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Alessandro Passardi, Manlio Monti, Caterina Donati, Flavia Foca, Flavia Pagan, Ilario Rapposelli, Silvia Ruscelli, Giulia Bartolini, Martina Valgiusti, Laura Matteucci, Francesco Sullo, Stefania Sbaffi, Laura Crudi, Giovanni Luca Frassineti, Carla Masini, Prospective Observational Study Comparing Calcium and Sodium Levofolinate in Combination with 5-Fluorouracil in the FOLFIRI Regimen, The Oncologist, Volume 26, Issue 8, August 2021, Pages e1314–e1319, https://doi.org/10.1002/onco.13762
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Abstract
The use of sodium levofolinate (Na-Lev) is safe in combination with continuous infusion 5-fluorouracil in patients with gastrointestinal tumors treated with the FOLFIRI regimen.
A comparison with calcium levofolinate (Ca-Lev) showed a similar toxicity profile. The advantages of Na-Lev over Ca-Lev might be the faster drug preparation and the shorter time of drug administration.
The objectives of this study were to compare the safety profiles of sodium levofolinate (Na-Lev) and calcium levofolinate (Ca-Lev) in combination with 5-fluorouracil (5-FU) in the FOLFIRI regimen and to measure the organizational impact of the introduction of Na-Lev on drug production and administration.
The study opened in November 2015 and closed in August 2019. Patients with gastrointestinal cancers who were candidates for treatment with the FOLFIRI regimen were included in this nonrandomized study. Age ≥18 years, life expectancy <3 months, adequate bone marrow reserve, adequate hepatic and renal function, and an ECOG performance status of 0–2 were required. Patients in the Ca-Lev arm received a 2-hour infusion of Ca-Lev followed by 5-FU, whereas those in the Na-Lev arm received Na-Lev and 5-FU administered in a single 48-hour pump.
Sixty patients were enrolled, 30 in each arm. Patient characteristics were balanced. Grade (G)1–2 adverse events occurred in 18 (60.0%) and 19 (63.4%) patients of Na-Lev and Ca-Lev cohorts, respectively, whereas G3–4 adverse events occurred in 12 (40.0%) and 11 (36.6%) patients, respectively. The use of Na-Lev enabled us to save approximately 13 minutes for drug preparation and 2 hours for treatment administration, per patient per cycle.
Na-Lev showed a reassuring toxicity profile and a favorable impact on drug preparation and administration.
Discussion
In gastrointestinal tumors, the association of 5-FU and folinate salts represents the cornerstone of chemotherapy as clinical trials have shown a better clinical response from the combination than from 5-FU alone [1–5]. Given that the simultaneous infusion of 5-FU and Ca-Lev produces precipitation as calcium carbonate and catheter clogging, the current standard of care is the sequential administration of a 2-hour infusion of Ca-Lev followed by 5-FU administered first as a bolus injection, then as a continuous infusion. Na-Lev has similar pharmacological properties to Ca-Lev and a higher solubility, enabling the concomitant administration with 5-FU in a single elastomeric pump [5].
In vitro studies showed that simultaneous treatment with Na-Lev and 5-FU produced a synergistic antitumor activity in tumor cell lines with respect to the simple additive activity of Ca-Lev in association with 5-FU. Conversely, the sequential administration of Na-Lev or Ca-Lev and 5-FU in the same cell lines induced an antagonistic effect [6].
Given the small sample size, the heterogeneity of enrolled patients in relation to tumor site and treatment line (Table 1), and the absence of randomization, it was not possible to draw any definitive conclusions about the effectiveness of the Na-Lev +5-FU combination. Several phase II clinical trials have suggested the noninferiority of Na-Lev with respect to Ca-Lev in terms of efficacy and a similar toxicity profile [7–16]. The toxicity profile was similar in the present trial, with a trend toward higher G1–2 mucositis in the Na-Lev arm and higher G1–2 nausea and vomiting in the Ca-Lev arm. The incidence of treatment delays, dose reductions, and discontinuation due to adverse events was similar.
