Adding α -difluoromethylornithine to procarbazine, N -(2-chloroethyl)-N ′-cyclohexyl- N -nitrosurea and vincristine (PCV) chemotherapy has no benefit in postradiotherapy treatment of glioblastoma multiforme

TRFATMFNTIINTFRVFNTION

Adding a-difluoromethylornithine to procarbazine, N-(2-chloroethyl)-N’-cyclohexyl-N-nitrosurea and vincristine (PCV) chemotherapy has no benefit in postradiotherapy treatment of glioblastoma multiforme Levin VA, Uhm JH, Jaeckle KA, Choucair A, Flynn PJ, Yung WKA, Prados MD, Bruner JM, Chang SM, Kyritsis AP, Gleason MI, Hess KR. Phase 111 randomized study of postradiotherapy chemotherapy with a-difluoromethylornithine-procarbazine, N-(2-chloroethyl)N’-cyclohexyl-N-nitrosurea, Vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme. Clin Cancer Res 2000; 6: 3878-3884.

QUESTION Inhbitors such as a-difluoromethylornithne-procarbazine can reduce cell proliferation, but show varying results on human tumors. Is the addition of a-difluoromethylornithne to nitrosoureabased combination chemotherapy with procarbazine, N-(2-chloroethyl)-N’-cyclohexyl-N-nitrosurea and vincristine (PCV) more effective in the post radiation treatment of those with glioblastoma multiforme?

DESIGN

Randomized controlled trial.

SETTING University of Texas MD Anderson Cancer Center; Metro-Minnesota Community Cancer Oncology Programs; University of California, San Francisco; September 1992-November 1999.

PATIENTS Two hundred and seventytwo adults (aged 16 ) with hstologcally confirmed glioblastoma who completed external beam radiotherapy, had no prior chemotherapy, and had a life expectancy of at least 8 weeks. Those with a disease or toxicity that could alter drug metabolism, with pregnancy, or with serious intercurrent illness were excluded. Median follow-up was 4 years.

+

INTERVENTIONS Withn 4 weeks of conventional radiation therapy, groups received either PCV alone or in combination with a-difluoromethylornithne-procarbazine (DFMO-PCV). Initial DFMO dose was 3 g/m2 orally every 8 hours for 14 days before and after N-(2-chloroethyl)N‘-cyclohexyl-N-nitrosurea treatment. 500 mL eflornithine solution containing 200 mg/mL DFMO was premixed. The DFMO-PCV cycle rotated every 8 weeks. PCV cycle was on a 6 week rotation. Details of PCV administration and blinding are not provided in this article. MAIN OUTCOME MEASURES to progression.

Survival; time

MAIN RESULTS There were no differences in median survival or median time to tumor progression (see Table 1). Both treatments were generally well-tolerated. DFMO-PCV was associated with diarrhoea and thrombocytopenia. Granulocytopenia was more frequent in the PCV group (see Table 2). CONCLUSION Glioblastoma multiforme tumors are resistant to alkylating agents. Adding DFMO to

Evidence Table I. Survival and tumor progression for glioblastoma multiforme treated with PCV and DFMO-PCV

5 year survival Median months survival Median months t o tumor progression

% PCV ( n = 138)

% DFMO-PCV ( n = 134)

P-value

Hazard ratio for survival/ progression (DFMO-PCV vs PCV alone)

8.7 11.1

6.2 10.5

> 0.05 > 0.05

N o t calculable I (0.9 t o 1 . 1 )

months

months

> 0.05

I (0.9 t o 1 . 1 )

4.4

4.6

months

months

Note: 95% confidence intervals in parentheses. The numbers of people at risk at different times are not provided so calculations of numbers needed t o treat are not possible.

0 ZOO/Harcourt Publishers Ltd doi: 10. I054/ebon.2001 .O 104, available online at http://www.idealibrary.com on

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Evidence-based Oncology (200 I) 2, 89-90

Evidence Table 2. High-grade adverse effects associated with PCV and DFMO-PCV treatment for glioblastoma multiforme

Grade 3 or 4 Diarrhea Nausea Vomiting Granulocytopenia Th rombocytopen ia Leukopenia Ototoxicity Anemia Infection

% PCV ( n = 138)

% DFMOPCV ( n = 134)

