Brachytherapy
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Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer Rakesh Kapoor1, Divya Khosla1,*, Arvind K. Shukla1, Ritesh Kumar1, Rajesh Gupta2, Arun S. Oinam1, Suresh C. Sharma1 1
Department of Radiotherapy and Oncology, Regional Cancer Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India 2 Department of Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
ABSTRACT
PURPOSE: To evaluate dosimetric and clinical outcome in patients of anal cancer treated with image-based interstitial high-dose-rate brachytherapy following chemoradiation. METHODS AND MATERIALS: Sixteen patients with anal cancer were treated with chemoradiation followed by brachytherapy boost with image-based high-dose-rate interstitial brachytherapy from January 2007 to June 2011. Two brachytherapy dose schedules were used: 21 Gy in seven fractions and 18 Gy in six fractions depending on response to chemoradiation. CT scan was done after placement of needles for confirmation of placement and treatment planning. Target volume was contoured on CT scans. Volumetric quality indices and dose parameters were calculated. RESULTS: The mean clinical target volume was 17.7 4.98 cm3, and the median overall tumor size was 4.2 cm (3.4e5 cm). The mean values of coverage index, dose homogeneity index, overdose volume index, dose non-uniformity ratio, and conformal index were 0.94, 0.83, 0.21, 0.37, and 0.88, respectively. With a median followup of 41 months (range, 20e67.2 months), preservation of the anal sphincter was achieved in 14 patients. The 1- and 2-year local control rates were 93.8% and 87.5%, respectively. Treatment was well tolerated and none of the patients developed Grade 3 or higher late toxicity. CONCLUSIONS: The combination of external beam radiotherapy with interstitial brachytherapy increases the dose to the tumor volume and limits the volume of irradiated normal tissue, thereby decreasing late toxicity. The use of image-based treatment planning provides better dose conformality with reduced toxicity and helps to prevent a geographic miss. Ó 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Anal cancer; High dose rate; Image based; Interstitial brachytherapy; Quality indices
Introduction The management of anal cancer has undergone an interesting and tremendous transformation over the last three decades. Definitive chemoradiation is now the standard first-line treatment for anal carcinoma. Brachytherapy has been shown to be a component of treatment in these patients. The combination of external beam radiotherapy (EBRT) with interstitial brachytherapy increases the dose
Received 15 February 2013; received in revised form 28 May 2013; accepted 23 September 2013. * Corresponding author. Department of Radiotherapy and Oncology, Regional Cancer Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Sector 12, Chandigarh 160012, India. Tel.: þ91-987-663-8478; fax þ91-172-2744401, þ91-172-2749338. E-mail address: [email protected] (D. Khosla).
to the tumor volume and simultaneously limits the volume of irradiated normal tissue, thereby decreasing late toxicity. There is very limited data on brachytherapy for anal cancer. Although high-dose-rate (HDR) brachytherapy is widely available, the published data on this technique for anal cancer treatment are limited. New tools for plan evaluation such as three-dimensional (3D) visualization and volumetric parameters calculated from the dose-volume histograms (DVHs) are now available in the modern treatment planning systems. DVHs can provide data about volumes or volume elements receiving a particular dose, along with quantitative parameters that can be derived so as to characterize the dose uniformity and conformality. Several volumetric irradiation indices quantifying the homogeneity of dose distribution have been formulated and applied to assessment of interstitial implants (1, 2).
1538-4721/$ - see front matter Ó 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2013.09.006
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R. Kapoor et al. / Brachytherapy
The present article details a single institution’s experience of 16 patients of anal cancer treated with concomitant chemoradiation followed by image-based HDR interstitial brachytherapy. This study was done to evaluate clinical outcome and toxicity and also to perform dosimetric analysis using various volumetric quality indices. To the best of our knowledge, this is the only study of its kind in anal cancer treatment.
Methods and materials This is a retrospective study of 16 patients of anal cancer treated with concomitant chemoradiation followed by image-based interstitial HDR brachytherapy at our institute from January 2007 to June 2011. Diagnosis was established by biopsy. All patients underwent clinical examination and a CT scan for disease extent and assessment of lymph node involvement. Tumors were classified according to the 2002 staging system of the American Joint Committee on Cancer (3). Treatment External beam irradiation All patients were treated with concomitant chemoradiation. CT-based treatment planning was performed for all patients. All patients underwent a planning CT scan in the treatment position on Light Speed VFX-16 CT simulator (GE Medical Systems, Waukesha, WI). EBRT was given as 3D conformal radiotherapy using anteroposteriorposteroanterior or multifield techniques. Initial radiation fields were to include the pelvis, anus, perineum, and inguinal nodes, with the superior field border at L5eS1 and the inferior border to include the anus with a minimum margin of 3 cm around the anus and tumor. Dose ranged from 40 to 45 Gy in 20e25 fractions in 4e5 weeks (equivalent dose in 2 Gy [EQD2] ranged from 40 to 44 Gy in 20e25#).
