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Originally published as JCO Early Release 10.1200/JCO.2005.03.8281 on November 28 2005 © 2006 American Society of Clinical Oncology.
Efaproxiral: Should We Hold Our Breath?Department of Radiation Oncology, University of California San Francisco, San Francisco, CA Suh et al1 breathe a bit of new life into two long-standing endeavors with their report in this issue of a phase III study of whole-brain radiotherapy (WBRT) and efaproxiral (RSR13), a hemoglobin modifier meant to increase tissue oxygenation. For decades, radiation oncologists have sought to enhance tumor control and patient survival by addressing the problem of hypoxia and, separately, to improve results of WBRT by sensitization, dose escalation, or altered fractionation. In this large randomized trial, efaproxiral added to WBRT and oxygen breathing increased median survival time from 4.4 to 5.4 months (P = .16) and the overall response rate from 38% to 46% (P = .10). Larger gains were seen in the combined non–small-cell lung cancer (NSCLC) and breast cancer subset, for whom the median survival time improved from 4.4 to 6.0 months (P = .07) and overall response rate improved from 41% to 54% (P = .01).1 HYPOXIA AND RADIORESISTANCE Since at least the early 1950s, hypoxic cells have been suspected as a cause of radioresistance. Hypoxic cells are two to three times more resistant to conventional radiation than normally oxygenated cells, although this effect occurs only at very low levels of oxygen.2 A partial pressure of 3 mmHg (an oxygen concentration of 0.5%) yields radiosensitivity midway between anaerobic and fully aerobic conditions, and there is essentially no difference in radiosensitivity for oxygen concentrations ranging from 2% to 100%.2 Poor oxygenation also affects angiogenesis, apoptosis, and other processes that may influence treatment outcome. It is difficult to determine the hypoxic fraction in patients’ tumors before or after maneuvers to increase oxygen levels, and the most relevant measure of hypoxia is not known clearly. The problem of anemia and hypoxia in cancer patients was reviewed recently by Varlotto and Stevenson,3 including a brief summary of strategies that have been used to address the problem of hypoxic cells: hyperbaric oxygen; carbogen breathing; hypoxic cell sensitizers such as misonidazole, etanidazole, and nimorazole; and the hypoxic cell cytotoxin tirapazamine. Some of these treatments appear to hold promise, but none has become firmly established. Efaproxiral is another drug that is meant to improve oxygenation of hypoxic tumor cells. It is a synthetic modifier of hemoglobin that reduces its oxygen-binding affinity, causing hemoglobin to release oxygen more readily into tissues; this action is unaffected by the blood-brain barrier. On the basis of preclinical data, it is expected that efaproxiral increases mean partial pressure of oxygen (PO2) in both normal and tumor tissue by about 5 to 15 mmHg.4 This increase in PO2 presumably will not affect the radiosensitivity of normal tissue, but it is hoped that it will reduce the fraction of severely hypoxic cells to overcome their radioresistance. For the protocol reported by Suh et al,1 efaproxiral was administered intravenously via a central access device at 75 or 100 mg/kg during 30 minutes, ending within 30 minutes of daily WBRT. Both treatment arms received standard WBRT to 30 Gy in 10 fractions during 2 weeks along with oxygen at 4 L/min per nasal cannula for 35 minutes before, during, and for at least 15 minutes after WBRT. Efaproxiral was fairly well tolerated; the most common adverse effect was grade 3 hypoxemia occurring in 11% of patients in the experimental arm compared with 1% in the control arm. If additional study shows that efaproxiral significantly improves local control or patient survival, this level of toxicity would be acceptable. WBRT Other investigators during the last several decades have attempted without success to improve the results of WBRT for brain metastases using higher doses, altered fractionations, and radiosensitizers.5 Before the availability of radiosurgery, WBRT was the treatment for all but a small minority of patients with a single metastasis who underwent surgical resection, usually followed by adjuvant WBRT. It was recognized that survival was only 3 to 5 months after WBRT for brain metastases and that one third to one half of all patients still died of neurologic causes. As stereotactic radiosurgery has become more widespread, a great deal of controversy has been generated and much more attention has been focused on the problem of brain metastases. A broader spectrum of options is being considered, ranging from supportive care alone in poor-prognosis patients to multiple sessions of radiosurgery alone for multiple metastases, omitting WBRT at both extremes. Nonetheless, essentially all participants in the controversy would concede that WBRT continues to play an important role in the treatment of brain metastases (and dural and cranial leptomeningeal metastases), and they would agree that a means of improving results of WBRT would be welcome. Suh et al1 offer efaproxiral as a way to boost the antitumor efficacy of standard-fractionation WBRT. The primary end point in the efaproxiral/WBRT study was survival time, which is difficult to improve given the fact that patients with brain metastases commonly die as a result of systemic disease progression. One would expect that the mechanism by which efaproxiral would augment survival would be through increasing response or duration of control of brain metastases. From better local control, improved survival, quality of life, neurocognitive function, and duration of functional independence could follow, although any gains would be diluted by adverse effects of systemic disease progression as well as adverse effects of treatment. Thus, it is not surprising or disappointing that the stand-alone survival results of this efaproxiral study are not that impressive. The median survival times of 5.4 months for the efaproxiral arm and 4.4 months for the control arm are not very different from other trials of WBRT5; the 6.0-month median survival time for 397 NSCLC and breast patients sounds more promising, and we are told that most of the difference was seen in breast cancer patients (n = 107; hazard ratio = 0.51; P = .003).1 A trial specifically in breast cancer patients is underway. Efaproxiral improved response of brain metastases to WBRT modestly.1 Complete response (CR), partial response, and overall response rates are summarized in Table 1 along with data reported previously in the literature, though it should be noted that response rates evaluated by patient appear lower than response rates evaluated by lesion. Suh et al1 found that efaproxiral increased the CR rate by patient from 6% to 11%. The overall response rate by patient increased from 38% to 46% for all histologies and from 41% to 54% for the NSCLC and breast cancer patients (P = .01).1 These response rates are similar to those reported previously using WBRT to 30 Gy in 10 fractions6,7 and they appear to be lower than the response rates observed after radiosurgery, with or without WBRT,8 but it is encouraging that there was a difference between the control and efaproxiral arms.
