- Email: [email protected]
What Approach will Lead to Cure of Glioblastoma Multiforme?: In Regard to Barani et al. (Int J Radiat Oncol Biol Phys 2007;68:324–333) and Jones and Sanghera (Int J Radiat Oncol Biol Phys 2007;68:441–448)
640
I. J. Radiation Oncology d Biology d Physics Departments of *Radiation Oncology and yAbdominal Surgery Leuven Cancer Institute UZ Gasthuisberg Leuven, Belgium doi:10.1016/j.ijrobp.2007.06.017
1. Bujko K, Bujko M, Pietrzak G. Clinical target volume for rectal cancer: In regards to Roels et al. (Int J Radiat Oncol Biol Phys 2006;65:1129–1142) [Letter]. Int J Radiat Oncol Biol Phys 2007;68:313. 2. Roels S, Duthoy W, Haustermans K, et al. Definition and delineation of the clinical target volume for rectal cancer. Int J Radiat Oncol Biol Phys 2006;65:1129–1142. 3. Nagtegaal ID, van de Velde CJ, Marijnen CA, et al. Low rectal cancer: A call for a change of approach in abdominoperineal resection. J Clin Oncol 2005;23:9257–9264. 4. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Eng J Med 2001;345:638–646. 5. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351: 1731–1740.
IS MASTECTOMY SUPERIOR TO BREAST-CONSERVING TREATMENT FOR YOUNG WOMEN?: IN REGARD TO COULOMBE ET AL. (INT J RADIAT ONCOL BIOL PHYS 2007;67:1282–1290) To the Editor: We read the article of Coulombe et al. (1) with great interest. A total of 2,398 patients (1,597 treated with breast-conserving surgery plus radiotherapy, and 801 treated with mastectomy) were evaluated in this retrospective study. As mentioned by the authors, one of the shortcomings of this study was that the groups were not balanced in many aspects. Nevertheless, they found that younger patients had a worse prognosis regarding all outcome measures. Local relapse-free survival (LRFS) and locoregional relapse-free survival were similar in the two groups at 10-year follow-up for patients aged 40–49 years, whereas disease relapse–free survival and breast cancer–specific survival were significantly better in the breast-conserving therapy (BCT) group. The authors interpreted this unexpected finding as a result of the imbalance between groups. They found no difference between the two treatment modalities in the 20- to 39-year-old age groups. However, the authors did not give information regarding median follow-up for each age group, cumulative 5-year local relapse rates, and time to distant metastases. The authors also considered a subgroup of patients with a tumor size of 2 cm or less, pathologically negative axillary lymph nodes, clear surgical margins, and no extensive intraductal component as ideal candidates for BCT. However, the difference regarding disease relapse–free survival and breast cancer–specific survival disappeared at 10-year follow-up in the 40- to 49-year-old age groups, when this subgroup of patients was analyzed separately. Another important issue is that LRFS rates were reported to be 86.3% for patients aged 20–39 years and 95.1% for the modified radical mastectomy (MRM) and BCT groups, respectively (p = 0.3). Based on this finding, the authors concluded that MRM was superior to BCT at 10-year follow-up. We would like to inquire why MRM was considered to be superior to BCT based on a p value of 0.3 regarding LRFS, whereas a similar even stronger relation in the opposite direction regarding distant metastasis-free survival (p = 0.17) was considered insignificant. We believe interpretation of the data through highly selected subgroups as in this article might be misleading in shaping the literature for future considerations. GOZDE YAZICI, M.D. UGUR SELEK, M.D. FERAH YILDIZ, M.D. GOKHAN OZYIGIT, M.D. MUSTAFA CENGIZ, M.D. Department of Radiation Oncology Hacettepe University Faculty of Medicine Ankara, Turkey
