A phase I study with an expanded cohort to assess the feasibility of intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with untreated ovarian, fallopian tube or primary peritoneal carcinoma: a Gynecologic Oncology Group study

Objective

To define the maximum tolerated dose (MTD) and assess the feasibility of intravenous (IV) paclitaxel, intraperitoneal (IP) carboplatin, and IP paclitaxel in women with newly diagnosed Stages II-IV ovarian, fallopian tube, or primary peritoneal carcinoma.

Methods

Patients received escalating doses of paclitaxel IV and carboplatin IP on day 1 and paclitaxel IP 60 mg/m² on day 8. A standard 3 + 3 design was used in the escalation phase. A two-stage group sequential design with 20 patients at the MTD was used in the feasibility phase. Patient-reported neurotoxicity was assessed pre and post treatment.

Results

Patients were treated with paclitaxel 175 mg/m² IV and carboplatin IP from AUC 5-7 on day 1 and paclitaxel 60 mg/m² IP on day 8. The MTD was estimated at carboplatin AUC 6 IP and 25 patients enrolled at this dose level. Within the first 4 cycles, seven (35%) of twenty evaluable patients had dose-limiting toxicities (DLTs) including grade 4 thrombocytopenia (1), grade 3 neutropenic fever (3), > 2 week delay due to ANC recovery (1), grade 3 LFT (1), and grade 3 infection (1). De-escalation to paclitaxel 135 mg/m² IV was given to improve the safety. After six evaluable patients completed 4 cycles without a DLT, bevacizumab was added and six evaluable patients completed 4 cycles with one DLT (grade 3 hyponatremia).

Conclusions

Paclitaxel at 175 mg/m² IV, carboplatin AUC 6 IP day 1 and paclitaxel 60 mg/m² IP day 8 yield 18-56% patients with DLTs. The tolerability of the regimen in combination with bevacizumab was indicated in a small cohort.     

Progression-free and overall survival of a modified outpatient regimen of primary intravenous/intraperitoneal paclitaxel and intraperitoneal cisplatin in ovarian, fallopian tube, and primary peritoneal cancer

Objective

GOG study 172 demonstrated improved progression-free (PFS) and overall (OS) survival for patients with stage III optimally debulked ovarian and peritoneal carcinoma treated with IV/IP paclitaxel and IP cisplatin compared to standard IV therapy. The inpatient administration, toxicity profile, and limited completion rate have been blamed for the lack of acceptance and widespread use of this regimen. We sought to evaluate the PFS, OS, toxicity, and completion rate of a modified outpatient IP regimen.

Methods

Using a prospectively maintained database, we evaluated the outcomes of patients who underwent primary optimal cytoreduction for stage III ovarian, tubal, or peritoneal carcinoma followed by IV/IP chemotherapy from 1/05-3/09. Our modified regimen was as follows: IV paclitaxel (135 mg/m²) over 3 h on day 1, IP cisplatin (75 mg/m²) on day 2, and IP paclitaxel (60 mg/m²) on day 8, given every 21 days for 6 cycles.

Results

We identified 102 patients who initiated the modified IV/IP regimen and completed chemotherapy. The median follow-up was 43 months. The median age at diagnosis was 57 years (range, 23-76). Primary disease site was: ovary, 77 (75%); fallopian tube, 13 (13%); peritoneum, 12 (12%). FIGO stage was: IIIA, 8 (8%); IIIB, 4 (4%); IIIC, 90 (88%). Residual disease after cytoreduction was: none, 58 (57%); ≤ 1 cm, 44 (43%). The most frequent grade 3/4 toxicities were: neutropenia, 12 (12%); gastrointestinal, 8 (8%); neurologic, 6 (6%). Eighty-two (80%) of 102 patients completed 4 or more cycles of IV/IP therapy; 56 (55%) completed all 6 cycles. The median PFS and OS were 29 and 67 months, respectively.

Conclusions

By modifying the GOG 172 treatment regimen, convenience, toxicity, and tolerability appear improved, with survival outcomes similar to those of GOG 172. This modified IV/IP regimen warrants further study.     

