A Phase II, Open-Label, Non-Randomized, Prospective Study Assessing Paclitaxel, Carboplatin and Metformin in the Treatment of Advanced Stage Ovarian Carcinoma
ABSTRACT
Objectives. The purpose of this study was to assess the efficacy and tolerability of a paclitaxel, carboplatin and metformin regimen in the first line treatment of advanced stage ovarian, fallopian tube, and primary peritoneal carcinoma.
Methods. Eligible subjects were treated with six cycles of intravenous paclitaxel (80 mg/m2), carboplatin (AUC 5 or 6), and oral metformin (850 mg). Study participants who completed their primary therapy and attained a clinically defined complete or partial response were subsequently treated with a planned 12 cycles of paclitaxel (135 mg/m2 every Q21 days) and metformin (850 mg, b.i.d.) maintenance therapy. The study’s primary clinical endpoints included clinical response, toxicity and patient survival.
Results. In the current investigation, 30 subjects received a median of 6 cycles (range, 5-6) of primary induction chemotherapy and were eligible for response evaluation; twenty-three patients exhibited a complete response, three study patients obtained a partial response, three patients demonstrated stable disease and another subject experienced progressive disease (a complete response rate of 86.7%). The subjects also received an aggregate 103 cycles (median= 12; range, 6-12) of maintenance chemotherapy. Grade 3–4 hematological toxicity included neutropenia (43.3%), thrombocytopenia (10%) and anemia (36.7%). There was no incidence of grade 3-4 neuropathy although 15 patients (50%) developed grade < 2 neurotoxicity. Additionally, we observed grade <2 diarrhea in 20 (66.7%) subjects. The median progression free survival was 21 months (range, 3-52) and overall median survival was 35 months (range, 15-61).
Conclusions. The results from our ovarian cancer study suggest that the combination of paclitaxel, carboplatin and metformin is associated with a reasonable toxicity profile and acceptable efficacy, particularly relative to previously reported chemotherapy regimens.
Keywords. ovarian cancer; metformin; chemotherapy; survival
1. Introduction
Ovarian cancer is the tenth most common malignancy among women, accounting for nearly 22,240 diagnoses annually in the United States [1]. The standard of care for patients diagnosed with advanced stage ovarian cancer is optimal debulking surgery with attendant taxane and platinum-based chemotherapy [2]. Despite favorable objective response rates, the risk for disease progression is regrettably high and 5-year survival rates are approximately 35% [1,3].
Ovarian cancer studies have evaluated the inclusion of additional cytotoxic agents to traditional therapy with the intent of further bolstering first line efficacy [4,5]. However, since chemotherapy is associated with significant patient toxicity, one should consider a novel medication’s increasingly cumulative impact on myelosuppression.
Observational investigations have reported that diabetes increases the risk of several malignancies, namely colorectal, endometrial, breast, and ovarian cancer [6-9]. Thereafter, studies have analyzed metformin, a medication for diabetes mellitus, especially since the treatment is reasonably well tolerated and presumably exhibits anti-neoplastic activity [10-12]. Pre-clinical evaluations have further asserted that metformin effectuates a growth-static effect, which may be attributed to the targeting of the PI3K/AKT/mTOR signal transduction pathway [11,12].
Previously, ovarian cancer retrospective investigations have depicted a favorable relationship between metformin use and patient outcomes [9, 13, 14]. Consequently, since metformin reportedly impedes tumor growth and enhances chemosensitivity [10,15], assessing the medication in combination with chemotherapy for the treatment of ovarian cancer is an intriguing endeavor [13,16]. The purpose of this study was to assess the feasibility, toxicity and efficacy of an incorporated paclitaxel, carboplatin, and metformin regimen in the management of advanced stage ovarian carcinoma.
2.Patients and methods
2.1 Study design
This was a phase II, single arm, two-stage, open label, non-randomized pilot study. An institutional review board approved this clinical investigation and every participant signed a consent form prior to enrollment.
2.2 Inclusionary criteria
Patients were required to have a histologic diagnosis of stage II-IV epithelial ovarian, fallopian tube, or primary peritoneal carcinoma and undergone neoadjuvant chemotherapy and interval debulking surgery followed by adjuvant chemotherapy or surgical extirpation and adjuvant chemotherapy. Optimal cyto-reduction was defined as tumor debulking with residual disease < 1 cm [17]. Eligible patients had adequate bone marrow, renal, hepatic function, absolute neutrophil count (ANC) of > 1500^3, platelets of > 100 k/ul, and a hemoglobin value > 9 g/dL.
Patients had to obtain an ECOG performance status of < 1 and commence with their first dose of paclitaxel, carboplatin and metformin within four weeks of their initial debulking surgery. Subjects may have a history of diabetes and be receiving treatment for their condition, metformin excepted.