Volume 69, Number 2, 2007 IN REPLY TO DR. YAZICI ET AL. To the Editor: We thank Drs. Yazici et al. for their interest in our study. However, they misinterpreted our conclusions. Dr. Yazici et al. state that we concluded that ‘‘Modified radical mastectomy (MRM) was considered to be superior to breast-conserving therapy (BCT) based on a p value of 0.3..’’ This statement is erroneous because our conclusion explicitly stated that ‘‘.differences were not statistically significant and did not translate into worse distant relapse–free survival (RFS) or breast cancer–specific survival. These data suggest that young age alone is not a contraindication to BCT.’’ (1). Any conservative therapy replacing a historic standard (in this case, mastectomy) should be held to a high standard in terms of whether survival outcomes are equivalent. We acknowledge the retrospective nature of our data and agree that any nonsignificant hint of a clinically meaningful difference should be interpreted with caution and viewed as hypothesis generating. The strength of our study was that we were able to report on a relatively large series of women younger than 50 years, a subgroup that is relatively underrepresented in the available randomized clinical trials of BCT vs. mastectomy (2–7). It is well known that young age is associated with increased risk for local recurrence, as confirmed in our study (2–5). Our populationbased data support the current practice of offering breast conservation to younger women and does not make the claim that mastectomy is superior to breast conservation. With limited data from prospective trials to define optimal management for young women with breast cancer, the question of the efficacy of breast-conserving surgery followed by radiation therapy in this important subgroup remains open, and studies addressing the issue should continue. SCOTT TYLDESLEY, M.D. IVO OLIVOTTO, M.D. PAULINE TRUONO, M.D. GENEVIEVE COULOMBE, M.D. MIRA KEYES, M.D. British Columbia Cancer Agency Vancouver, British Columbia, Canada doi:10.1016/j.ijrobp.2007.05.060 1. Coulombe G, Tyldesley S, Speers C, et al. Is mastectomy superior to breast-conserving treatment for young women? Int J Radiat Oncol Biol Phys 2007;67:1282–1290. 2. Voogd AC, Nielsen M, Peterse JL, et al. Differences in risk factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer: Pooled results of two large European randomized trials. J Clin Oncol 2001;19:1688–1697. 3. Arriagada R, Leˆ MG, Guinebretiere J-M, et al. Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients. Ann Oncol 2003;14:1617–1622. 4. Fisher ER, Anderson S, Tan-Chui E, et al. Fifteen-year prognostic discriminants for invasive breast carcinoma. National Surgical Adjuvant Breast and Bowel Project Protocol B-06. Cancer 2001;91(Suppl. 8): S1679–S1687. 5. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347: 1227–1232. 6. Poggi MM, Danforth DN, Sciuto LC, et al. Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: The National Cancer Institute Randomized Trial. Cancer 2003;98:697–702. 7. Blichert-Toft M, Rose C, Andersen JA, et al. Danish randomized trial comparing breast conservation therapy with mastectomy: Six years of life-table analysis. Danish Breast Cancer Cooperative Group. J Natl Cancer Inst Monogr 1992;11:19–25.
doi:10.1016/j.ijrobp.2007.05.061
WHAT APPROACH WILL LEAD TO CURE OF GLIOBLASTOMA MULTIFORME?: IN REGARD TO BARANI ET AL. (INT J RADIAT ONCOL BIOL PHYS 2007;68:324–333) AND JONES AND SANGHERA (INT J RADIAT ONCOL BIOL PHYS 2007;68:441–448)
1. Coulombe G, Tyldesley S, Speers C, et al. Is mastectomy superior to breast-conserving treatment for young-women? Int J Radiat Oncol Biol Phys 2007;67:1282–1290.