The feasibility of carboplatin-based intraperitoneal chemotherapy in ovarian cancer

Objective

To reduce toxicities in cisplatin-based intraperitoneal (IP) chemotherapy, we substituted carboplatin for cisplatin. The purpose of this study was to provide preliminary toxicity data of carboplatin-based IP chemotherapy and to evaluate the feasibility of this chemotherapy regimen in patients with ovarian cancer after primary debulking surgery.

Study design

The toxicity data of 19 primary ovarian cancer patients (IP group) who underwent carboplatin-based IP and intravenous (IV) combination chemotherapy (IP carboplatin AUC 5 on day 1, IV paclitaxel 175 mg/m² on day 2, and IP paclitaxel 60 mg/m² on day 8) after primary debulking surgery were retrospectively analyzed and compared to 34 patients (IV group) who were treated with standard platinum-based IV chemotherapy during the same period.

Results

The toxicity data in a total of 118 cycles were analyzed. Grade 3 or 4 leukopenia, neutropenia, and pain were more common in the IP group than the IV group. There were seven catheter-related complications. Fourteen patients (73.7%) were able to complete six cycles or more of IP chemotherapy. Survival results in the IP group were compared with those from the IV group; a prolonged progression-free survival was observed (26.6 vs. 20.7 months; p = 0.038). Compared to the previous results with cisplatin-based IP chemotherapy, there was no significant difference in hematologic events. However, gastrointestinal, neurologic, and metabolic events in this study were definitely lower compared to those of cisplatin-based IP chemotherapy.

Conclusions

Carboplatin-based IP and IV combination chemotherapy is feasible in patients with ovarian carcinoma after primary debulking surgery.     

A phase I study with an expanded cohort to assess the feasibility of intraperitoneal carboplatin and intravenous paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: A Gynecologic Oncology Group study

Objective

This study aimed to determine the first-cycle maximum tolerated dose (MTD) of intraperitoneal carboplatin in combination with intravenous paclitaxel and then assess the feasibility of this dose over multiple cycles.

Methods

Beginning at an intraperitoneal (IP) carboplatin dose area under the curve (AUC) of 5 and a fixed intravenous dose of 175 mg/m² paclitaxel, patients were entered on a dose-escalating phase evaluating first-cycle dose-limiting toxicity (DLT). After estimating the MTD, cohorts of 20 patients were then entered in an expanded phase to evaluate DLT over four cycles.

Results

Twenty-one patients were entered on the dose-escalating phase. A first-cycle MTD of carboplatin at AUC 8 was tolerated although thrombocytopenia was dose-limiting over multiple cycles. An additional 69 patients were treated in expanded cohorts. Only 5/90 (5.6%) patients discontinued treatment because of a port problem. Four-cycle DLT required de-escalation to a carboplatin AUC of 6, and even at that dose, there were 14 dose-limiting toxic effects in 40 patients (35%). Seven dose-limiting toxicities were due to neutropenia, and 6 were due to grade 3/4 thrombocytopenia. Six cycles of therapy were completed in 75% of eligible patients, but dose adjustments were required.

Conclusions

The first-cycle MTD did not predict the tolerability of this regimen over multiple cycles. Using an IP carboplatin dose of AUC 6 in combination with paclitaxel, the regimen can be administered with a high completion rate over multiple cycles. Because neutropenia is a frequent DLT, the addition of hematopoietic growth factors may permit a high completion rate while maintaining this dose.     

Patterns of recurrence in advanced epithelial ovarian, fallopian tube and peritoneal cancers treated with intraperitoneal chemotherapy

Objectives

To examine the distribution and outcomes of recurrent disease in patients with ovarian, fallopian tube and peritoneal cancers after optimal cytoreduction and adjuvant intraperitoneal (IP) chemotherapy.

Methods

All patients diagnosed with ovarian, fallopian tube, or peritoneal cancer between 2004 and 2009 who underwent optimal cytoreductive surgery and received adjuvant intravenous (IV) and IP chemotherapy with paclitaxel and a platinum-based agent were eligible. Age, performance status, tumor origin, stage, and grade were recorded. First recurrences were identified using CA125 values, radiographic studies, operative notes, and pathology reports. Sites of recurrence were classified as intraperitoneal (IP), extraperitoneal (EP) or distant. Kaplan-Meier estimates and Cox multivariate regression models were used to assess the associations between recurrent disease distribution and progression-free survival (PFS) and overall survival (OS).