| Variable . | ARM A: Na-Lev administration (n = 30), No. of patients (%) . | ARM B: Ca-Lev administration (n = 30), No. of patients (%) . | Overall (n = 60), n (%) . | p valuea . |
|---|---|---|---|---|
| Median age at start of treatment, (range), yr | 67 (36-82) | 67.5 (40-83) | 67 (36-83) | .958 |
| Gender | ||||
| Male | 21 (70.0) | 20 (66.7) | 41 (68.3) | .781 |
| Female | 9 (30.0) | 10 (33.3) | 19 (31.7) | |
| Previous line of therapy | ||||
| None | 2 (6.7) | 2 (6.7) | 4 (6.7) | .170 |
| 1 | 12 (40) | 19 (63.3) | 31 (51.7) | |
| 2 or more | 16 (53.3) | 9 (30.0) | 25 (41.6) | |
| Site of disease | ||||
| Stomach | 7 (23.3) | 2 (6.9) | 9 (15.3) | .365 |
| Pancreas | 11 (36.7) | 10 (34.5) | 21 (35.6) | |
| Colon rectum | 8 (26.6) | 10 (34.5) | 18 (30.5) | |
| Biliary tract | 2 (6.7) | 5 (17.2) | 7 (11.9) | |
| Other | 2 (6.7) | 2 (6.9) | 4 (6.7) | |
| Stage of disease | ||||
| II | 2 (6.7) | 6 (20.0) | 8 (13.3) | .303 |
| III | 8 (26.7) | 6 (20.0) | 14 (23.3) | |
| IV | 20 (66.6) | 18 (60.0) | 38 (63.4) | |
| ECOG PS | ||||
| ECOG 0 | 12 (40.0) | 17 (56.7) | 29 (48.3) | .196 |
| ECOG 1–2 | 18 (60.0) | 13 (43.3) | 31 (51.7) | |
| Best response to FOLFIRI | ||||
| Progressive disease | 18 (64.3) | 18 (62.1) | 36 (63.2) | .460 |
| Stable disease | 8 (28.6) | 6 (20.7) | 14 (24.6) | |
| Partial response | 2 (7.1) | 5 (17.2) | 7 (12.2) | |
| DPYD result | ||||
| Deficiency | 1 (4.5) | 0 (0.0) | 1 (2.9) | .435 |
| No deficiency | 21 (95.5) | 13 (100.0) | 34 (97.1) | |
| Unknown | 8 | 17 | 25 |
| Variable . | ARM A: Na-Lev administration (n = 30), No. of patients (%) . | ARM B: Ca-Lev administration (n = 30), No. of patients (%) . | Overall (n = 60), n (%) . | p valuea . |
|---|---|---|---|---|
| Median age at start of treatment, (range), yr | 67 (36-82) | 67.5 (40-83) | 67 (36-83) | .958 |
| Gender | ||||
| Male | 21 (70.0) | 20 (66.7) | 41 (68.3) | .781 |
| Female | 9 (30.0) | 10 (33.3) | 19 (31.7) | |
| Previous line of therapy | ||||
| None | 2 (6.7) | 2 (6.7) | 4 (6.7) | .170 |
| 1 | 12 (40) | 19 (63.3) | 31 (51.7) | |
| 2 or more | 16 (53.3) | 9 (30.0) | 25 (41.6) | |
| Site of disease | ||||
| Stomach | 7 (23.3) | 2 (6.9) | 9 (15.3) | .365 |
| Pancreas | 11 (36.7) | 10 (34.5) | 21 (35.6) | |
| Colon rectum | 8 (26.6) | 10 (34.5) | 18 (30.5) | |
| Biliary tract | 2 (6.7) | 5 (17.2) | 7 (11.9) | |
| Other | 2 (6.7) | 2 (6.9) | 4 (6.7) | |
| Stage of disease | ||||
| II | 2 (6.7) | 6 (20.0) | 8 (13.3) | .303 |
| III | 8 (26.7) | 6 (20.0) | 14 (23.3) | |
| IV | 20 (66.6) | 18 (60.0) | 38 (63.4) | |
| ECOG PS | ||||
| ECOG 0 | 12 (40.0) | 17 (56.7) | 29 (48.3) | .196 |
| ECOG 1–2 | 18 (60.0) | 13 (43.3) | 31 (51.7) | |
| Best response to FOLFIRI | ||||
| Progressive disease | 18 (64.3) | 18 (62.1) | 36 (63.2) | .460 |
| Stable disease | 8 (28.6) | 6 (20.7) | 14 (24.6) | |
| Partial response | 2 (7.1) | 5 (17.2) | 7 (12.2) | |
| DPYD result | ||||
| Deficiency | 1 (4.5) | 0 (0.0) | 1 (2.9) | .435 |
| No deficiency | 21 (95.5) | 13 (100.0) | 34 (97.1) | |
| Unknown | 8 | 17 | 25 |
a p-value from Chi-squaretest or Fisher's exact test as appropriate.
Abbreviations: Ca-Lev, calcium levofolinate; DPYD, dihydropyrimidine dehydrogenase; ECOG PS, Eastern Cooperative Oncology Group performance status; Na-Lev, sodium levofolinate.
| Variable . | ARM A: Na-Lev administration (n = 30), No. of patients (%) . | ARM B: Ca-Lev administration (n = 30), No. of patients (%) . | Overall (n = 60), n (%) . | p valuea . |
|---|---|---|---|---|
| Median age at start of treatment, (range), yr | 67 (36-82) | 67.5 (40-83) | 67 (36-83) | .958 |
