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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 6  |  Page : 1583-1588

Role of maintenance paclitaxel in epithelial ovarian cancer: An affordable option for poor resources countries (a Regional Cancer Institute study)


1 Department of Radiation Oncology, Acharya Tulsi Rgional Cancer Tratment and Research Institute, Bikaner, Rajasthan, India
2 S. P. Medical College, Bikaner, Rajasthan, India
3 Department of Radiation Oncology, SN Medical College Jodhpur, Rajasthan, India
4 Department of Radiotherapy, Acharya Tulsi Regional Cancer Treatment and Research Institute, Bikaner, Rajasthan, India

Date of Submission14-Apr-2021
Date of Acceptance19-Jun-2021
Date of Web Publication10-Sep-2022

Correspondence Address:
Surender Beniwal
Depatment of Medical Oncology, Acharya Tulsi Regional Cancer Treatment and Research Institute, SP Medical College, Bikaner
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_607_21

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 > Abstract 


Purpose: The purpose of the study is to assess the benefits of maintenance chemotherapy (CT) in epithelial ovarian cancer with CT and surgery. The primary and secondary endpoints of the study were progression-free survival (PFS) and overall survival (OS), respectively.
Patients and Methods: Three hundred patients with ovarian cancer (registered between January 2012 and December 2013) received 6 cycles of 3 weekly CT (injection paclitaxel 175 mg/m2 + injection carboplatin 6 AUC) and surgery. After 4 weeks of completion of the above treatment, patients were assessed for response with radiological imaging and serum CA125. Then, these patients were randomly allotted in two arms; 150 patients in Arm A received 6 cycles of single agent, 3 weekly injection paclitaxel 175 mg/m2 as maintenance therapy while 150 patients in Arm B, were on observation. The follow-up was done at 1 month, then 3 monthly in the 1st year and 6 monthly in the 2nd year to evaluate PFS and annually up to 5 years for OS.
Results: The PFS at 1 and 2 years was 91% and 80% in study arm and 65% and 50% in control arm; the differences were statistically significant (P = 0.010). The 5-year overall survival was 43% versus 38% in study and control arms, respectively (P = 0.410) and 5-year PFS was 28% versus 18% (P = 0.039) in maintenance and observation arm, respectively. Except for peripheral neuropathy, there was no statistically significant difference in toxicities between the two arms.
Conclusion: The study suggests that 6 cycles of single-agent paclitaxel maintenance therapy significantly prolongs the duration of PFS and better trends toward OS, though a large study is needed to come to a conclusion.

Keywords: Advanced epithelial ovarian cancer, maintenance paclitaxel, maintenance therapy


How to cite this article:
Beniwal S, Dhaka S, Rajani A, Jakhar SL, Kumar H S, Sharma N. Role of maintenance paclitaxel in epithelial ovarian cancer: An affordable option for poor resources countries (a Regional Cancer Institute study). J Can Res Ther 2022;18:1583-8

How to cite this URL:
Beniwal S, Dhaka S, Rajani A, Jakhar SL, Kumar H S, Sharma N. Role of maintenance paclitaxel in epithelial ovarian cancer: An affordable option for poor resources countries (a Regional Cancer Institute study). J Can Res Ther [serial online] 2022 [cited 2022 Dec 9];18:1583-8. Available from: https://www.cancerjournal.net/text.asp?2022/18/6/0/355657




 > Introduction Top


Ovarian cancer is the 6th most common cancer and the 7th leading cause of cancer deaths worldwide[1] among women. In India, it is the 3rd leading cancer in women and has the worst prognosis among all gynecological cancers.

There are several histological subtypes of ovarian cancer with different morphology. Currently used standard frontline treatments are still the same for all epithelial subtypes and consist of upfront surgery followed by chemotherapy (CT) based on a combination of platinum and paclitaxel.[2],[3],[4] If tumor is inoperable, then neoadjuvant CT may be taken into consideration. Surgery is an essential part of the treatment of most of cases of ovarian cancer. The main aim of surgery is to obtain a complete resection of all macroscopically visible diseases. Nowadays, the term “optimal debulking” or “optimal cytoreduction” (i.e., no residual tumor or <1 cm residual tumor at the end of surgery, respectively) is reserved for those situations in which no macroscopic residual disease has been left after surgery.[5],[6],[7]

