This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kwok, Y. Articles by Regine, W. F. Search for Related Content PubMed Articles by Kwok, Y. Articles by Regine, W. F. Related Articles Related Correspondence Social Bookmarking                            What's this?

In Reply:

Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD
Division of Neurosurgery, University of Kentucky Medical Center, Lexington, KY
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD

We would like to respond to several points raised by both groups regarding our editorial and the Maranzano et al study.^1,2

We find it strange that some of our European colleagues equate the safety and equivalency of hypofractionated schedules in bone and lung metastases as a justification for the safety of such regimens in malignant cord compression (MCC).^3-5 This is analogous to comparing apples and oranges. Even though overall pain and survival times are not different, it is well-recognized that the re-treatment rates are higher with single-fraction schemes compared with the more prolonged schedules in bone metastases.⁶ The consequence of progression in the bone metastases despite radiotherapy (eg, 8 Gy x 1) is the increase in pain, which leads to the increase in pain medication and usually another single 8 Gy fraction. The consequences of MCC progression despite radiotherapy, on the other hand, are paralysis and incontinence, which are devastating emotionally as well as physically. This usually contributes significantly to the direct demise of the patient. Macbeth cites a study by Rades et al⁷ that concludes that a single fraction of 8 Gy is relatively safe. However, the study by Maranzano advocates 8 Gy x 2, which is very different from 8 Gy x 1. Even in the former, in which the biologic equivalent dose (BED) is significantly higher than in the latter, it still may not be adequate in controlling disease in the long run while at the same time potentially increasing late toxicity. Macbeth also cites the study by Kramer et al⁵ that compared the standard 3 Gy x10 versus 8 Gy x 2 for palliation of advanced lung cancer as another study that demonstrates the safety of a short course of intense radiotherapy. This study found, not unlike the bone metastasis trials, that the standard fractionation has a much longer duration of palliative response. More importantly, this study found an improvement of survival for the standard fraction regimen; therefore, equating bone metastasis and palliative lung cancer patients to MCC patients with regards to short, hypofractionated regimens is wholly inappropriate and dangerously misleading.

Even more questionable is the conclusion drawn about the lack of radiation-induced myelopathy (RIM) from these bone- and lung-palliation trials as a basis for the apparent safety of hypofractionation for MCC. In the studies by Sundstrom et al,⁴ Kramer et al (which, by the way, advocates 3 Gy x 10 over the 8 Gy x 2 regimen) and others that claim to demonstrate that short, hypofractionated regimens are safe on the spinal cord, the spinal cords were essentially healthy. None of the bone metastasis and lung cancer palliation phase III studies cited by the authors were in patients with cord compression. The predominant mechanisms of cord injury by MCC are demyelination and vascular injury leading to ischemia. The predominant mechanism of RIM is endothelial damage, leading to intramedullary cord ischemia and irreversible damage.⁸ Although the former is acute and the latter late, the toxicities are very much related. There are plenty of clinic data on hypofractionation and vascular effects. For example, there are multiple articles demonstrating effectiveness of external beam radiotherapy for the obliteration of arteriovenous malformations (AVM).^9,10 An even more effective treatment for AVM is stereotactic radiosurgery (SRS). In studies by Flickinger et al¹¹ and others, dose response to single-dose SRS for AVM obliteration starts at doses as low as 8 Gy, with obliterations starting as soon as 6 months or earlier.¹¹

Apparently not considered by the authors, it is entirely possible that a compressed spinal cord has a lower threshold for RIM from a short, hypofractionated schedule compared with healthy cords as referenced in those of lung cancer and bone metastasis. If the 13 patients (a full 5% of the entire study) who progressed to paraplegia without in-field recurrence did not progress because of late radiation toxicity as the authors propose, then what rational explanation could exist to explain this unfortunate sequela? It is entirely conceivable that the paraplegia was the result of late effect of large fractions. Are our colleagues suggesting another unknown mechanism? To our knowledge, there has never been a paraneoplastic syndrome described that causes paralysis below the level of the cord compression. Not only is it entirely conceivable, but it is likely that the late effect of hypofractionation had a significant role in the manifestation of paraplegia. We find it disappointing that this two-hit phenomenon (ie, physical and radiation-induced vascular insults) is not considered by those who advocate a short, hypofractionated regimen. As systemic therapy improves for patients with metastatic disease, this 5% rate may increase if fractionation schedule such as those advocated by Maranzano et al is widely accepted.