Results

One hundred forty-three patients met the criteria for inclusion. The majority were Stage III (86%) and serous histology (77%). Eighty-four (58.7%) received IV/IP paclitaxel/cisplatin per GOG-172 and 59 (41.3%) received IV/IP paclitaxel/carboplatin. Seventy-two percent completed 6 cycles. Ninety (62.9%) patients manifested a recurrence. One-hundred twelve sites of recurrence were identified with 70 (62.5%) IP and 42 (37.5%) EP and distant sites. Nineteen (21%) recurred in more than one site, i.e. both IP and EP locations. Site of recurrence did not impact OS, however, patients who recurred in multiples sites had significantly worse OS (p < 0.001).

Conclusion

Approximately 40% of patients treated with IP chemotherapy have a first recurrence outside the peritoneal cavity. Though site of recurrence did not affect OS those with multi-focal recurrence demonstrate worse survival.     

CA125 regression in ovarian cancer patients treated with intravenous versus intraperitoneal platinum-based chemotherapy: a gynecologic oncology group study

Objective

CA125 is a non-specific marker of peritoneal irritation which has the potential for false elevation during intraperitoneal treatment. The purpose of this study is to identify the rate of CA125 regression during intraperitoneal (IP) versus intravenous (IV) chemotherapy for ovarian cancer.

Methods

GOG 114, a randomized control trial evaluating IP and IV treatment, includes an intensive CA125 measurement schema with weekly CA125 levels until ≤ 35 units/ml for both IP- and IV-treated patients. Rate of CA125 normalization, median CA125 values for each treatment cycle, as well as clinical and pathologic features were compared between the treatment groups. Baseline CA125 levels and rate of CA125 decline were evaluated with respect to overall survival.

Results

CA125 data were available for 223 patients who received IV cisplatin/paclitaxel and for 231 patients who received IV carboplatin followed by IP cisplatin/paclitaxel. Standard prognostic criteria and baseline CA125 values were similar between the treatment groups. For treatment cycles in which IP-treatment was administered, there was no statistically significant difference in CA125 levels between IV- and IP-treated patients. The rate of CA125 normalization was similar between IV- and IP-treated patients (p = 0.55). Patients with low pre-chemotherapy CA125 levels which rapidly declined during treatment demonstrated a survival advantage (p < 0.0001).

Conclusions

No difference in CA125 decline was identified between IP- and IV-treated patients undergoing a weekly CA125 monitoring schedule. This data supports the utilization of standard CA125 response criteria in the therapeutic monitoring for patients receiving IP treatment.     

Treatment Tolerance and Side Effects of Intraperitoneal Carboplatin and Dose-Dense Intravenous Paclitaxel in Ovarian Cancer

Objective

To describe the frequency of clinically significant side effects associated with adjuvant intraperitoneal (IP) carboplatin and intravenous (IV) dose-dense paclitaxel chemotherapy for epithelial ovarian cancer (EOC).

Preliminary toxicity analysis of intraperitoneal carboplatin in combination with intravenous paclitaxel chemotherapy for patients with carcinoma of the ovary, peritoneum, or fallopian tube

The objective of this study was to provide preliminary toxicity data of multiple-cycle combination chemotherapy with intraperitoneal (IP) carboplatin and intravenous (IV) paclitaxel for further clinical trials. The toxicity data of 42 patients with mullerian carcinoma who underwent IP carboplatin therapy in combination with IV paclitaxel were retrospectively analyzed. Chemotherapy was repeated through the Bard IP port placed at initial surgery using IV paclitaxel at 175 mg/m2 followed by IP carboplatin. The doses of carboplatin were either at area under the curve (AUC) = 5, 6, 6.5, 7, or 7.5. The toxicity data in a total of 237 cycles were analyzed. The median number of cycles for IP chemotherapy was 6 (range: 3-12). The incidences of maximal grade toxicities in all cycles were: grade (G)2/3 nausea/vomiting, 23.8%; G2/3 constipation, 42.9%; G2 abdominal pain, 28.6%; G2/3 sensory neuropathy, 14.3%; motor neuropathy, 4.8%; myalgia/arthralgia 33.4%; G3/4 neutrocytopenia, 85.4%; and G3/4 anemia, 35.4%. These were not related to the dose of carboplatin. The incidences of G3 thrombocytopenia in relation to the dose of carboplatin were AUC = 5, 0%; 6, 31.6%; 6.5, 44.4%; 7, 25.0%; and 7.5, 80%. G4 thrombocytopenia did not occur. A dose of carboplatin between AUC = 6 and 7 with IV paclitaxel at 175 mg/m2 is warranted for further evaluation.     

