Table 3. Metronomic (low dose) chemotherapy studies
| Cancer Type | No of Pts | Results | Toxicities Grade 3/4 |
Ref.
|
| Advanced Cancer | ||||
| CAP 2x500 mg bid, Celecoxib 2x400 mg bid. continuously | 37 | 17/37 non-PD | no |
20
|
| CYC 50 mg od, Rofecoxib 25 mg od, VBL 3 mg/m2 i.v. q1w, 50% of pts received Minocycline 100 mg orally bid | 47 | 14/47 non-PD | neutropenia 10/2 anemia 2/10 thrombopenia 1/0 |
21
|
| VP-16 25 mg/m2 d1-14, CYC 25 mg/m2 d15-28, Celecoxib 100-400 mg/d d1-28 | 17 | 7/17 non-PD | neutropenia 1/0 anemia 0/2 thrombopenia 0/4 |
22
|
| VIN 20-50 mg thrice a week, escalated by 10 mg increments in successive cohorts | 62 | 25/52 non-PD | neutropenia 0/2 |
23
|
| TRO 50-150 mg daily | 31 | 17/31 non-PD | none |
24
|
| CYC average 52 mg od continuously | 24 | TTF 6,4 months | Nausea 2/0 |
25
|
| CYC 50 mg od, Celecoxib 400 mg bd for 7 days each week, MTX 2,5 mg bd for 2 consecutive days each week | 69 | 23/67 non-PD | Fatigue 11/0 |
26
|
| Pediatric cancer advanced | ||||
| VIN 1,5 mg/m2d1,8,15,22, CYC 25 mg/m2 od d1-21, MTX 15 mg/m2 twice weekly d21-42, followed by a 1 week break | 12 | 7/12 non-PD | anaemia 0/1 nonfebrile neutropenia 0/1 |
27
|
| Colorectal aCncer | ||||
| OXA 85 mg/m2d1, LV 200 mg/m2 d1, i.v. bolus 5-FU 400 mg/m2d1, 22h infusion of 5-FU 600 mg/m2 d1, followed by 10 day daily oral UFT 200 mgm2/LV 30 mg/m2, every 2 weeks | 28 | 10/28 non-PD SD not assessed | no |
28
|
| CPT-11 continuously 3 out of 4 weeks, escalating per cohort 1,4 mg/m2/d, 2,8 mg/m2/d, 4,2 mg/m2/d | 20 | 4/20 non-PD | no |
29
|
| S-1 80 mg/m2 d3-7,10-14, 17-21, CPT-11(with escalating dosages) from 40 mg/m2 d1,8,15, qd 29 | 16 | 15/16 non-PD | diarrhoea 1/0 |
30
|
| Glioblastoma |
||||
| VP-16 35 mg/m2 d1-21, alternating every 21 days with CYC 2mg/kg KG, in comb. with THAL 50-200 mg, escalating up to 1200 mg, Celecoxib 2x200 mg up to 2x400 mg. | 48 | 31/48 non-PD | constipation 3/2 fatigue 1/0 leukopenia 7/6 nausea 4/0 |
31
|
| MTX 5 mg 2x/ week, CYC 100 mg od | 10 | 10/10 PD | no |
32
|
| TMZ 40 mg/m2 od | 12 | 7/12 non-PD | no |
33
|
| Childhood brain tumors | ||||
| Topotecan po 0,8 mg/m2 d1-21, qd28 | 26 | 6/26 non-PD | neutropenia 6/4 leucopenia 8/1 thrombocytopenia 6/2 |
34
|
| Head and neck cancer | ||||
| PAC 80 mg/m2 i.v. q1w | 33 | 20/33 non-PD | no |
35
|
| Lymphoma | ||||
| CYC 50 mg od, MTX 2,5 mg 4x/ week, Celecoxib 400 mg bid | 41 | 33/41 non-PD | No Grading fatigue nausea neutropenia anemia |
36
|
| CYC 50 mg od, Celecoxib 400 mg bid | 35 | 19/35 non-PD | fatigue 6/0 thrombopenia 5/0 ASAT/ALAT ↑ 1/0 |
37
|