| Gender | ||||
| Male | 21 (70.0) | 20 (66.7) | 41 (68.3) | .781 |
| Female | 9 (30.0) | 10 (33.3) | 19 (31.7) | |
| Previous line of therapy | ||||
| None | 2 (6.7) | 2 (6.7) | 4 (6.7) | .170 |
| 1 | 12 (40) | 19 (63.3) | 31 (51.7) | |
| 2 or more | 16 (53.3) | 9 (30.0) | 25 (41.6) | |
| Site of disease | ||||
| Stomach | 7 (23.3) | 2 (6.9) | 9 (15.3) | .365 |
| Pancreas | 11 (36.7) | 10 (34.5) | 21 (35.6) | |
| Colon rectum | 8 (26.6) | 10 (34.5) | 18 (30.5) | |
| Biliary tract | 2 (6.7) | 5 (17.2) | 7 (11.9) | |
| Other | 2 (6.7) | 2 (6.9) | 4 (6.7) | |
| Stage of disease | ||||
| II | 2 (6.7) | 6 (20.0) | 8 (13.3) | .303 |
| III | 8 (26.7) | 6 (20.0) | 14 (23.3) | |
| IV | 20 (66.6) | 18 (60.0) | 38 (63.4) | |
| ECOG PS | ||||
| ECOG 0 | 12 (40.0) | 17 (56.7) | 29 (48.3) | .196 |
| ECOG 1–2 | 18 (60.0) | 13 (43.3) | 31 (51.7) | |
| Best response to FOLFIRI | ||||
| Progressive disease | 18 (64.3) | 18 (62.1) | 36 (63.2) | .460 |
| Stable disease | 8 (28.6) | 6 (20.7) | 14 (24.6) | |
| Partial response | 2 (7.1) | 5 (17.2) | 7 (12.2) | |
| DPYD result | ||||
| Deficiency | 1 (4.5) | 0 (0.0) | 1 (2.9) | .435 |
| No deficiency | 21 (95.5) | 13 (100.0) | 34 (97.1) | |
| Unknown | 8 | 17 | 25 |
| Variable . | ARM A: Na-Lev administration (n = 30), No. of patients (%) . | ARM B: Ca-Lev administration (n = 30), No. of patients (%) . | Overall (n = 60), n (%) . | p valuea . |
|---|---|---|---|---|
| Median age at start of treatment, (range), yr | 67 (36-82) | 67.5 (40-83) | 67 (36-83) | .958 |
| Gender | ||||
| Male | 21 (70.0) | 20 (66.7) | 41 (68.3) | .781 |
| Female | 9 (30.0) | 10 (33.3) | 19 (31.7) | |
| Previous line of therapy | ||||
| None | 2 (6.7) | 2 (6.7) | 4 (6.7) | .170 |
| 1 | 12 (40) | 19 (63.3) | 31 (51.7) | |
| 2 or more | 16 (53.3) | 9 (30.0) | 25 (41.6) | |
| Site of disease | ||||
| Stomach | 7 (23.3) | 2 (6.9) | 9 (15.3) | .365 |
| Pancreas | 11 (36.7) | 10 (34.5) | 21 (35.6) | |
| Colon rectum | 8 (26.6) | 10 (34.5) | 18 (30.5) | |
| Biliary tract | 2 (6.7) | 5 (17.2) | 7 (11.9) | |
| Other | 2 (6.7) | 2 (6.9) | 4 (6.7) | |
| Stage of disease | ||||
| II | 2 (6.7) | 6 (20.0) | 8 (13.3) | .303 |
| III | 8 (26.7) | 6 (20.0) | 14 (23.3) | |
| IV | 20 (66.6) | 18 (60.0) | 38 (63.4) | |
| ECOG PS | ||||
| ECOG 0 | 12 (40.0) | 17 (56.7) | 29 (48.3) | .196 |
| ECOG 1–2 | 18 (60.0) | 13 (43.3) | 31 (51.7) | |
| Best response to FOLFIRI | ||||
| Progressive disease | 18 (64.3) | 18 (62.1) | 36 (63.2) | .460 |
| Stable disease | 8 (28.6) | 6 (20.7) | 14 (24.6) | |
| Partial response | 2 (7.1) | 5 (17.2) | 7 (12.2) | |
| DPYD result | ||||
| Deficiency | 1 (4.5) | 0 (0.0) | 1 (2.9) | .435 |
| No deficiency | 21 (95.5) | 13 (100.0) | 34 (97.1) | |
| Unknown | 8 | 17 | 25 |
a p-value from Chi-squaretest or Fisher's exact test as appropriate.
Abbreviations: Ca-Lev, calcium levofolinate; DPYD, dihydropyrimidine dehydrogenase; ECOG PS, Eastern Cooperative Oncology Group performance status; Na-Lev, sodium levofolinate.
In our experience, the simultaneous administration of Na-Lev and 5-FU led to a 2-hour reduction in the duration of chemotherapy, representing a distinct advantage for patients and hospitals. Moreover, with respect to drug preparation, a single elastomeric pump containing both Na-Lev and 5-FU rather than the 5-FU elastomeric pump and separate Ca-Lev bag resulted in a time saving of 13 minutes (6.8 minutes [SD, 5.7] for Na-Lev vs. 19.3 [SD: 2.3] for Ca-Lev) per patient per cycle.
In conclusion, Na-Lev showed a reassuring toxicity profile and a favorable impact on drug preparation and delivery.
