Phase I Trial of Taxol as a Radiation Sensitizer with Cisplatin in Advanced Cervical Cancer

doi:10.1006/gyno.1997.4851

Gynecologic Oncology

Volume 67, Issue 2, November 1997, Pages 131-136

https://doi.org/10.1006/gyno.1997.4851 Get rights and content

Abstract

Objective.The aim of this study was to determine tolerable doses and potential toxicities of taxol, administered weekly, with concomitant cisplatin and radiation therapy in advanced cervical cancer.

Methods.Patients with cervical cancer, either with evidence of distant metastatic disease at presentation or otherwise at high risk for recurrent disease, were eligible for this phase I study. Taxol was administered weekly as a 3-hr intravenous infusion in addition to the prescribed radiation therapy. The starting dose was 10 mg/m²/week and escalated at 10 mg/m²/week increments if tolerated by successive cohorts of three new patients. Cisplatin was given every 3 weeks at 50 mg/m². Chemotherapy was continued until radiation was completed. For each patient quality of life was assessed weekly during therapy.

Results.Sixteen patients, undergoing a total of 102 cycles, have been enrolled. Dose escalation of taxol from 10 mg/m²/week to 50 mg/m²/week was well tolerated, with no significant change in quality of life during therapy. Two radiation fractions (0.5%) were delayed due to toxicity from this chemotherapy regimen. Of 102 cycles, 6 resulted in grade 2 and 1 in grade 3 neutropenia, and no patient developed >grade 2 anemia or thrombocytopenia. Three patients developed GI-related toxicities and 1 patient presented with urosepsis during treatment. There was a 93% response rate to this regimen, with 10 patients (63%) presently having no evidence of disease.

Conclusions.This study has demonstrated that up to 50 mg/m²/week of taxol is well tolerated in patients undergoing radiation therapy for advanced cervical cancer. A phase II trial will assist in determining the efficacy of taxol as a radiation sensitizer in these patients.