To the Editor: Two stimulating articles dealing, at least in part, with treatment optimization in glioblastoma multiforme (GBM) concluded that efforts to intensify postoperative radiotherapy essentially failed to improve the
Letters to the editor outcome (1, 2). In their general discussion of radiotherapy for central nervous system malignancies, Barani et al. (1) suggested on page 331 that radiotherapy should be delivered in a neural stem cell-preserving manner with fractional doses significantly .3 Gy and a total treatment time of \2 weeks (intensified accelerated hypofractionation) and referred to a publication by Floyd et al. (3). The latter study used 50 Gy in 5-Gy fractions to treat GBM patients. The median time to progression and overall survival were 6 and 7 months, respectively. These values were comparable to historical controls. Although 25 Gy in 5-Gy fractions resulted in inferior results in another study, dose escalation to five fractions of 6 or 7 Gy also resulted in a median time to progression and overall survival of 5 and 7 months, respectively (4). When using the estimate by Jones and Sanghera (2) (i.e., an a/b value of 9 Gy for GBM), a biologically equivalent dose of 39, 50, 62, and 78 Gy could be calculated for these hypofractionated regimens of 25, 30, 35, and 50 Gy, respectively. The outcome of these, admittedly small studies, argues against a continuously rising dose– effect curve between the 50- and 78-Gy equivalent dose and questions the usefulness of additional dose escalation with such hypofractionated treatment. Jones and Sanghera (2) calculated a relatively modest effect of temozolomide added to radiotherapy, when expressed as the equivalent to a radiation dose (9.1 Gy given in 2-Gy fractions). The combination of temozolomide and radiotherapy improved the median progression-free survival from 5 to 6.9 months in the European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada trial and, importantly, also improved overall survival (5). It is, however, unknown whether this was caused by radiosensitization, additive cell kill, or spatial cooperation (i.e., killing of tumor cells in low-dose regions outside the target volume). The question arises whether the disappointing results of dose escalation have mainly been caused by limitations in target volume definition with standard imaging methods and whether biologic imaging will improve the outcome. However, even advanced diagnostic tools are unlikely to detect occasional tumor cells outside of the bulky area. As obvious lessons from the past, neither chemotherapy nor whole-brain radiotherapy solved the problem of microscopic deposits. With whole-brain radiotherapy doses as high as 46.8 Gy and a local boost to a cumulative dose of 78 Gy, both with 1.3-Gy fractions twice daily, the median survival remained at 7 months (6). What would be the result of this approach if combined with temozolomide? Would we experience increasing numbers of extracranial relapse? Also, what would be the quality of life for those surviving for $2 years? I doubt we will ever know, because we have started to investigate in different directions, based on biologically sound data. CARSTEN NIEDER, M.D. Radiation Oncology Unit Department of Internal Medicine and Skin Diseases Nordlandssykehuset HF Bodø, Norway doi:10.1016/j.ijrobp.2007.06.047 1. Barani I, Benedict SH, Lin PS. Neural stem cells: Implications for the conventional radiotherapy of central nervous system malignancies. Int J Radiat Oncol Biol Phys 2007;68:324–333. 2. Jones B, Sanghera P. Estimation of radiobiologic parameters and equivalent radiation dose of cytotoxic chemotherapy in malignant glioma. Int J Radiat Oncol Biol Phys 2007;68:441–448. 3. Floyd NS, Woo SY, Teh BS, et al. Hypofractionated intensity-modulated radiotherapy for primary glioblastoma multiforme. Int J Radiat Oncol Biol Phys 2004;58:721–726. 4. Nieder C, Nestle U, Walter K, et al. Hypofractionated stereotactic radiotherapy for malignant glioma: A phase I/II study. J Radiosurg 1999;2: 107–111. 5. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352:987–996. 6. Nieder C, Nestle U, Ketter R, et al. Hyperfractionated and acceleratedhyperfractionated radiotherapy for glioblastoma multiforme. Radiat Oncol Invest 1999;7:36–41.
IN REPLY TO DR. NIEDER To the Editor: We did not conclude that outcomes cannot be improved and, in contrast to this suggestion, tentatively explored ways in which the therapeutic index might be improved. Most advances in oncology tend to
641