Trial Information
| Diseases | Pancreatic cancer, colorectal cancer, gastric cancer, biliary tract: gallbladder cancer, and chloangiocarcinoma |
| Stage of Disease/Treatment | Metastatic/advanced |
| Prior Therapy | No designated number of regimens |
| Type of Study | Phase II |
| Primary Endpoint | Toxicity |
| Secondary Endpoint | Deliverability |
| Additional Details of Endpoints or Study Design | |
| The primary endpoint was to compare the safety profiles of Na-Lev and Ca-Lev levofolinate in combination with 5-FU in the FOLFIRI regimen. The secondary endpoint was to measure the organizational impact of the introduction of Na-Lev on drug production and administration. | |
| Investigator's Analysis | Correlative endpoints met but not powered to assess activity |
| Diseases | Pancreatic cancer, colorectal cancer, gastric cancer, biliary tract: gallbladder cancer, and chloangiocarcinoma |
| Stage of Disease/Treatment | Metastatic/advanced |
| Prior Therapy | No designated number of regimens |
| Type of Study | Phase II |
| Primary Endpoint | Toxicity |
| Secondary Endpoint | Deliverability |
| Additional Details of Endpoints or Study Design | |
| The primary endpoint was to compare the safety profiles of Na-Lev and Ca-Lev levofolinate in combination with 5-FU in the FOLFIRI regimen. The secondary endpoint was to measure the organizational impact of the introduction of Na-Lev on drug production and administration. | |
| Investigator's Analysis | Correlative endpoints met but not powered to assess activity |
Trial Information
| Diseases | Pancreatic cancer, colorectal cancer, gastric cancer, biliary tract: gallbladder cancer, and chloangiocarcinoma |
| Stage of Disease/Treatment | Metastatic/advanced |
| Prior Therapy | No designated number of regimens |
| Type of Study | Phase II |
| Primary Endpoint | Toxicity |
| Secondary Endpoint | Deliverability |
| Additional Details of Endpoints or Study Design | |
| The primary endpoint was to compare the safety profiles of Na-Lev and Ca-Lev levofolinate in combination with 5-FU in the FOLFIRI regimen. The secondary endpoint was to measure the organizational impact of the introduction of Na-Lev on drug production and administration. | |
| Investigator's Analysis | Correlative endpoints met but not powered to assess activity |
| Diseases | Pancreatic cancer, colorectal cancer, gastric cancer, biliary tract: gallbladder cancer, and chloangiocarcinoma |
| Stage of Disease/Treatment | Metastatic/advanced |
| Prior Therapy | No designated number of regimens |
| Type of Study | Phase II |
| Primary Endpoint | Toxicity |
| Secondary Endpoint | Deliverability |
| Additional Details of Endpoints or Study Design | |
| The primary endpoint was to compare the safety profiles of Na-Lev and Ca-Lev levofolinate in combination with 5-FU in the FOLFIRI regimen. The secondary endpoint was to measure the organizational impact of the introduction of Na-Lev on drug production and administration. | |
| Investigator's Analysis | Correlative endpoints met but not powered to assess activity |
Drug Information: Arm A: Na-Lev
| Generic Name | Na-lev |
| Trade Name | Sodium levofolinate (Na-Lev) |
| Dose | 200 mg/m2 |
| Route | Continuous intravenous infusion (CIV) |
| Schedule of Administration | FOLFIRI with Na-Lev consisted of irinotecan 180 mg/m2 given as a 90-minute infusion, bolus 5-FU 400 mg/m2 followed by Na-Lev 200 mg/m2, and 5-FU 2,400 mg/m2 as a 48-hour infusion (in the same elastomeric pump) on day 1 every 2 weeks. |
| Generic Name | Na-lev |
| Trade Name | Sodium levofolinate (Na-Lev) |
| Dose | 200 mg/m2 |
| Route | Continuous intravenous infusion (CIV) |
| Schedule of Administration | FOLFIRI with Na-Lev consisted of irinotecan 180 mg/m2 given as a 90-minute infusion, bolus 5-FU 400 mg/m2 followed by Na-Lev 200 mg/m2, and 5-FU 2,400 mg/m2 as a 48-hour infusion (in the same elastomeric pump) on day 1 every 2 weeks. |
Drug Information: Arm A: Na-Lev
| Generic Name | Na-lev |
| Trade Name | Sodium levofolinate (Na-Lev) |
| Dose | 200 mg/m2 |
| Route | Continuous intravenous infusion (CIV) |
| Schedule of Administration | FOLFIRI with Na-Lev consisted of irinotecan 180 mg/m2 given as a 90-minute infusion, bolus 5-FU 400 mg/m2 followed by Na-Lev 200 mg/m2, and 5-FU 2,400 mg/m2 as a 48-hour infusion (in the same elastomeric pump) on day 1 every 2 weeks. |