We must not fool ourselves into thinking that we are accurate in predicting the survival of our patients. In the past, studies have demonstrated the "horizon effect," in which the predictions in the short-term are more accurate than in the long-term.¹² In fact, Mackillop and Quirt¹³ demonstrated that although oncologists are fairly accurate in predicting cure rates, we are very poor at predicting survival times. Furthermore, Chow et al¹⁴ did not demonstrate this effect, but did show that radiation oncologists in general are not accurate at all in predicting survival times. Although the predicted survivals were in general overly optimistic in the study by Chow, it is not unusual for our patients to outlive our expectations. Although the criterion of "short" life expectancy was 6 months in the Maranzano et al study, a full 15% of patients survived at least 1 year. Undoubtedly, this was a result of including patients with good Karnofsky performance status, primaries expected to have prolonged survivals (eg, prostate and breast) and very radiosensitive histologies. It is likely that these factors allowed just enough time for the late radiation toxicity to appear. Neither the conclusion in the abstract nor that in the text mentions this short–life expectancy criteria.

The BED calculation and the linear-quadratic model were never intended for single fraction or hypofractionated schemes as designed in the Maranzano et al trial. The errors inherent in the calculations for these schedules have been well recognized. Thus, the argument that the two arms in the Maranzano et al trial are equivalent to 40 to 45 Gy in conventional fractionation (ie, 1.8 to 2.0 Gy) is not accurate when one compares to a single or two large fractions.¹⁵ Although we agree that 30 Gy in 10 fractions, as well the multitude of hypofractionation schemes, is probably sufficient for those with limited expected survival, we do not believe it is sufficient for long-term control. Maranzano et al state that phase III decompressive surgery study (surgery followed by radiotherapy v radiotherapy alone) by Patchell¹⁶ cannot be used to justify surgery because it has been published only in abstract form, and that the trial was stopped early. These are extremely weak arguments. There are multiple examples in which standards of care have been changed from an abstract presentation. For example, the Stupp regimen¹⁷ for glioblastoma (ie, radiotherapy plus temozolomide) was utilized widely well before the article was published. Regardless, the study has now been published in its entirety.¹⁸ Furthermore, the Patchell study was closed early after only 101 patients of the planned accrual of 200 patients were accrued when early stopping rules were met. Early stopping rules dictate that a much higher standard of proof is required than is the case if the study goes its full length and accrual.¹⁹ The fact that this study was able to be stopped early means that the level of statistical significance was much higher than is usually required to certify a finding as meaningful, and is a major strength of the data and not in any way a reason to question the results. Interim analysis demonstrated significant advantage to decompressive surgery to radiotherapy in terms of longer ambulatory and urinary continence rates, gain in ability to walk for nonambulatory patients, and decrease in corticosteroid and opioid requirements. In this study, 32 patients (16 in each group) entered the study unable to ambulate; patients in the surgery group regained the ability to walk in a significantly greater proportion than patients in the radiation alone group 10 of 16 (62%) versus 3 of 16 (19%), P = .01. The poor result in the radiation alone arm is similar to the result in the Maranzano et al study (29%). We do not advocate surgery in all patients. However, because radiation alone (ie, at the 30 Gy in 10-fraction dose equivalent) is in our opinion relatively ineffective for MCC, we feel that dose escalation is a worthwhile approach for those with reasonable expected survival who are not eligible for surgery.

The Hippocratic tenet of primum non nocere is one of the most important principles in medicine. If it is possible that the hypofractionated schemes presented in the Maranzano et al trial cause a 5% risk of paraplegia, which is considered by many to be significant, is it not incumbent upon us to at least acknowledge that our treatment may first cause harm? The standard arm (5 Gy x 3, 4-day rest, 3 Gy x 5; 30 Gy total in 2 weeks) chosen in the Maranzano et al article does not decrease the overall treatment time. It delivers 2 weeks of therapy with only two fractions fewer at the expense of potentially increasing late radiation toxicity. Although there are patterns of care studies for bone metastasis trials that show that 30 Gy in 10 fractions is the most common regimen used in Europe, even after multiple randomized studies demonstrating the equivalency of 8-Gy single-fraction regimen, such studies do not exist for MCC. As demonstrated by the reluctance of the European community to adapt the 8 Gy x 1 regimen for bone metastases, we also suspect that such short, hypofractionated regimens are not universally utilized in Europe.²⁰ Instead, like in the United States we strongly suspect that the regimen of 30 Gy in 10 fractions is commonly used in Europe, as evidence by studies of Rades et al and others. Therefore, we take exception to the statement that we were belittling the study by Maranzano et al. We were instead pointing out potentially serious and dangerous flaws in the study interpretation and the need for continued clinical trials given the poor results achieved with radiotherapy alone in patients with MCC.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Kwok Y, Regine WF, Patchell RA: Radiation therapy alone for spinal cord compression: Time to improve upon a relatively ineffective status quo. J Clin Oncol 23:3308-3310, 2005