A Phase I Study of Paclitaxel, Doxorubicin, and Cisplatin in Patients with Previously Untreated Epithelial Ovarian Cancer

Objective.Although doxorubicin is not currently popular as a primary agent in ovarian cancer, overviews of previous studies suggest that the inclusion of doxorubicin may have improved outcome. The purpose of this phase I study was to determine the maximal dose of doxorubicin that could be added to standard doses of paclitaxel and cisplatin with G-CSF support.Methods.Women with FIGO stage III or IV epithelial ovarian cancer were primarily treated with escalating doses of doxorubicin in combination with paclitaxel (135 mg/m²over 24 h) and cisplatin (75 mg/m²) every 3 weeks. Doxorubicin was started at 30 mg/m²and escalated by 10 mg/m²per treatment level. All patients received G-CSF support.Results.Eleven patients were treated at two dose levels. Dose limiting toxicity (DLT) was reached at the 40 mg/m²dose of doxorubicin. All patients experienced grade 4 neutropenia although none required hospitalization. DLT included renal toxicity and prolonged thrombocytopenia. Despite vigorous antiemetic regimens 60% of patients experienced severe nausea and vomiting. Nine patients were assessable for response. Eight patients have had a complete clinical response (89%). Of the five patients undergoing second-look laparotomy two were negative.Conclusions.The maximum tolerated dose of doxorubicin in this three-drug regimen is 30 mg/m²with standard doses of paclitaxel and cisplatin. Hematologic toxicity is manageable using G-CSF. Doxorubicin appears to increase the renal toxicity of cisplatin which may be exaggerated by marked nausea and vomiting. This is an active but toxic regimen and alternative sequences and strategies should be evaluated.     

A phase I study of concurrent weekly topotecan and cisplatin chemotherapy with whole pelvic radiation therapy in locally advanced cervical cancer: a gynecologic oncology group study

Purpose

To determine the maximum tolerated dose (MTD) and acute dose-limiting toxicities (DLT) of intravenous topotecan administered with weekly cisplatin during pelvic radiation therapy in patients with locally advanced cervical cancer.

Methods

Patients were treated at one of two dose levels receiving intravenous topotecan at 0.5 mg/m² and cisplatin at either 30 or 40 mg/m² given weekly for 6 weeks concurrently with pelvic radiation and intracavitary brachytherapy. The primary endpoint for the escalation study was acute dose-limiting toxicities occurring within 30 days of completing radiation therapy.

Results

Eleven patients were enrolled. Dose-limiting toxicity consisting of Grade 3 nausea and vomiting lasting > 24 h in one patient and grade 3 febrile neutropenia in another patient occurred at the first dose level of weekly topotecan 0.5 mg/m² and cisplatin 40 mg/m². This necessitated de-escalation to weekly cisplatin 30 mg/m² in combination with topotecan 0.5 mg/m² and pelvic radiation. This dose level was tolerable in 6 evaluable patients with only one DLT consisting of grade 4 thrombocytopenia, grade 3 abdominal pain and grade 3 elevated gamma glutamyl transpeptidase (GGT).

Conclusions

In women with locally advanced cervical cancer, intravenous topotecan 0.5 mg/m² and cisplatin 30 mg/m² given weekly for 6 weeks with concurrent pelvic radiation and intracavitary brachytherapy were tolerable. Further expansion of the feasibility cohort of this study was suspended based on the results of a phase 3 trial comparing the efficacy of platinum combinations in advanced and recurrent cervical cancer.     

Results of oxaliplatin-based hyperthermic intraperitoneal chemotherapy in recurrent ovarian granulosa cell tumors

Objectives

To assess the efficacy and morbidity of cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) for relapsed ovarian granulosa cell tumors (OGCT).

Study design

Between 2007 and 2009, patients with relapsed OGCT who had been treated with HIPEC after CRS in our institution were retrospectively analyzed.

