Best Published Trial Outcomes for Newly Diagnosed Anaplastic Glioma
by Stephen Western
Trials for newly diagnosed anaplastic glioma (astrocytoma, oligodendroglioma or oligoastrocytoma) are relatively scarce in the literature, in comparison with trials for recurrences or for glioblastoma. Most of these trials published outcomes prior to the temozolomide era, including trials with the formerly standard chemotherapy drugs BCNU, and the PCV combination regimen. Pending results from the ongoing phase III CATNON and CODEL trials (see Currently Recruiting Trials - High Grade Glioma), the most appropriate conventional treatment for anaplastic glioma patients in the temozolomide era remains a matter of speculation. The most outstanding outcomes in trials or retrospective studies for anaplastic astrocytoma patients are discussed below.
As discussed on the Recurrent Anaplastic Glioma trials page, there has until now been no trial for anaplastic glioma with stratification and randomization of patients according to IDH1 status. This fact confounds interpretation of all prior trials for lower grade gliomas, as the trial outcomes would be largely influenced by the distribution of patients with IDH1 mutant versus wild-type gliomas. Future trials which include IDH-status in their design and analysis will be included on this page.
Trials or studies including surgery as an eligibility requirement
Photodynamic therapy for newly diagnosed anaplastic astrocytoma
Photodynamic Therapy, already discussed on several pages on this site, seems like the best kept secret of neuro-oncology, not often talked about despite some outstanding successes. One of the most outstanding of these was a retrospective study involving patients treated at the Royal Melbourne Hospital between 1986 and 2000, using one of the first-generation photosensitizers, haemetaporphyrin derivative (1). While new and much improved photosensitizers currently exist, this study still reports some of the best outcomes in the literature for newly diagnosed and recurrent anaplastic astrocytoma, as well as recurrent glioblastoma.
In this study, 30 newly diagnosed anaplastic astrocytoma (AA) patients (median age 38) were given photodynamic therapy, with laser light applied to the resection cavity at the time of surgery. All patients received conventional radiation therapy sometime following surgery/photodynamic therapy. The median survival for these 30 patients was 77 months (over six year). While this is a favorable outcome in comparison to other anaplastic glioma trials, it must be remembered that all patients in the photodynamic therapy study had resectable surface tumours, and received maximal tumour resection. In comparison, a retrospective study (2) from Japan enrolling anaplastic astrocytoma patients undergoing radiotherapy with or without ACNU chemotherapy during a similar time period (1981-2002) showed that 56 AA patients undergoing a gross total resection had a median survival of 86.4 months, while 76 patients having either a gross total resection or a subtotal (over 75%) resection had a median survival of 63 months. It is therefore unclear to what extent photodynamic therapy, as opposed to the effects of surgery alone, contributed to the 77 month median survival outcome in the Australian study. Three and five year survival rates for this group were 73% and 63%, which is comparable to other retrospective studies involving radiation therapy and PCV or TMZ chemotherapy.
Of much greater significance, the approximately 17 patients who received over 230 Joules per square centimeter of laser light, had a median survival of approximately 11 years, seen in the Kaplan-Meier diagram in the published study. By Kaplan-Meier estimate, about 60% of these patients lived to 10 years, and about 30% to 15 years. Only 12% of these patients had been censored at the ten year mark due to lack of follow-up, as seen on the Kaplan-Meier diagram. To my knowledge, no other prospective trial or retrospective study for IDH1 undefined anaplastic astrocytoma patients have matched these results, even when only patients receiving total or subtotal resections are included. Newly diagnosed patients who are unable to seek this treatment however, may derive just as much benefit from photodynamic therapy at recurrence, if required. Unfortunately there are few centers or trials providing effective doses of modern photosensitizers.
Importantly, IDH1-mutant glioma patients may especially benefit from photodyamic therapy. In two studies published by Korean researchers in 2003 and 2007, prior to the discovery of IDH mutations in glioma, it was shown that normal IDH1 (called cytosolic isocitrate dehydrogenase in these studies) provided protection against damage from photodynamically-induced singlet oxygen (3). In contrast, cells with reduced expression of normal IDH1 were vulnerable to this treatment. It is highly likely that mutant-IDH1 cells, with their impaired production of the reducing agent NADPH and their decreased levels of glutathione (antioxidant) would be especially sensitive to photodynamic therapy, as suggested by these early studies.
It is hoped that more trials using newer, better third-generation photosensitizers will be initiated soon. A recent small Japanese prospective trial for newly diagnosed glioma patients reported outstanding results with a newer-generation photosensitizer, talaporfin sodium (Abstract).
Photodynamic therapy of high grade glioma - long term survival. Stylli et al. 2005.
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Prognostic significance of surgery and radiation therapy in cases of anaplastic astrocytoma: retrospective analysis of 170 cases. Nomiya et al. 2007.
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Regulation of singlet oxygen-induced apoptosis by cytosolic NADP+-dependent isocitrate dehydrogenase. Kim et al. 2007.
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This page was created on 04/14/2014 and last updated on 10/30/2014