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for brachytherapy because of the risk of long-term anal stenosis and decrease in internal anal sphincter function], thickness of lesion not to exceed 1 cm). The procedure was carried out in the lithotomy position. Interstitial brachytherapy was performed using Syed Neblett Classic Multiple use Rectal Template (Best Medical International, Springfield, VA). First, meticulous examination was carried out under general anesthesia to determine the extent of residual tumor. The longitudinal length of tumor along the anorectum, circumferential involvement of lumen, and thickness of tumor were assessed. The circumferential involvement was marked on perianal skin. Needle implantation was performed under general anesthesia using the Syed Neblett rectal template (Best Medical International), which was fixed to the perineum and an intra-anal obturator was inserted to separate the other side of the anal canal, to spare it from irradiation. The needles were placed at least 2 cm beyond the longitudinal length of tumor and 1 cm along the anal verge or lowermost extent of tumor. CT scan was done after placement of needles for confirmation of placement and treatment planning. The target volume was contoured on CT scan images. The target volume was defined by the combination of information, including CT scan and clinical findings. Computerized planning for interstitial HDR brachytherapy was done on Oncentra MasterPlan treatment planning system (Nucletron, an Elekta company [Elekta AB, Stockholm, Sweden]) (Fig. 1). Volume-based optimization was done. The catheter separation was 1 cm and the source step size ranged from 2.5 to 5 mm. The dose per fraction was 300 cGy delivered twice daily with an interfraction interval of 6e8 hours. Two brachytherapy dose schedules were used: 21 Gy in seven fractions (n 5 7) and 18 Gy in six fractions (n 5 9) depending on response to EBRT. The biologically effective dose (BED) and the equivalent dose in 2 Gy [EQD2] to the tumor using the
Concomitant chemotherapy All patients received concomitant chemoradiation; 5fluorouracil plus cisplatin (n 5 6), mitomycin C plus 5FU (n 5 10). Chemotherapy in the cisplatin-based group included cisplatin, 75 mg/m2 intravenously on Days 1 and 29, and fluorouracil, 1000 mg/m2/d by continuous infusion on Days 1e4, 29e32. Chemotherapy in the mitomycinbased group included mitomycin, 12 mg/m2 intravenous bolus on Day 1, and fluorouracil, 1000 mg/m2/d by continuous infusion on Days 1e4 and 29e32. Brachytherapy Brachytherapy procedure was done after completion of EBRT under general anesthesia. Patients were considered eligible for interstitial brachytherapy if they had good general status and good response to radiation (defined as tumor regression more than 50%, tumor involving !2/3 of the anal canal circumference [as $2/3 is a contraindication
Fig. 1. The clinical target volume (dotted red) covered with 100% isodose line. (For interpretation of the references to color in figure legend, the reader is referred to the web version of this article.)
R. Kapoor et al. / Brachytherapy
linear-quadratic model (a/b 5 10 Gy) were calculated using the formulas:
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EQD2 5 n d ð1 þ d=ða=bÞ Þ=ð1 þ 2=ða=bÞÞ Where n 5 no. of fractions, d 5 dose per fraction, (a/b) 5 linear quadratic parameter. Biologically effective dose and EQD2 of the combined EBRT and brachytherapy doses are summarized in Table 1. Dosimetric analysis Dosimetric indices were used to assess the quality of interstitial implant. The volumetric quantifiers include the coverage index (CI), dose homogeneity index (DHI), overdose volume index (ODI), conformal index (COIN), and dose non-uniformity ratio (DNR). DNR that is characteristic of the implant geometry was determined by using the cumulative DVH for implant, whereas the other indices by using DVH for target volume. The parameters used for dosimetric analysis are defined as: a) CI: The fraction of the target volume that receives a dose equal to or greater than the reference dose (1) Eq. 1. CI 5 TVDref =TV
ð1Þ
b) Relative DHI: This is defined as the ratio of the target volume that receives a dose in the range of 1.0e1.5 times of the reference dose to the volume of the target that receives a dose equal to or greater than the reference dose (1) Eq. 2. DHI 5 TVDref TV1:5Dref TVDref ð2Þ c) ODI: This is the ratio of the target volume that receives a dose equal to or more than 2.0 times of the reference dose to the volume of the target that receives a dose equal to or greater than the reference dose (1) Eq. 3. ODI 5 TV2:0Dref =TVDref
ð3Þ
d) DNR: This is the ratio of the target volume that receives a dose equal to or greater than 1.5 times of the reference dose to the volume of the target that receives a dose equal to or greater than the reference dose (4) Eq. 4. DNR 5 TV1:5Dref =TVDref
ð4Þ
Table 1 Biologically effective dose (BED) and the equivalent dose in 2 Gy (EQD2) to the tumor using the linear-quadratic model Dose to tumor
Total BED
EQD2
EBRT 40 Gy/20 fractions þ brachytherapy dose of 21 Gy/7 fractions EBRT 45 Gy/25 fractions þ brachytherapy dose of 18 Gy/6 fractions
75.3 Gy10
62.75 Gy
76.4 Gy10
63.67 Gy
3
e) COIN: Baltas et al. (5) Eq. 5 defined COIN for quantifying the conformality. COIN 5 c1 xc2
BED 5 n d ð1 þ d=ða=bÞÞ
EBRT 5 external beam radiotherapy.
-
ð5Þ
where c1 5 PTVref/VPTV and c2 5 PTVref/Vref. The PTVref is the volume of planning target volume (PTV) receiving a dose equal to or greater than reference dose. The VPTV is the volume of the PTV, and Vref is the volume receiving a dose equal to or greater than reference dose. Conditions for an ideal implant are where the values of quality indices should be as follows CI 5 1, EI 5 0, DHI 5 1, ODI 5 0, and DNR 5 0. Clinical analysis The initial response was evaluated by digital rectal examination 3 months after completion of treatment. Toxicity was graded by use of Radiation Therapy Oncology Group morbidity-scoring criteria. After completion of brachytherapy, patients were followed-up every 3 months for the first 2 years and subsequently every 4e6 months until the fifth year. Follow-up evaluations consisted of a history, physical, and digital rectal examination. An abdominal CT scan was obtained yearly on follow-up or earlier if clinically indicated. For calculating local control using the KaplaneMeier method, the time interval was taken from the date of registration to the time of the event. For calculating local control, event was either local disease progression or local recurrence and patients were censored at the time of last follow-up or death, which ever earlier. All statistical analyses were performed using SPSS version 15.0 (International Business Machines, Inc., Armonk, NY).
Results All patients completed the customized brachytherapy schedules. The patients’ ages ranged from 30 to 74 years, with a median of 55 years. Patient characteristics are shown in Table 2. Table 2 Patient characteristics Sex Male Female Most common clinical presentation (n) Mean duration of symptoms (mo) HIV positive Histologic grade
Stage group (TNM)
TNM 5 Tumor, Nodes, Metastasis.
