Phase 1 Study of Tirapazamine in Combination With Radiation and Weekly Cisplatin in Patients With Locally Advanced Cervical Cancer

2010 ◽  
Vol 20 (5) ◽  
pp. 827-833 ◽  
Author(s):  
Danny Rischin ◽  
Kailash Narayan ◽  
Amit M. Oza ◽  
Linda Mileshkin ◽  
David Bernshaw ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Pulmonary Embolism ◽  
Dose Level ◽  
Locally Advanced ◽  
External Beam Radiation ◽  
Advanced Cervical Cancer ◽  
Locally Advanced Cervical Cancer ◽  
Level 1 ◽  
Grade 3 ◽  
Experienced Grade

Introduction:Hypoxia is an adverse prognostic factor in locoregionally advanced cervical cancer treated with radiation. The aim of this phase I study was to develop a well-tolerated regimen that added tirapazamine to the standard regimen of radiation and weekly low-dose cisplatin.Methods:Eligible patients had previously untreated carcinoma of the cervix, stages IB2 to IVA. The starting schedule was radiotherapy (45-50.4 Gy external beam radiation followed by brachytherapy), with concomitant weekly intravenous cisplatin, 40 mg/m2 on weeks 1 to 6 and weekly intravenous tirapazamine, 290 mg/m2 in weeks 1 to 5.Results:Eleven patients were enrolled. The median age was 52 years (range, 31-65 years). Ten patients had squamous cell carcinoma and 1 patient had adenocarcinoma; 5 patients had stage 1B2 disease, 1 had stage IIA, 3 had stage IIB-3, 1 had stage IIIB, and 1 had stage IVA. The first 2 patients on dose level 1 experienced a dose-limiting toxicity (DLT): 1 experienced grade 3 alanine amino transferase elevation and grade 4 pulmonary embolism, and 1 experienced grade 3 ototoxicity. Doses were decreased to dose level −1 with a 30-mg/m2 dose of cisplatin and a 260-mg/m2 dose of tirapazamine. Three patients were treated without any DLTs. Six patients were then treated on dose level −1a: a 35-mg/m2 dose of cisplatin and a 260-mg/m2 doses of tirapazamine with 2 DLTs-grade 3 neutropenia with dose omission and grade 4 pulmonary embolism with major hemodynamic compromise. Three of 10 evaluable patients have experienced locoregional failure.Conclusions:The combination of weekly tirapazamine and cisplatin with radiation for locally advanced cervical cancer was associated with more toxicity than anticipated with the recommended dose level being tirapazamine 260 mg/m2 and cisplatin 30 mg/m2. Further study of this weekly schedule is not warranted.

A phase I study of tirapazamine in combination with radiation and weekly cisplatin in patients with locally advanced cervical cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5543-5543
Author(s):  
D. Rischin ◽  
K. Narayan ◽  
A. Oza ◽  
L. Mileshkin ◽  
D. Bernshaw ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Pulmonary Embolism ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Locally Advanced ◽  
Advanced Cervical Cancer ◽  
Locally Advanced Cervical Cancer ◽  
Level 1 ◽  
Grade 3

