Table 6.
Completed clinical therapy studies for metastatic PPGLs
| Author | Therapy | Patient number (n) | Complete response | Partial response | Stable disease | Median OS/PFS/TTP |
|---|---|---|---|---|---|---|
| Niemeijer et al, 2014 | CVD chemotherapy | Meta-analysis from 4 studies: n = 50 (special efficacy in SDHB mutation carriers) | 4% | 37% | 14% | PFS in 2 studies 20 and 40 months, respectively |
| Asai et al., 2017 | CVD chemotherapy | N = 23 | 4% | 22% | 22% | OS/PFS responders vs nonresponders 4.6 vs 2 years and 1.7 vs 0.3 years, respectively |
| Deutschbein et al., 2015 | CVD chemotherapy | N = 8 | 0% | 25% | 38% | PFS 5.4 months (2.5-26.8 months) |
| Tanabe et al., 2013 | CVD chemotherapy | N = 17 | 0% | 47.1%1 | 23.5% | PFS responders 40 months |
| Huang et al., 2008 | CVD chemotherapy* | N = 18 (n = 8 with SDHB orSDHD mutation) | 11% | 44% | OS responders/nonresponders 3.8/1.8 years | |
| Averbuch et al., 1988 | CVD chemotherapy* | N = 14 | 57% (complete plus partial response) | PFS 21 months (7 to >34 months) | ||
| Jawed et al., 2018 | Prolonged CVD chemotherapy (median 20.5 cycles) | N = 12 (all with SDHB mutations) | 16.7% (2/12) | 66.7% (8/12) | 0%2 | OS/PFS 3.3/2.6 years |
| Ayala-Ramirez et al., 2012 | different chemotherapy regimens | N = 54 (n = 52 evaluable) (all progressive disease at baseline) | 33%3 | OS responders/nonresponders 6.4/3.7 years | ||
| Hadoux et al., 2014 | Temozolomide monotherapy | N = 15 (n = 10 with SDHB mutations) | 0% | 33%4 | 47%4 | PFS 13.3 months |
| Tena et al., 2018 | Metronomic low-dose temozolomide plus high dose Lanreotide Autogel | N = 2 (case reports) | 0% | 0% | 100% | OS (n = 2) not reached, PFS 13 months (n = 1), PFS not reached after 27 months (n = 1) |
| Van Hulsteijn et al., 2014 | [131I]-MIBG | Meta-analysis from 17 studies: n = 243 | 3% | 27% | 52% | PFS in 2 studies 23.1 and 28.5 months, respectively |
| Loh et al., 1997 | [131I]-MIBG | Meta-analysis n = 116 | 30% (complete plus partial response) | |||
| Thorpe et al., 2020 | [131I]-MIBG | N = 125 (n = 88 evaluable) | 1% | 33% | 53% | OS responders vs nonresponders 6.3/2.4 years |
| Gonias et al., 2009 | [131I]-MIBG (phase II, prospective) | N = 50 (n = 49 evaluable) | 22% (complete plus partial response) | 43% | 5-year OS 64% | |
| Wakbayashi et al., 2019 | HSA [131I]-MIBG (phase I, prospective) | N = 20 | 10% | 65% | 6-months OS/PFS 100%/80% | |
| Noto et al., 2018 | HSA [131I]-MIBG (phase I, prospective) | N = 21 | 19% | 2-year OS 62% | ||
| Pryma et al. 2019 | HSA [131I]-MIBG (phase II, prospective) | N = 68 (evaluable n = 64) patients | 0% | 23% | 69% | OS 36.7 months: 18 months after one cycle/ 44 months after 2 cycles |
| Nastos et al., 2017 | [131I]-MIBG vs [177Lu] / [90Y] DOTATATE (PRRT) | N = 22 Patients (n = 11 MIBG, n = 9 DOTATATE, n = 2 combinations, n = 15 PGL, n = 7 PCC) (all progressive disease at baseline) | MIBG: 63% vs DOTATATE 100% | OS/PFS MIBG 41.2/20.6 months vs OS/PFS DOTATATE 60.8/38.5 months Subgroup PGLs: OS/PFS MIBG 22.8/14.4 months vs OS/PFS DOTATATE 60.8/38.5 months (P < 0.05) |
||
| Van Essen et al., 2006 | [177Lu] DOTATATE | N = 12 (n = 1 PCC, n = 5 HN, n = 6 other PGLs) | 0% | 16.7%5 | 50%5 | TTP 11 and 5 months, respectively in 2 patients, median TTP to progression not reached in PGL patients |
| Zovato et al., 2012 | [177Lu] DOTATATE | N = 4 PGLs (with SDHD mutation) (n = 2 thoracic PGLs, n = 2 HNPGLs) (all progressive disease at baseline) | 0% | 50% | 50% | - |
| Forrer et al., 2008 | [90Y] DOTATOC, 3 combined with [177Lu] DOTATATE | N = 28 (n = 9 PCC, n = 19 PGL) (all progressive disease at baseline) | 0% | 25%1 | 46.4% | TTP 3 to >42 months, median TTP 18 ± 14 (6-44) months |
| Kong et al., 2017 | [177Lu] DOTATATE, 9 combined with radiosensitizing chemotherapy | N = 20 (n = 8 PCC, n = 5 HNPGLs, n = 5 abd. PGLs, n = 2 HN plus abd. PGLs) (n = 7 SDHB, n = 1 SDHD, n = 2 no mutation, n = 10 unknown) | 0% | 36%1 | 50% | PFS 39 months, OS not reached |