Results

We identified 7 patients who had undergone CRS plus HIPEC. Macroscopically complete cytoreduction had been performed in all patients. The location of the recurrence was exclusively the pelvis in 2 cases and both the pelvis and abdomen in 5 cases. We had administered an intraperitoneal perfusion of oxaliplatin (460 mg/m²) or oxaliplatin (360 mg/m²) plus irinotecan (360 mg/m²) heated up to 41–43 °C for 30 min. No post-operative mortality nor any grade IV morbidity (according to the Clavien and Dindo classification) had occurred. One lymphocyst (grade III) had appeared which had twice required percutaneous drainage. Six patients had experienced extra-abdominal complications (all grade II). Median follow-up after CRS plus HIPEC was 32 months (range, 25–56). Among the 7 patients, 2 are disease free, 3 had relapsed with peritoneal carcinomatosis and 2 had relapsed with liver metastases.

Conclusions

HIPEC (using oxaliplatin or oxaliplatin plus irinotecan) should not be recommended to treat relapsed OGCT.     

A phase I trial of intraperitoneal sustained-release paclitaxel microspheres (Paclimer) in recurrent ovarian cancer: a Gynecologic Oncology Group study

OBJECTIVES: Paclimer is a biodegradable polymer microsphere formulation containing 10% (w/w) paclitaxel that is designed to provide a sustained-release form of paclitaxel after intraperitoneal (IP) administration. The goals of this phase I study were to determine the maximum tolerated dose (MTD) of IP paclitaxel microspheres and the pharmacology of paclitaxel after IP paclitaxel microsphere administration. METHODS: Twelve patients with recurrent or persistent ovarian or primary peritoneal carcinoma were treated. After placement of an IP catheter, patients were treated with escalating doses of IP paclitaxel microspheres administered with 2 l of normal saline following premedication. Treatment could be repeated once, 8 weeks after initial treatment. The starting dose was 60 mg/m2 and no intrapatient dose escalation was used. RESULTS: One dose-limiting toxicity consisting of abdominal pain, ileus and bowel obstruction was seen with the second cycle of therapy in one patient who received 900 mg/m2. Patients received up to 1200 mg/m2 without further evidence of dose-limiting toxicities (DLT). The study was discontinued before MTD was defined due to the manufacturer's decision to suspend further clinical development of paclitaxel microspheres. Pharmacokinetic analysis showed a trend toward a dose-dependent effect of IP paclitaxel microspheres on measured plasma paclitaxel levels. Sustained paclitaxel levels were maintained throughout all 8 weeks of therapy; however, paclitaxel concentrations were well below the plasma concentrations associated with toxicity. In one patient, laparoscopy revealed extensive adhesions, fat necrosis, foreign body giant cell reaction and detectable residual polymer filaments 7 months after completion of treatment with paclitaxel microspheres. CONCLUSIONS: IP administration of paclitaxel microspheres is well tolerated up to 1200 mg/m2 without defining MTD. The low but persistent detection of plasma paclitaxel indicates that paclitaxel continues to be released for at least 8 weeks after IP paclitaxel microsphere treatment. The finding of significant peritoneal abnormalities, including the presence of residual polymer filaments, months after IP Paclimer treatment suggests that the polymer preparation used in Paclimer degrades slowly.     

Investigating the relative efficacies of combination chemotherapy of paclitaxel/carboplatin, with or without anthracycline, for endometrial carcinoma

Purpose

Recently a combination of paclitaxel and carboplatin (TC) (without an anthracycline) has begun to be used as an adjuvant or remission induction therapy, without any critical supportive evidence of its efficacy relative to a combination chemotherapy of taxane, platinum and anthracycline such as TEC (paclitaxel, epirubicin and carboplatin). The aim of our present study was to conduct the required clinical evaluations of the relative effectiveness of TC compared to TEC.

Methods

A retrospective comparison between the efficacy of TEC and TC regimens used for endometrial carcinoma at the Osaka University Hospital and the Osaka Medical Center for Cancer and Cardiovascular Diseases in Osaka, Japan, respectively, from 1999 to 2009 was performed. The clinical characteristics of the patients who received either TEC or TC were not significantly different, and TEC and TC therapies were initiated based on similar indications for chemotherapy. TEC regimen was paclitaxel (150?mg/m²), epirubicin (50?mg/m²) and carboplatin (AUC 4). TC regimen consisted of paclitaxel (175?mg/m²) and carboplatin (AUC 5).