Nieder et al have performed excellent analyses of the influence of tumor characteristics, radiation dose, and fractionation on response and control of brain metastases after WBRT.6,9 They have pointed out that response may be a less sensitive measure of treatment efficacy for brain metastases than actuarial local freedom from progression (FFP).9 The high focal dose made possible by radiosurgery significantly improves actuarial FFP probability without necessarily affecting the response rate, perhaps by reducing proliferative potential of tumor cells. Some lesions remain visible for years after radiosurgery without progressing. Suh et al1 do not directly provide FFP results for the efaproxiral/WBRT study; the progression-free survival curves shown in their Figure 1B are dominated by deaths, and the 1-year radiographic and clinical progression data presented in their Table 5 provide less insight than actuarial curves and fail to show any efaproxiral benefit. I would like to have seen how efaproxiral affected actuarial local FFP, freedom from new brain metastases, and overall CNS control with censoring at last imaging follow-up, given that these end points more closely reflect the mechanisms by which I would expect efaproxiral to improve outcome in patients with brain metastases.
Relevant to the strategy of combining WBRT with oxygen breathing and efaproxiral, other investigators have studied response or FFP of brain metastases as a function of tumor imaging characteristics that may relate to degree of hypoxia. After WBRT to 30 Gy in 10 fractions, Nieder et al6 found that CR and overall response rates were 39% and 63%, respectively, for 142 lesions without radiographic evidence of necrosis, 15% and 53% for 99 lesions with less than 50% necrosis, and 11% and 57% for 95 lesions with Despite the fact that I would like to have seen actuarial FFP data and also could not help but speculate that many of the patients included in this study may have been eligible for radiosurgery based on number and size of brain metastases, I want to congratulate the authors for completing this large prospective, randomized trial showing that efaproxiral may improve results of WBRT, at least for breast cancer patients. It is unfortunate that improvements were not seen in other tumor types, but I look forward to seeing results of the breast cancer study. Breast cancer patients tend to live longer and to have more treatment-responsive disease, allowing greater opportunity for clinical and imaging follow-up. It will also be interesting to see results of efaproxiral in combination with radiation for other tumors for which there is good evidence that hypoxia exists and confers a poorer outcome, such as head and neck cancer, advanced cervical cancer, andglioblastomas, although I am not overly optimistic. Author’s Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. Author Contributions
REFERENCES
1. Suh JH, Stea B, Nabid A, et al: Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. J Clin Oncol 24:106-114, 2006 2. Hall EJ: The oxygen effect and reoxygenation, in: Radiobiology for the Radiologist (ed 4). Philadelphia, PA, JB Lippincott, pp 133-152, 1994 3. Varlotto J, Stevenson MA: Anemia, tumor hypoxemia, and the cancer patient. Int J Radiat Oncol Biol Phys 63:25-36, 2005[CrossRef][Medline] 4. Hou H, Khan N, O’Hara JA, et al: Increased oxygenation of intracranial tumors by efaproxyn (efaproxiral), an allosteric hemoglobin modifier: In vivo EPR oximetry study. Int J Radiat Oncol Biol Phys 61:1503-1509, 2005[CrossRef][Medline] 5. Sneed PK, Larson DA, Wara WM: Radiotherapy for cerebral metastases. Neurosurg Clin N Am 7:505-515, 1996[Medline] 6. Nieder C, Berberich W, Schnabel K: Tumor-related prognostic factors for remission of brain metastases after radiotherapy. Int J Radiat Oncol Biol Phys 39:25-30, 1997[CrossRef][Medline] 7. Antoniou D, Kyprianou K, Stathopoulos GP, et al: Response to radiotherapy in brain metastases and survival of patients with non-small cell lung cancer. Oncol Rep 14:733-736, 2005[Medline] 8. Goodman KA, Sneed PK, McDermott MW, et al: Relationship between pattern of enhancement and local control of brain metastases after radiosurgery. Int J Radiat Oncol Biol Phys 50:139-146, 2001[Medline] 9. Nieder C, Nestle U, Walter K, et al: Dose/effect relationships for brain metastases. J Cancer Res Clin Oncol 124:346-350, 1998[Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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50% necrosis. Among newly diagnosed or recurrent brain metastases treated with radiosurgery ± WBRT, Goodman et al