Maintenance therapy is mainly consisting of the administration of some additional cycles of CT beyond the 6 cycles of paclitaxel and carboplatin. Two strategies have been studied; the first one is to continue with some of the agents already used if the patient has not progressed. The rationale behind this approach is to keep cancer under control for a longer time after initial treatment. On the other hand, nonresistant, slowly-dividing tumor cells that were inadequately exposed to cycle-dependent cytotoxic agents during the initial treatment period may be substantially reduced in number or completely eliminated with the continuation of CT. The second option is to introduce a new agent without cross resistance with those previously used to eliminate those clones of cells resistant to upfront CT. The first food and drug administration approved as maintenance therapy was bevacizumab, 2016. Since then, (poly ADP-ribose polymerase) inhibitors were approved as maintenance therapy in ovarian cancer: niraparib, olaparib, and rucaparib. Few studies have proved the benefit of maintenance therapy, discussed below [Table 1].
Table 1: Similar studies of maintenance chemotherapy in ovarian cancer

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The overall survival (OS) is approximately 45%, primarily due to the late stage at diagnosis of disease and aggressive biology also constitutes to poor OS based on histopathology. Many other factors include the amount of residual disease after surgery, inappropriate management, and poor compliance to therapy; all together are responsible for the dismal survival. The aim of this study to evaluate the role of maintenance therapy in survival improvement, primarily focusing on progression-free survival (PFS) and OS.


 > Patients and Methods Top


This was a randomized prospective study conducted at a regional cancer center in North-West India. The study protocol included 300 patients with ovarian cancer, who were registered from January 2012 to December 2013.

Eligibility criteria

Patients with locally advanced, histologically proved Stage III–IV epithelial ovarian cancer who attained complete response after primary cytoreduction and six cycles of paclitaxel/platinum-based CT were included in the study. Tumor stage and histological diagnosis were determined by the international federation of gynecology and obstetrics (FIGO) criteria and WHO, respectively. Tumors were graded as well, moderate, or poorly differentiated. Other criteria included as age up to 70 years, eastern cooperative oncology group performance status 0–2 without any hematological, cardiac, renal, or liver function abnormality, and no previous history of treatment for ovarian cancer and no other concurrent malignancy.

Study design

The patients with ovarian cancer received initial six cycles of 3 weekly CT (in the form of injection paclitaxel 175 mg/m2 + injection carboplatin 6 areas under the curve) and surgery as a standard treatment. After 4 weeks of completion of this above standard treatment, patients were assessed for the response of treatment with radiological imaging and CA125. Then, 300 eligible patients, who had achieved clinically complete response, were randomly allocated to either observation (i.e., control arm) or six cycles of single-agent injection paclitaxel 175 mg/m2 (3-h infusion) every 3 weeks as maintenance therapy (i.e., study arm). Total 150 patients were included in each arm. Randomization was done by the simple randomization method. The follow-up was done at 1, 3, 6 months, 1 and 2 years to assess PFS and up to 5 years to assess OS. Toxicity assessment was done at the end of standard treatment, 1, 3, and 6 months.

Patients were under monitoring after every course of CT. In each monitoring, patients were assessed for treatment response, control of symptoms, and any treatment-related toxicity by doing complete blood counts, biochemistry profile consisting of renal function test (RFT) and liver function test (LFT), chest X-ray, USG abdomen, and pelvis. Toxicities including hematological, renal, biochemical, skin reactions, peripheral neuropathy, and disease response were assessed. After 1 month of completion of standard treatment, patients were called for the first follow-up visit and were assessed for treatment response and toxicities. On 1- and 3-month follow-up visit complete general physical examination, CA-125, CBC, LFT, RFT, chest X-ray, and USG abdomen pelvis were done for treatment response, toxicity evaluation, and metastatic assessment. The subsequent follow-up at 2–4 monthly for 2 years and 3–6 months for 5 years, then annually after 5 years; an additional contrast-enhanced computed tomography abdomen-pelvis was performed with the detailed systemic examination, CA-125, CBC, LFT, RFT, and chest X-ray to evaluate the recurrence, distant metastasis.

Endpoints

The primary endpoint of the study was PFS according to the intention to treat criteria. The secondary endpoint was OS and toxicity evaluation. PFS was the time from the date of randomization to the date of progression. Progression was defined as the appearance of a new lesion or asymptomatic raised CA-125 level at two consecutive tests, which were measured 1-month apart. OS was defined time from date of randomization to date of death due to any cause.

Statistical considerations

All statistical analyses were performed by using IBM SPSS(version 20.0) Collaboration and Development services, NY. US. Assessment of OS was done by using the Kaplan–Meier method, and PFS was done by Chi-square method.