follow the use of combinations of therapies, and it is important to determine the relative contributions of each form of therapy. The mathematical modeling presented in our study represents a scientific approach that is more commonly used in engineering and the physical sciences than in medicine. The calculation of the optimal dose per fraction to improve tumor cell kill (but for the same degree of normal tissue effects) produces values well below 2 Gy. The modeled patient population (in our Fig. 7) gives sufficient room for encouragement. We are confident that combinations of perhaps several (rather than single) cytotoxic drugs, with future advances derived from molecular biology and better forms of radiotherapy (including protons ions and boron neutron capture therapy in subtle combinations) to eliminate hypoxia and reduce unnecessary radiation to normal tissues, may bring significant improvements to what is presently a dismal condition. In all such combinations, the aim should be to minimize treatment-related toxicity. Hypofractionated therapy—unless given to very small volumes—should not be encouraged in the central nervous system because of the high fractionation sensitivity. Excessive radiation to the brain can result in poor quality of life and reduced survival. It is vital that future research protocols should use the most advanced radiotherapy techniques and optimal radiation dose schedules with the best available molecular-based therapies. BLEDDYN JONES, M.D. PAUL SANGERA, F.R.C.R. Department of Clinical Oncology Queen Elizabeth Hospital Birmingham, United Kingdom doi:10.1016/j.ijrobp.2007.06.046
IN REPLY TO DR. NIEDER To the Editor: We would like to thank Dr. Nieder for the insightful comments regarding past efforts in glioblastoma multiforme (GBM) to dose-intensify postoperative radiotherapy regimens. We agree with Dr. Nieder that survival outcomes of postoperative dose-intensified radiotherapy regimens in general suggest a lack of isoeffective dose-response beyond the current standard regimen of 60 Gy (delivered in 30 daily fractions). The motivation for intensified accelerated hypofractionation treatment is manifold. First, currently available biologic or cytotoxic therapies are not designed to discriminate between neural stem cells (NSCs) and cancer stem cells. NSCs are believed to be critical for the maintenance of normal brain homeostasis, including the response to tumor- and treatment-related injury. In contrast, the cancer stem cell is the purported ‘‘cell-of-origin’’ in high-grade gliomas. Thus, therapeutic discrimination between these two cell types would appear to be essential if the therapeutic index is to be improved. Given that NSCs are not widespread in the mammalian brain but are well confined to the subventricular and subgranular zones, therapeutic discrimination might currently be achieved by selective targeting of the tumor volumes and sparing of the NSC compartments. Second, cancer stem cells are relatively radioresistant and can give rise to multiple clones of varying radiosensitivities. The hypofractionated treatment regimen is best suited to address this relative radioresistance variation. Third, clones isolated from the human glioma cell line have exhibited similar great variation in cell kinetic parameters (e.g., potential doubling time), suggesting that repopulation could be an important factor influencing treatment outcomes with the current regimens. Such tumor cell kinetics are best addressed with an aggressively accelerated treatment regimen. Given that even the most aggressive regimens to date have resulted in clinical outcomes similar to those seen with nonaccelerated treatments, perhaps additional abbreviation of the overall treatment time is warranted. In summary, the greatest therapeutic gains are likely to be realized when intensified accelerated hypofractionated treatment is delivered to tumor volumes in a manner that spares the native NSC niches (subventricular and subgranular zones) from the radiation dose. IGOR J. BARANI, M.D. PECK-SUN LIN, PH.D. STANLEY H. BENEDICT, PH.D. Department of Radiation Oncology Virginia Commonwealth University Richmond, VA doi:10.1016/j.ijrobp.2007.06.045
I. J. Radiation Oncology d Biology d Physics Departments of *Radiation Oncology and yAbdominal Surgery Leuven Cancer Institute UZ Gasthuisberg Leuven, Belgium doi:10.1016/j.ijrobp.2007.06.017
1. Bujko K, Bujko M, Pietrzak G. Clinical target volume for rectal cancer: In regards to Roels et al. (Int J Radiat Oncol Biol Phys 2006;65:1129–1142) [Letter]. Int J Radiat Oncol Biol Phys 2007;68:313. 2. Roels S, Duthoy W, Haustermans K, et al. Definition and delineation of the clinical target volume for rectal cancer. Int J Radiat Oncol Biol Phys 2006;65:1129–1142. 3. Nagtegaal ID, van de Velde CJ, Marijnen CA, et al. Low rectal cancer: A call for a change of approach in abdominoperineal resection. J Clin Oncol 2005;23:9257–9264. 4. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Eng J Med 2001;345:638–646. 5. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351: 1731–1740.