13 3 Bleeding (14) 12.4 1 Well differentiatedd8 Moderately differentiatedd6 Poorly differentiatedd2 IId11 (T2N0M0d4) (T3N0M0d7) IIIAd3 (T2N1M0d1) (T3N1M0d2) IIIBd2 (T2N2M0d1) (T3N2M0d1)
4
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Brachytherapy was performed at a median of 24 days (range, 15e38 days) after EBRT. The median number of needles used was 5 (range, 5e8). Implant was single plane in 15 patients and double plane in one patient. The median treated length was 6 cm (range, 5e7 cm). The mean clinical target volume was 17.7 4.98 cm3, and the median overall tumor size was 4.2 cm (3.4e5 cm). The median D90 for clinical target volume was 20.39 Gy (17.22e22.42 Gy). The mean V100, V150, and V200 were 96.95 2.08%, 47.51 6.04%, and 21.28 7.7%, respectively. The volumetric quantifiers that include CI, DHI, ODI, DNR, and COIN are mentioned in Table 3. Patients were analyzed for local control and survival outcome. The median follow-up was 41 months (range, 20e67.2 months), and no patient was lost to follow-up. Of 16 patients, two had local failure at 7.8 and 19 months, respectively, which was salvaged by abdominoperineal resection (APR). Both were alive and disease-free at last followup. Preservation of the anal sphincter was achieved in 14 patients (87.5%). One patient died of liver metastasis. The 1- and 2year local control rates were 93.8% and 87.5%, respectively. Toxicity The most common toxicity was Grade 2 radiation mucositis, which occurred in eight cases (50%) and Grade 3 mucositis in three patients (18.75%). Grade 1 acute dermatitis occurred in seven patients, Grade 2 in six patients, and Grade 3 in three patients. Seven patients experienced acute proctitis: Grade 1 in five cases, Grade 2 in two. Late Grade 1 dermatitis occurred in two and Grade 2 in one patient. Late Grade 2 subcutaneous toxicity in the form of fibrosis occurred in four patients. Only one patient had occasional incontinence (such as, with coughing, sneezing). No other late toxicity was seen. No patient has developed Grade 3 or higher late toxicity in our study.
Discussion Surgery was the primary treatment in anal cancer 30 years ago. APR with resulting permanent colostomy was the preferred surgical procedure and was associated with a 5-year survival of around 40% to 70% with poor outcomes for those with larger tumors and nodal metastases Table 3 Volumetric quantifiers Indices
Mean standard deviation (range)
CI DHI ODI DNR COIN
0.94 0.83 0.21 0.37 0.88
0.07 0.13 0.07 0.22 0.15
(0.74e1) (0.55e0.98) (0.07e0.34) (0.21e0.45) (0.55e0.94)
CI 5 coverage index; DHI 5 dose homogeneity index; ODI 5 overdose volume index; DNR 5 dose non-uniformity ratio; COIN 5 conformal index.
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(6). Nigro pioneered neoadjuvant chemoradiation in anal cancer to convert unresectable cases to resectable. There was no surgical pathologic evidence of tumor found in three patients treated with this approach, which led to the concept of definitive chemoradiation (7) and further paved the way to organ preserving approach in anal cancer with high rates of success. There is limited literature on the use of interstitial brachytherapy as boost in anal cancer. In the present study, we evaluated the clinical and dosimetric results of 3D image-based interstitial brachytherapy and observed high local control rates and anal sphincter preservation rates with acceptable toxicity. The use of 3D image-based brachytherapy further allows optimization of plan, thereby providing conformal dose coverage to target volume with minimum possible dose to surrounding normal tissues. Iridium-192 (192Ir) sources have been used most, and single-plane implants are preferred over multiplanar implants to avoid significant tissue toxicities, including necrosis. Interstitial implantation is used more often in some European institutions. Although HDR brachytherapy is widely available, there is limited clinical experience with it in anal cancers. Saarilahti et al. (8) reported outcomes in terms of acute and late radiotherapy-related adverse events following intensity modulated radiotherapy (IMRT) and HDR brachytherapy in anal cancer. Of 59 patients, 20 were treated by IMRT and 39 by conventional 3D-radiotherapy. In 29 patients, the boost dose to the primary tumor was given by HDR brachytherapy: 30 patients were treated only by EBRT. Interstitial brachytherapy was given in one or two 5e6 Gy weekly fractions. They concluded that IMRT significantly reduces acute radiotherapy-associated adverse events in patients treated by chemoradiotherapy for anal cancer. A combination of external radiotherapy and HDR brachytherapy may reduce the risk of late radiation proctitis. Doniec et al. (9) evaluated transrectal ultrasoundeguided HDR brachytherapy following chemoradiation in 50 patients of anal cancer. Within 4e6 weeks after EBRT, interstitial Ir-192 HDR brachytherapy was administered to the tumor bed by two fractions of 6 or 4 Gy. In five patients (10%), tumor recurrence occurred or the tumor did not respond to therapy and four (8%) developed distant lymph nodes or organ metastases. Five patients (10%) had to undergo salvage APR because of non-responding tumors, recurrence or suspected recurrence. Specific disease-related 5-year survival was 82%. Therapy-associated complications in terms of sphincter necrosis and incontinence were observed in three patients (6%). Thus, concluded that transrectal ultrasoundeguided brachytherapy permits excellent local tumor control and results in minimal treatment-related morbidity. Oehler-J€anne et al. (10) compared brachytherapy boost with external beam boost and concluded that interstitial Ir-HDR implant boost with break and EBRT boost without break yield similar results. Acute skin toxicity is reduced with brachytherapy boost but long-term morbidity and quality of life are identical. Brachytherapy boost is most beneficial in early