Pvalue

0 3 4 23 6 21 0 4 I

6 2 5 17 24 17 0 7 I

< 0.05 > 0.05 > 0.05 < 0.05 < 0.05 > 0.05 > 0.05 > 0.05 > 0.05

Number of people needed to treat to harm one person with DFMO-PCV

17 (10 t o 51) N o t statistically significant N o t statistically significant I 7 (6 t o -29) 6 (4 t o 10) N o t statistically significant ~

N o t statistically significant N o t statistically significant

% Absolute risk Relative risk for increase from DFMO-PCV v DFMO-PCV PCV alone

6 (2 t o 10) - I (-4to3) 2(-3t06) 6 ( - 3 t 0 15) 18 (10 t o 26) - 4 ( - I3 t o 5) ~

~

0.7 (0 t o 2.3) I .4 (0.3 t o 2.6) 0.8 (0.3 t o 1.3) 4.3 (3.5 t o 5) 0.8 (0.3 t o 1.3) ~

2( - 3 t o 8) O(-3to3)

1.5 (0.5 t o 2.5) I (0.9 t o 3)

Note: 95% confidence intervals in parentheses. Number of deaths due t o treatment not reported. Non-significant number needed t o treat figures and confidence intervals have not been calculated. The article text suggests that granulocytopenia is more evident in the PCVgroup. The derived ‘number needed t o treat’ and risk figures suggest non-significance but this may be due t o rounding-off error in the estimates used.

post-radiotherapy PCV treatment has no additional benefit in glioblastoma. Souces offunding: Paflb sqported bi National Institutes Of Health grant.

Corre~pondenceto: VALevin, Dqartment OfNeuro Oncology, Universig of Texas M.D. Anderson Cancer Centre, 1515 Hdcombe BouLevad Box 100, Houston, E ~ a s77030 (e-maik [email protected]).

Commentary

There remains a tremendous need for effective treatment strategies for high-grade gliomas and it is doubtful that variations of any of the previously tried methods will turn into a ‘magic bullet’. Patients should be encouraged t o participate in ongoing clinical trials evaluating novel therapeutic approaches so that those with promise can be appropriately embraced o r discarded.

Glioblastomas are notoriously resistant tumors which remain a therapeutic frustration despite increasingly aggressive treatment. Radiation therapy prolongs survival, only t o a median of 36 weeks, compared t o 14 weeks for supportive care alone.’ The benefit of nitrosourea-based chemotherapy has been marginal and the best that can be claimed is that it has increased the proportion of patients surviving longer than 18 months from 5 t o I 5%.2,3 All attempts t o significantly improve this dismal outcome, including the use of altered fractionation radiotherapy, radiosensitizers, radiosurgery, dose intensification of chemotherapy, o r exploiting synergistic relationships in known chemotherapy regimens have n o t achieved their goal. It is not often that therapy for high-grade glioma shows enough promise in vitro and subsequently in phase I and II clinical trials t o warrant a phase 111 randomized study. Unfortunately, the present study provides little good news for glioblastoma patients o r their physicians. The results of a counterpart study are not yet available t o allow assessment of this regimen in patients with anaplastic astrocytomas. The study suggests that younger patients may benefit from the regimen. This suggestion is intriguing, but should be viewed with caution. Results from pediatric trials utilizing adjuvant chemotherapy have also shown dismal results (5 year progression-free survival of I 6 f 7%) after excluding patients with discordant pathology? In addition, a review of long-term survivors from t w o randomized prospective Brain Tumor Study Group trials found that neither age nor any other prognostic factor was useful for predicting who would benefit from chemotherapy?

Evidence-based Oncology (200 I) 2,89-90

Regina Jakacki, MD Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA Literature cited

I. Walker MD, Alexander E, Hunt WE et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplstic gliomas. A cooperative clinical trial. J Neurosurg 1978; 49:

333-343.

2. DeAngelis LM, Burger PC, Green SB, CairncrossJG. Malignant glioma: who benefits from adjuvant chemotherapy? Ann Neurol 1998; 44: 69 1-695. 3. Walker MD, Green SB, Byar DP et al. Randomized comparison of radiotherapy and nitrosoureas for the treatment of malignant gliomas. Cancer 1983; 52:

997- 1007. 4. Finlay J, Boyett JM, Yates A] et al. Randomized Phase 111 trial in childhood and high-grade astrocytoma comparing vincristine, lomustine and prednisone with the eight-drugs-in- I -day regimen. J Clin Oncol 1995; 13:

112-123. Level and quality of evidence (See Table A): I c

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