Reappraisal of the use of procarbazine in the treatment of lymphomas and brain tumors

Figures & data

Table 1 COPP-ABVD, standard-dose BEACOPP, and increased-dose BEACOPP dosage regimens (Diehl et al 2003)

	COPP-ABVDa		Standard-dose	BEACOPPb	Increased-dose
BEACOPPb
	Single dose (mg/m^2)	Days given	Single dose (mg/m^2)	Days given	Single dose (mg/m^2)	Days given
Bleomycin	10 iv	29 and 43	10 iv	8	10 iv	8
Etoposide	−	−	100 iv	1–3	200 iv	1–3
Doxorubicin	25 iv	29 and 43	25 iv	1	35 iv	1
Cyclophosphamide	650 iv	1 and 8	650 iv	1	1200 iv	1
Vincristine	1.4 iv	1 and 8	1.4 iv	8	1.4 iv	8
Procarbazine	100 po	1–14	100 po	1–7	100 po	1–7
Prednisone	40 po	1–14	40 po	1–14	40 po	1–14
Vinblastine	6 iv	29 and 43	-	-	-	-
Dacarbazine	375 iv	29 and 43	-	-	-	-

a Note: aregimen repeated on day 57;

b regimen repeated on day 22.

Abbreviations: BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone; COPP-ABVD, alternating cyclophosphamide, vincristine, procarbazine, and prednisone with doxorubicin, bleomycin, vinblastine, and dacarbazine; iv, intravenous; po, oral.

Table 2 Outcome of treatment and five-year survival rates with COPP-ABVD, standard-dose BEACOPP, and increased-dose BEACOPP (Diehl et al 2003)

	COPP-ABVD (n = 260)	Standard-dose BEACOPP (n = 469)	Increased-dose BEACOPP (n = 466)
Complete remission	85 (80–89)	88 (85–91)	96 (93–97)
Early progression	10 (7–15)	8 (5–10)	2 (1–4)**†
Freedom from treatment failure at 5 years	69 (63–75)	76 (72–80)*	87 (83–91)**†
Overall survival at 5 years	83 (78–87)	88 (85–91)	91 (88–94)*

Note: Values given as percentage (95% confidence interval); Early progression defined as progression during treatment or within 3 months after the end of treatment;

* p < 0.05 vs COPP-ABVD;

** p < 0.001 vs COPP-ABVD;

† p < 0.001 vs standard-dose BEACOPP.

Abbreviations: BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone; COP-ABVD, alternating cyclophosphamide, vincristine, procarbazine, and prednisone with doxorubicin, bleomycin, vinblastine, and dacarbazine.

Table 3 PCV and intensified PCV regimens

	PCV	Intensified PCV	Days of administration	Frequency
Procarbazine	60 mg/m^2 po	75 mg/m^2 po	8–21	Every 6–8 weeks
Lomustine	110 mg/m^2 po	130 mg/m^2 po	8 and 29
Vincristine	1.4 mg/m^2 iv	1.4 mg/m^2 iv	1

Abbreviations: PCV, procarbazine, lomustine (CCNU), vincristine.

Table 4 Use of single-agent procarbazine or procarbazine-containing regimens to treat glioma