| Generic Name | Na-lev |
| Trade Name | Sodium levofolinate (Na-Lev) |
| Dose | 200 mg/m2 |
| Route | Continuous intravenous infusion (CIV) |
| Schedule of Administration | FOLFIRI with Na-Lev consisted of irinotecan 180 mg/m2 given as a 90-minute infusion, bolus 5-FU 400 mg/m2 followed by Na-Lev 200 mg/m2, and 5-FU 2,400 mg/m2 as a 48-hour infusion (in the same elastomeric pump) on day 1 every 2 weeks. |
Drug Information: Arm B: Ca-Lev
| Generic Name | Ca-lev |
| Trade Name | Calcium levofolinate (Ca-Lev) |
| Dose | 200 mg/m2 |
| Route | IV |
| Schedule of Administration | FOLFIRI with Ca-Lev consisted of irinotecan 180 mg/m2 given as a 90-minute infusion, Ca-Lev 200 mg/m2 given as a 2-hour infusion, 5-FU 400 mg/m2 bolus, and 5-FU 2,400 mg/m2 as a 48-hour infusion on day 1 every 2 weeks. |
| Generic Name | Ca-lev |
| Trade Name | Calcium levofolinate (Ca-Lev) |
| Dose | 200 mg/m2 |
| Route | IV |
| Schedule of Administration | FOLFIRI with Ca-Lev consisted of irinotecan 180 mg/m2 given as a 90-minute infusion, Ca-Lev 200 mg/m2 given as a 2-hour infusion, 5-FU 400 mg/m2 bolus, and 5-FU 2,400 mg/m2 as a 48-hour infusion on day 1 every 2 weeks. |
Drug Information: Arm B: Ca-Lev
| Generic Name | Ca-lev |
| Trade Name | Calcium levofolinate (Ca-Lev) |
| Dose | 200 mg/m2 |
| Route | IV |
| Schedule of Administration | FOLFIRI with Ca-Lev consisted of irinotecan 180 mg/m2 given as a 90-minute infusion, Ca-Lev 200 mg/m2 given as a 2-hour infusion, 5-FU 400 mg/m2 bolus, and 5-FU 2,400 mg/m2 as a 48-hour infusion on day 1 every 2 weeks. |
| Generic Name | Ca-lev |
| Trade Name | Calcium levofolinate (Ca-Lev) |
| Dose | 200 mg/m2 |
| Route | IV |
| Schedule of Administration | FOLFIRI with Ca-Lev consisted of irinotecan 180 mg/m2 given as a 90-minute infusion, Ca-Lev 200 mg/m2 given as a 2-hour infusion, 5-FU 400 mg/m2 bolus, and 5-FU 2,400 mg/m2 as a 48-hour infusion on day 1 every 2 weeks. |
Patient Characteristics: Arm A: Na-Lev
| Number of Patients, Male | 21 |
| Number of Patients, Female | 9 |
| Stage | IV |
| Age | Median (range): 67 (36–82) years |
| Performance Status: ECOG | 0 — 12 1 — 18 2 — 0 3 — 0 Unknown — 0 |
| Cancer Types or Histologic Subtypes | Stomach, 7; pancreas, 11; Colon rectum, 8; biliary tract, 2; other, 2 |
| Number of Patients, Male | 21 |
| Number of Patients, Female | 9 |
| Stage | IV |
| Age | Median (range): 67 (36–82) years |
| Performance Status: ECOG | 0 — 12 1 — 18 2 — 0 3 — 0 Unknown — 0 |
| Cancer Types or Histologic Subtypes | Stomach, 7; pancreas, 11; Colon rectum, 8; biliary tract, 2; other, 2 |
Patient Characteristics: Arm A: Na-Lev
| Number of Patients, Male | 21 |
| Number of Patients, Female | 9 |
| Stage | IV |
| Age | Median (range): 67 (36–82) years |
| Performance Status: ECOG | 0 — 12 1 — 18 2 — 0 3 — 0 Unknown — 0 |
| Cancer Types or Histologic Subtypes | Stomach, 7; pancreas, 11; Colon rectum, 8; biliary tract, 2; other, 2 |
| Number of Patients, Male | 21 |
| Number of Patients, Female | 9 |
| Stage | IV |
| Age | Median (range): 67 (36–82) years |
| Performance Status: ECOG | 0 — 12 1 — 18 2 — 0 3 — 0 Unknown — 0 |
| Cancer Types or Histologic Subtypes | Stomach, 7; pancreas, 11; Colon rectum, 8; biliary tract, 2; other, 2 |
Patient Characteristics: Arm B: Ca-Lev
| Number of Patients, Male | 20 |
| Number of Patients, Female | 10 |
| Stage | IV |
| Age | Median (range): 67.5 (40–83) years |
| Performance Status: ECOG | 0 — 17 1 — 13 2 — 0 3 — 0 Unknown — 0 |
| Cancer Types or Histologic Subtypes | Stomach, 2; pancreas, 10; Colon rectum, 10; biliary tract, 5; other, 2 |
| Number of Patients, Male | 20 |
| Number of Patients, Female | 10 |
| Stage | IV |
| Age | Median (range): 67.5 (40–83) years |
| Performance Status: ECOG | 0 — 17 1 — 13 2 — 0 3 — 0 Unknown — 0 |
| Cancer Types or Histologic Subtypes | Stomach, 2; pancreas, 10; Colon rectum, 10; biliary tract, 5; other, 2 |
Patient Characteristics: Arm B: Ca-Lev
| Number of Patients, Male | 20 |
| Number of Patients, Female | 10 |
| Stage | IV |
| Age | Median (range): 67.5 (40–83) years |
| Performance Status: ECOG | 0 — 17 1 — 13 2 — 0 3 — 0 Unknown — 0 |
| Cancer Types or Histologic Subtypes | Stomach, 2; pancreas, 10; Colon rectum, 10; biliary tract, 5; other, 2 |