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stage tumors but the advantage of it seems to be limited due to its invasiveness, doctor dependence, and logistic circumstances. Caution has been raised regarding the use of interstitial brachytherapy boost, which might result in anal necrosis and sphincter incontinence. A range of 8e36 Gy for brachytherapy boost has been used in prior studies with an incontinence Grade 1e2 from 3% to 18% (10e12). In our study, occasional incontinence was seen in one patient, and none of the patients had sphincter necrosis. Comparing with the incontinence rates reported in the literature, the dose schedules used in our study were quite well tolerated. There is lack of consensus on doses and fractionation schedules used for HDR interstitial brachytherapy with very limited published data. Image-based brachytherapy has been used in cervical and vaginal cancers and has shown improved local control rates with decreased or acceptable toxicities (13, 14). There is limited literature on dosimetric and clinical results of HDR brachytherapy in anal cancer. To the best of our knowledge, there is no study on the use of 3D imagebased HDR brachytherapy in anal cancer. The advantage of image-based brachytherapy planning is that differential loading of needles can be done with better sparing of uninvolved circumferential anorectal mucosa. Homogeneous dose distribution is an important issue because fibrosis and necrosis can develop in the volumes irradiated by high doses. A number of quality indices have been developed to evaluate low dose rate and HDR interstitial implants, such as CI, DHI, and DNR proposed by Saw and Suntharalingam (15, 16) and Saw et al. (4) for LDR interstitial brachytherapy and was further adopted by Meertens et al. (1) for the evaluation of HDR interstitial implants. Hence, in this study, we have used the quality indices values as defined by Meertens et al. (1). An ideal implant is when CI is equal to 1, DHI equal to 1, ODI and DNR are 0 (17). Kolotas et al. (18) reported COIN values between 0.61 and 0.76, whereas Baltas et al. (5) aimed to achieve a COIN value above 0.64 by using their CT-based planning system. Major et al. (19) reported a mean COIN, DHI, and ODI of 0.82, 0.68, and 0.17, respectively. Beriwal et al. (14) also analyzed quality indices in 3D image-based brachytherapy in vaginal cancers and reported COIN 0.91, DHI 0.5, and ODI 0.17, respectively. The mean values of CI, DHI, ODI, DNR, and COIN in our series were 0.94, 0.83, 0.21, 0.37, and 0.88, respectively. There is no consensus on what degree of conformality is acceptable in interstitial brachytherapy. Conformality can depend considerably on the shape of the target volume. For a highly irregular PTV, which frequently occurs in clinical situations, perfect conformality cannot be obtained, whereas for target volumes of regular shape, the reference isodose surface can be tailored more readily to PTV. IMRT has the potential to minimize acute and late adverse events, by reducing the dose to genitals, perineum, small bowel, and bladder in comparison with conventional parallel-opposed anterior-posterior/posterior-anterior fields.
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With IMRT, it is possible to reduce total treatment time by abandoning gap (20). It may also facilitate dose escalation of the tumor, with improved sparing of surrounding normal tissues, thereby reducing the risk of normal tissue toxicity. Various studies have demonstrated the efficacy and safety of IMRT in conjunction with concomitant chemotherapy (21e23). In the Radiation Therapy Oncology Group 0529 multi-institutional prospective study, use of IMRT resulted in low rates of gastrointestinal, genitourinary, and dermatologic toxicity, with excellent 2-year rates of overall and colostomy-free survival. Dose-painted IMRT was associated with significant sparing of acute Grade 2 þ hematologic and Grade 3 þ dermatologic and gastrointestinal toxicity. Although DP-IMRT proved feasible, the high pretreatment planning revision rate emphasizes the importance of realtime radiation quality assurance for IMRT trials (20). In subset of patients in Indian context where IMRT facilities are not available, interstitial brachytherapy may be used and treatment may be completed within short time. Brachytherapy offers the potential for individualized escalation of the target dose in a small volume while respecting the tolerance of normal tissues. The integration of 3D planning results in an increase in accuracy with higher degree of dose conformality and avoidance of surrounding normal tissues and may improve patient outcomes. The fractionation schedules used were well tolerated with a low incidence of acute or later toxicities. The drawbacks of our study are its retrospective nature and small number of patients. At this point of time, with median followup of 41 months, there is good clinical and dosimetric correlation as shown in our patients. As there is less Grade 3 acute toxicity with no late Grade 3 toxicity, this correlation may be taken as an indicator of acceptable outcome. But due to small number of patients, it is difficult to make any recommendation. Conclusion In the treatment of anal cancer, interstitial brachytherapy following chemoradiation offers high local control and anal sphincter preservation rates with acceptable toxicity. Image-based interstitial brachytherapy further allows dose escalation in the target while respecting normal tissue tolerance. It helps in better interpretation of target delineation and accurate volume optimization of dose distribution. Acknowledgments Conflicts of interest statement: The authors declare no conflicts of interest in the preparation of the manuscript or during the study. No financial grants were obtained during the study period. References [1] Meertens H, Borger J, Steggerda M, et al. Evaluation & optimisation on interstitial brachytherapy dose distributions. In: Mould RF,
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R. Kapoor et al. / Brachytherapy Battermann JJ, Martinez AA, Speiser BL, editors. Brachytherapy from radium to optimisation. Veenendaal, The Netherlands: Nucletron International; 1994. p. 300e306. Low DA, Williamson JF. The evaluation of optimized implants for idealized implant geometries. Med Phys 1995;22:1477e1485. Greene FL, Page DL, Fleming ID, et al, editors. AJCC Cancer Staging Manual. 6th edn. New York: Springer; 2002. 125e130. Saw CB, Suntharalingam N, Wu A. Concept of dose nonuniformity in interstitial brachytherapy. Int J Radiat Oncol Biol Phys 1993;26: 519e527. Baltas D, Kolotas C, Geramani K, et al. A conformal index (COIN) to evaluate implant quality and dose specification in brachytherapy. Int J Radiat Oncol Biol Phys 1998;40:515e524. Ryan DP, Compton CC, Mayer RJ. Carcinoma of the anal canal. N Engl J Med 2000;342:792e800. Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: A preliminary report. Dis Colon Rectum 1974;17:354e356. Saarilahti K, Arponen P, Vaalavirta L, et al. The effect of intensitymodulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer. Radiother Oncol 2008;87:383e390. Doniec JM, Schniewind B, Kovacs G, et al. Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy. Surg Endosc 2006;20:673e678. Oehler-J€anne C, Seifert B, L€utolf UM, et al. Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma. Brachytherapy 2007;6:218e226. Sandhu AP, Symonds RP, Robertson AG, et al. Interstitial iridium192 implantation combined with external radiotherapy in anal cancer: Ten years experience. Int J Radiat Oncol Biol Phys 1998;40: 575e581. L opez Guerra JL, Lozano AJ, Pera J, et al. Twenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy. Clin Transl Oncol 2011;13:472e479.
