Table 4.
Prospective Clinical Trials of Intrathecal Therapies in LM
| Publication | Protocol | Treatment | N | Cancer type | Median OS | Additional results |
|---|---|---|---|---|---|---|
| Intrathecal therapies | ||||||
| Gutin et al, 1977 | Phase II | Thiotepa 10 mg/m2 IT and 10 mg IT | 13 | Solid and hematologic tumors | NA | 8 CR, 2 PR, 3 PD |
| Hitchins et al, 1987 | RCT | MTX 15 mg IT | 22 | Solid and hematologic tumors | 12 weeks, (range, 1–152) | RR = 61% concurrent IFRT, N = 11 |
| MTX 15 mg IT + cytarabine 50 mg/m2 IT | 20 | Solid and hematologic tumors | 7 weeks, (range, 1–105) | RR = 45% concurrent IFRT, N = 11 |
||
| Meyers et al, 1991 | Phase II | Alpha interferon 1 × 106 IU/mg protein IT | 9 | Solid and hematologic tumors | 4 months (range, 1–10) | RR = 44% significant neurotoxicity = 78% |
| Grossman et al, 1993 | RCT | MTX 10 mg IT | 28 | Solid and hematologic tumors | 15.9 weeks (range, 4 days—61.3 weeks) | 0 CR, 9 SD, 19 PD concurrent IFRT allowed |
| Thiotepa 10 mg IT | 24 | Solid and hematologic tumors | 14.1 weeks (range, 4 days—61.3 weeks) | 0 CR, 3 SD, 20 PD concurrent IFRT allowed |
||
| Chamberlain et al, 1996 | Phase II | MTX 2 mg IT (first line), cytarabine 30 mg IT (second line), thiotepa 10 mg IT (third line) | 16 | Melanoma | 4 months (range, 2–8) | IT MTX RR = 25% (total N = 16) IT cytarabine RR = 38% (total N = 13) IT thiotepa RR = 28% (total N = 7) preceding IFRT, N = 14 |
| Chamberlain et al, 1998 | Prospective NOS | MTX 2 mg IT (first line), cytarabine 30 mg IT (second line), thiotepa 10 mg IT (third line) | 32 | NSCLC | 5 months (range, 1-12) | IT MTX RR = 43% (total N = 32) IT cytarabine RR = 50% (total N = 16) IT thiotepa RR = 33% (total N = 6) preceding IFRT, N = 16 |
| Glantz et al, 1999 | Phase III | Liposomal cytarabine 50 mg IT | 31 | Solid tumors | 105 days (range NA) | RR = 26% median TTNP = 58 days median LM-specific survival = 343 days |
| MTX 10 mg IT | 30 | Solid tumors | 78 days (range NA) | RR = 20% Median TTNP = 30 days median LM-specific survival = 98 days |
||
| Esteva et al, 2000 | Phase II | Cytarabine 100 mg IT | 10 | Breast | 30 weeks (range, 5–58 weeks) | RR = 22% (95% CI: 3–60) preceding IFRT, N = 2 |
| Orlando et al, 2002 | Phase II | Thiotepa 10 mg IT, MTX 15 mg IT, hydrocortisone 30 mg IT (day 1) + cytarabine 70 mg IT, MTX 15 mg IT, hydrocortisone 30 mg IT (day 5) | 13 | Breast | NA | No observed response or clinical improvement in symptoms concurrent WBRT, N = 7 |
| Jaeckle et al, 2002 | Phase IV | Liposomal cytarabine 50 mg IT | 110 | Solid tumors | 95 days (range, 7–791+) | RR = 27% (95% CI: 17–39) median TTNP = 55 days (range, 0–584+) median LM-specific survival = 170 days (range, 7–791) concurrent IFRT, N = 24 |
| Chamberlain et al, 2002 | Phase II | Alpha interferon 1 × 106 IU IT | 22 | Solid and hematologic tumors | 18 weeks (range, 5–69) | RR = 45% median DOR = 16 weeks (range, 8–40) chronic fatigue (KPS reduction of 20 points after induction and 30 points during maintenance) = 91% concurrent IFRT, N = 12 |
| Chamberlain et al, 2006 | Phase II | Etoposide 0.5 mg IT | 27 | Solid and hematologic tumors | 10 weeks (range, 4–52) | RR = 27% median TTNP = 20 weeks (range, 8–40) 6-month neurologic PFS = 11% |
| Groves et al, 2008 | Phase II | Topotecan 0.4 mg IT | 62 | Solid and hematologic tumors | 15 weeks (95% CI: 13–24) | RR = 21% median TTP = 7 weeks (95% CI: 6–11) 13-week neurologic PFS = 30% (95% CI: 20–45) |
| Ursu et al, 2015 | Phase I | CpG-28 IT and SQ | 29 | Solid tumors | 15 weeks (range, 3–300) | median PFS = 7 weeks (range, 1–81) |
| Bonneau et al, 2018 | Phase I | Trastuzumab 30–150 mg IT (MTD = 150 mg IT) | 16 | HER2-positive breast | 7.3 months (range, 12 days—27.9 months) | 2 CR, 6 SD, 4 PD |