5543 Background and Purpose: Hypoxia is an adverse prognostic factor in locoregionally advanced cervical cancer treated with radiation. GOG are currently studying the hypoxic cytotoxin, tirapazamine (TPZ) in combination with biweekly intermediate dose cisplatin (CIS) and radiation in a large phase III trial. The aim of this phase I study was to develop a better tolerated regimen that added TPZ to the standard regimen of radiation and weekly low dose CIS. Methods: Eligible patients had previously untreated carcinoma of the cervix, Stages IB2 - IVA. The starting schedule was radiotherapy (45 to 50.4 Gy external beam radiation followed by brachytherapy), with concomitant weekly CIS 40 mg/m2 weeks 1–6 and weekly TPZ 290 mg/m2 (prior to CIS) in weeks 1–5. Results: Between 3/05 and 7/06 eleven patients were enrolled, median age (range) 52 (31–65), squamous cell carcinoma 10, adenocarcinoma 1, 1B2–5, IIA-1, IIB-3, IIIB- 1, IVA-1. The first 2 patients on dose level 1 experienced a dose limiting toxicity (DLT), one grade 3 ALT (SGPT) elevation and grade 4 pulmonary embolism and one grade 3 ototoxicity. Doses were decreased to dose level -1 CIS 30 mg/m2 and TPZ 260 mg/m2. Three patients were treated without any DLTs. Six patients were then treated on dose level -1a, CIS 35 mg/m2 and TPZ 260 mg/m2, with 2 DLTs: grade 3 neutropenia with dose omission and grade 4 pulmonary embolism with major hemodynamic compromise. The sixth patient on dose level -1a withdrew from the trial in week 2 after being advised about the DLTs observed on this dose level. 3 additional patients will be accrued on dose level -1 to confirm safety of this dose level. One patient has relapsed in pelvic nodes, all other patients remain disease-free with a median followup of 10 months (range 5 - 21) Conclusions: The combination of weekly TPZ and CIS with radiation for locally advanced cervical cancer was associated with more toxicity than anticipated with the recommended dose level being TPZ 260 mg/m2, CIS 30 mg/m2. No significant financial relationships to disclose.

scholarly journals Oncothermia in HIV-Positive and -Negative Locally Advanced Cervical Cancer Patients in South Africa

2013 ◽  
Vol 2013 ◽  
pp. 1-3
Author(s):  
Carrie A. Strauss ◽  
Jeffrey A. Kotzen ◽  
Ans Baeyens ◽  
Irma Maré
Keyword(s):  
South Africa ◽  
Cervical Cancer ◽  
Cancer Patients ◽  
Standard Treatment ◽  
Locally Advanced ◽  
External Beam Radiation ◽  
Hiv Positive ◽  
Advanced Cervical Cancer ◽  
Treatment Toxicity ◽  
Locally Advanced Cervical Cancer

Aim. Investigate the clinical, economic, and cellular effects of the addition of oncothermia to standard treatment for HIV-positive and -negative locally advanced cervical cancer patients in public healthcare in South Africa. Objectives. Evaluate the effect that the addition of oncothermia has on local disease control, progression-free survival, overall survival at 2 years, treatment toxicity, quality of life, economic impact, and HIV status of participants. Radiobiology investigations will evaluate thermoradiosensitivity and the molecular markers for thermoradiosensitivity. Methodology. Phase III randomised clinical trial involving 236 HIV-negative and -positive stage IIb-III locally advanced cervical cancer patients. Treatment includes cisplatin, external beam radiation, and brachytherapy. The study group will receive oncothermia treatments. Participants will be monitored for two years after completion of treatment. Hypothesis. The addition of oncothermia to standard treatment protocols will result in improved clinical response without increasing treatment toxicity in HIV-positive patients or raising healthcare costs.

scholarly journals Concurrent Definitive Chemoradiation Incorporating Intensity-Modulated Radiotherapy Followed by Adjuvant Chemotherapy in High Risk Locally Advanced Cervical Squamous Cancer: A Phase Ⅱ Study.

2021 ◽  
Author(s):  
Gong-yi ZHANG ◽  
ZHANG Rong ◽  
Ping BAI ◽  
Shu-min LI ◽  
Yuan-yuan ZHANG ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Locally Advanced ◽  
Intensity Modulated Radiotherapy ◽  
Advanced Cervical Cancer ◽  
Free Survival ◽  
Locally Advanced Cervical Cancer ◽  
Intensity Modulated ◽  
Grade 3