| Pred 20 mg, CYC 50 mg, VP-16 50 mg, PCZ 50 mg od, dose adjustment according to WBC count | 22 | 15/22 non-PD | G 3+4 combined infection 3 anemia 1 thrombopenia 1 |
38
|
| Pred 20 mg, CYC 50 mg, VP-16 50 mg, PCZ 50 mg daily, dose adjustment according to WBC count | 75 | 51/75 non-PD SD not assessed | G 3+4 combined infection 8 gastrointestinal 4 thrombopenia 8 |
39
|
| VBL 6mg/m2 + DOX 25 mg/m2 w1,3,5,7,9,11, VCR 1,4 mg/m2 + BLEO 5 units/m² w2,4,6,8,10,12, mustard 6mg/m2 w1,5,9 + VP-16 60 mg/m2 2x/week w3,7,11, Pred 40 mg/m2 every other day w1-10 | 142 | 126/142 non-PD | G 3+4 combined neutropenia 140 anemia 44 thrombopenia 1 fatigue 10 |
40
|
| Metastatic Breast Cancer | ||||
| CYC 50 mg od d1-21, qd29 + MA 80 mg bid | 29 | 12/29 non-PD | none |
41
|
| (Arm A):CYC 50 mg od + MTX 2,5 mg bid d1+4 (Arm B):CYC 50 mg od + MTX 2,5 mg bid d1+4 + THAL 200 mg od | 171 | Arm A: 36/86 non-PD ArmB: 35/85 non-PD | G 3+4 combined ASAT/ALAT ↑ 9 neutropenia 4 lymphopenia 3 anemia 2 |
42
|
| Dalteparin 5000 U s.c. od + CYC 50 mg od + MTX 2,5 mg bid twice weekly, Pred 5 mg od | 41 | 10/41 non-PD | ASAT/ALAT ↑ 11/0 |
43
|
| Letrozole plus/minus CYC 50 mg od | 141 | LET 53/57 non-PD LET - CYC 54/57 non-PD | CHF 0/3 atrial flutter 1/0 skeletal fractures 3/0 (Causing 1 death) |
44
|
| MTX 2,5 mg bid d1+2 each week + CYC 50 mg od | 64 | 22/63 non-PD | ASAT/ALAT ↑ 9/0 |
45
|
| MTX 2,5 mg d1+2 each week + CYC 50 mg od | 42 | 13/42 non-PD | neutropenia 3/1 ASAT/ALAT ↑ 2/0 |
46
|
| VIN 70 mg/m2 d1,3,5, 3 weeks on 1 week off | 34 | 24/34 non-PD | neutropenia 3/0 anemia 3/0 thrombopenia 1/0 |
47
|
| TRO 3x50 mg daily or TRO 3x150 mg d1-10, qd28 | 53 | 20/53 non-PD | leukopenia 4/0 thrombopenia 0/2 anemia 3/3 nausea 4/1 |
48
|
| Arm A: PAC 175 mg/m2 d1, q3w +/- trastuzumab Arm B:PAC 80 mg/m2 weekly +/- trastuzumab | 577 | Arm A: 78/225 non-PD Arm B: 145/346 non-PD |
leucopenia 38/9 thrombopenia 7/2 anemia 23/1 neutropenia 41/23 neurosensory 111/1 fatigue 31/1 |
49
|
| Arm A: CYC 100 mg/m2 po d1-14 + MTX 40 mg/m2 iv d1,8 + 5-FU 600 mg/m2 iv d1,8, q4w Arm B:CYC 600 mg/m2 iv d1 + MTX 40 mg/m2 iv d1 + 5-FU 600 mg/m2 iv d1, q3w | 254 | Arm A: 88/125 non-PD Arm B: 61/129 non-PD |
leucopenia 45/7 thrombopenia 4/3 nausea 68/9 |
50
|
| Arm A: CYC 50 mg od Arm B: CYC 50 mg od + MTX 2,5 mg twice weekly | 61 | Arm A: 12/22 non-PD Arm B: 20/39 non-PD |
leukopenia 2/0 thrombocytopenia 1/0 |
51
|
| CYC 65 mg/m2 od d1-14 + Capecitabine 1g/m2 twice daily d1-14, qd21 | 66 | 20/66 non-PD | Hand-foot-s. 3/0 Anorexia 4 (grade 3+4 combined) |
52
|
| VIN po 30 mg od continuously (starting dose) + Capecitabine 800 mg/m2 bid (starting dose) d1-14, qd21 | 36 | 12/36 non-PD SD not documented |