| Number of Patients, Male | 20 |
| Number of Patients, Female | 10 |
| Stage | IV |
| Age | Median (range): 67.5 (40–83) years |
| Performance Status: ECOG | 0 — 17 1 — 13 2 — 0 3 — 0 Unknown — 0 |
| Cancer Types or Histologic Subtypes | Stomach, 2; pancreas, 10; Colon rectum, 10; biliary tract, 5; other, 2 |
Primary Assessment Method: Arm A: Na-Lev
| Number of Patients Screened | 32 |
| Number of Patients Enrolled | 32 |
| Number of Patients Evaluable for Toxicity | 30 |
| Number of Patients Evaluated for Efficacy | 28 |
| Evaluation Method | RECIST 1.0 |
| Response Assessment PR | n = 2 |
| Response Assessment SD | n = 8 |
| Response Assessment PD | n = 18 |
| Number of Patients Screened | 32 |
| Number of Patients Enrolled | 32 |
| Number of Patients Evaluable for Toxicity | 30 |
| Number of Patients Evaluated for Efficacy | 28 |
| Evaluation Method | RECIST 1.0 |
| Response Assessment PR | n = 2 |
| Response Assessment SD | n = 8 |
| Response Assessment PD | n = 18 |
Primary Assessment Method: Arm A: Na-Lev
| Number of Patients Screened | 32 |
| Number of Patients Enrolled | 32 |
| Number of Patients Evaluable for Toxicity | 30 |
| Number of Patients Evaluated for Efficacy | 28 |
| Evaluation Method | RECIST 1.0 |
| Response Assessment PR | n = 2 |
| Response Assessment SD | n = 8 |
| Response Assessment PD | n = 18 |
| Number of Patients Screened | 32 |
| Number of Patients Enrolled | 32 |
| Number of Patients Evaluable for Toxicity | 30 |
| Number of Patients Evaluated for Efficacy | 28 |
| Evaluation Method | RECIST 1.0 |
| Response Assessment PR | n = 2 |
| Response Assessment SD | n = 8 |
| Response Assessment PD | n = 18 |
Secondary Assessment Method: Arm B: Ca-Lev
| Number of Patients Screened | 32 |
| Number of Patients Enrolled | 30 |
| Number of Patients Evaluable for Toxicity | 30 |
| Number of Patients Evaluated for Efficacy | 29 |
| Evaluation Method | RECIST 1.0 |
| Response Assessment CR | n = 0 |
| Response Assessment PR | n = 5 |
| Response Assessment SD | n = 6 |
| Response Assessment PD | n = 18 |
| Number of Patients Screened | 32 |
| Number of Patients Enrolled | 30 |
| Number of Patients Evaluable for Toxicity | 30 |
| Number of Patients Evaluated for Efficacy | 29 |
| Evaluation Method | RECIST 1.0 |
| Response Assessment CR | n = 0 |
| Response Assessment PR | n = 5 |
| Response Assessment SD | n = 6 |
| Response Assessment PD | n = 18 |
Secondary Assessment Method: Arm B: Ca-Lev
| Number of Patients Screened | 32 |
| Number of Patients Enrolled | 30 |
| Number of Patients Evaluable for Toxicity | 30 |
| Number of Patients Evaluated for Efficacy | 29 |
| Evaluation Method | RECIST 1.0 |
| Response Assessment CR | n = 0 |
| Response Assessment PR | n = 5 |
| Response Assessment SD | n = 6 |
| Response Assessment PD | n = 18 |
| Number of Patients Screened | 32 |
| Number of Patients Enrolled | 30 |
| Number of Patients Evaluable for Toxicity | 30 |
| Number of Patients Evaluated for Efficacy | 29 |
| Evaluation Method | RECIST 1.0 |
| Response Assessment CR | n = 0 |
| Response Assessment PR | n = 5 |
| Response Assessment SD | n = 6 |
| Response Assessment PD | n = 18 |
| AE . | Arm A: Na-Lev (n = 30), no. patients (%) . | Arm B: Ca-Lev (n = 30), no. patients (%) . | ||
|---|---|---|---|---|
| G1/G2 . | G ≥ 3 . | G1/G2 . | G ≥ 3 . | |
| Neutropenia | 4 (13.3) | 6 (20.0) | 4 (13.3) | 4 (13.3) |
| Anemia | 7 (23.3) | 0 (0.0) | 4 (13.3) | 1 (3.3) |
| Febrile neutropenia | 0 (0.0) | 1 (3.3) | 0 (0.0) | 2 (6.7) |
| Trombocytopenia | 1 (3.3) | 0 (0.0) | 5 (16.7) | 0 (0.0) |
| Fatigue | 17 (56.7) | 1 (3.3) | 16 (53.3) | 1 (3.3) |
| Loss of appetite | 8 (26.7) | 0 (0.0) | 7 (23.3) | 1 (3.3) |
| Constipation | 1 (3.3) | 0 (0.0) | 4 (13.3) | 0 (0.0) |
| Diarrhea | 5 (16.7) | 3 (10.0) | 7 (23.3) | 1 (3.3) |
| Dysgeusia | 1 (3.3) | 0 (0.0) | 1 (3.3) | 0 (0.0) |
| Mucositis | 13 (43.3) | 0 (0.0) | 4 (13.3) | 1 (3.3) |
| Nausea | 4 (13.3) | 0 (0.0) | 14 (46.7) | 0 (0.0) |
| Vomiting | 2 (6.7) | 0 (0.0) | 9 (30.0) | 0 (0.0) |
| Cardiovascular toxicity | 6 (20.0) | 0 (0.0) | 4 (13.3) | 0 (0.0) |
| Infection | 2 (6.7) | 0 (0.0) | 7 (23.3) | 0 (0.0) |
| Hepatotoxicity | 4 (13.3) | 1 (3.3) | 3 (10.0) | 1 (3.3) |
| Neurological toxicity | 0 (0.0) | 0 (0.0) | 2 (6.7) | 0 (0.0) |