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[13] P€otter R, Dimopoulos J, Bachtiary B, et al. 3D conformal HDRbrachy- and external beam therapy plus simultaneous cisplatin for high-risk cervical cancer: Clinical experience with 3 year followup. Radiother Oncol 2006;79:80e86. [14] Beriwal S, Rwigema JC, Higgins E, et al. Three-dimensional imagebased high-dose-rate interstitial brachytherapy for vaginal cancer. Brachytherapy 2012;11:176e180. [15] Saw CB, Suntharalingam N. Quantitative assessment of interstitial implants. Int J Radiat Oncol Biol Phys 1990;20:135e139. [16] Saw CB, Suntharalingam N. Reference dose rates for single- and double-plane 192Ir implants. Med Phys 1988;15:391e396. [17] Kehwar TS, Akber SF, Passi K. Qualitative dosimetric and radiobiological evaluation of high-dose-rate interstitial brachytherapy implants. Int J Med Sci 2008;5:41e49. [18] Koltas C, Baltas D, Zamboglou N. CT-based interstitial HDR brachytherapy. Strahlenther Onkol 1999;175:419e427. [19] Major T, Polgar C, Fodor J, et al. Conformality and homogeneity of dose distributions in interstitial implants at idealized target volumes: A comparison between the Paris and dose-point optimized systems. Radiother Oncol 2002;62:103e111. [20] Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: A phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-c for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2013;86:27e33. [21] Kachnic LA, Tsai HK, Coen JJ, et al. Dose-painted intensitymodulated radiation therapy for anal cancer: A multi-institutional report of acute toxicity and response to therapy. Int J Radiat Oncol Biol Phys 2012;82:153e158. [22] Pepek JM, Willett CG, Wu QJ, et al. Intensity-modulated radiation therapy for anal malignancies: A preliminary toxicity and disease outcomes analysis. Int J Radiat Oncol Biol Phys 2010;78:1413e1419. [23] Bazan JG, Hara W, Hsu A, et al. Intensity-modulated radiation therapy versus conventional radiation therapy for squamous cell carcinoma of the anal canal. Cancer 2011;117:3342e3351.
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Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer Rakesh Kapoor1, Divya Khosla1,*, Arvind K. Shukla1, Ritesh Kumar1, Rajesh Gupta2, Arun S. Oinam1, Suresh C. Sharma1 1
Department of Radiotherapy and Oncology, Regional Cancer Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India 2 Department of Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
ABSTRACT
PURPOSE: To evaluate dosimetric and clinical outcome in patients of anal cancer treated with image-based interstitial high-dose-rate brachytherapy following chemoradiation. METHODS AND MATERIALS: Sixteen patients with anal cancer were treated with chemoradiation followed by brachytherapy boost with image-based high-dose-rate interstitial brachytherapy from January 2007 to June 2011. Two brachytherapy dose schedules were used: 21 Gy in seven fractions and 18 Gy in six fractions depending on response to chemoradiation. CT scan was done after placement of needles for confirmation of placement and treatment planning. Target volume was contoured on CT scans. Volumetric quality indices and dose parameters were calculated. RESULTS: The mean clinical target volume was 17.7 4.98 cm3, and the median overall tumor size was 4.2 cm (3.4e5 cm). The mean values of coverage index, dose homogeneity index, overdose volume index, dose non-uniformity ratio, and conformal index were 0.94, 0.83, 0.21, 0.37, and 0.88, respectively. With a median followup of 41 months (range, 20e67.2 months), preservation of the anal sphincter was achieved in 14 patients. The 1- and 2-year local control rates were 93.8% and 87.5%, respectively. Treatment was well tolerated and none of the patients developed Grade 3 or higher late toxicity. CONCLUSIONS: The combination of external beam radiotherapy with interstitial brachytherapy increases the dose to the tumor volume and limits the volume of irradiated normal tissue, thereby decreasing late toxicity. The use of image-based treatment planning provides better dose conformality with reduced toxicity and helps to prevent a geographic miss. Ó 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Anal cancer; High dose rate; Image based; Interstitial brachytherapy; Quality indices
Introduction The management of anal cancer has undergone an interesting and tremendous transformation over the last three decades. Definitive chemoradiation is now the standard first-line treatment for anal carcinoma. Brachytherapy has been shown to be a component of treatment in these patients. The combination of external beam radiotherapy (EBRT) with interstitial brachytherapy increases the dose
Received 15 February 2013; received in revised form 28 May 2013; accepted 23 September 2013. * Corresponding author. Department of Radiotherapy and Oncology, Regional Cancer Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Sector 12, Chandigarh 160012, India. Tel.: þ91-987-663-8478; fax þ91-172-2744401, þ91-172-2749338. E-mail address: [email protected] (D. Khosla).
to the tumor volume and simultaneously limits the volume of irradiated normal tissue, thereby decreasing late toxicity. There is very limited data on brachytherapy for anal cancer. Although high-dose-rate (HDR) brachytherapy is widely available, the published data on this technique for anal cancer treatment are limited. New tools for plan evaluation such as three-dimensional (3D) visualization and volumetric parameters calculated from the dose-volume histograms (DVHs) are now available in the modern treatment planning systems. DVHs can provide data about volumes or volume elements receiving a particular dose, along with quantitative parameters that can be derived so as to characterize the dose uniformity and conformality. Several volumetric irradiation indices quantifying the homogeneity of dose distribution have been formulated and applied to assessment of interstitial implants (1, 2).
1538-4721/$ - see front matter Ó 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2013.09.006
2
R. Kapoor et al. / Brachytherapy
The present article details a single institution’s experience of 16 patients of anal cancer treated with concomitant chemoradiation followed by image-based HDR interstitial brachytherapy. This study was done to evaluate clinical outcome and toxicity and also to perform dosimetric analysis using various volumetric quality indices. To the best of our knowledge, this is the only study of its kind in anal cancer treatment.