53
|
|
| CYC 100 mg od d1-14 + CAP 1500 mg bid d 8-21, qd21 | 80 | 54/80 non-PD | leucopenia 15/0 lymphopenia 10/3 |
54
|
| 50 mg od continuously + MTX 2,5 mg po bid d2+4 every week + 1 mg 1E10 anti-idiotype MAb (racotumomab) s.c.bi-weekly x 5 | 21 | 13/21 non-PD | nausea/vomiting 1/0 |
55
|
| CAP 1500 mg 0d | 58 | 50/58 non-PD | G 3+4 combined Hand-foot-s. 3 |
56
|
| Melanoma | ||||
| Arm A TRO 3x50 mg od Arm B TRO 3x50 mg od + Rofecoxib 25 mg/od + Pioglitazone 60 mg od |
76 |
Arm A: 2/32 non-PD |
hematologic 8/0 (not differentiated) |
57
|
| CYC 50-100 mg 3 weeks out of 4 | 13 | 6/13 non-PD | G 3+4 combined lymphopenia 5 neutropenia 2 |
58
|
| PAC 10 mg/m2 96 hours weekly ci, Celecoxib 400mg bid | 20 | 4/20 Non-PD | G 3+4 combined DVT/PE 3 anemia 1 sepsis 1 |
59
|
| TREO 500 mg od, Rofecoxib 25 mg od | 12 | 5/12 non-PD | no |
60
|
| Adrenocortical Carcinoma | ||||
| GEM 800 mg/m2 d1+8, qd21, i.v. 5-FU 200 mg/m2/d continuously without interruption in first 6 patients, CAP 1500 mg/d in subsequent patients. Mitotane for all Patients. | 28 | 13/28 non-PD | G 3+4 combined leukopenia 6 thrombopenia 1 mucositis 1 |
61
|
| Neuroendocrine carcinomas | ||||
| 5-FU iv 200 mg/m2 continuously+ LAR Octreotide 20 mg q4w | 29 | 27/29 non-PD | diarrhoea 1/0 hand-foot-S. 2/0 mucositis 1/0 |
62
|
| Non small cell lung cancer | ||||
| VIN 40-70 mg trice per week, CDDP 70-85 mg/m2 i.v. d1 q3w | 26 | 15/24 non-PD | neutropenia 3/5 anemia 1/1 |
63
|
| DOC 25 mg/m2 d1,8,15, qd29, TRO 50 mg od | 21 | 13/21 non-PD | neutropenia 4/0 alopecia 5/0 nausea 2/0 |
64
|
| CDDP 30 mg/m2 d1,8,14, 28 + VP-16 50 mg/m2 d1-21, qd29 | 31 | 18/31 non-PD | anemia 10/0 leukopenia 7/0 thrombopenia 3/0 Crea and BUN ↑ 3/0 |
65
|
| Ovarian Cancer | ||||
| Case Report CYC 50 mg od | 1 | non-PD | none |
66
|
| Arm A: PAC 180 mg/m2 d1 + carboplatin AUC 6 d1, qd21 Arm B: PAC 80 mg/m2 d1,8,15 + carboplatin AUC 6 d1, qd21 | 631 | Arm A: 114/135 non-PD Arm B: 125/147 non-PD |
G 3+4 combined neutropenia 562 thrombopenia 256 anemia 351 nausea 68 fatigue 23 |
67
|
| Gestational Trophoblastic Neoplasia | ||||
| Arm A: MTX 30 mg/m2 IM weekly Arm B: Dactinomycin 1,25 mg/m2 i,v, beweekly | 216 | Arm A: 57/107 non-PD Arm B: 76/109 non-PD |
neutropenia 3/1 thrombopenia 1/0 anemia 6/0 nausea 2/0 |
68
|
| Multiple Myeloma | ||||
| CYC 50 mg bid for 21 days, THAL 200 mg/d, Pred 50 mg od. qd29 | 37 | 30/37 non-PD | leukopenia 10/5 febr. neutrop. 4/0 hyperglycemia 5/2 sensory neuropathy 4/0 |
69
|
| Prostate Cancer | ||||
| Case Report TRO 100 mg od |
1 | non-PD | none |
70
|
