In Regards to Dr. Garden et al. (Int J Radiat Oncol Biol Phys 2007;67:438–444)

Int. J. Radiation Oncology Biol. Phys., Vol. 68, No. 1, pp. 313–316, 2007 Copyright © 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter

LETTERS TO THE EDITOR 6. Bujko M, Bujko K, Skoczylas J. Lower order of the fields for patients with recital cancer treated with total mesorectal irradiation [Abstract]. Radiother Oncol 2002;64(Suppl. 1):S150

CLINICAL TARGET VOLUME FOR RECTAL CANCER: IN REGARD TO ROELS ET AL. (INT J RADIAT ONCOL BIOL PHYS 2006;65:1129 –1142) To the Editor: We read with great interest the article by Roels et al. dealing with an important issue of the clinical target volume (CTV) delineation for rectal cancer (1). The inferior pelvic subsite (IPS) has been identified as one of the 5 predominant areas of risk for local recurrence. The IPS includes the anal sphincter complex with the surrounding perianal and ischiorectal space. According to the author’s proposal, the CTV should also include the IPS when the surgeon aims for sphincter-saving procedure and the tumor is located within 6 cm from the anal margin. We do not agree with such proposal. In the literature, recurrences in the IPS have been reported only in patients who have undergone abdominoperineal resection (APR). These recurrences likely originate from contamination of cancer cells during surgery. It seems that the levators constitute an effective barrier against cancer spread down to the ischiorectal space in patients undergoing anterior resection. To our knowledge, no case of nodal metastasis in the ischiorectal fossa from rectal cancer has been reported. The sphincters and superficial–perianal part of the ischiorectal fossa are organs at risk for early and late adverse effects. Impairment of anorectal function, that is, enhancement of anterior resection syndrome, is a serious late complication of preoperative or postoperative radiotherapy for rectal cancer (2, 3). Excluding the inferior part of the anal canal from the CTV is a strategy to prevent radiation-induced fecal incontinence (4). Irradiation of the superficial–perianal part of the ischiorectal fossa results in an enhancement of the risk of delayed perineal wound healing after APR and in the painful acute skin reaction. Marijnen et al. (5) reported that 31% of 174 patients irradiated preoperatively with perineum included into the fields had perineal wound complications in comparison with 18% of 40 patients in whom the perineum was not irradiated. In conclusion, IPS should be included in CTV in cases of postoperative irradiation in patients who have undergone APR. For those requiring radiotherapy after anterior resection and for those treated preoperatively, we propose sparing the IPS (if not grossly invaded) as much as possible. Outlining the upper edge of the sphincter by contrast enema corresponds with the most distal part of mesorectum and may be used as a helpful landmark for the CTV contouring (6).

IN REGARDS TO DR. GARDEN ET AL. (INT J RADIAT ONCOL BIOL PHYS 2007;67:438 – 444) To the Editor: We read with great interest the article by Garden et al. (1) on T1/2 oropharyngeal tumors treated with simultaneously integrated intensity-modulated radiotherapy boost (SIB-IMRT) with 2.2 Gy/day to 66 Gy. The authors mention being reluctant to administer this regimen to patients who receive simultaneous chemotherapy. According to our data (2, 3) and clinical experience with 42 patients treated in a prospective protocol, this schedule was shown to be effective, well tolerated, and safe when combined with chemotherapy (cisplatin 1 ⫻ 40 mg/m2/week) for locally advanced tumors (Table 1). Pure SIB-IMRT was used, with 2.2 Gy/day to 66 Gy (n ⫽ 38) or 68.2 Gy (n ⫽ 4) mean dose to the gross tumor volume plus a margin of at least 1–1.5 cm (planning target volume 1). A dose of 54 Gy was delivered to the elective volume. The median follow-up was 33.5 months (range, 8 –57 monthes). Of 42 patients, 23 (55%) presented with locally advanced T3/4 or recurrent disease (Table 1). Sites involved were oropharynx (27), oral cavity (5), hypopharynx (4), larynx (1), nasopharynx (3), and paranasal sinus (2). To spare mucosal tissue, oral mucosa and pharyngeal areas out of the planning target volumes were contoured separately. A feeding tube was inserted in 33% of patients, in part before IMRT (in 1 patient for 12 months; all others became tube independent 1– 4 months after IMRT). The mean body weight loss at the end of treatment was ⫺7% (range, ⫹5% to ⫺16%); 1 year later, half the patients had regained their initial weight or more, half measured mean ⫺10% (range, ⫺5% to ⫺15%). In patients with T1/2 tumors, no persistent Grade 3/4 late effects have been observed. One patient with a large T4 oro-hypopharynx-larynx tumor developed Grade 4 laryngeal fibrosis. Since then, in patients with more than half of the larynx involved, SIB single doses have been limited to ⱕ2.0 Gy. One patient with a T3 hypopharyngeal tumor developed Grade 3 dysphagia; all other 32 locoregionally controlled patients with ⱖ1 year follow-up showed no or minimal dysphagia (Grade 0 –1); xerostomia Grade 0 –1, 2, or 3 was observed in 27, 3, and 0 patients, respectively. A small mandible bone sequester in a patient with a T3 oropharyngeal tumor was removed with a minor surgical procedure. In 3 patients with T3 oropharyngeal tumors and in 1 with a T4 hypopharyngeal tumor, a transient subacute mucosal ulcer