2. Maranzano E, Bellavita R, Rossi R, et al: Short-course versus split-course radiotherapy in metastatic spinal cord compression: Results of a phase III, randomized, multicenter trial. J Clin Oncol 23:3358-3365, 2005

3. Hartsell WF, Scott CB, Bruner DW, et al: Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 97:798-804, 2005[Abstract/Free Full Text]

4. Sundstrom S, Bremnes R, Aasebo U, et al: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: A national phase III trial. J Clin Oncol 22:801-810, 2004[Abstract/Free Full Text]

5. Kramer GW, Wanders SL, Noordijk EM, et al: Results of the Dutch national study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer. J Clin Oncol 23:2962-2970, 2005[Abstract/Free Full Text]

6. Wu JS, Wong R, Johnston M, et al: Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys 55:594-605, 2003[CrossRef][Medline]

7. Rades D, Stalpers L, Veninga T, et al: Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression. J Clin Oncol 23:3366-3375, 2005[Abstract/Free Full Text]

8. St Clair WH, Arnold SM, Sloan AE, et al: Spinal cord and peripheral nerve injury: Current management and investigations. Semin Radiat Oncol 13:322-332, 2003[CrossRef][Medline]

9. Chen MN, Imaya H, Nakazawa S: Four cases of intracranial AVM successfully treated by radiation therapy. No Shinkei Geka 18:1161-1166, 1990[Medline]

10. Hida K, Shirato H, Isu T, et al: Focal fractionated radiotherapy for intramedullary spinal arteriovenous malformations: 10-year experience. J Neurosurg 99:34-38, 2003 (suppl 1)[CrossRef][Medline]

11. Flickinger JC, Pollock BE, Kondziolka D, et al: A dose-response analysis of arteriovenous malformation obliteration after radiosurgery. Int J Radiat Oncol Biol Phys 36:873-879, 1996[CrossRef][Medline]

12. Oxenham D, Cornbleet MA: Accuracy of prediction of survival by different professional groups in a hospice. Palliat Med 12:117-118, 1998[Free Full Text]

13. Mackillop WJ, Quirt CF: Measuring the accuracy of prognostic judgments in oncology. J Clin Epidemiol 50:21-29, 1997[CrossRef][Medline]

14. Chow E, Davis L, Panzarella T, et al: Accuracy of survival prediction by palliative radiation oncologists. Int J Radiat Oncol Biol Phys 61:870-873, 2005[CrossRef][Medline]

15. Guerrero M, Li XA: Extending the linear-quadratic model for large fraction doses pertinent to stereotactic radiotherapy. Phys Med Biol 49:4825-4835, 2004[CrossRef][Medline]

16. Patchell RA, Tibbs PA, Regine WF, et al: A randomized trial of direct decompressive resection in the treatment of spinal cord compression caused by metastasis. Proc Am Soc Clin Oncol 22:1, 2003 (abstr 2)

17. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005[Abstract/Free Full Text]

18. Patchell R, Tibbs P, Regine WF, et al: A randomized trial of direct decompressive surgical resection in the treatment of spinal cord compression caused by matastatic cancer. Lancet 366:643-648, 2005[CrossRef][Medline]

19. O'Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics 35:549-556, 1979[CrossRef][Medline]

20. Lievens Y, Kesteloot K, Rijnders A, et al: Differences in palliative radiotherapy for bone metastases within Western European countries. Radiother Oncol 56:297-303, 2000[CrossRef][Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Correspondence

• Radiotherapy Alone or Surgery in Spinal Cord Compression? The Choice Depends on Accurate Patient Selection
  Ernesto Maranzano, Rita Bellavita, and Romina Rossi
  JCO 2005 23: 8270-8272 [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kwok, Y. Articles by Regine, W. F. Search for Related Content PubMed Articles by Kwok, Y. Articles by Regine, W. F. Related Articles Related Correspondence Social Bookmarking                            What's this?