| Cutaneous toxicity | 1 (3.3) | 0 (0.0) | 1 (3.3) | 0 (0.0) |
| Electrolyte alteration | 9 (30.0) | 2 (6.7) | 12 (40.0) | 1 (3.3) |
| Other | 4 (13.3) | 0 (0.0) | 10 (33.3) | 0 (0.0) |
| AE . | Arm A: Na-Lev (n = 30), no. patients (%) . | Arm B: Ca-Lev (n = 30), no. patients (%) . | ||
|---|---|---|---|---|
| G1/G2 . | G ≥ 3 . | G1/G2 . | G ≥ 3 . | |
| Neutropenia | 4 (13.3) | 6 (20.0) | 4 (13.3) | 4 (13.3) |
| Anemia | 7 (23.3) | 0 (0.0) | 4 (13.3) | 1 (3.3) |
| Febrile neutropenia | 0 (0.0) | 1 (3.3) | 0 (0.0) | 2 (6.7) |
| Trombocytopenia | 1 (3.3) | 0 (0.0) | 5 (16.7) | 0 (0.0) |
| Fatigue | 17 (56.7) | 1 (3.3) | 16 (53.3) | 1 (3.3) |
| Loss of appetite | 8 (26.7) | 0 (0.0) | 7 (23.3) | 1 (3.3) |
| Constipation | 1 (3.3) | 0 (0.0) | 4 (13.3) | 0 (0.0) |
| Diarrhea | 5 (16.7) | 3 (10.0) | 7 (23.3) | 1 (3.3) |
| Dysgeusia | 1 (3.3) | 0 (0.0) | 1 (3.3) | 0 (0.0) |
| Mucositis | 13 (43.3) | 0 (0.0) | 4 (13.3) | 1 (3.3) |
| Nausea | 4 (13.3) | 0 (0.0) | 14 (46.7) | 0 (0.0) |
| Vomiting | 2 (6.7) | 0 (0.0) | 9 (30.0) | 0 (0.0) |
| Cardiovascular toxicity | 6 (20.0) | 0 (0.0) | 4 (13.3) | 0 (0.0) |
| Infection | 2 (6.7) | 0 (0.0) | 7 (23.3) | 0 (0.0) |
| Hepatotoxicity | 4 (13.3) | 1 (3.3) | 3 (10.0) | 1 (3.3) |
| Neurological toxicity | 0 (0.0) | 0 (0.0) | 2 (6.7) | 0 (0.0) |
| Cutaneous toxicity | 1 (3.3) | 0 (0.0) | 1 (3.3) | 0 (0.0) |
| Electrolyte alteration | 9 (30.0) | 2 (6.7) | 12 (40.0) | 1 (3.3) |
| Other | 4 (13.3) | 0 (0.0) | 10 (33.3) | 0 (0.0) |
Abbreviations: AE, adverse event; Ca-Lev, calcium levofolinate; G, grade; Na-Lev, sodium levofolinate.
| AE . | Arm A: Na-Lev (n = 30), no. patients (%) . | Arm B: Ca-Lev (n = 30), no. patients (%) . | ||
|---|---|---|---|---|
| G1/G2 . | G ≥ 3 . | G1/G2 . | G ≥ 3 . | |
| Neutropenia | 4 (13.3) | 6 (20.0) | 4 (13.3) | 4 (13.3) |
| Anemia | 7 (23.3) | 0 (0.0) | 4 (13.3) | 1 (3.3) |
| Febrile neutropenia | 0 (0.0) | 1 (3.3) | 0 (0.0) | 2 (6.7) |
| Trombocytopenia | 1 (3.3) | 0 (0.0) | 5 (16.7) | 0 (0.0) |
| Fatigue | 17 (56.7) | 1 (3.3) | 16 (53.3) | 1 (3.3) |
| Loss of appetite | 8 (26.7) | 0 (0.0) | 7 (23.3) | 1 (3.3) |
| Constipation | 1 (3.3) | 0 (0.0) | 4 (13.3) | 0 (0.0) |
| Diarrhea | 5 (16.7) | 3 (10.0) | 7 (23.3) | 1 (3.3) |
| Dysgeusia | 1 (3.3) | 0 (0.0) | 1 (3.3) | 0 (0.0) |
| Mucositis | 13 (43.3) | 0 (0.0) | 4 (13.3) | 1 (3.3) |
| Nausea | 4 (13.3) | 0 (0.0) | 14 (46.7) | 0 (0.0) |
| Vomiting | 2 (6.7) | 0 (0.0) | 9 (30.0) | 0 (0.0) |
| Cardiovascular toxicity | 6 (20.0) | 0 (0.0) | 4 (13.3) | 0 (0.0) |
| Infection | 2 (6.7) | 0 (0.0) | 7 (23.3) | 0 (0.0) |
| Hepatotoxicity | 4 (13.3) | 1 (3.3) | 3 (10.0) | 1 (3.3) |
| Neurological toxicity | 0 (0.0) | 0 (0.0) | 2 (6.7) | 0 (0.0) |
| Cutaneous toxicity | 1 (3.3) | 0 (0.0) | 1 (3.3) | 0 (0.0) |
| Electrolyte alteration | 9 (30.0) | 2 (6.7) | 12 (40.0) | 1 (3.3) |
| Other | 4 (13.3) | 0 (0.0) | 10 (33.3) | 0 (0.0) |
| AE . | Arm A: Na-Lev (n = 30), no. patients (%) . | Arm B: Ca-Lev (n = 30), no. patients (%) . | ||
|---|---|---|---|---|
| G1/G2 . | G ≥ 3 . | G1/G2 . | G ≥ 3 . | |
| Neutropenia | 4 (13.3) | 6 (20.0) | 4 (13.3) | 4 (13.3) |
| Anemia | 7 (23.3) | 0 (0.0) | 4 (13.3) | 1 (3.3) |
| Febrile neutropenia | 0 (0.0) | 1 (3.3) | 0 (0.0) | 2 (6.7) |
| Trombocytopenia | 1 (3.3) | 0 (0.0) | 5 (16.7) | 0 (0.0) |
| Fatigue | 17 (56.7) | 1 (3.3) | 16 (53.3) | 1 (3.3) |
| Loss of appetite | 8 (26.7) | 0 (0.0) | 7 (23.3) | 1 (3.3) |
| Constipation | 1 (3.3) | 0 (0.0) | 4 (13.3) | 0 (0.0) |
| Diarrhea | 5 (16.7) | 3 (10.0) | 7 (23.3) | 1 (3.3) |
| Dysgeusia | 1 (3.3) | 0 (0.0) | 1 (3.3) | 0 (0.0) |
| Mucositis | 13 (43.3) | 0 (0.0) | 4 (13.3) | 1 (3.3) |
| Nausea | 4 (13.3) | 0 (0.0) | 14 (46.7) | 0 (0.0) |
| Vomiting | 2 (6.7) | 0 (0.0) | 9 (30.0) | 0 (0.0) |
| Cardiovascular toxicity | 6 (20.0) | 0 (0.0) | 4 (13.3) | 0 (0.0) |
| Infection | 2 (6.7) | 0 (0.0) | 7 (23.3) | 0 (0.0) |
| Hepatotoxicity | 4 (13.3) | 1 (3.3) | 3 (10.0) | 1 (3.3) |
| Neurological toxicity | 0 (0.0) | 0 (0.0) | 2 (6.7) | 0 (0.0) |
| Cutaneous toxicity | 1 (3.3) | 0 (0.0) | 1 (3.3) | 0 (0.0) |
| Electrolyte alteration | 9 (30.0) | 2 (6.7) | 12 (40.0) | 1 (3.3) |
| Other | 4 (13.3) | 0 (0.0) | 10 (33.3) | 0 (0.0) |
Abbreviations: AE, adverse event; Ca-Lev, calcium levofolinate; G, grade; Na-Lev, sodium levofolinate.
