 1, 3, and 5 [n=6]). Patients with stable or responsive disease who had not experienced prolonged thrombocytopenia (platelet count<20 109 cells/L for>7 days) in cycle 2 were eligible to receive four additional cycles. Patients received platelet transfusion (single donors when available or 4 units from random donors) for severe thrombocytopenia (platelet count<20 109 cells/L). Clinical and Laboratory Monitoring Patients were monitored by history taking; physical examinations; and laboratory tests, including complete blood counts (three times weekly and daily during the expected platelet count nadir), serum chemistry, urinalysis, chest radiography, and electrocardiography. Serum samples were screened for antibodies three times before the study and weekly during the study by using enzyme-linked immunosorbent assays based on full-length TPO, truncated TPO, and c-mpl receptor (14). Reactive sera were tested by using a bioassay based on inhibition of the TPO-dependent cell line. Neutralizing antibodies were defined as those that were inhibitory on bioassay and associated with clinically significant thrombocytopenia. Statistical Analysis Hematologic toxicity in cycle 1 (no rhTPO) was compared with that in cycle 2 (during which rhTPO was given) as the degree and duration of thrombocytopenia and time to platelet recovery (Wilcoxon signed-rank test) and the proportion of patients requiring platelet transfusions (McNemar test). The difference in the platelet count nadirs between two cycles (cycle 2 cycle 1) was analyzed for dose response by using one-factor (dose) analysis of variance with a linearity test and multiple comparisons test (SPSS, Inc., Chicago, Illinois). Role of the Funding Source Recombinant human thrombopoietin and partial funding for the study were provided by Genentech, Inc. (South San Francisco, California). The collection, analysis, and interpretation of data and the decision to submit the manuscript for publication were under the control of the principal investigator. Results Patients Twenty-nine patients were enrolled in the trial. All were evaluable except for one who declined treatment after one chemotherapy cycle. Twenty-five patients had previously received chemotherapy. Recombinant Human Thrombopoietin Treatment before Chemotherapy Treatment with a single dose of rhTPO before chemotherapy (n=16) resulted in a dose-dependent increase in platelet counts (mean count at baseline, 277 109 cells/L; maximum mean count, 462 109 cells/L [P<0.001]). After a peak response around day 15, platelet counts gradually decreased. No major changes were seen in leukocyte counts (mean count at baseline, 6.74 109 cells/L; mean count after treatment, 7.26 109 cells/L) or hemoglobin values (baseline value, 119.3 2.7 g/L; post-treatment value, 121.4 2.7 g/L). Recombinant Human Thrombopoietin Treatment after Chemotherapy Twenty-eight patients received rhTPO after carboplatin therapy (16 in the dose-escalation phase and 12 in the dose-expansion phase). Dose-Escalation Phase Therapy with rhTPO significantly reduced both the degree of thrombocytopenia (platelet count nadir, 53 109 cells/L and 35 109 cells/L [P=0.005]) and its duration (days on which platelet count was<50 109 cells/L, 3 and 6 [P=0.002]) in cycle 2 compared with cycle 1 (Table). At an rhTPO dose of 0.6 g/kg, the mean platelet count nadir did not differ between cycle 1 and cycle 2, but in cycle 2 it was twofold higher at 1.2 g/kg, 1.7-fold higher at 2.4 g/kg, and 1.2-fold higher at 3.6 g/kg. No linear dose response was seen (P=0.181). However, the difference in platelet count nadir was greater (P=0.027) for patients who received rhTPO at 1.2 and 2.4 g/kg than in those that received it at 0.6 and 3.6 g/kg. Because no greater benefit was seen at 2.4 g/kg, 1.2 g/kg was the lowest active dose and was considered the optimal biological dose for this regimen. Table. Effect of Recombinant Human Thrombopoietin Treatment on Carboplatin-Induced Thrombocytopenia and Platelet Recovery Dose-Expansion Phase To better assess the safety and activity of rhTPO at the optimal biological dose, six patients received cycles of carboplatin alone until they experienced thrombocytopenia (platelet count<30 109 cells/L). Recombinant human thrombopoietin was used in subsequent cycles as a secondary prophylaxis (1.2 g/kg), with the same schedule (days 2, 4, 6, and 8). As shown in the Figure, five of the six patients required platelet transfusion in cycle 1. Therapy with rhTPO decreased the severity of thrombocytopenia and eliminated the need for platelet transfusion in three patients and reduced the need for transfusion in one patient. Figure. Platelet counts after therapy with recombinant human thrombopoietin (1.2 g/kg administered on days 2, 4, 6, and 8) used as secondary prophylaxis after carboplatin treatment (cycle 2) ( solid line ) compared with those obtained by using carboplatin treatment alone (cycle 1) ( dotted line ). arrowheads stars Six additional patients received rhTPO (1.2 g/kg) 1 day before chemotherapy (day 1) and on days 1, 3, and 5 to determine whether the degree of protection could be further augmented. Five of the 6 patients experienced thrombocytopenia (platelet count<30 109 cells/L) in cycle 1 and received rhTPO in cycle 2. As with the original schedule, the need for platelet transfusion was eliminated in 3 of these 5 patients. The sixth patient experienced severe thrombocytopenia in cycle 2 and received rhTPO in cycle 3. After rhTPO therapy, this patients platelet count nadir increased and the need for platelet transfusion was eliminated. Thus, of 12 patients who received rhTPO as secondary prophylaxis, 11 initiated rhTPO therapy in cycle 2 and 1 initiated it in cycle 3. In this group, rhTPO increased the platelet count nadir by twofold and reduced the duration of severe thrombocytopenia by 4 days (Table). Platelet Transfusion and Recovery The need for platelet transfusion was markedly reduced with rhTPO (Table). Specifically, in the group that received rhTPO at the optimal biological dose (1.2 g/kg), 75% of patients required platelet transfusion in cycle 1 compared with 25% in cycle 2 (P=0.013). The number of transfusions required was reduced by 69% (16 compared with 5 transfusions). Therapy with rhTPO significantly enhanced platelet recovery (P<0.001) (Table). In cycle 2, 67% of patients recovered platelet counts of at least 100 109 cells/L by day 21,