| Mrugala et al, 2019 | Phase II | Liposomal cytarabine 50 mg IT + HD-MTX 8g/m2 | 3 | Breast | 8.2 months (range, 5.5–11.3) | median PFS = 1.4 months (range, 1.3–8.2) |
| Pan et al, 2019 | Phase I | Pemetrexed 10–15 mg IT (MTD = 10 mg IT) | 13 | NSCLC (EGFR-mutant or ALK-positive, N = 11) | 3.8 months (range, 0.3–14) | RR = 31% DCR = 54% median neurologic PFS = 2.5 months (range, 0.3–12.5) |
| Fan et al, 2021 | Phase I/II | Pemetrexed 50 mg IT + dexamethasone 5 mg IT | 30 | EGFR-mutant NSCLC | 9.0 months (95% CI: 6.6–11.4) | Clinical RR = 84.6% 2 CR, 13 OR, 7 PR, 3 SD, 1 PD |
| Li et al, 2023 | Phase I | Pemetrexed 30–50 mg IT (RD = 30 mg IT) | 23 | EGFR-mutant and ALK-positive NSCLC | 9.5 months (range, 2.9—NR) | ORR = 43.5% (95% CI: 23.2–63.8) DCR = 82.6% (95% CI: 61.2–95.0 median PFS = 6.3 months (range, 0.8—NR) |
| Kumthekar et al, 2023 | Phase I/II | Trastuzumab 10–80 mg IT (RP2D = 80 mg) | 34 | HER2-positive cancers | 8.3 months (95% CI: 5.2–19.6) at RP2D (N = 26) | Median PFS = 2.2 months (95% CI 1.0–7.4) at RP2D (N = 26) In HER2-positive breast cancer patients at RP2D (N = 23), median PFS = 2.8 months (95% CI 1.8–7.8) and median OS = 10.5 months (95% CI 5.2–20.9) |
| Oberkampf et al, 2023 | Phase II | Trastuzumab 150 mg IT |
19 | HER2-positive breast | 7.9 months (range, 0.2–27.8+) | Median LM-PFS = 5.9 months (range, 0.2–25.5) |
| Combination of intrathecal and systemic therapies | ||||||
| Boogerd et al, 2004 | RCT | PBC + MTX 10 mg IT (first line), cytarabine 40 mg IT (second line) | 17 | Breast | 18.3 weeks (standard error 6.7) | Median TTNP = 23 weeks neurologic improvement = 41% and stabilization = 18% neurologic toxicity = 47% |
| PBC without IT chemotherapy | 18 | Breast | 30.3 weeks (standard error 10.9) | Median TTNP = 24 weeks neurologic improvement = 39% and stabilization = 28% neurologic toxicity = 6% |
||
| Le Rhun et al, 2020 | Phase III | PBC + liposomal cytarabine 50 mg IT | 36 | Breast | 7.3 months (95% CI: 3.9–9.6) | Median LM-PFS = 3.8 months (95% CI: 2.3–6.8) |
| PBC without IT chemotherapy | 37 | Breast | 4.0 months (95% CI: 2.2–6.3) | Median LM-PFS = 2.2 months (95% CI: 1.3–3.1) | ||
| Glitza Oliva et al, 2023 | Phase I | Nivolumab 5–50 mg IT (RD = 50 mg IT) + Nivolumab 240 mg IV q2 weeks | 25 | Melanoma | 4.9 months (range NA) | OS at 26 weeks = 44% OS at 52 weeks = 26% |
| Intrathecal radiolabeled isotopes | ||||||
| Coakham et al, 1998 | Phase I | 131 I- monoclonal antibodies | 40 | Solid and hematologic tumors | NA | Mean OS = 39 months in responders, 4 months in non-responders OS at 1 year = 50% |
| Tringale et al, 2023 | Phase I | 131-I-omburtamab | 27 | Primary brain leptomeningeal tumors (20 medulloblastoma, 7 ependymoma) | Medulloblastoma: 1.9 years (95% CI 0.9–10.9) Ependymoma: 6.7 years (95% CI: 0.4–12.9) |
Medulloblastoma median PFS = 0.4 years (95% CI: 0.1–1.7) Ependymoma median PFS = 0.4 years (range, 0.2–1.9) |
Abbreviations: LM, leptomeningeal metastases; OS, overall survival; IT, intrathecal; NA, not available; CR, complete response; PR, partial response; PD, progressive disease; RCT, randomized controlled trial; MTX, methotrexate; RR, response rate; IFRT, involved field radiation therapy; SD, stable disease; NOS, not otherwise specified; NSCLC, non-small cell lung cancer; TTNP, time to neurologic progression; WBRT, whole-brain radiation therapy; DOR, duration of response; KPS, Karnofsky performance status; PFS, progression-free survival; CI, confidence interval; CpG, cytidine phosphate guanosine; SQ, subcutaneous; MTD, maximum tolerated dose; HER2, human epidermal growth factor receptor 2; HD, high dose; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; DCR, disease control rate; OR, obvious response; RD, recommended dose; ORR, objective response rate; RP2D, recommended phase II dose; PBC, physician’s best choice systemic and, if needed, radiation therapy; IV, intravenous.