Results

TEC was demonstrated to provide significantly better survival than TC as an adjuvant therapy for resected Stage III/IV diseases (p?=?0.017 for progression-free survival and p?=?0.014 for overall survival, by the log-rank test). However, in recurrent or more advanced cases, TC and TEC demonstrated similar effects on survival (p?=?0.55 for progression-free survival and p?=?0.63 for overall survival).

Conclusions

TEC should be offered as an adjuvant therapy to Stage III/IV patients. TC may be considered for recurrent or unresectable cases as a remission induction therapy.     

Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal chemotherapy in optimal stage III ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study

OBJECTIVES: To evaluate reasons for discontinuing intraperitoneal (IP) chemotherapy, and to compare characteristics of patients who did versus did not successfully complete six cycles of IP chemotherapy. METHODS: In a phase III trial, women with optimal stage III ovarian or peritoneal carcinoma were randomly allocated to receive IP therapy (paclitaxel 135 mg/m(2) intravenously (IV) over 24 h, cisplatin 100 mg/m(2) IP day 2, paclitaxel 60 mg/m(2) IP day 8) every 21 days for six cycles. Patients unable to receive IP therapy were treated with the alternate (IV) regimen. Variables compared included surgical procedures prior to enrollment, timing of IP catheter insertion, and primary and contributing reasons for discontinuing IP therapy. RESULTS: Among 205 eligible patients randomly allocated to the IP arm, 119 (58%) did not complete six cycles of IP therapy. Forty (34%) patients discontinued IP therapy primarily due to catheter complications and 34 (29%) discontinued for unrelated reasons. Hysterectomy, appendectomy, small bowel resection, and ileocecal resection were not associated with failure to complete six cycles. IP therapy was not initiated in 16% of patients who did versus 5% of those who did not have a left colon or rectosigmoid colon resection (P = 0.015). There was no association between timing of catheter insertion and failure to complete IP therapy. CONCLUSIONS: In this multi-institutional setting, it was difficult to deliver six cycles of IP therapy without complications. There appears to be an association between rectosigmoid colon resection and the inability to initiate IP therapy. Catheter choice, timing of insertion, and how surgical treatment of ovarian cancer influences the successful completion of intraperitoneal chemotherapy require further study.     

A phase I study of paclitaxel, topotecan, cisplatin and Filgrastim in patients with newly diagnosed advanced ovarian epithelial malignancies: a Gynecologic Oncology Group study

OBJECTIVES: To determine a recommended dose level (RDL) of paclitaxel, cisplatin and topotecan in women with previously untreated epithelial ovarian or peritoneal cancer as a possible experimental arm in a future Gynecologic Oncology Group phase III study. METHODS: Patients with newly diagnosed stage III or IV disease were treated with paclitaxel 175 mg/m2/3 h, followed 2 h later by cisplatin 50 mg/m2 on day 1. Topotecan was administered on consecutive days as a 30-minute infusion, beginning after cisplatin on day 1, receiving either 5 days beginning at 0.3 mg/m2 (cohort 1), or 3 days beginning at 0.5 mg/m2 (cohort 2). Treatment was given every 21 days for a maximum of 8 cycles. RESULTS: Forty-five evaluable patients were enrolled in the two cohorts. Thrombocytopenia and prolonged neutropenia were the major dose-limiting toxicities. Dose-limiting neutropenia was seen at the first dose level, thus all subsequent dose escalations included Filgrastim. The RDL of cohort 1 was paclitaxel 175 mg/m2/3 h, cisplatin 50 mg/m2 and topotecan 0.5 mg/m2 daily x 5 with Filgrastim. The RDL of cohort 2 was paclitaxel 175 mg/m2/3 h, cisplatin 50 mg/m2 and topotecan 0.75 mg/m2 daily x 3 with Filgrastim. CONCLUSION: In women with previously untreated epithelial ovarian or peritoneal cancer the combination of paclitaxel, cisplatin and topotecan is feasible. However, this treatment requires the use of Filgrastim and attenuated dosing of topotecan in both a 5-day and 3-day topotecan infusion schedule.     