2.3 Exclusionary criteria
Subjects with a history of treatment comprising radiotherapy or chemotherapy were excluded from study participation. Additionally, any subject with a concomitant or previous malignancy within the past three years (non-melanoma skin cancer notwithstanding) was excluded from study consideration. Participants could not be treated with metformin or have been on the medication within the previous 6 months. Study participants were also required to have a total bilirubin 1.5 mg/dL x upper limit normal (ULN), aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN, serum creatinine 1.5 mg/dL. Also, subjects with septicemia, severe infection, borderline tumor diagnosis, acute hepatitis, severe gastrointestinal bleeding, history of congestive heart failure, angina, or myocardial infarction within the past six months were excluded from the study.
2.4 Treatment plan
Pre-medications (e.g., anti-emetics, hydration, antihistamines, corticosteroids, etc.) were administered in accordance with institutional guidelines. Eligible subjects received six cycles of primary induction chemotherapy. All study participants received paclitaxel (80 mg/m2), which was infused over 60-90 minutes. Carboplatin (AUC 5 or 6) was administered over approximately 30 minutes (Day 1 only). Paclitaxel (80mg/m2) was repeated on Day 8 and Day 15. Metformin (850 mg oral) was given once daily x 4 weeks, and then 850 mg oral BID every 21 or 28 days, thereafter.
2.5 Maintenance therapy
Patients who achieved a clinically-defined complete or partial response following
primary induction chemotherapy received paclitaxel (135 mg/m2) every 3 to 4 weeks for a planned 12 cycles. They also continued to receive metformin (850 mg oral BID) for up to 5 years. Subjects with persistent or progressive disease following cycle 6 were removed from the study.
2.6 Response evaluation
The overall response rate was determined following cycle 6. Clinical response was assessed by clinical, serologic, and radiographic means according to the RECIST criteria [18]. Chest x-ray and abdominal/pelvic CT scans were performed prior to initial treatment and before cycles one and two. A complete response (CR) was defined by a normalization of CA-125 with confirmatory assessment no sooner than 28 days after the initial normal assessment [19]. The CR date reflected the first CA-125 within normal limits. A partial response (PR) was determined by a > 50% decrease from baseline in serum CA–125 but with values remaining above normal. The value exhibiting the decrease was confirmed by an additional value no sooner than 28 days after the first value. The PR date reflected the first CA-125 with a decrease of at least 50%.
When a normal CA-125 was exhibited at baseline, progressive disease was defined as a CA-125 value > 2 times the ULN. In patients who obtained a CA-125 above the ULN at baseline, progressive disease was defined as two times the lowest value observed for that patient. Stable disease was characterized by disease that does not fulfill the criteria for complete response, partial response, or progressive disease. After cycle 6, a chest x-ray and CT scans of the abdomen and pelvis were repeated to determine the objective response rate.
2.7 Toxicity analysis
All patients who completed > 3 cycles of chemotherapy were included in the toxicity analysis, which was graded using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [20]. Granulocyte colony-stimulating factor were initiated at the discretion of the treating physician. Patients were removed from the study if they incurred significant dose limiting toxicity and were subsequently treated with every 3 weeks paclitaxel and carboplatin chemotherapy.
2.8 Survival assessment
Progression-free survival was defined as the length of time from the date of initial induction chemotherapy until clinical, radiological, or CA-125 progression. Overall survival was defined as time from the date of entry until patient expiration, with all causes of death treated equally.
2.9 Statistical analyses
All statistical analyses were conducted using MedCalc statistical software for biomedical research (version 18.10 for Windows). The initial data analysis was conducted by employing a descriptive statistical approach. Survival analyses were conducted via Kaplan Meier.
3. Results:
3.1 Patient demographics
From August 2013 until December 2016, we identified 37 advanced stage ovarian patients for our study, seven of whom withdrew from the study, primarily for elective reasons. Ultimately, we accrued 30 subjects, of which the median age was 62 years (range, 26-88) and BMI was 28.35 kg/mg2 (range, 19.2-51.35). Sixteen (53.3%) patients were treated with neoadjuvant chemotherapy and 14 (46.7%) underwent adjuvant chemotherapy. Optimal debulking surgery was achieved in 27 (90%) patients (Please see Table 1). The median number of induction chemotherapy and maintenance therapy cycles administered was 6 (range, 5-6) and 12 (range, 6-12), respectively.
3.2 Response evaluation
In the group of evaluable patients, 23 (76.7%) achieved a complete response to the initial 6 cycles of the chemotherapy treatment regimen and 3 (10%) subjects obtained a partial response, which resulted in a complete response rate was 86.7% (Table 2). Additionally, 3 subjects (10%) had stable disease and one study participant (3.3%) had progressive disease.