Abstract Background Although the prognosis of locally advanced cervical cancer has improved dramatically, survival for those with stage ⅢB-ⅣA disease or lymph nodes metastasis remains poor. It is believed that the incorporation of intensity-modulated radiotherapy into the treatment of cervical cancer might yield an improved loco-regional control, whereas more cycles of more potent chemotherapy after the completion of concurrent chemotherapy was associated with a diminished distant metastasis. We therefore initiated a non-randomized prospective phaseⅡ study to evaluate the feasibility of incorporating both these two treatment modality into the treatment of high risk locally advanced cervical cancer. Objectives to determine whether the incorporation of intensity-modulated radiotherapy and the addition of adjuvant paclitaxel plus cisplatin regimen into the treatment policy for patients with high risk locally advanced cervical cancer might improve their oncologic outcomes. Study Design: Patients were enrolled if they had biopsy proven stage ⅢA-ⅣA squamous cervical cancer or stage ⅡB disease with metastatic regional nodes. Intensity-modulated radiotherapy was delivered with dynamic multi-leaf collimators using 6MV photon beams. Prescription for PTV ranged from 45.0 ~ 50.0Gy at 1.8Gy ~ 2.0Gy/fraction in 25 fractions. Enlarged nodes were contoured separately and PTV-nodes were boosted simultaneously to a total dose of 50.0–65 Gy at 2.0- 2.6Gy/fraction in 25 fractions. A total dose of 28 ~ 35Gy high-dose- rate brachytherapy was prescribed to point A in 4 ~ 5 weekly fractions using an iridium- 192 source. Concurrent weekly intravenous cisplatin at 30mg/m2 was initiated on the first day of radiotherapy for over 1-hour during external-beam radiotherapy. Adjuvant chemotherapy was scheduled within 4 weeks after the completion of concurrent chemo-radiotherapy and repeated 3 weeks later. Paclitaxel 150 mg/m2 was given as a 3-hour infusion on day1, followed by cisplatin 35 mg/m2 with 1-hour infusion on day1-2 (70 mg/m2 in total). Results Fifty patients achieved complete response 4 weeks after the completion of the treatment protocol, whereas 2 patients had persistent disease. After a median follow-up period of 66 months, loco-regional (including 2 persistent disease), distant, and synchronous treatment failure occurred in 4 ,5, and 1, respectively. The 5-year disease-free survival, loco-regional recurrence-free survival, distant-metastasis recurrence-free survival was 80.5%, 90.3%, and 88.0%, respectively. Four of the patients died of the disease, and the 5-year overall survival was 92.1%. Most of the toxicities reported during concurrent chemo-radiotherapy were mild and transient. The occurrence of hematological toxicities elevated mildly during adjuvant chemotherapy, as 32% (16/50) and 4% (2/50) patients experienced grade 3–4 leukopenia and thrombocytopenia, respectively. Grade 3–4 late toxicities were reported in 3 patients. Conclusions The incorporation of intensity-modulated radiotherapy and adjuvant paclitaxel plus cisplatin chemotherapy were highly effective and well-tolerated in the treatment of high-risk locally advanced cervical cancer. The former yields an improved loco-regional control, whereas distant metastases could be effectively eradicated with mild toxicities when adjuvant regimen was prescribed.

Use of carboplatinum as neoadjuvant setting for patients affected by locally advanced cervical cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15553-e15553
Author(s):  
Carlo De Cicco Nardone ◽  
Francesco Plotti ◽  
Michela Angelucci ◽  
Roberto Montera ◽  
Patrizio Damiani ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Response Rate ◽  
Locally Advanced ◽  
Complete Response ◽  
World Health ◽  
Advanced Cervical Cancer ◽  
Locally Advanced Cervical Cancer ◽  
Grade 3 ◽  
Health Organization

e15553 Background: The aim of this study is to evaluate the efficacy and safety of the combination of carboplatin and paclitaxel as neoadjuvant chemotherapy (NACT) in patients affected by locally advanced cervical cancer. Methods: Between June 2007 to May 2009, all patients with diagnosis of IB2-IIB cervical cancer were considered eligible for this protocol. All enrolled patients received 3 cycles of carboplatin (AUC6) and paclitaxel at 175 mg/mq in neadjuvant setting. The chemotherapy induced toxicity and response to the treatment were evaluated according to World Health Organization criteria. Results: We have enrolled 23 patients with diagnosis of locally advanced cervical cancer. A total of 22 patients completed planned 3 cycles of neoadjuvant chemotherapy. After 3 cycles of chemotherapy 9 out of 23 patients (42%) showed a complete response, 7 patients (35%) partial response, 5 patients (16%) stable disease and 2 patients (11%) showed disease progression. The most common toxicity was haematologic (43%), extra haematologic toxicities were nausea/vomiting, neuropathy and alopecia, that occurred in 45%, 13% and 25% respectively. No renal and grade 3 and 4 haematologic toxicities were registered. Conclusions: Our results suggest that the use of carboplatin, in neadjuvant setting, is a well tolerated drug, produces manageable toxicity with a response rate similar to standard cisplatin. Then, it rappresents a valid alternative in patients affected by locally advanced cervical cancer.