| Pinato et al., 2016 | 177[Lu]-DOTATATE | N = 5 abd. PGLs (with SDHB mutation) | 0% | 20% | 60% | PFS 17 (0-78) months/mean OS 53 months (median OS not reached) |
| Puranik et al., 2015 | [90Y] DOTATOC n = 4 combined with 177[Lu]-DOTATATE* | N = 9 HN PGLs | 0% | 0% | 100% | - |
| Yadav et al., 2019 | 177[Lu]-DOTATATE | N = 25 PGLs | 0% | 28% | 56% | PFS 32 months, OS not reached |
| Imhof et al. 2011 | [90Y] DOTATOC (phase II, prospective) | N = 39 (n = 11 PCCs, n = 28 PGLs) (all progressive disease at baseline) | ns | 18% | ns | Mean OS in PCC/PGL 32/82 months |
| Vyakaranam et al., 2019 | 177[Lu]-DOTATATE | N = 22 (n = 11 sympathetic PGLs, 2 HNPGLs, n = 9 PCCs) | 0% | 9% | 91% | PFS 21.6 months |
| Zandee et al., 2019 | 177[Lu]-DOTATATE | N = 30 (n = 17 parasympathetic PGLs, n = 10 sympathetic PGLs, n = 3 PCCs) | 0% | 23% | 67% | **PFS in PGL#/PCC 13/10 months, respectively |
| Satapathy et al., 2019 | 177[Lu] /[90Y] -DOTATATE, [90Y] DOTATOC | Meta-analysis from 12 studies: n = 201 | 0% | 25%6 | 59%6 | - |
| Taieb et al., 2019 | [90Y]/ 177[Lu]-DOTATATE | Meta-analysis n = 234 | 90% (partial response plus stable disease) | |||
| Jaiswal et al., 2020 | 177[Lu]-DOTATATE | N = 15 (n = 4 PCCs, n = 4 sympathetic PGLs, n = 5 HNPGLs, n = 1 PCC + sympathetic PGL, n = 1 HNPGL + sympathetic PGL) | 0% | 7% | 73% | PFS/OS not reached after 27 months |
| Ayala-Ramirez et al., 2012 | TKI sunitinib (retrospective) | N = 17 (n = 14 evaluable) | 0% | 21% (3/14) | 36% (5/14) | PFS 4.1 months 62.5% (5/8) with stable disease or partial response SDHB mutation carriers) |
| O`Kane et al., 2019 | TKI sunitinib (phase II, prospective) | N = 25 (n = 23 evaluable) | 0% | 13% (3/23) (2/3 SDHA/B mutation) | 70% (16/23) | PFS 13.4 months (all patients with SDHx mutations partial response or stable disease) |
| NCT01967576 (completed, preliminary data) | TKI axitinib (phase II, prospective) |
N = 14 (n = 12 evaluable) | 0% | 41.7% | 41.7% | PFS 7.7 months (3.3.-16.8 months) |
| Jasim et al., 2017 | TKI pazopanib* | N = 7 (6 evaluable) | 17% | PFS/OS 6.5/14.8 months | ||
| Oh et al., 2012 | MTORC1 inhibitor everolimus (phase II, prospective) | N = 7 | 0% | 0% | 71% (5/7) | PFS 3.8 months |
| Druce et al., 2009 | MTORC1 inhibitor everolimus | N = 4 | 0% | 0% | 25% (1/4) | PFS 3 months (n = 1) |
| Naing et al., 2020 | Pembrolizumab (phase II, prospective) | N = 9 (n = 8 evaluable) | 0% | 0% | 75% | 27-weeks PFS 43% |
| Jimenez et al., 2020 | Pembrolizumab (phase II, prospective) | N = 11 | 9% | 64% | PFS 5.7 months (4.37 months-not reached) (n = 1 SDHD mutation stable disease for 24 months, n = 1 SDHB mutation tumor shrinkage >30%) | |
| NCT03165721 (completed, preliminary data) | DNA Methyltransferase inhibitor SGI-110 (guadecitabin) (phase II, prospective) | N = 1 | PFS 3.9 months |
Studies are retrospective unless indicated as prospective.
Minor response: any shrinkage of tumor which does not fulfill the criteria of partial response. If not indicated otherwise, reported minor/minimal response is included in “Stable disease.”
Black letters: potentially specifically interesting for cluster 1; gray letters: potentially specifically interesting for cluster 2.
Abbreviations: CVD, cyclophosphamide/vincristine/dacarbazine; HNPGL, head and neck paraganglioma; MIBG, meta-iodobenzylguanidine; OS, overall survival; PCC, pheochromocytoma; PFS, progression-free survival; PGL, paraganglioma; PPGL, pheochromocytoma/paraganglioma; SDHA/B/D, succinate dehydrogenase subunit A/B/D; TKI, tyrosine kinase inhibitor; TTP, time to progression.
1 Minor/minimal response included
2 Minor/minimal response excluded (2/12)
3 Overall response rate
4 According to RECIST plus PERCIST
5 Including all 12 patients of which only 11 were evaluable
6 This meta-analysis provides an overall response rate of 25% (n=179) and a disease control rate of 84% (n=151)
* prospective
**Overall PFS 30 months, parasympathetic PGL 91 months
# sympathetic