Methods and materials This is a retrospective study of 16 patients of anal cancer treated with concomitant chemoradiation followed by image-based interstitial HDR brachytherapy at our institute from January 2007 to June 2011. Diagnosis was established by biopsy. All patients underwent clinical examination and a CT scan for disease extent and assessment of lymph node involvement. Tumors were classified according to the 2002 staging system of the American Joint Committee on Cancer (3). Treatment External beam irradiation All patients were treated with concomitant chemoradiation. CT-based treatment planning was performed for all patients. All patients underwent a planning CT scan in the treatment position on Light Speed VFX-16 CT simulator (GE Medical Systems, Waukesha, WI). EBRT was given as 3D conformal radiotherapy using anteroposteriorposteroanterior or multifield techniques. Initial radiation fields were to include the pelvis, anus, perineum, and inguinal nodes, with the superior field border at L5eS1 and the inferior border to include the anus with a minimum margin of 3 cm around the anus and tumor. Dose ranged from 40 to 45 Gy in 20e25 fractions in 4e5 weeks (equivalent dose in 2 Gy [EQD2] ranged from 40 to 44 Gy in 20e25#).
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for brachytherapy because of the risk of long-term anal stenosis and decrease in internal anal sphincter function], thickness of lesion not to exceed 1 cm). The procedure was carried out in the lithotomy position. Interstitial brachytherapy was performed using Syed Neblett Classic Multiple use Rectal Template (Best Medical International, Springfield, VA). First, meticulous examination was carried out under general anesthesia to determine the extent of residual tumor. The longitudinal length of tumor along the anorectum, circumferential involvement of lumen, and thickness of tumor were assessed. The circumferential involvement was marked on perianal skin. Needle implantation was performed under general anesthesia using the Syed Neblett rectal template (Best Medical International), which was fixed to the perineum and an intra-anal obturator was inserted to separate the other side of the anal canal, to spare it from irradiation. The needles were placed at least 2 cm beyond the longitudinal length of tumor and 1 cm along the anal verge or lowermost extent of tumor. CT scan was done after placement of needles for confirmation of placement and treatment planning. The target volume was contoured on CT scan images. The target volume was defined by the combination of information, including CT scan and clinical findings. Computerized planning for interstitial HDR brachytherapy was done on Oncentra MasterPlan treatment planning system (Nucletron, an Elekta company [Elekta AB, Stockholm, Sweden]) (Fig. 1). Volume-based optimization was done. The catheter separation was 1 cm and the source step size ranged from 2.5 to 5 mm. The dose per fraction was 300 cGy delivered twice daily with an interfraction interval of 6e8 hours. Two brachytherapy dose schedules were used: 21 Gy in seven fractions (n 5 7) and 18 Gy in six fractions (n 5 9) depending on response to EBRT. The biologically effective dose (BED) and the equivalent dose in 2 Gy [EQD2] to the tumor using the
Concomitant chemotherapy All patients received concomitant chemoradiation; 5fluorouracil plus cisplatin (n 5 6), mitomycin C plus 5FU (n 5 10). Chemotherapy in the cisplatin-based group included cisplatin, 75 mg/m2 intravenously on Days 1 and 29, and fluorouracil, 1000 mg/m2/d by continuous infusion on Days 1e4, 29e32. Chemotherapy in the mitomycinbased group included mitomycin, 12 mg/m2 intravenous bolus on Day 1, and fluorouracil, 1000 mg/m2/d by continuous infusion on Days 1e4 and 29e32. Brachytherapy Brachytherapy procedure was done after completion of EBRT under general anesthesia. Patients were considered eligible for interstitial brachytherapy if they had good general status and good response to radiation (defined as tumor regression more than 50%, tumor involving !2/3 of the anal canal circumference [as $2/3 is a contraindication
Fig. 1. The clinical target volume (dotted red) covered with 100% isodose line. (For interpretation of the references to color in figure legend, the reader is referred to the web version of this article.)
R. Kapoor et al. / Brachytherapy
linear-quadratic model (a/b 5 10 Gy) were calculated using the formulas:
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EQD2 5 n d ð1 þ d=ða=bÞ Þ=ð1 þ 2=ða=bÞÞ Where n 5 no. of fractions, d 5 dose per fraction, (a/b) 5 linear quadratic parameter. Biologically effective dose and EQD2 of the combined EBRT and brachytherapy doses are summarized in Table 1. Dosimetric analysis Dosimetric indices were used to assess the quality of interstitial implant. The volumetric quantifiers include the coverage index (CI), dose homogeneity index (DHI), overdose volume index (ODI), conformal index (COIN), and dose non-uniformity ratio (DNR). DNR that is characteristic of the implant geometry was determined by using the cumulative DVH for implant, whereas the other indices by using DVH for target volume. The parameters used for dosimetric analysis are defined as: a) CI: The fraction of the target volume that receives a dose equal to or greater than the reference dose (1) Eq. 1. CI 5 TVDref =TV
ð1Þ
b) Relative DHI: This is defined as the ratio of the target volume that receives a dose in the range of 1.0e1.5 times of the reference dose to the volume of the target that receives a dose equal to or greater than the reference dose (1) Eq. 2. DHI 5 TVDref TV1:5Dref TVDref ð2Þ c) ODI: This is the ratio of the target volume that receives a dose equal to or more than 2.0 times of the reference dose to the volume of the target that receives a dose equal to or greater than the reference dose (1) Eq. 3. ODI 5 TV2:0Dref =TVDref
ð3Þ
d) DNR: This is the ratio of the target volume that receives a dose equal to or greater than 1.5 times of the reference dose to the volume of the target that receives a dose equal to or greater than the reference dose (4) Eq. 4. DNR 5 TV1:5Dref =TVDref
ð4Þ
Table 1 Biologically effective dose (BED) and the equivalent dose in 2 Gy (EQD2) to the tumor using the linear-quadratic model Dose to tumor
Total BED
EQD2
EBRT 40 Gy/20 fractions þ brachytherapy dose of 21 Gy/7 fractions EBRT 45 Gy/25 fractions þ brachytherapy dose of 18 Gy/6 fractions
75.3 Gy10
62.75 Gy
76.4 Gy10
63.67 Gy
3
e) COIN: Baltas et al. (5) Eq. 5 defined COIN for quantifying the conformality. COIN 5 c1 xc2
BED 5 n d ð1 þ d=ða=bÞÞ
EBRT 5 external beam radiotherapy.
