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Year : 2020  |  Volume : 57  |  Issue : 4  |  Page : 491--493

Feasibility of using pemetrexed as a salvage regimen in heavily pre-treated patients with ovarian cancer: A retrospective review

Peter Dottino, Matthew Dashkoff, Ann Marie Beddoe 
 Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine, New York, United States of America

Correspondence Address:
Ann Marie Beddoe
Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine, New York
United States of America

How to cite this article:
Dottino P, Dashkoff M, Beddoe AM. Feasibility of using pemetrexed as a salvage regimen in heavily pre-treated patients with ovarian cancer: A retrospective review.Indian J Cancer 2020;57:491-493

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Dottino P, Dashkoff M, Beddoe AM. Feasibility of using pemetrexed as a salvage regimen in heavily pre-treated patients with ovarian cancer: A retrospective review. Indian J Cancer [serial online] 2020 [cited 2020 Nov 30 ];57:491-493
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Over the past three decades, survival among all patients with ovarian cancer has improved. Characteristically, however, 5-year survival from advanced epithelial ovarian cancer, the most common presentation of this disease, continues to be low[1],[2] with overall survival (OS) between 34.5 and 41.3 months.[3] Despite initial response rates of >70% to surgery and first-line chemotherapy, most patients will relapse and require additional treatment. Advances in surgical management, improvements in multi-drug and neoadjuvant chemotherapy regimens, and increasing use of pathway inhibitors are some factors that have contributed to a subset of patients who continue to respond to repeated treatment regimens and are living with ovarian cancer as a “chronic” disease.[2],[4]

Combination chemotherapy using paclitaxel with a platinum compound has been almost universally adopted as the standard first-line regimen for the treatment of advanced ovarian cancer.[5] More recent addition of targeted therapies to first-line treatment include bevacizumab, a drug that inhibits angiogenesis, and olaparib, a drug that inhibits the DNA repair enzyme, poly (ADP-ribose) polymerase (PARP).[2] According to National Comprehensive Cancer Network (NCCN) guidelines, treatment for recurrent ovarian cancer is determined by sensitivity to platinum, with platinum-resistant tumors defined as recurrences that occur less than 6 months after completion of chemotherapy and platinum-sensitive tumors those that relapse at least 6 months or more after platinum-based therapy has been completed. Re-treatment with front-line therapy, carboplatin/paclitaxel/bevacizumab, or treatment with carboplatin/doxorubicin are among the currently available therapy options.[6],[7]

For patients with persistent/recurrent disease who have been administered most of the recommended treatments, the search for novel therapies has been undertaken to combat resistance, poor response rates, and dose-limiting toxicities as the number of administered treatment lines increase. One such agent pemetrexed is a novel antifolate agent that targets multiple enzymes essential for the formation of purine and pyrimidine nucleotides, thus, inhibiting DNA synthesis and cell proliferation.[8]

We reviewed the charts of 18 patients with “chronic” ovarian cancer treated with pemetrexed between 2010 and 2014 to assess tolerability and side effects of this regimen. We selected 13 patients who were diagnosed with recurrent papillary serous carcinoma and were heavily pre-treated with multiple salvage regimens prior to treatment with pemetrexed. The average age of patients was 62.7 years with a range of 49–81 years. All patients had advanced stage III or IV ovarian papillary serous adenocarcinoma and previous treatment with at least one taxane-platinum combination. Patients received an average of 7.5 varied chemotherapy regimens prior to starting pemetrexed combination therapy. A total of 74 cycles of pemetrexed were administered to this cohort. Patients received an average of 5.7 cycles of pemetrexed (range 3–12 cycles), however, the majority of patients (61.5%) received between 3 and 5 cycles, while one patient each received 7, 9,11, and 12 cycles. The most common drug combined with pemetrexed was oxaliplatin (nine patients), followed by carboplatin (two patients) and cisplatin (one patient); in one patient pemetrexed was combined with cisplatin for 3 cycles and oxaliplatin for 2 cycles. Pemetrexed was given at a dose of 350–500 mg/m2, carboplatin at area under the curve (AUC) 4–5, and oxaliplatin at 80–100 mg/m2. All patients were treated with folic acid prior to and throughout their treatment, and vitamin B12 was administered every third cycle of treatment.

Two patients (15.3%) failed to respond to pemetrexed and experienced a significant increase (>50% from baseline) CA-125 after four treatments, at which time the chemotherapy regimen was changed or surgical management was offered based on imaging findings. In 11 patients (84.6%), an incremental decrease in CA-125 was seen over the treatment period. A >20–50% drop in CA-125 following the first cycle of treatment was seen in seven patients (53.8%); a 10% drop in CA-125 was seen in one patient (7.8%) whose treatment was discontinued because of dose-limiting neuropathy after three cycles. Three patients (7.6%) demonstrated a moderate early response, but subsequently had plateauing of CA-125 levels. Patients who responded to the first cycle based on 20–50% drop in CA-125 went on to receive between 5 and 12 cycles of pemetrexed before CA-125 levels began to increase. The average decrease between the initial and nadir values was 72.4%. Patients remained on pemetrexed for an average 5.5 months before a significant rise in CA-125 prompted discontinuation and workup.

The most common hematologic toxicity was grade 3–4 neutropenia occurring in two patients (15.3%), one requiring neupogen for nadir count 0.2. Non-hematologic grade 2–4 toxicities included fatigue/weakness (50.0%), and mild-to-severe neuropathy/paresthesias occurred in seven patients (58.3%). Neurotoxic side effects occurred in seven patients (53.8%). All but one of these patients was treated with oxaliplatin while the remaining patients were treated with cisplatin. Neurotoxic symptoms experienced included pharyngo-laryngeal dysesthesia ranging from heaviness and odd sensation in the tongue to numbness around the mouth, and in one patient, severe cold-dependent muscular contractions of the upper extremities were noted. This patient failed to wear gloves during winter upon leaving the chemotherapy suite. All cold-related neurotoxic manifestations were reversed with heat exposure or within 5 days of completing chemotherapy. One patient experienced a serious adverse event for periorbital edema after the first cycle. She was treated with steroids that resolved the edema and the patient was able to receive four additional cycles using pre- and post-treatment dexamethasone without further recurrence of periorbital edema. Only one patient discontinued therapy because of treatment-related toxicity. No deaths were reported during the course of treatment with pemetrexed. The combination of pemetrexed and platinum was well tolerated in a cohort of very heavily pre-treated patients with ovarian cancer. Although responses were short-lived, it could be considered as an interim salvage regimen to stabilize or decrease the burden of disease prior to initiating other forms of therapy.

A recent literature review by Egloff and Jatoi[9] on the use of pemetrexed in 376 ovarian cancer patients in a clinical trial setting reported response rates of 9–84% when pemetrexed was administered as either a single or a double agent. In this review, the authors also presented their experience on 13 patients treated at the Mayo Clinic with a median of two cycles of pemetrexed (range 1–10) given alone or with either carboplatin or bevacizumab. These patients were previously treated with a median of four regimens, and the median survival from starting pemetrexed was 4.8 months. A more recent literature review supports the findings that pemetrexed has demonstrable activity in recurrent ovarian cancer with a favorable toxicity profile, however, clinical trials comparing its activity to recommended treatments are still lacking and should be pursued.[10]

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