 > Results Top


From January 2012 to December 2013, a total of 300 patients enrolled. The patient's characteristics were comparable in both arms [Table 2]. Local control and OS were assessed on various follow-ups up to 5 years [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8].
Table 2: Patients characteristics

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Table 3: Follow-up at 3 months

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Table 4: Follow-up at 6 months

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Table 5: Follow-up at 1 year

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Table 6: Follow-up at 2 years

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Table 7: Follow-up at 3 years

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Table 8: Follow-up at 5 years

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The 2-year PFS was 23 months in the study arm and 17 months in the control arm. Above all tables summarize that the median PFS was significantly longer for the study group with maintenance therapy (23 vs. 17 months; P ≤ 0.05). The 5-year PFS was 28% versus 18% (P = 0.039) while 5-year OS was 43% versus 38% (P = 0.410) in maintenance and observation arms, respectively. There was no significant difference in toxicities except for higher peripheral neuropathy in the study arm.

[Figure 1] compares maintenance CT (Arm A) and observation (Arm B), after standard treatment in locally advancer epithelial ovarian cancer with respect to OS (5-year OS was 43% vs. 38%, hazard ratio: 1.174; 95% confidence interval: 0.864–1.597; P = 0.3037).
Figure 1: Survival Curve (Kaplan meier curve)

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[Figure 2] shows toxicities in Arm A and Arm B. There were 50 patients in each arm who developed Grades 1 and 2 peripheral neuropathy at the end of standard treatment. At 1 month after completion of standard treatment, 60 and 45 patients in the study and control arm, respectively, developed Grades 1 and 2 peripheral neuropathy while ten patients developed Grade 3 peripheral neuropathy in the study. Due to severe grade 3 toxicity four patients had excluded from the study. At 3 months, 80 patients in the study and 45 patients in the control arm developed Grades 1 and 2 peripheral neuropathy while five patients developed Grade 3 peripheral neuropathy. At 6 months, 60 and 40 patients in study and control arm, respectively, developed Grades 1 and 2 while five patients developed Grade 3 peripheral neuropathy.
Figure 2: Toxicity profile

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 > Discussion Top


Paclitaxel/platinum-based CT produces satisfactory response rates in patients with advanced epithelial ovarian cancer. However, almost 75% of patients who achieve clinical response and 50% of those who obtain a pathologic complete response will relapse within 2 years.[7],[8],[9],[10] The search for effective consolidation therapies, therefore, represents a high priority for this malignancy, and different treatment modalities have been tested. Both whole-abdomen radiotherapy and intraperitoneal P32 have been widely used after first-line CT but not found significant improvement in PFS or OS in clinical studies. Furthermore, radiotherapy is generally associated with an increased rate of bowel complications.[11],[12],[13],[14] Few more similar studies are discussed below in [Table 7].

The 2-year PFS was 23 months in the study arm and 17 months in the control arm. Above all table summarizes that the median PFS was significantly longer for the study group with maintenance therapy (23 vs. 17 months; P ≤ 0.05). The 5-year PFS was 28% versus. 18% (P = 0.039) while 5-year OS was 43% versus 38% (P = 0.410) in maintenance and observation arms, respectively. There was no significant difference in toxicities except for higher peripheral neuropathy in the study arm [Table 9][15],[16],[17],[18],[19],[20],[21],[22]<.
Table 9: Similar studies of maintenace paclitaxel in ovarian cancer

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This study also confirms the promising results of most of the above studies as PFS is significantly increased and the favorable trend toward OS but not statistically significant.

The limitations of this study were suboptimal radiological investigations (CXR and USG) during follow-up; histopathologic subtypes of epithelial ovarian tumors were not considered and no head-to-head comparison was done with standard of care (e.g., bevacizumab maintenance therapy). These factors can impact the results obtained.


 > Conclusion Top


The study suggests that 6 cycles of single-agent paclitaxel maintenance therapy significantly prolong the duration of PFS but showed no significant improvement in OS.

Financial support and sponsorship

Nil.

conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Pignata S, Scambia G, Ferrandina G, Savarese A, Sorio R, Breda E, et al. Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin as first-line treatment for patients with ovarian cancer: The MITO-2 randomized phase III trial. J Clin Oncol 2011;29:3628-35.  Back to cited text no. 13
    
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Markman M, Liu PY, Wilczynski S, Monk B, Copeland LJ, Alvarez RD, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 2003;21:2460-5.  Back to cited text no. 15
    
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Mannel RS, Brady MF, Kohn EC, Hanjani P, Hiura M, Lee R, et al. A randomized phase III trial of IV carboplatin and paclitaxel × 3 courses followed by observation versus weekly maintenance low-dose paclitaxel in patients with early-stage ovarian carcinoma: A Gynecologic Oncology Group Study. Gynecol Oncol 2011;122:89-94.  Back to cited text no. 22
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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