3.3 Toxicity data
Grade 3/4 neutropenia was observed in 43.3% of patients although there were no admissions for febrile neutropenia. Moreover, grade 3/4 thrombocytopenia and anemia were identified in 10% and 36.7% of subjects, correspondingly. Fifteen (50%) patients developed <2 neuropathy and 20 (66.7%) study participants exhibited <2 diarrhea. Tables 3 and 4 illustrate the hematological and non-hematological toxicity patient occurrences.
3.4 Patient survival
Currently, 20 patients have experienced progressive disease and the overall median progression free survival was 21 months (range, 3-52). In terms of overall survival (OS), 6 subjects died, and the median OS was 35 months (range, 15-61). Currently, patient follow-up has exceeded 41 months.
4. Discussion
Metformin potentiates an anti-tumorigenic effect via increased insulin sensitivity, hepatic gluconeogenesis inhibition, and reduced hyperglycemia [21,22]. The medication reportedly confers anti-neoplastic properties in ovarian cancer [6-9] and may bolster the efficacy of first line treatment. We present our experience studying a novel regimen encompassing paclitaxel, carboplatin and metformin in the treatment of advanced stage ovarian carcinoma.
In the current investigation, we observed a total response rate of 86.7%, which is comparable to the 86% documented in prior ovarian cancer triplet chemotherapy studies [4,23] but higher than the 67-80% described in paclitaxel, carboplatin and bevacizumab evaluations [3,24]. We conjecture that our favorable response rate was attributed to metformin’s impact on chemotherapy potentiation, an effect that has been similarly observed in breast cancer patients who experienced a higher pathologic complete response rate following treatment comprising metformin and tamoxifen [25].
We also encountered grade 3/4 neutropenia and thrombocytopenia in 43.3% and 10% of the study patients, respectively; these results were more favorable than the toxicity data recounted by Romanini et al. (grade 3/4 leukopenia and thrombocytopenia occurred in 59% and 37% of patients) who utilized epidoxorubicin, paclitaxel, and carboplatin in the treatment of advanced stage ovarian carcinoma [4]. Alternatively, our findings were slightly higher than what was described in the Perren et al. [24] phase 3 trial incorporating bevacizumab, carboplatin and paclitaxel for the treatment of advanced stage ovarian cancer (17% for grade 3/4 neutropenia and 3% for thrombocytopenia).
In terms of non-hematologic toxicity, 50% of patients developed <2 neuropathy although there was no incidence of grade 3 neuropathy, consistent with the Tiersten et al. study involving dose-dense carboplatin and paclitaxel for the treatment of ovarian cancer [26]. We also observed grade <2 diarrhea in in 66.7% of patients, with no incidence of grade 3 diarrhea, that accorded with previously recounted studies that employed metformin in the management of pancreatic or breast cancer [27,28].
We ascertained a progression free survival of 21 months in the current study, which resembled the 22.4 months described by Fleming et al. [29] in their ovarian cancer patients who were treated with first line dose-dense paclitaxel, carboplatin and bevacizumab. Additionally, our results were equivalent to the 19.5 months reported by Romanini et al. with their triplet regimen [4]. The study patients’ overall survival was 35 months, which was less than the 36 months recounted by Romanini et al. [4] or the 36.6 months documented in the Perren et al. [24] investigation, although their surveillance periods were further prolonged. Interestingly, despite the equivalent progression free survival benefits to two of the aforesaid studies, our patients had a higher rate of optimal cytoreductive surgery (90% vs. 83%) [4, 29], not to mention the appreciable benefit the current subjects may have derived from maintenance therapy [30].
The results from ovarian and endometrial cancer studies have suggested that metformin is associated with improved overall survival [9,13,31]. However, while the clinical implications associated with metformin remain anecdotal, we conjecture that the current study regimen’s attendant toxicity and reasonable efficacy warrant further consideration in the management of advanced stage ovarian carcinoma.
When contemplating our modest findings, one could speculate that the tumor microenvironment is essential to drug penetration; and in preclinical studies evaluating cancer cell survival, metformin induced cell cycle arrest but was ultimately ineffective [32]. Moreover, in pancreatic cancer, randomized control studies have demonstrated that metformin only benefits patients without metastatic disease [27], a circumstance to which most advanced stage ovarian cancer patients does not apply. Hence, the overall disease burden in advanced stage ovarian cancer may be too formidable for the metformin to effectuate a therapeutic benefit, particularly at conventional doses [7].
We recognize the shortcomings of a single arm investigation with a limited patient population. The study patients’ survival findings were only moderately compelling, nevertheless, we do not proclaim the impact of metformin to be negligible. Theoretically, the medication should be further evaluated at higher doses or with alternative chemotherapy regimens, and within the context of a randomized methodology. Furthermore, after methodically collecting tumor and blood specimens, we are interested in evaluating if there is any relationship between biomarkers and a clinical response to metformin.
Funding source
This study was funded by the Women’s Cancer Research Foundation.
Conflict of interest statement
The authors declare that there are no conflicts associated with this manuscript.