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ð5Þ
where c1 5 PTVref/VPTV and c2 5 PTVref/Vref. The PTVref is the volume of planning target volume (PTV) receiving a dose equal to or greater than reference dose. The VPTV is the volume of the PTV, and Vref is the volume receiving a dose equal to or greater than reference dose. Conditions for an ideal implant are where the values of quality indices should be as follows CI 5 1, EI 5 0, DHI 5 1, ODI 5 0, and DNR 5 0. Clinical analysis The initial response was evaluated by digital rectal examination 3 months after completion of treatment. Toxicity was graded by use of Radiation Therapy Oncology Group morbidity-scoring criteria. After completion of brachytherapy, patients were followed-up every 3 months for the first 2 years and subsequently every 4e6 months until the fifth year. Follow-up evaluations consisted of a history, physical, and digital rectal examination. An abdominal CT scan was obtained yearly on follow-up or earlier if clinically indicated. For calculating local control using the KaplaneMeier method, the time interval was taken from the date of registration to the time of the event. For calculating local control, event was either local disease progression or local recurrence and patients were censored at the time of last follow-up or death, which ever earlier. All statistical analyses were performed using SPSS version 15.0 (International Business Machines, Inc., Armonk, NY).
Results All patients completed the customized brachytherapy schedules. The patients’ ages ranged from 30 to 74 years, with a median of 55 years. Patient characteristics are shown in Table 2. Table 2 Patient characteristics Sex Male Female Most common clinical presentation (n) Mean duration of symptoms (mo) HIV positive Histologic grade
Stage group (TNM)
TNM 5 Tumor, Nodes, Metastasis.
13 3 Bleeding (14) 12.4 1 Well differentiatedd8 Moderately differentiatedd6 Poorly differentiatedd2 IId11 (T2N0M0d4) (T3N0M0d7) IIIAd3 (T2N1M0d1) (T3N1M0d2) IIIBd2 (T2N2M0d1) (T3N2M0d1)
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R. Kapoor et al. / Brachytherapy
Brachytherapy was performed at a median of 24 days (range, 15e38 days) after EBRT. The median number of needles used was 5 (range, 5e8). Implant was single plane in 15 patients and double plane in one patient. The median treated length was 6 cm (range, 5e7 cm). The mean clinical target volume was 17.7 4.98 cm3, and the median overall tumor size was 4.2 cm (3.4e5 cm). The median D90 for clinical target volume was 20.39 Gy (17.22e22.42 Gy). The mean V100, V150, and V200 were 96.95 2.08%, 47.51 6.04%, and 21.28 7.7%, respectively. The volumetric quantifiers that include CI, DHI, ODI, DNR, and COIN are mentioned in Table 3. Patients were analyzed for local control and survival outcome. The median follow-up was 41 months (range, 20e67.2 months), and no patient was lost to follow-up. Of 16 patients, two had local failure at 7.8 and 19 months, respectively, which was salvaged by abdominoperineal resection (APR). Both were alive and disease-free at last followup. Preservation of the anal sphincter was achieved in 14 patients (87.5%). One patient died of liver metastasis. The 1- and 2year local control rates were 93.8% and 87.5%, respectively. Toxicity The most common toxicity was Grade 2 radiation mucositis, which occurred in eight cases (50%) and Grade 3 mucositis in three patients (18.75%). Grade 1 acute dermatitis occurred in seven patients, Grade 2 in six patients, and Grade 3 in three patients. Seven patients experienced acute proctitis: Grade 1 in five cases, Grade 2 in two. Late Grade 1 dermatitis occurred in two and Grade 2 in one patient. Late Grade 2 subcutaneous toxicity in the form of fibrosis occurred in four patients. Only one patient had occasional incontinence (such as, with coughing, sneezing). No other late toxicity was seen. No patient has developed Grade 3 or higher late toxicity in our study.
Discussion Surgery was the primary treatment in anal cancer 30 years ago. APR with resulting permanent colostomy was the preferred surgical procedure and was associated with a 5-year survival of around 40% to 70% with poor outcomes for those with larger tumors and nodal metastases Table 3 Volumetric quantifiers Indices
Mean standard deviation (range)
CI DHI ODI DNR COIN
0.94 0.83 0.21 0.37 0.88
0.07 0.13 0.07 0.22 0.15
(0.74e1) (0.55e0.98) (0.07e0.34) (0.21e0.45) (0.55e0.94)
CI 5 coverage index; DHI 5 dose homogeneity index; ODI 5 overdose volume index; DNR 5 dose non-uniformity ratio; COIN 5 conformal index.