KRZYSZTOF BUJKO, M.D., PH.D.,* MAGDALENA BUJKO, M.D.,† LUCYNA PIETRZAK, M.D. Departments of *Radiotherapy I and † II, M. Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland. doi:10.1016/j.ijrobp.2006.12.047

Table 1. Characteristics of the collective (n ⫽ 42)

1. 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. 2. Peeters KC, van de Velde CJ, Leer JW, et al. Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: Increased bowel dysfunction in irradiated patients—a Dutch colorectal cancer group study. J Clin Oncol 2005; 23:6199 – 6206. 3. Lundby L, Jensen VJ, Overgard J, et al. Long-term colorectal function after postoperative radiotherapy for colorectal cancer. Lancet 1997;350: 564. 4. Vordermark D, Schwab M, Ness-Dourdoumas R, et al. Association of anorectal dose-volume histograms and impaired fecal continence after 3D conformal radiotherapy for carcinoma of the prostate. Radiother Oncol 2003;69:209 –214. 5. Marijnen CAM, Kapiteijn E, van de Velde CJH, et al. Acute side effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary in rectal cancer: Report of a multicenter randomized trial. J Clin Oncol 2002;20:817– 825.

Parameter Primary GTV (cm3) 2-y local control 2-y nodal control 2-y disease-free survival 2-y overall survival Feeding tube used Persistent late Grade 3 or 4 effects Cisplatin chemotherapy

T1/2 (n ⫽ 19)

T3/4, recurrent (n ⫽ 23)

14.5 (1–54) 95 100 95 100 21

38 (11–141) 72 77 70 76 43

0 89

Abbreviation: GTV ⫽ gross tumor volume. Values are percentage (number) or mean (range). * Grade 4 laryngeal fibrosis, Grade 3 dysphagia. 313

9 (2)* 83

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developed at the site of former tumor/SIB. In these 4 patients, ulcers healed 1, 3, 3, and 7 months later (see Table 4 in Studer et al. [2]). Thus, we consider SIB-IMRT with chemotherapy as described with single doses up to 2.2 Gy to planning target volume 1 to be safe and well tolerated. GABRIELA STUDER, M.D. CHRISTOPH GLANZMANN, M.D. Department of Radiation Oncology University Hospital Zurich Zurich, Switzerland doi:10.1016/j.ijrobp.2007.01.020 1. Garden AS, Morrison WH, Wong P-F, et al. Disease-control rates following intensity-modulated radiation therapy for small primary oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2007;67:438 – 444. 2. Studer G, Huguenin PU, Davis JB, et al. IMRT using simultaneously integrated boost (SIB) in head and neck cancer patients. Radiat Oncol 2006;1:7. 3. Studer G, Lutolf UM, Davis JB, et al. IMRT in hypopharyngeal tumors. Strahlenther Onkol 2006;182:331–335.

ADDENDUM TO: BASIC IMMUNOLOGY OF ANTIBODY TARGETED RADIOTHERAPY: IN REGARD TO WONG (INT J RADIAT ONCOL BIOL PHYS 2006;66: S8 –S14) To the Editor: This interesting review by Wong (1) has omitted some important data in its tables. Missing from the list of antibody/antigens in Table 1 is the melanoma-associated chondroitin sulfate proteoglycan, an antigen expressed by melanoma cells that is targeted by the monoclonal antibody 9.2.27. This benign murine antibody has a very low immune response and is not toxic to targeted melanoma cells. However, when labeled with 213Bi, an ␣-emitting radioisotope, the conjugate is highly cytotoxic to targeted melanoma cells. A phase I trial of this conjugate for intralesional targeted ␣-therapy for melanoma has been completed and published (2). Human anti-mouse antibody responses were not observed in the 16 subjects. However, single intralesional injections into subcutaneous melanomas caused massive cell death. An ongoing trial of systemic ␣-therapy for Stage 4 melanoma has reported partial responses for 10% of 33 subjects (personal communication, Raja C et al.). The unfortunate omission of 213Bi and 225Ac from Table 4 gives the wrong impression about the importance of these ␣-emitting radioisotopes. Bismuth-213 is milked from the 225Ac generator. It has a 46-min half life and emits an 8.35-MeV ␣ with an 80-␮m range. A 440-keV ␥-ray is also emitted that can be used for single photon emission tomography imaging with a high-energy collimator. Considerable preclinical data are available for 213Bi, which is undergoing clinical trials in Australia (personal communication, Raja C et al.), the United States (3), and Europe (4) for melanoma, myeloid leukemia, and lymphoma. The Memorial Sloan-Kettering Cancer Center is also running a phase I trial for 225Ac-labeled monoclonal antibody for myeloid leukemia. 225Ac has a 10-day half-life and decays by emission of four ␣-particles to stable 209 Bi. It is a highly cytotoxic agent. BARRY J. ALLEN, D.SC. Centre for Experimental Radiation Oncology St. George Cancer Care Centre Kogarah, NSW, Australia doi:10.1016/j.ijrobp.2007.01.036 1. Wong JYC. Basic immunology of antibody targeted radiotherapy. Int J Radiat Oncol Biol Phys 2006;66(Suppl.):S8 –S14. 2. Allen Barry J, Raja C, Rizvi SMA, et al. Intralesional targeted alpha therapy for metastatic melanoma. Cancer Biol Ther 2005;4:1318 –1324. 3. Jurcic JG, Larson SM, Sgouros G, et al. Targeted alpha particle immunotherapy for myeloid leukemia. Blood 2002;100:1233–1239. 4. Schmidt D, Neumann F, Antke C, et al. Phase 1 clinical study on alpha-therapy for non-Hodgkin lymphoma. In: Morgenstern A, ed. Fourth alpha-immunotherapy symposium. ITU: Dusseldorf, Germany; pp 12.