IS MASTECTOMY SUPERIOR TO BREAST-CONSERVING TREATMENT FOR YOUNG WOMEN?: IN REGARD TO COULOMBE ET AL. (INT J RADIAT ONCOL BIOL PHYS 2007;67:1282–1290) To the Editor: We read the article of Coulombe et al. (1) with great interest. A total of 2,398 patients (1,597 treated with breast-conserving surgery plus radiotherapy, and 801 treated with mastectomy) were evaluated in this retrospective study. As mentioned by the authors, one of the shortcomings of this study was that the groups were not balanced in many aspects. Nevertheless, they found that younger patients had a worse prognosis regarding all outcome measures. Local relapse-free survival (LRFS) and locoregional relapse-free survival were similar in the two groups at 10-year follow-up for patients aged 40–49 years, whereas disease relapse–free survival and breast cancer–specific survival were significantly better in the breast-conserving therapy (BCT) group. The authors interpreted this unexpected finding as a result of the imbalance between groups. They found no difference between the two treatment modalities in the 20- to 39-year-old age groups. However, the authors did not give information regarding median follow-up for each age group, cumulative 5-year local relapse rates, and time to distant metastases. The authors also considered a subgroup of patients with a tumor size of 2 cm or less, pathologically negative axillary lymph nodes, clear surgical margins, and no extensive intraductal component as ideal candidates for BCT. However, the difference regarding disease relapse–free survival and breast cancer–specific survival disappeared at 10-year follow-up in the 40- to 49-year-old age groups, when this subgroup of patients was analyzed separately. Another important issue is that LRFS rates were reported to be 86.3% for patients aged 20–39 years and 95.1% for the modified radical mastectomy (MRM) and BCT groups, respectively (p = 0.3). Based on this finding, the authors concluded that MRM was superior to BCT at 10-year follow-up. We would like to inquire why MRM was considered to be superior to BCT based on a p value of 0.3 regarding LRFS, whereas a similar even stronger relation in the opposite direction regarding distant metastasis-free survival (p = 0.17) was considered insignificant. We believe interpretation of the data through highly selected subgroups as in this article might be misleading in shaping the literature for future considerations. GOZDE YAZICI, M.D. UGUR SELEK, M.D. FERAH YILDIZ, M.D. GOKHAN OZYIGIT, M.D. MUSTAFA CENGIZ, M.D. Department of Radiation Oncology Hacettepe University Faculty of Medicine Ankara, Turkey
Volume 69, Number 2, 2007 IN REPLY TO DR. YAZICI ET AL. To the Editor: We thank Drs. Yazici et al. for their interest in our study. However, they misinterpreted our conclusions. Dr. Yazici et al. state that we concluded that ‘‘Modified radical mastectomy (MRM) was considered to be superior to breast-conserving therapy (BCT) based on a p value of 0.3..’’ This statement is erroneous because our conclusion explicitly stated that ‘‘.differences were not statistically significant and did not translate into worse distant relapse–free survival (RFS) or breast cancer–specific survival. These data suggest that young age alone is not a contraindication to BCT.’’ (1). Any conservative therapy replacing a historic standard (in this case, mastectomy) should be held to a high standard in terms of whether survival outcomes are equivalent. We acknowledge the retrospective nature of our data and agree that any nonsignificant hint of a clinically meaningful difference should be interpreted with caution and viewed as hypothesis generating. The strength of our study was that we were able to report on a relatively large series of women younger than 50 years, a subgroup that is relatively underrepresented in the available randomized clinical trials of BCT vs. mastectomy (2–7). It is well known that young age is associated with increased risk for local recurrence, as confirmed in our study (2–5). Our populationbased data support the current practice of offering breast conservation to younger women and does not make the claim that mastectomy is superior to breast conservation. With limited data from prospective trials to define optimal management for young women with breast cancer, the question of the efficacy of breast-conserving surgery followed by radiation therapy in this important subgroup remains open, and studies addressing the issue should continue. SCOTT TYLDESLEY, M.D. IVO OLIVOTTO, M.D. PAULINE TRUONO, M.D. GENEVIEVE COULOMBE, M.D. MIRA KEYES, M.D. British Columbia Cancer Agency Vancouver, British Columbia, Canada doi:10.1016/j.ijrobp.2007.05.060 1. Coulombe G, Tyldesley S, Speers C, et al. Is mastectomy superior to breast-conserving treatment for young women? Int J Radiat Oncol Biol Phys 2007;67:1282–1290. 2. Voogd AC, Nielsen M, Peterse JL, et al. Differences in risk factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer: Pooled results of two large European randomized trials. J Clin Oncol 2001;19:1688–1697. 3. Arriagada R, Leˆ MG, Guinebretiere J-M, et al. Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients. Ann Oncol 2003;14:1617–1622. 4. Fisher ER, Anderson S, Tan-Chui E, et al. Fifteen-year prognostic discriminants for invasive breast carcinoma. National Surgical Adjuvant Breast and Bowel Project Protocol B-06. Cancer 2001;91(Suppl. 8): S1679–S1687. 5. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347: 1227–1232. 6. Poggi MM, Danforth DN, Sciuto LC, et al. Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: The National Cancer Institute Randomized Trial. Cancer 2003;98:697–702. 7. Blichert-Toft M, Rose C, Andersen JA, et al. Danish randomized trial comparing breast conservation therapy with mastectomy: Six years of life-table analysis. Danish Breast Cancer Cooperative Group. J Natl Cancer Inst Monogr 1992;11:19–25.