Phase II study of interval debulking surgery followed by intraperitoneal chemotherapy for advanced ovarian cancer: A Kansai Clinical Oncology Group study (KCOG9812)

ObjectiveIntraperitoneal chemotherapy (IP) is known to be effective after optimal primary debulking surgery (PDS) for ovarian cancer (OC). Here, we conducted a phase II study to investigate its effectiveness after interval debulking surgery (IDS).MethodsThirty-seven patients with FIGO stage IIIB-IV and suboptimal (≥ 1 cm diameter) residual disease after PDS were enrolled. Carboplatin (AUC 4 IV, Day 1) and cisplatin (50 mg/m² IV, Day 3) were given q21d for 3 cycles. After IDS, paclitaxel (175 mg/m² IV Day 1 or 60 mg/m² IV Days 1, 8, and 15, since 2000) and cisplatin (75 mg/m² IP Day 2) were given q21d for 4 cycles. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS) and adverse events (CTCAE ver. 2.0). Clinical manifestations at first recurrence and subsequent treatment were also surveyed.ResultsOf the 37 patients, high-grade, serous adenocarcinoma was found in 33. Stages IIIB, IIIC, and IV were found in 2, 24, and 11 patients, respectively. After IDS, 23 patients had no macroscopic residual tumor. No patients had permanent enterostomy, febrile neutropenia, or platelet transfusion. The treatment protocol was completed in 22 patients, and discontinued in 5 due to IP catheter-related complications. Median PFS and OS were 22 and 57 months, respectively. Among the 28 patients with recurrence, 10 had no intraperitoneal disease at first recurrence. Among the 8 patients who underwent surgical cytoreduction, 6 had no residual tumor, while 2 had a < 1-cm-diameter residual tumor.ConclusionIP after IDS for patients with initially suboptimally debulked OC was effective.     

Iniparib plus paclitaxel and carboplatin as initial treatment of advanced or recurrent uterine carcinosarcoma: a Gynecologic Oncology Group Study

Objective

To estimate the activity and tolerability of iniparib plus paclitaxel and carboplatin as initial therapy of uterine carcinosarcoma.

Methods

Eligible patients had advanced, persistent or recurrent carcinosarcoma of the uterus, measurable disease and no prior chemotherapy. Patients received paclitaxel 175 mg/m² IV over 3 h followed by carboplatin area under the curve (AUC) = six over 30 min on day one of 21 day cycles plus iniparib 4 mg/kg IV over 1 h twice weekly beginning on day one. Treatment continued until disease progression or adverse effects prohibited further therapy. Common Terminology Criteria for Adverse Events (CTCAE) v3.0 was used to grade adverse events. The primary endpoint was tumor response. The study was conducted with a 2-stage group sequential design, targeting 20 and 25 patients in each stage. The study was designed to distinguish between 45% versus 65% responding with alpha = 10% and 90% power.

Results

Twenty-two patients were entered onto the study with five excluded from analysis, leaving 17 evaluable for analysis. Treatment resulted in the expected hematologic and non-hematologic toxicities of the paclitaxel-carboplatin backbone. The observed proportion responding was 23.5% (4/17 patients). The two-sided, 90% confidence interval for the true probability of response was 8.5-46.1%. The required minimal number of responses to proceed to second stage was eight.

Conclusions

Iniparib plus paclitaxel and carboplatin did not show significant activity to warrant further study. The rate of exclusion upon central pathology review (23%) suggests that review of pathology slides for confirmation of eligibility is important in this tumor type.     

Ifosfamide, paclitaxel, and carboplatin, a novel triplet regimen for advanced, recurrent, or persistent carcinoma of the cervix: a phase II trial

Objectives

(1) To determine the response rate of advanced, recurrent, or persistent carcinoma of the cervix to ifosfamide, paclitaxel, and carboplatin chemotherapy; (2) to determine the progression free interval and survival rate in patients treated with this regimen; (3) to describe the toxicities associated with this regimen; and (4) to evaluate the quality of life of patients while on treatment.

Methods

Eligible patients had histologically proven stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. Chemotherapy was given on day 1 of a 28-day cycle: mesna (600 mg/m²) prior to ifosfamide (2 g/m²), paclitaxel (175 mg/m²), carboplatin (AUC 5). Response rates were determined according to RECIST criteria. Toxicity was graded according the National Cancer Institute's common toxicity criteria. Quality of life measurements were obtained using the FACT-Cx.