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(6). Nigro pioneered neoadjuvant chemoradiation in anal cancer to convert unresectable cases to resectable. There was no surgical pathologic evidence of tumor found in three patients treated with this approach, which led to the concept of definitive chemoradiation (7) and further paved the way to organ preserving approach in anal cancer with high rates of success. There is limited literature on the use of interstitial brachytherapy as boost in anal cancer. In the present study, we evaluated the clinical and dosimetric results of 3D image-based interstitial brachytherapy and observed high local control rates and anal sphincter preservation rates with acceptable toxicity. The use of 3D image-based brachytherapy further allows optimization of plan, thereby providing conformal dose coverage to target volume with minimum possible dose to surrounding normal tissues. Iridium-192 (192Ir) sources have been used most, and single-plane implants are preferred over multiplanar implants to avoid significant tissue toxicities, including necrosis. Interstitial implantation is used more often in some European institutions. Although HDR brachytherapy is widely available, there is limited clinical experience with it in anal cancers. Saarilahti et al. (8) reported outcomes in terms of acute and late radiotherapy-related adverse events following intensity modulated radiotherapy (IMRT) and HDR brachytherapy in anal cancer. Of 59 patients, 20 were treated by IMRT and 39 by conventional 3D-radiotherapy. In 29 patients, the boost dose to the primary tumor was given by HDR brachytherapy: 30 patients were treated only by EBRT. Interstitial brachytherapy was given in one or two 5e6 Gy weekly fractions. They concluded that IMRT significantly reduces acute radiotherapy-associated adverse events in patients treated by chemoradiotherapy for anal cancer. A combination of external radiotherapy and HDR brachytherapy may reduce the risk of late radiation proctitis. Doniec et al. (9) evaluated transrectal ultrasoundeguided HDR brachytherapy following chemoradiation in 50 patients of anal cancer. Within 4e6 weeks after EBRT, interstitial Ir-192 HDR brachytherapy was administered to the tumor bed by two fractions of 6 or 4 Gy. In five patients (10%), tumor recurrence occurred or the tumor did not respond to therapy and four (8%) developed distant lymph nodes or organ metastases. Five patients (10%) had to undergo salvage APR because of non-responding tumors, recurrence or suspected recurrence. Specific disease-related 5-year survival was 82%. Therapy-associated complications in terms of sphincter necrosis and incontinence were observed in three patients (6%). Thus, concluded that transrectal ultrasoundeguided brachytherapy permits excellent local tumor control and results in minimal treatment-related morbidity. Oehler-J€anne et al. (10) compared brachytherapy boost with external beam boost and concluded that interstitial Ir-HDR implant boost with break and EBRT boost without break yield similar results. Acute skin toxicity is reduced with brachytherapy boost but long-term morbidity and quality of life are identical. Brachytherapy boost is most beneficial in early
R. Kapoor et al. / Brachytherapy
stage tumors but the advantage of it seems to be limited due to its invasiveness, doctor dependence, and logistic circumstances. Caution has been raised regarding the use of interstitial brachytherapy boost, which might result in anal necrosis and sphincter incontinence. A range of 8e36 Gy for brachytherapy boost has been used in prior studies with an incontinence Grade 1e2 from 3% to 18% (10e12). In our study, occasional incontinence was seen in one patient, and none of the patients had sphincter necrosis. Comparing with the incontinence rates reported in the literature, the dose schedules used in our study were quite well tolerated. There is lack of consensus on doses and fractionation schedules used for HDR interstitial brachytherapy with very limited published data. Image-based brachytherapy has been used in cervical and vaginal cancers and has shown improved local control rates with decreased or acceptable toxicities (13, 14). There is limited literature on dosimetric and clinical results of HDR brachytherapy in anal cancer. To the best of our knowledge, there is no study on the use of 3D imagebased HDR brachytherapy in anal cancer. The advantage of image-based brachytherapy planning is that differential loading of needles can be done with better sparing of uninvolved circumferential anorectal mucosa. Homogeneous dose distribution is an important issue because fibrosis and necrosis can develop in the volumes irradiated by high doses. A number of quality indices have been developed to evaluate low dose rate and HDR interstitial implants, such as CI, DHI, and DNR proposed by Saw and Suntharalingam (15, 16) and Saw et al. (4) for LDR interstitial brachytherapy and was further adopted by Meertens et al. (1) for the evaluation of HDR interstitial implants. Hence, in this study, we have used the quality indices values as defined by Meertens et al. (1). An ideal implant is when CI is equal to 1, DHI equal to 1, ODI and DNR are 0 (17). Kolotas et al. (18) reported COIN values between 0.61 and 0.76, whereas Baltas et al. (5) aimed to achieve a COIN value above 0.64 by using their CT-based planning system. Major et al. (19) reported a mean COIN, DHI, and ODI of 0.82, 0.68, and 0.17, respectively. Beriwal et al. (14) also analyzed quality indices in 3D image-based brachytherapy in vaginal cancers and reported COIN 0.91, DHI 0.5, and ODI 0.17, respectively. The mean values of CI, DHI, ODI, DNR, and COIN in our series were 0.94, 0.83, 0.21, 0.37, and 0.88, respectively. There is no consensus on what degree of conformality is acceptable in interstitial brachytherapy. Conformality can depend considerably on the shape of the target volume. For a highly irregular PTV, which frequently occurs in clinical situations, perfect conformality cannot be obtained, whereas for target volumes of regular shape, the reference isodose surface can be tailored more readily to PTV. IMRT has the potential to minimize acute and late adverse events, by reducing the dose to genitals, perineum, small bowel, and bladder in comparison with conventional parallel-opposed anterior-posterior/posterior-anterior fields.
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With IMRT, it is possible to reduce total treatment time by abandoning gap (20). It may also facilitate dose escalation of the tumor, with improved sparing of surrounding normal tissues, thereby reducing the risk of normal tissue toxicity. Various studies have demonstrated the efficacy and safety of IMRT in conjunction with concomitant chemotherapy (21e23). In the Radiation Therapy Oncology Group 0529 multi-institutional prospective study, use of IMRT resulted in low rates of gastrointestinal, genitourinary, and dermatologic toxicity, with excellent 2-year rates of overall and colostomy-free survival. Dose-painted IMRT was associated with significant sparing of acute Grade 2 þ hematologic and Grade 3 þ dermatologic and gastrointestinal toxicity. Although DP-IMRT proved feasible, the high pretreatment planning revision rate emphasizes the importance of realtime radiation quality assurance for IMRT trials (20). In subset of patients in Indian context where IMRT facilities are not available, interstitial brachytherapy may be used and treatment may be completed within short time. Brachytherapy offers the potential for individualized escalation of the target dose in a small volume while respecting the tolerance of normal tissues. The integration of 3D planning results in an increase in accuracy with higher degree of dose conformality and avoidance of surrounding normal tissues and may improve patient outcomes. The fractionation schedules used were well tolerated with a low incidence of acute or later toxicities. The drawbacks of our study are its retrospective nature and small number of patients. At this point of time, with median followup of 41 months, there is good clinical and dosimetric correlation as shown in our patients. As there is less Grade 3 acute toxicity with no late Grade 3 toxicity, this correlation may be taken as an indicator of acceptable outcome. But due to small number of patients, it is difficult to make any recommendation. Conclusion In the treatment of anal cancer, interstitial brachytherapy following chemoradiation offers high local control and anal sphincter preservation rates with acceptable toxicity. Image-based interstitial brachytherapy further allows dose escalation in the target while respecting normal tissue tolerance. It helps in better interpretation of target delineation and accurate volume optimization of dose distribution. Acknowledgments Conflicts of interest statement: The authors declare no conflicts of interest in the preparation of the manuscript or during the study. No financial grants were obtained during the study period. References [1] Meertens H, Borger J, Steggerda M, et al. Evaluation & optimisation on interstitial brachytherapy dose distributions. In: Mould RF,
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