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Synergistic antitumor effect of combined paclitaxel with FEN1 inhibitor in cervical cancer cells
2018, DNA Repair
Studies on cervical cancer are urgently required to improve clinical outcomes. As a major anticancer drug for cervical cancer, paclitaxel has been used for many years in clinical therapy but its therapeutic efficacy is limited by common obstacle from cancer cells. The enhanced DNA repair pathways of cancer cells have been proved to survive DNA damage induced by chemotherapeutic drug. Inhibitors of specific DNA repair pathway can sensitize cancer cells to the treatment of chemotherapeutic drugs. In this paper we found that the effect of paclitaxel can be significantly improved when used in combination with FEN1 inhibitor SC13, suggesting a synergistic mechanism between the two compounds. Our studies suggest that FEN1 inhibition could be a novel strategy of tumor-targeting therapy for cervical cancer. Our work also revealed that paclitaxel demonstrates stronger synergistic effect with SC13 than other common used chemical drugs such as doxorubicin, carboplatin or camptothecin on cervical cancer cells.
Phase II study of concurrent chemoradiotherapy with weekly cisplatin and paclitaxel in patients with locally advanced uterine cervical cancer: The JACCRO GY-01 trial
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However, 1 of the patients in the present study experienced a grade 4 cerebral hemorrhage 1.5 years after irradiation, which is unlikely to have any direct causal relationship with the study, suggesting that the late event rates between the studies may be considered comparable. Several clinical studies of CCRT with CDDP and PTX in the treatment of cervical cancer have been reported to date [10,11,15–18]. Chen et al. [15] and Pignata et al. [16] reported the efficacy of CCRT with CDDP and PTX with response rates of ≥ 90% in their phase I studies.
A multicenter phase II trial was conducted to assess the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with weekly cisplatin (CDDP) and paclitaxel (PTX) in patients with locally advanced uterine cervical cancer.
Patients with FIGO stage III–IVA uterine cervical cancer without para-aortic lymphadenopathy were enrolled. Patients received definitive radiotherapy (RT) consisting of external beam whole-pelvic RT and high-dose-rate intracavitary brachytherapy. The cumulative linear quadratic equivalent dose was 62–65 Gy prescribed at point A. weekly CDDP at 30 mg/m² and PTX at 50 mg/m² were administered concurrently with RT for ≥ 5 courses.
Sixty-eight of the 70 registered patients were eligible. The complete response rate was 76.5% (95% confidence interval [CI], 66.4–86.6%). With a median follow-up of 27 months (range, 7.9–33.5), the 2-year cumulative progression-free survival and the 2-year cumulative overall survival rates were 83.8% (95% CI, 75.1–92.6%) and 92.7% (95% CI, 86.4–98.9%), respectively. The pelvic cumulative disease progression-free and the 2-year cumulative distant metastasis rates were 89.6% (95% CI, 82.3–96.9%) and 13.2% (95% CI, 5.2–21.3%), respectively. The 2-year cumulative late complication rates were 25% for all grades, 13.2% for grade 1, 5.9% for grade 2, 2.9% for grade 3, and 2.9% for grade 4.
For locally advanced cervical cancer, CCRT with weekly CDDP 30 mg/m² and PTX at 50 mg/m² demonstrated favorable antitumor activity, and was feasible and safe with respect to the protocol-specified serious adverse reactions and events. Evaluation of this regimen in phase III trials is warranted.
Quality of life (QOL) in women treated for gynecologic malignancies with radiation therapy: A literature review of patient - Reported outcomes
2014, Gynecologic Oncology
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Pelvic radiation therapy has several known acute and long term toxicities. Acute treatment-related toxicities include dermatitis, mucositis, diarrhea, and dysuria, among others [1,2]. These side effects can generally be managed with skin creams, anti-diarrhea medications, and pain medications, and may resolve shortly after the completion of therapy.
To summarize the literature on quality of life for patients treated with definitive radiation for gynecologic cancers, with a specific focus on patient reported outcomes.
A literature review was performed to summarize studies about patient-reported outcomes and quality of life in women with gynecologic malignancies who were treated with definitive radiation therapy. Summaries are by disease site, including endometrial, cervical and vulvar cancers.
Over 20 different survey instruments have been used to describe patient-reported outcomes for women treated with radiation for gynecologic cancer. Regardless of disease site, all patients describe a degree of compromise in physical and social functioning, as well as sexual dysfunction. Specific symptoms which are most bothersome for patients vary by disease site, such as bowel concerns predominating for endometrial cancer patients, while body image is more concerning for cervical cancer patients.
Several quality of life concerns exist for women treated with radiation therapy for gynecologic malignancies. Significant overlap exists in the QOL issues affecting these patients. Whether to combine or separate surveys by diagnosis, treatment type, age, or time point should be explored further. Assessing patients' psychological, emotional, and physical concerns helps to understand long-term adjustment, enabling incorporation of these domains into future trials that will ultimately improve patient well-being.
A prospective phase II study of chemoradiation followed by adjuvant chemotherapy for FIGO stage I-IIIA (1988) uterine papillary serous carcinoma of the endometrium
2013, Gynecologic Oncology
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By comparison, Martinez et al. reported a 14% rate of chronic gastrointestinal toxic effects in patients treated with WAPI [7]. Our paclitaxel dose of 50 mg/m2 weekly, which we chose on the basis of published findings indicating that this dose is associated with minimal and manageable toxic effects [16–18], may have been too high for our relatively elderly patients (mean age, 63 years); a dose of 40 mg/m2 weekly might have been better tolerated. Another potential means of reducing bowel toxic effects, the use of IMRT, was not allowed in our study.
To prospectively evaluate tumor control, survival, and toxic effects in patients with International Federation of Gynecology and Obstetrics (1988) stage I–IIIA papillary serous carcinoma of the endometrium treated with concurrent chemoradiation and adjuvant chemotherapy.