doi:10.1016/j.ijrobp.2007.05.061
WHAT APPROACH WILL LEAD TO CURE OF GLIOBLASTOMA MULTIFORME?: IN REGARD TO BARANI ET AL. (INT J RADIAT ONCOL BIOL PHYS 2007;68:324–333) AND JONES AND SANGHERA (INT J RADIAT ONCOL BIOL PHYS 2007;68:441–448)
1. Coulombe G, Tyldesley S, Speers C, et al. Is mastectomy superior to breast-conserving treatment for young-women? Int J Radiat Oncol Biol Phys 2007;67:1282–1290.
To the Editor: Two stimulating articles dealing, at least in part, with treatment optimization in glioblastoma multiforme (GBM) concluded that efforts to intensify postoperative radiotherapy essentially failed to improve the
Letters to the editor outcome (1, 2). In their general discussion of radiotherapy for central nervous system malignancies, Barani et al. (1) suggested on page 331 that radiotherapy should be delivered in a neural stem cell-preserving manner with fractional doses significantly .3 Gy and a total treatment time of \2 weeks (intensified accelerated hypofractionation) and referred to a publication by Floyd et al. (3). The latter study used 50 Gy in 5-Gy fractions to treat GBM patients. The median time to progression and overall survival were 6 and 7 months, respectively. These values were comparable to historical controls. Although 25 Gy in 5-Gy fractions resulted in inferior results in another study, dose escalation to five fractions of 6 or 7 Gy also resulted in a median time to progression and overall survival of 5 and 7 months, respectively (4). When using the estimate by Jones and Sanghera (2) (i.e., an a/b value of 9 Gy for GBM), a biologically equivalent dose of 39, 50, 62, and 78 Gy could be calculated for these hypofractionated regimens of 25, 30, 35, and 50 Gy, respectively. The outcome of these, admittedly small studies, argues against a continuously rising dose– effect curve between the 50- and 78-Gy equivalent dose and questions the usefulness of additional dose escalation with such hypofractionated treatment. Jones and Sanghera (2) calculated a relatively modest effect of temozolomide added to radiotherapy, when expressed as the equivalent to a radiation dose (9.1 Gy given in 2-Gy fractions). The combination of temozolomide and radiotherapy improved the median progression-free survival from 5 to 6.9 months in the European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada trial and, importantly, also improved overall survival (5). It is, however, unknown whether this was caused by radiosensitization, additive cell kill, or spatial cooperation (i.e., killing of tumor cells in low-dose regions outside the target volume). The question arises whether the disappointing results of dose escalation have mainly been caused by limitations in target volume definition with standard imaging methods and whether biologic imaging will improve the outcome. However, even advanced diagnostic tools are unlikely to detect occasional tumor cells outside of the bulky area. As obvious lessons from the past, neither chemotherapy nor whole-brain radiotherapy solved the problem of microscopic deposits. With whole-brain radiotherapy doses as high as 46.8 Gy and a local boost to a cumulative dose of 78 Gy, both with 1.3-Gy fractions twice daily, the median survival remained at 7 months (6). What would be the result of this approach if combined with temozolomide? Would we experience increasing numbers of extracranial relapse? Also, what would be the quality of life for those surviving for $2 years? I doubt we will ever know, because we have started to investigate in different directions, based on biologically sound data. CARSTEN NIEDER, M.D. Radiation Oncology Unit Department of Internal Medicine and Skin Diseases Nordlandssykehuset HF Bodø, Norway doi:10.1016/j.ijrobp.2007.06.047 1. Barani I, Benedict SH, Lin PS. Neural stem cells: Implications for the conventional radiotherapy of central nervous system malignancies. Int J Radiat Oncol Biol Phys 2007;68:324–333. 2. Jones B, Sanghera P. Estimation of radiobiologic parameters and equivalent radiation dose of cytotoxic chemotherapy in malignant glioma. Int J Radiat Oncol Biol Phys 2007;68:441–448. 3. Floyd NS, Woo SY, Teh BS, et al. Hypofractionated intensity-modulated radiotherapy for primary glioblastoma multiforme. Int J Radiat Oncol Biol Phys 2004;58:721–726. 4. Nieder C, Nestle U, Walter K, et al. Hypofractionated stereotactic radiotherapy for malignant glioma: A phase I/II study. J Radiosurg 1999;2: 107–111. 5. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352:987–996. 6. Nieder C, Nestle U, Ketter R, et al. Hyperfractionated and acceleratedhyperfractionated radiotherapy for glioblastoma multiforme. Radiat Oncol Invest 1999;7:36–41.