| Variable . | Arm . | |
|---|---|---|
| ARM A: Na-Lev (n = 207), n (%) . | ARM B: Ca-Lev (n = 222), n (%) . | |
| Median number of treatment cycles (IQR) | 10 (6–16) | 9 (6–13) |
| Treatment delay | 10 (4.8) | 15 (6.7) |
| Dose reduction | 15 (7.2) | 11 (4.9) |
| Discontinuation due to AE | 0 (0.0) | 3 (1.3) |
| Variable . | Arm . | |
|---|---|---|
| ARM A: Na-Lev (n = 207), n (%) . | ARM B: Ca-Lev (n = 222), n (%) . | |
| Median number of treatment cycles (IQR) | 10 (6–16) | 9 (6–13) |
| Treatment delay | 10 (4.8) | 15 (6.7) |
| Dose reduction | 15 (7.2) | 11 (4.9) |
| Discontinuation due to AE | 0 (0.0) | 3 (1.3) |
Abbreviations: AE, adverse event; CA-Lev, calcium levofolinate; IQR, interquartile range; Na-Lev, sodium levofolinate.
| Variable . | Arm . | |
|---|---|---|
| ARM A: Na-Lev (n = 207), n (%) . | ARM B: Ca-Lev (n = 222), n (%) . | |
| Median number of treatment cycles (IQR) | 10 (6–16) | 9 (6–13) |
| Treatment delay | 10 (4.8) | 15 (6.7) |
| Dose reduction | 15 (7.2) | 11 (4.9) |
| Discontinuation due to AE | 0 (0.0) | 3 (1.3) |
| Variable . | Arm . | |
|---|---|---|
| ARM A: Na-Lev (n = 207), n (%) . | ARM B: Ca-Lev (n = 222), n (%) . | |
| Median number of treatment cycles (IQR) | 10 (6–16) | 9 (6–13) |
| Treatment delay | 10 (4.8) | 15 (6.7) |
| Dose reduction | 15 (7.2) | 11 (4.9) |
| Discontinuation due to AE | 0 (0.0) | 3 (1.3) |
Abbreviations: AE, adverse event; CA-Lev, calcium levofolinate; IQR, interquartile range; Na-Lev, sodium levofolinate.
Assessment, Analysis, and Discussion
| Completion | Study completed; study completed |
| Investigator's Assessment | Correlative endpoints met but not powered to assess activity |
| Completion | Study completed; study completed |
| Investigator's Assessment | Correlative endpoints met but not powered to assess activity |
Assessment, Analysis, and Discussion
| Completion | Study completed; study completed |
| Investigator's Assessment | Correlative endpoints met but not powered to assess activity |
| Completion | Study completed; study completed |
| Investigator's Assessment | Correlative endpoints met but not powered to assess activity |
Our work presents safety data on the use of sodium levofolinate (Na-Lev) instead of calcium levofolinate (Ca-Lev) in combination with 5-fluorouracil (5-FU) in patients with gastrointestinal tumors who are candidates for treatment with the FOLFIRI regimen. Some phase II clinical trials have suggested the noninferiority of Na-Lev with respect to Ca-Lev in terms of efficacy, and a similar toxicity profile. Although calcium levofolinate is the gold standard, our results suggest that sodium levofolinate may be a good alternative as it has a similar toxicity profile: we observed a trend toward higher grade (G)1–2 mucositis in the Na-Lev arm and higher G1–2 nausea and vomiting in the Ca-Lev arm. The incidence of treatment delays, dose reductions, and discontinuation due to adverse events was similar. Unfortunately, given the small sample size, the heterogeneity of enrolled patients in relation to tumor site and treatment line, and the absence of randomization, it was not possible to draw any definitive conclusions about the effectiveness of the Na-Lev +5-FU combination. We found some advantages of Na-Lev over Ca-Lev in terms of preparation process and administration. Na-Lev showed a reassuring toxicity profile and a favorable impact on drug preparation and delivery, but a randomized trial would be needed to give more consistency to these data.
ClinicalTrials.gov Identifier: NCT04680104
Sponsor: None
Principal Investigator: Alessandro Passardi
IRB Approved: Yes
Acknowledgments
The authors thank Gráinne Tierney and Cristiano Verna for editorial assistance.
Disclosures
The authors indicated no financial relationships.
References
Author notes
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