A phase I study of docetaxel as a radiosensitizer for locally advanced squamous cell cervical cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5053-5053
Author(s):  
E. A. Alvarez ◽  
A. H. Wolfson ◽  
J. M. Pearson ◽  
M. Crisp ◽  
N. C. Lambrou ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Study ◽  
Locally Advanced ◽  
Concurrent Radiotherapy ◽  
Level 1 ◽  
Experienced Grade

5053 Background: Concomitant radiotherapy with cisplatin chemotherapy is the standard of care for locally advanced squamous cell cervical cancer (LASCCC). Alternatives to cisplatin are needed due to patient intolerance or toxicity. Taxanes have demonstrated clinical cytotoxic activity to SCCC and in-vitro radio-sensitization. This study was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly docetaxel with concurrent radiotherapy for the primary treatment of LASCCC. Methods: Twenty-three patients with FIGO stage IIB-IVA LASCCC without para-aortic lymph node involvement were screened and 13 enrolled in a dose-escalating phase I study. Docetaxel dose levels were 20 mg/m2, 30 mg/m2 and 40 mg/m2 given intravenously every 7 days for 6 cycles. Three patients were treated at each dose level and six patients received the MTD. Radiation therapy (RT) delivered a total dose of approximately 85 Gy to Point “A”. RT was administered with megavoltage external beam irradiation (EBI) at 1.8 Gy/fraction (fx) for 30 fxs to the pelvis over 6 weeks using a 4-field “box” technique for the first 25 fxs. A midline shield was applied for the last 5 fxs. Following EBI, patients underwent low-dose-rate brachytherapy. Results: Thirteen patients completed 4 - 6 cycles of chemotherapy. The other patients withdrew consent or needed alternative treatment before initiating the study. Reasons for completing less than 6 cycles were: noncompliance (5), adverse event (2), progression (1). One patient was lost to follow-up after 4 cycles. DLT’s were not observed at the 20 mg/m2 dose level. At the 30 mg/m2 dose level, 1/4 patient had a treatment-unrelated pelvic abscess and celiotomy. Another had progression 4 months after treatment. At the 40 mg/m2 dose level, 1/6 patients had progression and experienced grade 2 pneumonia, not treatment related. DLT was not observed in 6 patients at the 40 mg/m2 level. Overall, 5/13 (38%) experienced grade 2 diarrhea, 5 had grade 2 hematologic toxicity, and 2 had grade 2 hypersensitivity. Seven of 9 patients (78%) had no evidence of disease with follow-up ranging from 10–21 months. Conclusions: The recommended phase II dose of docetaxel administered weekly with concurrent radiotherapy for LASCCC is 40 mg/m2. The phase II trial is underway. No significant financial relationships to disclose.

A phase II study of dose-dense neoadjuvant chemotherapy with weekly paclitaxel and carboplatin followed by chemoradiation in locally advanced cervical carcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5104-5104
Author(s):  
Rajkumar Bikramjit Singh ◽  
Lalit Kumar ◽  
Subhash Chandra ◽  
B. K Mohanti ◽  
Sushmita Pathy ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Response Rate ◽  
Locally Advanced ◽  
Weekly Paclitaxel ◽  
Advanced Cervical Cancer ◽  
Locally Advanced Cervical Cancer ◽  
Grade 3 ◽  
Dose Dense