Results

Twenty-eight patients participated in this study, with 21 evaluable for response rate. Overall, 7 patients (33%) had a demonstrated objective response (4 complete responses, 3 partial responses). Stable disease was documented in 3 patients. The overall median survival for all patients was 10 months. Median progression free survival for evaluable patients was 5.0 months. Bone marrow suppression was the most common toxicity. There were no negative effects of this treatment regimen on quality of life assessments.

Conclusion

Ifosfamide, paclitaxel, and carboplatin is an effective regimen in treating advanced or recurrent carcinoma of the cervix and has an acceptable toxicity profile.     

Phase II study of paclitaxel in combination with carboplatin for patients with recurrent or persistent uterine sarcoma

Objective

To evaluate the efficacy and toxicity of combined paclitaxel and carboplatin treatment for persistent or recurrent uterine sarcoma.

Methods

Paclitaxel was administrated at 175?mg/m² intravenously over 3?h plus carboplatin at AUC 5 intravenously over 30?min every 3-week cycle in patients with recurrent or progressive uterine sarcoma, who were unsuitable candidates for curative treatment with either surgery or radiotherapy. The Simon’s two-stage optimal design was chosen for defining the total number of patients required for the phase II study. A total of 13 patients were entered in the study at the first stage of trial. A median of four cycles were administrated per patient, with a range of one to nine cycles. Prior to the study, 4 (30.8?%) of the 13 patients had received radiotherapy or chemotherapy. The response was measured by evaluation of the size of the mass by CT scan.

Results

The overall response rate was 15.4?% (2/13), with two patients exhibiting partial responses. There was 1 (7.7?%) case of stable disease and 9 (69.2?%) cases of progression disease. The median progression free survival was 2.23?months (95?% confidence interval 1.94–3.67). Peripheral neuropathy and hematologic toxicity, including anemia and neutropenia, were the most frequent adverse events. One patient died from treatment-related toxicities.

Conclusions

Paclitaxel in combination with carboplatin demonstrated acceptable levels of toxicity, but it was not active in the treatment of recurrent or progressive uterine sarcoma. This regimen might have limited role for advanced uterine sarcomas.     

Clinical effects of irinotecan hydrochloride in combination with cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer

Objective

To evaluate the toxicity and efficacy of irinotecan plus cisplatin neoadjuvant chemotherapy (NACT) for cervical cancer.

Methods

A total of 120 cases with cervical cancer were divided into 2 groups and retrospectively reviewed: Sixty FIGO IB2-IIB patients in NACT group were treated with 2 cycles of irinotecan 60 mg/m² on days 1 and 8 plus cisplatin 60 mg/m² on day 1 followed by surgery. Sixty FIGO IB2-IIB patients in control group were treated directly with surgery.

Results

The 60 patients in NACT group received a total of 120 cycles. Grades III and IV neutropenia and diarrhea were seen in 15.8% and 11.7%, respectively, of all chemotherapy cycles. Six (10.0%) patients achieved complete remission, 33 (55.0%) achieved partial remission, 21 (35.0%) remained stable, and none had disease progression. Postoperatively the deep cervical stromal invasion and positivity of surgical margins were significantly fewer in the NACT group. The pelvic lymph node metastasis rate of responders to NACT was significantly lower than that of non-responders (12.8% vs 38.1%). With a median follow-up of 29 and 30 months, the intra-pelvic recurrence rate of the NACT group was significantly lower than that of the control group (3/60 vs 11/60, p = 0.023), the 2-year recurrence-free survival and the 2-year overall survival was 82.3% and 86.1% in the NACT group, and 86.3%, 87.9% in the control group with no significant difference. Multivariate analysis showed that response to NACT was the only factor associated with survival (p = 0.036).

Conclusion

Irinotecan plus cisplatin NACT for cervical cancer has high efficacy and tolerable toxicity, and can significantly reduce the rates of deep cervical stromal invasion and positive surgical margins. Pelvic lymph node metastasis decreases significantly in responders compared with non-responders. The response to NACT can be considered as an independent prognostic factor.