Volume 68, Number 1, 2007 BE CAREFUL IN GETTING COST-EFFECTIVENESS CONCLUSIONS FROM A DEBATABLE TRIAL! To the Editor: In the article by Thomas et al., surgery plus radiotherapy results in a cost-effective treatment compared with radiotherapy alone in metastatic epidural spinal cord compression (MESCC) (1). This analysis is derived from the trial by Patchell et al., in which MESCC patients have a significantly better outcome if upfront surgery is done before radiotherapy (2). We have several comments regarding this latter trial. Only selected patients were recruited (i.e., patients with a good medical status, expected survival of at least 3 months, and nonradiosensitive tumors, and spinal cord compression restricted to a single area). These selection criteria caused a long-lasting accrual of only 101 valuable patients in more than 10 consecutive years (2). In fact, the population examined does not represent the majority of MESCC patients treated in the daily clinical practice where surgery is rarely indicated and radiotherapy alone remains the treatment of choice. The accrual was not homogeneous among the 7 participant institutions (1, 1, 1, 2, 12, 14, and 70 patients entered in the trial, respectively) and, probably, not all eligible patients were actually considered for this trial. This results in a possible patient selection bias. A tailored surgery was properly done, but this surgery approach can be given only where neurosurgery departments with large experience in this field are available. Only 45% of patients treated with radiotherapy recover or maintain the ambulatory function, with respect to the 75% of those undergoing surgery. In our and in other experiences about 60 –70% of patients respond to radiotherapy (3–5). Therefore, the scarce results obtained with radiotherapy alone could be due both to the exclusion of patients with radiosensitive tumor histologies and to an inappropriate patient selection in the radiotherapy-alone group. In fact, 18 of 51 (35%) patients treated without surgery had a spinal cord instability, a condition in which stabilization of the spine is considered mandatory in the majority of published trials as well as in good clinical practice. This foresaid criticism can escape the reader’s attention and convince him that all MESCC patients must be treated with surgery plus radiotherapy. Thomas et al., with an appropriate analysis, found evidence that treatment of MESCC with surgery plus radiotherapy is cost-effective, but their analysis is based on a population deriving from a debatable trial. There are selected situations in which surgery is surely indicated before radiotherapy, but in clinical practice radiotherapy alone remains the firstline approach for the majority of patients with MESCC (6). ERNESTO MARANZANO, M.D. FABIO TRIPPA, M.D. Department of Radiation Oncology S. Maria Hospital Terni, Italy doi:10.1016/j.ijrobp.2006.12.040 1. Thomas KC, Nosyk B, Fisher CG, et al. Cost-effectiveness of surgery plus radiotherapy versus radiotherapy alone for metastatic epidural spinal cord compression. Int J Radiat Oncol Biol Phys 2006;66:1212–1218. 2. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: A randomised trial. Lancet 2005;366:643– 648. 3. Loblaw A, Perry J, Chambers A, et al. Systematic review of the diagnosis and management of malignant extradural spinal cord compression: The Cancer Care Ontario Practice Guidelines Initiative’s Neuro-oncology Disease Group. J Clin Oncol 2005;23:2028 –2037. 4. Rades D, Stalpers LJA, Veninga T, et al. Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression. J Clin Oncol 2005;23:3366 –3375. 5. 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 2005;23:8270 – 8272. 6. Maranzano E, Bellavita R, Rossi R. Radiotherapy alone or surgery in spinal cord compression? The choice depends on accurate patient selection. J Clin Oncol 2005;23:3358 –3365.

IN REPLY TO DRS. MARANZANO AND TRIPPA To the Editor: We believe that the results of the cost-effectiveness analysis by Thomas et al. (1) were produced using a study that was both internally and externally valid. We address each point of criticism in turn.