| CYC 100–150 mg per day alternately. Mesna 400 mg od for three weeks followed by one week of rest | 8 | 5/8 non-PD | G 2+3 combined neutropenia 8 |
71
|
| CYC 50 mg/m2/d od | 80 | 26/80 non-PD SD not assessed | lymphopenia 19/0 anemia 1/0 leukopenia 1/0 |
72
|
| CYC 50 mg od, DEXA 1 mg od | 17 | 9/17 non-PD | none |
73
|
| CYC 500 mg/m2 i.v. d1, from day 2 CTX 50 mg od, Celecoxib 200 mg bid, DEXA 1 mg od | 28 | 9/28 non-PD | none |
74
|
| DOC iv three escalated doses 30, 40, 50 mg/m2, Zoledronic acid 2 mg fixed dose, all q2w. Arm A: DOC→ZOL Arm B: ZOL→DOC | 22 | Arm A: 6/9 non-PD Arm B: 13/13 PD |
anemia 3/0 |
75
|
| CYC 50 mg od, DEXA 1 mg od | 34 | PSA-Response 24/34 non-PD | Grading and Number of pts. not differentiated anemia neutropenia flu-like symptoms gastrointestinal S. |
76
|
| CYC 50 mg od + MTX 2,4 mg po twice weekly | 58 | PSA- Response 15/58 non-PD Measurable disease 7/17 |
leukopenia 4/0 thrombocytopenia 2/0 |
77
|
| Renal cell carcinoma | ||||
| Etoricoxib 60 mg od + Pioglitazone 60 mg od + Interferon-α 4,5 MU sc three times a week + Capecitabine 1g/m2 td for 14 days, qd21 | 45 | 16/45 non-PD | hand-foot-s. 16/0 diarrhea 4/0 pneumonia 2/0 |
78
|
| Malignant vascular tumors | ||||
| Pioglitazone 45 mg od, Rofecoxib 25 mg od, after 14 days TRO 3x50 mg od | 6 | 6/6 non-PD | none |
79
|
| Sarcomas | ||||
| Pioglitazone 45 mg/ od, Rofecoxib 25 mg od, TRO 3x50 mg od | 1 | non-PD | none |
80
|
| VP-16 po 100 mg d1-21, qd29 | 26 | 12/26 non-PD | febr. neutrop. 0/2 1 death due to sepsis |
81
|
| Sarcoma and melanoma | ||||
| Pioglitazone 45 mg od + Rofecoxib 25 mg od + after 14 days TRO 3x50 mg od | 40 | 11/40 non-PD | none |
82
|
| Esophagogastric Cancer | ||||
| Arm A: EPI 50 mg/m2 d1 + CDDP 60 mg/m2 d1, q3w, 5-FU 200 mg/m2/d d1-21 Arm B: MMC 7mg/m2 d1, q6w, + CDDP 60 mg/m2 d1, q3w + 5-FU 300 mg/m2/d d1-21 |
580 | Arm A: 182/284 non-PD Arm B: 188/276 non-PD | G 3+4 combined leucopenia 61 neutropenia 142 anemia 49 thrombopenia 50 nausea 54 fatigue 87 |
83
|
Abbreviations: CAP=Capecitabin, CYC= Cyclophosphamide, VP-16= Vepesid, VIN= Vinorelbine, TRO= Trofosfamide, OXA= Oxaliplatin, 5-FU= 5-Fluorouracil, LV= Leucovorin, CPT-11= Irinotecan, THAL= Thalidomide, MTX= Methothrexate, TMZ= Temozolomide, , PAC= Paclitaxel, PCZ= Procarbazin, DOX= Doxorubicin, BLEO= Bleomycin, VCR= Vincristin, MA= Megestat, TREO= Treosulfan, GEM= Gemcitabin, CDDP= Cisplatin, DOC= Docetaxel, EPI= Epirubicin, od= once daily, twice daily, DEXA= Dexamethason, MMC= Mitomycin, non-PD = no progressive disease, 1qw weekly, 2qw = bi-weekly, 3qw=every three weeks, bid = bis in die (twice a day)