Thirty-two patients were enrolled from October 2001 through July 2009. Patients underwent full surgical disease staging and postoperative concurrent weekly paclitaxel (50 mg/m²) and pelvic RT to 45 Gy plus a vaginal cuff boost followed by 4 cycles of adjuvant paclitaxel (135 mg/m²).
Thirty patients (94%) were evaluable (3 with stage IA disease, 11 IB, 3 IC, 1 IIB, and 12 IIIA). Eighteen patients (60%) received all 5 planned courses of concurrent chemotherapy, 10 (33%) received 4 courses, and 2 (7%) received 3 courses. All 30 patients received RT; 27 (90%) received the full dose, 2 received 43.2 Gy, and 1 received 39.6 Gy owing to toxic effects. Twenty-three patients (77%) completed all 4 cycles of adjuvant paclitaxel, 3 (10%) completed 3 cycles, 2 (7%) completed 2 cycles, and 2 received no adjuvant therapy. Overall survival (OS), progression-free survival (PFS), and local control rates for all patients were 93%, 87%, and 87%, respectively, at 2 years and 85%, 83%, and 87%, respectively, at 5 years. Six patients developed (20%) grade 3/4 toxicities from the treatment. Four patients (13%) had grade 3 or more severe bowel complications and two patients developed symptomatic pelvic fractures.
Treatment with concurrent paclitaxel and pelvic RT followed by 4 courses of systemic paclitaxel produced favorable results in patients with surgically staged I–III UPSC.
Maximum Tolerated Dose and Early Response - Results of a Phase I Trial of Paclitaxel and Cisplatin with Radiation Therapy in Carcinoma of the Cervix<sup>1</sup>
2009, Clinical Oncology
Citation Excerpt :
Phase I trials using paclitaxel and cisplatin once a week have shown that doses of 40–60 mg/m2/week of paclitaxel with 30–50 mg/m2/week of cisplatin were well tolerated. The most common toxicities described were neutropenia and diarrhoea [9–12]. The early response rate was 97.7% with a complete response rate of 84.9%.
Cisplatin-based chemotherapy with radiotherapy is currently the standard treatment for locally advanced carcinoma of the cervix. Recent studies have shown a better response with the addition of newer chemotherapeutic agents. The aim of this phase I study was to establish the maximum tolerated dose (MTD) of paclitaxel in combination with cisplatin as a radiosensitiser along with radiation therapy in the treatment of carcinoma of the cervix and to analyse the toxicity profile of the combination regimen.
In total, 21 newly diagnosed patients with squamous cell carcinoma of the cervix, International Federation of Gynecology and Obstetrics stage IB to IIIB were included in this trial. All patients received external beam radiation therapy to the pelvis (50 Gy in 25 fractions) delivered by conventional four-field box technique followed by low dose rate brachytherapy. Concurrent chemotherapy was administered with weekly cisplatin (30 mg/m²) and an escalating dose of weekly paclitaxel starting at 10 mg/m² up to 50 mg/m² (according to the modified Fibonacci series).
The MTD of weekly paclitaxel was found to be 40 mg/m². The dose-limiting toxicity that occurred in our patients at a dose of 50 mg/m² weekly paclitaxel was grade 3 proctitis and vaginitis.
In this phase I trial of concurrent radiation and combination chemotherapy with weekly paclitaxel and cisplatin (30 mg/m²/week), the MTD of paclitaxel was found to be 40 mg/m². This combination was feasible, with an acceptable toxicity profile.
A phase I/II study of extended field radiation therapy with concomitant paclitaxel and cisplatin chemotherapy in patients with cervical carcinoma metastatic to the para-aortic lymph nodes: A gynecologic oncology group study
2009, Gynecologic Oncology
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There had been one previous trial looking at the combination of paclitaxel and cisplatin with radiation therapy in cervical cancer. Chen, et al. reported on a phase I study of escalating doses of paclitaxel as a radiation sensitizer in combination with cisplatin [15]. The results demonstrated a well-tolerated dose range starting at 10 mg/m2 weekly and advancing to 50 mg/m2 weekly in combination with cisplatin 50 mg/m2 every three weeks.
To determine the maximum tolerated dose (MTD) of weekly paclitaxel and cisplatin chemotherapy concurrent with extended field irradiation in women with cervical cancer metastatic to the para-aortic nodes.
Patients with carcinoma of the cervix and histologically documented para-aortic node metastases were eligible for this phase I/II trial. Chemotherapy agents were administered weekly concurrent with extended field radiation with escalating doses of paclitaxel from 30–50 mg/m² in each of three cohorts of three patients each. A phase II cohort was then evaluated at the selected maximum tolerated dose (MTD).
The MTD was determined to be cisplatin 40 mg/m² (maximum dose of 70 mg) and paclitaxel 40 mg/m² administered weekly for six cycles concurrent with extended field radiation therapy. There were 19 evaluable patients for the phase II analysis of toxicity and efficacy. Grade three and four gastrointestinal toxicity was seen in 6 and neutropenia in 7. Radiation therapy was successfully completed in 36.8% of patients at eight weeks and in 68.4% of patients at nine weeks, with a median time to completion was 56 days. A total of 27 evaluable patients were enrolled, twelve are dead (mean survival of those deceased is 25 months), and 15 (56%) are alive, and have been followed for a mean of 48 months (range 25–68; median of 46 months).
Paclitaxel and cisplatin combination chemotherapy concurrent with extended field pelvic para-aortic irradiation can be administered at the described MTD and shows a higher than previously reported disease-free survival in relation to historical data. The 56% survival to date, and 50% estimated 48 month survival, warrants validation in a larger prospective cohort. Central radiation dose reduction is being considered in the next trial to decrease late toxicity of regimen.

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Regular ArticlePhase I Trial of Taxol as a Radiation Sensitizer with Cisplatin in Advanced Cervical Cancer

Abstract

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Taxol stabilizes mictotubules in mouse fibroblast cells

Proc Natl Acad Sci U.S.A.

Taxol: a novel investigational antimicrotubule agent

J Natl Cancer Inst

Phase II study of paclitaxel in metastatic melanoma

Cancer

Phase II trial of taxol, an active drug in metastatic breast cancer

J Natl Cancer Inst

Regular Article
Phase I Trial of Taxol as a Radiation Sensitizer with Cisplatin in Advanced Cervical Cancer