Docetaxel for Patients With Paclitaxel-Resistant Müllerian Carcinoma

PURPOSE To determine the efficacy and toxicity of docetaxel in patients with müllerian carcinoma resistant to paclitaxel. PATIENTS AND METHODS Thirty-two patients with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who failed paclitaxel-based chemotherapy received either 100 or 75 mg/m(2) of docetaxel every 3 weeks. Resistance to paclitaxel was defined as either progression of disease during treatment, failure to achieve regression of disease after at least four courses, or rapid recurrence (within 6 months) after completion of therapy. RESULTS Eighteen patients were treated on a formal protocol and fourteen with the commercially available docetaxel. Thirty were assessable for response. Toxicities were thoroughly evaluated in the 18 patients on protocol. Twenty-seven patients (85%) had epithelial ovarian cancer. The overall response rate was 23% (one complete and six partial responses), with a median survival time of 44 weeks (9.5 months). Nine patients had stable disease and 14 progressive disease. Among 19 patients who progressed during prior paclitaxel treatment, two (11%) responded to docetaxel, compared with five (45%) of 11 patients in other paclitaxel-resistance categories. The responders had a median taxane-free interval (ie, the time between the last paclitaxel and first docetaxel treatment) of 73 weeks, compared with 19 weeks for the nonresponder group. Toxic effects were as expected. CONCLUSION Docetaxel is an active chemotherapeutic agent in patients with müllerian carcinoma previously treated with paclitaxel-based chemotherapy, especially in the patients who had a long taxane-free interval after a previous short response to paclitaxel.

Phase II Trials of Docetaxel (Taxotere@) in Advanced Ovarian Cancer-an Updated Overview