IN REPLY TO DR. NIEDER To the Editor: We did not conclude that outcomes cannot be improved and, in contrast to this suggestion, tentatively explored ways in which the therapeutic index might be improved. Most advances in oncology tend to
641
follow the use of combinations of therapies, and it is important to determine the relative contributions of each form of therapy. The mathematical modeling presented in our study represents a scientific approach that is more commonly used in engineering and the physical sciences than in medicine. The calculation of the optimal dose per fraction to improve tumor cell kill (but for the same degree of normal tissue effects) produces values well below 2 Gy. The modeled patient population (in our Fig. 7) gives sufficient room for encouragement. We are confident that combinations of perhaps several (rather than single) cytotoxic drugs, with future advances derived from molecular biology and better forms of radiotherapy (including protons ions and boron neutron capture therapy in subtle combinations) to eliminate hypoxia and reduce unnecessary radiation to normal tissues, may bring significant improvements to what is presently a dismal condition. In all such combinations, the aim should be to minimize treatment-related toxicity. Hypofractionated therapy—unless given to very small volumes—should not be encouraged in the central nervous system because of the high fractionation sensitivity. Excessive radiation to the brain can result in poor quality of life and reduced survival. It is vital that future research protocols should use the most advanced radiotherapy techniques and optimal radiation dose schedules with the best available molecular-based therapies. BLEDDYN JONES, M.D. PAUL SANGERA, F.R.C.R. Department of Clinical Oncology Queen Elizabeth Hospital Birmingham, United Kingdom doi:10.1016/j.ijrobp.2007.06.046
IN REPLY TO DR. NIEDER To the Editor: We would like to thank Dr. Nieder for the insightful comments regarding past efforts in glioblastoma multiforme (GBM) to dose-intensify postoperative radiotherapy regimens. We agree with Dr. Nieder that survival outcomes of postoperative dose-intensified radiotherapy regimens in general suggest a lack of isoeffective dose-response beyond the current standard regimen of 60 Gy (delivered in 30 daily fractions). The motivation for intensified accelerated hypofractionation treatment is manifold. First, currently available biologic or cytotoxic therapies are not designed to discriminate between neural stem cells (NSCs) and cancer stem cells. NSCs are believed to be critical for the maintenance of normal brain homeostasis, including the response to tumor- and treatment-related injury. In contrast, the cancer stem cell is the purported ‘‘cell-of-origin’’ in high-grade gliomas. Thus, therapeutic discrimination between these two cell types would appear to be essential if the therapeutic index is to be improved. Given that NSCs are not widespread in the mammalian brain but are well confined to the subventricular and subgranular zones, therapeutic discrimination might currently be achieved by selective targeting of the tumor volumes and sparing of the NSC compartments. Second, cancer stem cells are relatively radioresistant and can give rise to multiple clones of varying radiosensitivities. The hypofractionated treatment regimen is best suited to address this relative radioresistance variation. Third, clones isolated from the human glioma cell line have exhibited similar great variation in cell kinetic parameters (e.g., potential doubling time), suggesting that repopulation could be an important factor influencing treatment outcomes with the current regimens. Such tumor cell kinetics are best addressed with an aggressively accelerated treatment regimen. Given that even the most aggressive regimens to date have resulted in clinical outcomes similar to those seen with nonaccelerated treatments, perhaps additional abbreviation of the overall treatment time is warranted. In summary, the greatest therapeutic gains are likely to be realized when intensified accelerated hypofractionated treatment is delivered to tumor volumes in a manner that spares the native NSC niches (subventricular and subgranular zones) from the radiation dose. IGOR J. BARANI, M.D. PECK-SUN LIN, PH.D. STANLEY H. BENEDICT, PH.D. Department of Radiation Oncology Virginia Commonwealth University Richmond, VA doi:10.1016/j.ijrobp.2007.06.045