Combined Radiotherapy and Interferon Alpha 2b Can Lead to Increases in Toxicity

Abstract & Commentary

Synopsis: The use of concomitant/sequential radiotherapy (RT) and interferon (IFN) as adjuvant therapy following resection of high-risk malignant melanoma appears to be increasing. This report from 3 centers in Utah pooled data in order to highlight the potential for unexpected toxicities when using this combination therapy. They recommend that clinicians remain vigilant until the radiosensitizing effects of IFN are better characterized.

Source: Hazard LJ, et al. Int J Radiat Oncol Biol Phys. 2002;52:796-800.

Over the past 10 years or more, various studies have shown that IFN has radiosensitizing properties in vivo that can cause toxicity.1,2 The precise mechanism for this effect is unknown. Investigators believe that accumulation of cells in the G2-M phase of the cell cycle, a radiosensitive phase, may play a role. Compromised damage repair and altered oncogene expression might be important, too. Hazard and colleagues identified a set of unusual complications in a pooled series of 10 malignant melanoma patients treated at LDS, the University of Utah, and the Browning Cancer Center in Ogden, Utah, between 1995 and 2001. These patients received radiotherapy and IFN-alpha 2b either together or within 1 month of the completion of radiotherapy. All patients were felt to be at high risk for recurrence by virtue of either deep invasion and/or regional nodal involvement.

Six patients received IFN during RT, and the remainder received it less than a month after RT was completed. Seven patients received 2 Gy per fraction to a dose of 50 Gy, one received 1.8 Gy per fraction to 45 Gy, one received 2.5 Gy per fraction to 52.5 Gy, and one received 4 and 6 Gy fractions to a total dose of 36 Gy. All patients who received concomitant RT/IFN were given maintenance subcutaneous doses of IFN that were not otherwise specified. The others received high-dose IFN after RT, and those doses were not specified, either.

Three of the 6 patients treated concomitantly developed unexpected toxicities, including 2 with soft tissue radionecrosis and 1 with a brachial plexopathy. In the second group, among patients who received IFN following RT, one patient developed brain necrosis and another suffered from a brachial plexopathy.

Hazard et al concluded that, although their report is essentially an anecdotal review without any statistical power, there remain many unanswered questions in terms of the interactions between RT and IFN. To some extent, the effects of this combination are somewhat unpredictable, and great care should be taken when treating this kind of patient.

Comment by Edward J. Kaplan, MD

The IFNs are considered to be biologic response modifiers whose exact mechanism of action is unknown. They modulate cell proliferation and host immune response. Trials with IFNs began in the late 1970s, but it was not until 1995 that IFN-alpha 2b was approved by the FDA after ECOG 1684 demonstrated a survival benefit in the adjuvant setting. Advocates of IFN suffered a setback when ECOG 1690 showed a relapse-free survival benefit, but no overall survival benefit. The controversy abated after the results from ECOG 1694 published last year again showed a statistically significant RFS and OS benefit.3 Commercially available forms of IFN are IFN-alpha 2a (Roferon-Aâ, Roche), IFN-alpha 2b (Intron-Aâ, Schering), and IFN-alpha 2c (Boehringer Ingelheim).

Like IFN, favorable results have been reported with postoperative radiotherapy used as adjuvant treatment for high-risk melanoma patients.4 Although an occasional case report has appeared describing unexpected synergies with concomitant IFN and RT,5 and a recent paper described an instance of radiation recall dermatitis following IFN administration 5 days after completion of 30 Gy RT to the neck,6 few clinical trial reports on concomitant/sequential RT/IFN have been published.

A basic literature search turned up 1 completed Phase I trial on RT/IFN with cisplatin for mesothelioma (Fox Chase CC-96087) and 3 closed Phase I/II trials including: one for RT/IFN for Stage III or recurrent melanoma (Moffitt CC-11543); one for RT/IFN for high grade glioma (Cancer Biotherapy Study Group 95-08); and another for RT/IFN for Stage III NSCLC (Univ. of Rochester). Only the last study has been reported.7 One small Phase II study from Mexico reported on RT/IFN for Stages III/IV cervix cancer,8 and publication of the only 2 Phase III trials of which I am aware is pending. The first is RTOG-9304, which looked at RT/IFN for locally advanced NSCLC. Hazard et al provided some details of the results, including increases in Grade 3,4 acute toxicity and in Grade 4 late radiation pneumonitis in the combined modality arm. However, without the entire report, we are still not sure whether those differences were statistically significant. The other Phase III trial is ECOG 3697, which evaluated high-dose IFN with hypofractionated RT in patients with nodal metastases. This trial is closed, but the results have not been published yet.

It is difficult to know how to proceed when faced with a patient who may be a candidate for combined/sequential RT/IFN. The unexpected toxicities observed in the Hazard et al report occurred at dose levels which were not unusual, and the toxicities were fairly severe. It seems that it did not matter whether the IFN was administered with or after RT, since the percentages of patients affected were roughly the same in both groups, ie, about half. That number seems higher than what has been reported in the few papers published, but it does underscore the need for all of us to remain vigilant, and proceed with caution. Hazard et al mentioned 1 patient whom they felt developed brain radionecrosis that was attributed to IFN radiosensitization, but my understanding is that IFN exhibits poor penetration of the blood-brain barrier when no tumor is there to disrupt it.

Hazard et al have reported on an interesting phenomenon that deserves further study. Perhaps an IFN Working Group might be required to make sense of the different studies soon to be reported. It is curious that while all phases of studies are being conducted, Hazard et al rightly point out that the optimal dose and schedule for combined RT/IFN has yet to be determined.

Dr. Kaplan is Acting Chairman, Department of Radiation Oncology, Cleveland Clinic Florida, Ft. Lauderdale, FL; Medical Director, Boca Raton Radiation Therapy Regional Center, Deerfield Beach, FL.

References

1. Maasilta P, et al. Int J Radiat Oncol Biol Phys. 1992; 23:863-868.

2. Valvaara R, et al. Acta Oncol. 1992;31:429-431.

3. Kirkwood JM, et al. J Clin Oncol. 2001;19:2370-2380.

4. Cooper JS, et al. Cancer J. 2001;7:498-502.

5. Nguyen NP, et al. Cancer Invest. 2001;19:261-265.

6. Thomas R and Stea B. J Clin Oncol. 2002;20:355-357.

7. McDonald S, et al. Int J Radiat Oncol Biol Phys. 1993; 27:613-619.

8. Verastegui-Aviles E, et al. Int J Gynecol Cancer. 1999; 9:401-405.