Docetaxel (Taxotere) has been studied at a dose of 100 mg/m2 i.v. as a one hour infusion every 3 weeks, in four phase II trials in patients with extensively pretreated ovarian cancer. A total of 340 patients were treated, including 256 patients in two separate EORTC (European Organization for Research and Treatment of Cancer) trials and 84 patients in two trials in the U.S.A. All patients had received prior cisplatin or carboplatin therapy and the treatment-free interval was less than 4 months in 155 patients. The overall response rate using conventional UICC criteria was 30% among 315 evaluable cases (95% confidence interval: 24-36%). Among 155 patients whose disease was most refractory (i.e. treatment-free interval was less than 4 months), the overall response rate was 28% (95% confidence interval: 19-36%). Response duration ranged from 4 to 17 months. Grade IV neutropenia was a common finding and fluid retention was observed. The incidence of febrile neutropenia ranged from 8 to 44% of patients with two deaths (i.e. 0.6% of the total treated) related to neutropenic sepsis. Docetaxel and paclitaxel (Taxol) have comparable activities in ovarian cancer. Ongoing studies with docetaxel include its use in patients as part of first-line therapy, as well as in patients refractory to paclitaxel. To prevent the development of fluid retention, these now involve the routine use of steroid prophylaxis. It is expected that docetaxel will prove to be an important addition to the drugs available for the treatment of ovarian cancer.

Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix.

PURPOSE A phase II study was performed to evaluate the antitumor activity and toxicity of irinotecan (CPT-11), a water-soluble derivative of camptothecin, in patients with prior chemotherapy-treated squamous cell cancer of the cervix. PATIENTS AND METHODS Forty-two patients were included in the study. The median age was 44 years (range, 24 to 59 years). The median Zubrod performance status was 1. All patients were refractory to first-line chemotherapy and 88% had received prior radiotherapy. The initial dose of CPT-11 was 125 mg/m2 given as a weekly 90-minute intravenous infusion for 4 weeks, every 6 weeks. Subsequent doses were unchanged, reduced, or omitted according to toxicity grade. RESULTS Forty-two patients were assessable for response. The overall response rate was 21%. The median time to response was 6 weeks and the median duration of response was 12 weeks. The overall median duration of survival was 6.4 months. A statistically significant survival advantage (median of 12.6 v 5.1 months) was found in patients whose disease responded to the treatment (P < .015). The major dose-limiting toxic effects (grade > or = 3) were nausea and vomiting (45%), diarrhea (24%), and granulocytopenia (36%). Grade > or = 3 anemia was encountered in 62% of patients and the incidence of thrombocytopenia was negligible. Less severe side effects were alopecia (48%), drug fever (43%), anorexia (33%), fatigue (33%), skin rash (21%), stomatitis (14%), and allergic reaction (9%). The gastrointestinal intolerance was dose-related. The incidence of bone marrow depression did not decrease with dose reduction, possibly because of a cumulative effect or hematologic intolerance by a subset of patients. CONCLUSIONS CPT-11 has significant activity in refractory cervical carcinoma. Gastrointestinal intolerance and hematologic toxicity must be monitored carefully. Further studies of alternative schedules may improve the tolerance and response rate.

Carboplatin reinduction after taxane in patients with platinum-refractory epithelial ovarian cancer.

PURPOSE To determine the activity of carboplatin in patients with ovarian cancer who progressed on taxane (paclitaxel or docetaxel) therapy. PATIENTS AND METHODS Thirty-three patients with ovarian cancers refractory to platinum and taxane therapy were treated with single-agent carboplatin reinduction once the disease progressed on a taxane. The starting dose of carboplatin was 300 mg/m2 at 28-day intervals. RESULTS Patients were a median age of 56 years (range, 31 to 80), had a median Zubrod performance status of 1 (range, 0 to 2) and had received a median of three prior chemotherapy regimens (range, two to eight) and one pretaxane platinum regimen (range, one to three). Twenty-six patients had a platinum-free interval of at least 12 months at the time of posttaxane re-treatment with carboplatin. There were seven of 33 (21%) partial responses, with a median duration of 7+ months (range, 2+ to 12+). Responses were noted only in patients with at least a 12-month platinum-free interval and an initial sensitivity to a taxane. The therapy was well tolerated and neurotoxicity was absent. CONCLUSION A subset of patients with platinum-refractory disease that initially responded to a taxane and who eventually have a platinum-free interval of at least 1 year may respond to carboplatin reinduction. This finding may be secondary to paclitaxel or docetaxel therapy that leads to the reversal of platinum resistance, or the prolonged platinum-free interval permits the loss of resistance to platinum by the tumor. Carboplatin reinduction should be considered in the treatment of patients whose ovarian cancer progresses after an initial sensitivity to a taxane and who had a prolonged platinum-free interval.