	Study design	N	Diagnosis	Treatment	Results
Rodriguez et al 1989	Open	99	Recurrent malignant central nervous system tumors	Procarbazine	Glioblastoma multiforme: response + stabilization rate 27% and MTP 30 weeks. Other anaplastic gliomas: response + stabilization rate 28% and MTP 49 weeks
Newton et al 1990	Open	35	Recurrent glioblastoma or anaplastic astrocytoma	Procarbazine	After 2 courses, 2 patients had CR, 7 had PR, 11 had stable disease and 15 had progression.
Yung et al 2000 21%	RCT	225	Glioblastoma multiforme	Procarbazine vs	6-month progression-free survival 8% with procarbazine vs
			at first relapse	temozolamide	with temozolamide, median progression-free survival 8.32 vs. 12.4 weeks, and 6-month overall survival 44% vs. 60%
Brandes et al 1999	Open	51	Recurrent high-grade glioblastoma or anaplastic astrocytoma	Procarbazine + high-dose tamoxifen	4% CR, 26% PR, 32% stable disease. Overall response rate 30%. MTP 13 weeks for glioblastoma and 33 weeks for anaplastic astrocytoma.
Newlands et al 2003	-	28	Anaplastic astrocytoma, glioblastoma multiforme or low-grade glioma	Temozolamide alone for course 1 followed by procarbazine + temozolami de for subsequent courses	Overall, there were 10 (36%) responses lasting from 2 to 17+ months. Clinical impression of the investigators that the combination was somewhat more effective.
Levin et al 1985	Open	148	Glioblastoma multiforme, other anaplastic gliomas	BCNU vs PCV	Glioblastoma multiforme: MTP 31 vs 32 weeks for PCV vs BCNU. Other gliomas: MTP 123 and 77 weeks for PCV and BCNU.
Levin et al 1990	Reanalysis of RCT		Glioblastoma or other anaplastic gliomas	RT/hydroxyurea + PCV or BCNU	Longer survival and time to tumor progression with PCV vs BCNU
Sandberg-Wollheim et al 1991	RCT	171	Grade III/IV astrocytoma	PCV with or without RT	MTP 21 weeks, median survival 53 weeks, 18% survived e ≥2 years
Jeremic et al 1992	Open	133	Anaplastic astrocytoma, glioblastoma multiforme	modified PCV vs VM-26 +CCNU	MTP and survival 2-fold higher with PCV at 50th and 25th percentiles for anaplastic astrocytoma
Kim et al 1996	Open	32	Grade III/IV oligoastrocytoma or anaplastic oligodendroglioma	PCV	31% CR and 59% PR. MTP 15.4 months overall and 23.2 months for those with grade III tumors
Prados et al 1999	Retrospective review	432	Anaplastic astrocytoma	PCV vs BCNU	No difference in survival between groups
Levin, Uhm, et al 2000	Randomized	272	Glioblastoma	PCV vs. PCV + alpha-difluoromethylornithine	Overall survival 14.2 vs 3.3 months (median) and 8.7% vs 6.2% at 5 years
Kappelle et al 2001	Open	63	Recurrent glioblastoma multiforme	PCV	3%CR, 8% PR and 25% stable disease. MTP 13 weeks. Median survival 33 weeks.
MRC 2001	RCT	674	Grade III/IV astrocytoma	RT vs RT + PCV	After median follow-up of 3 years, 310 patients given RT and 307 given RT + PCV died. Median survival 9.5 months with RT and 10 months for with RT + PCV
Buckner et al 2003	Open	28	Newly diagnosed low-grade oligodendroglioma or oligoastrocytoma	PCV	8/28 (29%) and 13/25 (52%) eligible patients had tumor regression as assessed by the physician and a blinded neuron-radiology reviewer, respectively.
Brandes et al 2004	Open	37	Recurrent anaplastic oligodendroglioma or oligoastrocytoma	PCV	30% CR, 30% PR, 22% stable disease. MTP 12.3 months.
Stege et al 2005	Open	2 1	Newly diagnosed and recurrent oligodendroglioma and mixed oligoastrocytomas	PCV	3/5 recurrent and 13/16 newly diagnosed responded. MTP in the newly diagnosed >24 months.
van den Bent et al 2006	RCT	368	Newly diagnosed anaplastic oligodendroglioma or anaplastic oligoastrocytoma	RT vs RT + PCV	Progression free survival significantly increased with RT + PCV vs. RT (hazard ratio 0.68; 95% CI 0.53; 0.87, p = 0.0018). No difference in overall survival (hazard ratio 0.85; 95% CI 0.65; 1.11).
Coyle et al 1990	Open	31	Recurrent glioma	mechlorethamine, vincristine, procarbazine	Response rate 52%. Median duration of response 42 weeks.
Kyritsis et al 1996	Open	77	Recurrent malignant glioma	6-thioguanine, procarbazine, lomustine, hydroxyurea	MTP 9 weeks glioblastoma, 24 weeks anaplastic glioma. PR 2/30 and 11/47.
Hildebrand et al 1998	Open	37	Glioblastoma, anaplastic astrocytoma	Dibromodulcitol, BNCU, procarbazine	Response rate 55% with anaplastic astrocytoma, 12% with glioblastoma
Levin, Lamborn et al 2000	Open	59	Astrocytoma, ependyoma	6-thioguanine, procarbazine, dibromodulcitol, lomustine, vincristine	Survival: 4/17 glioblastoma multifore, 11/25 nonglioblastoma astrocytoma, 6/17 ependyoma

Abbreviations: BNCU, carmustine; CR, complete response; MTP, median time to progression; PCV, procarbazine, lomustine (CCNU), and vincristine; PR, partial response; RCT, randomized controlled trial; RT, radiotherapy; VM-26, teniposide.

Figure 1 Median progression-free survival and overall survival in patients with newly diagnosed anaplastic oligodendroglioma treated with radiotherapy alone or radiotherapy plus PCV (procarbazine, CCNU, and vincristine) (van den Bent et al 2006).

Figure 2 Percentage of patients with progression-free survival after 2 years and overall survival after 5 years in patients with newly diagnosed anaplastic oligodendroglioma treated with radiotherapy alone or radiotherapy plus PCV (procarbazine, CCNU, and vincristine) (van den Bent et al 2006).

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