5104 Background: We prospectively studied dose dense neoadjuvant chemotherapy (NACT) designed for an enhanced cell kill, better local control and eradication of micrometastases prior to standard concurrent chemoradiation (CRT) in locally advanced cervical cancer. Methods: Between June 2010 and December 2011, 21 patients (median age - 51 years, range 35 - 67) of cervical cancer with locally advanced disease received NACT using paclitaxel (60mg/m2) and carboplatin (AUC-2) weekly for 6 doses. Patients (pts) then received concurrent CRT (external and brachytherapy) with weekly cisplatin (40mg/m2 for 6 doses) at a mean interval of 15 days (range 7–20 days). The primary end-point was response rate i.e. complete response (CR) and partial response (PR) 12 weeks post CRT. Results: Baseline stages were: stage 2A - 19%, 3B - 71.4%, 4A - 9.5%. Squamous cell carcinoma and adenocarcinoma constituted 95.2% and 4.7% pts respectively. Following NACT, 66.6% pts responded (CR -9.5% %; PR – 57.1 %), 23.8% had stable disease (SD) and 4.7% had progressive disease (PD). A total of 18 pts completed NACT and CRT of which 17 were in CR and 1 in PR. One patient with stage 4A disease developed vesicovaginal fistula at end of NACT for which she underwent pelvic exenteration and was in pathological CR. After NACT, one patient developed choroid metastases and was taken off study protocol while another patient was lost to follow up. At a mean follow up 5.8 months (range 1 - 14), 90% pts were in CR, 5% in PR and 5% had PD. During NACT, Grade 3/4 neutropenia, thrombocytopenia and anemia were seen in 33.3%, 4.7% & 9.5% of pts, respectively and grade 3/4 non-hematological toxicities in 9.5% pts. Following CRT, Grade 3/4 neutropenia, thrombocytopenia and anemia were seen in 25%, 5% and 10% of pts, respectively while 20% pts had grade 3/4 non-hematological toxicities. G-CSF was used in 30% pts during NACT and 25% pts during CRT, respectively. Conclusions: NACT with weekly paclitaxel and carboplatin followed by radical CRT is feasible and is associated with a high response rate in locally advanced cervical cancer. This approach needs to be studied in a phase III trial.

The Effect of Body Mass Index and Weight Change on Late Gastrointestinal Toxicity in Locally Advanced Cervical Cancer Treated With Intensity-modulated Radiotherapy

2018 ◽  
Vol 28 (7) ◽  
pp. 1377-1386 ◽  
Author(s):  
Jie Lee ◽  
Chih-Long Chang ◽  
Jhen-Bin Lin ◽  
Meng-Hao Wu ◽  
Fang-Ju Sun ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Cervical Cancer ◽  
Locally Advanced ◽  
Intensity Modulated Radiotherapy ◽  
Normal Weight ◽  
Gastrointestinal Toxicity ◽  
Advanced Cervical Cancer ◽  
Locally Advanced Cervical Cancer ◽  
Intensity Modulated ◽  
Grade 3

ObjectiveTo evaluate the effects of body mass index (BMI) and weight change during radiotherapy on the development of toxicity in patients with locally advanced cervical cancer (LACC) treated with intensity-modulated radiotherapy (IMRT).MethodsA total of 245 patients were analyzed after undergoing definitive IMRT treatment between 2004 and 2015 for stage IB2 to stage IVA LACC. The patients were divided into 3 groups: underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5–24.9 kg/m2), and overweight (BMI ≥25.0 kg/m2). The relationships between toxicity, clinical factors, and the bowel dose-volume histogram were analyzed. V45 indicated the bowel volume that received a radiation dose of 45 Gy.ResultsThe median follow-up period was 63 months. The V45 was similar among the 3 groups. The 5-year rates of grade 3 or higher late gastrointestinal toxicities were 18.6%, 4.0%, and 4.2% for the underweight, normal weight, and overweight groups, respectively (P = 0.002). In the multivariable analysis, underweight (hazard ratio, 13.99; 95% confidence interval, 3.22-60.82; P < 0.001) and weight loss (> −5%) (hazard ratio, 5.91; 95% confidence interval, 1.75-19.98; P = 0.004) were significant predictors of grade 3 or higher-grade late gastrointestinal toxicities.ConclusionA BMI of less than 18.5 kg/m2 and weight loss (> −5%) were associated with a higher risk of grade ≥3 or higher late gastrointestinal toxicity in patients with LACC treated with definitive IMRT. Future research on the development of a standardized and structured approach to improve the therapeutic ratio for the supportive care of patients with LACC is needed.

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