Abstract
Studies of supportive therapy in oncology must be interpreted carefully, considering the balance between convenience and safety. Further prospective studies may be necessary for applying the short-term vitamin supplementation to all patients who undergo pemetrexed-based therapy.
We thank Singh et al. [1] for their interest in our study of shortened vitamin supplementation prior to cisplatin-pemetrexed therapy [2]. They discussed similarities and differences between our trial and their retrospective study [3] and raised three issues: the reasonability of delaying the initiation of standard chemotherapy only for vitamin supplementation; the possibility of simplifying vitamin B12 supplementation by injecting it every 3 weeks along with pemetrexed; and the efficiency of biomarkers versus homocysteine for predicting toxicities caused by pemetrexed.
The first clinical question was the inducement for our study. It is obvious that vitamin supplementation must be started before administering pemetrexed [4, 5], but there is no clear rationale for the lead-in time of 1 week. We showed that the lead-in time for vitamin supplementation could be shortened to 24–48 hours in the multicenter prospective study [2]. In a retrospective study at a single institute conducted by Singh et al. [3], vitamin supplementation was started on the same day as cisplatin/pemetrexed administration, and grade 3/4 neutropenia occurred in 10.8% of the patients. The proportion itself was not high, but it is considerable that the dose of cisplatin (65 mg/m2) was smaller than global standard, and 24.3% of the patients required granulocyte-colony stimulating factor administration [3]. In addition, grade 3/4 thrombocytopenia and diarrhea in their study [3] were relatively more frequent than in the study by Scagliotti et al. [6]. The cause of the difference between our trial and the study by Singh et al. is not clear. One explanation may be the retained lead-in time of 24 hours in our study, enabling vitamin B12 to pervade major organs.
As Singh et al. indicated, vitamin B12 administration every 3 weeks seems to have little impact on the antitumor effect of pemetrexed; however, the procedure of intramuscular injection itself causes pain and has risks such as hematoma and nerve damage. The risk-benefit balance between the added risks and the convenience of simplifying the treatment schedule should be carefully considered.
When pemetrexed is administered without vitamin supplementation, it is broadly accepted that pretreatment homocysteine and methylmalonic acid predict severe toxicities caused by pemetrexed [4]. In the multivariate analysis, baseline performance status (PS) also predicted grade 4 neutropenia, and baseline neutrophil count predicted grade 4 thrombocytopenia and grade 3/4 mucositis [4]. PS is particularly important as a known predictive marker for toxicities of chemotherapy. Whether the results of our study can be extrapolated to patients with poor PS is unknown. We believe that further prospective studies are necessary for applying short-term vitamin supplementation to all patients who undergo pemetrexed-based therapy.
Disclosures
Yusuke Takagi: Taiho Pharmaceutical (RF), Merck Sharp and Dohme Corp. (E); Yukio Hosomi: Eli Lilly, Chugai, MSD, Yakult (RF), Eli Lilly, Chugai, Ono, AstraZeneca, Taiho (H). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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