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Reirradiation and stereotactic radiotherapy for tumors in the lung: Dose summation and toxicity
Radiotherapy and Oncology 107 (2013) 423–427
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SBRT of lung cancer
Reirradiation and stereotactic radiotherapy for tumors in the lung: Dose summation and toxicity Thomas R. Meijneke, Steven F. Petit, Davy Wentzler, Mischa Hoogeman, Joost J. Nuyttens ⇑ Department of Radiation Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 31 December 2012 Received in revised form 20 March 2013 Accepted 24 March 2013 Available online 3 May 2013 Keywords: Reirradiation Lung cancer Toxicity Dose accumulation
a b s t r a c t Purpose: To assess the accumulated dose and the toxicity after reirradiation for tumors in the lung using non-rigid registration. Material and methods: Twenty patients with a tumor in the lung were reirradiated with or after stereotactic radiotherapy. The summed dose distribution was calculated using non-rigid registration. All doses were recalculated to an equivalent dose of 2 Gy per fraction (EQD2). The median follow-up time was 12 months (range 2–52). Results: The median Dmax of the lung in the summed plans was 363 Gy3 (range 123–590). The median accumulated V20 of the lungs was 15.2%. Seven patients had in the heart and the trachea an accumulated dose P70 Gy3, with a median Dmax of the heart of 115 Gy3 and 89 Gy3 for the trachea. Eight patients had in the esophagus an accumulated dose P70 Gy3, with a median accumulated dose of 85 Gy3. No grade 3– 5 toxicity was observed. Conclusion: Reirradiation of the lung with or after stereotactic radiotherapy is feasible to a median Dmax of 363 Gy3 to the lung, as low toxicity was observed. Ó 2013 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 107 (2013) 423–427
Although recent biological and technological advances in lung cancer management have been made, disease recurrence is still the dominant cause of death after initial treatment of lung cancer [1]. When surgery or chemotherapy is not an option as treatment of a local recurrence, radiotherapy can be considered [2]. For patients who previously received irradiation, an additional radiotherapy treatment (or reirradiation) is often limited by the radiation tolerance of the anatomic structures surrounding the tumor. The potential toxicity to the surrounding tissues, like the spinal cord, the esophagus and other critical structures, limits the high dose needed to treat the tumor [3]. Throughout the years, various studies have tried to report the maximum doses that are acceptable for surrounding tissues for reirradiation [4,5]. Several authors did retreat small groups of patients with primary lung tumors and reported their results. Reirradiation to a median cumulative absolute dose of 80–110 Gy was feasible, however with a short median survival of 3–8 months because most treatments were given as palliative treatment [3,6–10]. These authors did report the toxicity, but the volume of field overlap and the accumulated dose to the tumor region and to the organs at risk were never reported. Therefore, the goal of the present study was to determine the accumulated dose–volume parameters
⇑ Corresponding author. Address: Department of Radiotherapy, Erasmus MCDaniel den Hoed Cancer Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail address: [email protected] (J.J. Nuyttens). 0167-8140/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.radonc.2013.03.015
to organs at risk after two irradiations in a group of 20 patients with cancer in the lung.
Methods and materials Patients and treatment From 2005 to 2012, 48 patients were reirradiated to the lung. Twenty patients were included in this study as they fulfilled the following criteria: (1) stereotactic body radiotherapy (SBRT) as first or second treatment, (2) an overlap of the two separate dose distributions (3) a treatment plan made by Xio (version 4.64.00, Elekta, Stockholm, Sweden) or Multiplan (version 2.2.0 or 3.5.3, Accuray, Sunnyvale, USA). All 20 patients received a curative treatment as the first treatment, 14 patients were first treated with curative SBRT and 6 patients with conventional chemoradiotherapy (1 concurrent, 5 sequential). The reirradiation consisted of 18 stereotactic treatments with curative intention, one curative conventional treatment and one palliative irradiation. Two patients received chemotherapy prior to the SBRT. SBRT was only used if the patient had only one PET-positive tumor in his body. All 6 patients who first got a conventional, curative irradiation were then treated using SBRT. The choice of the treatment schedule did depend on the proximity of the organs at risk as esophagus, trachea, mainstem bronchus and spinal cord and on the previous dose these organs at risk received. For peripheral tumors, 3 fractions were used,
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Reirradiation for tumors in the lung
Table 1 An overview of the treatment schedules. Reirradiation
First radiation EQD2 (Gy3)
Median GTV (cc)
Total dose Number of (Gy) fractions
EQD2 (Gy10)
50-60 51–60 51–60 51 51 45 48 48 32 36 36 30 20
83-110 130–180 20 115–150 204–276 4 115–150 204–276 6 115 204 6 115 204 0.2 71 108 82 72 106 47 72 106 43 48 70 103 48 65 110 48 65 9 33 36 270 23 28 589
5 3 3 3 3 5 6 6 4 6 6 10 5
Median PTV (cc)
Total dose Number of (Gy) fractions
EQD2 (Gy10)
46 14 19 20 4 147 93 102 197 189 28 822 1734
60 51–60 60 50 30 60 60 45 60 50 45 48 60
150 276 12 115–150 204–276 2 65 72 73 50 50 106 100 198 0.2 150 276 15 110 180 32 49 54 109 150 276 21 52 55 240 44 43 84 72 106 70 150 276 53
3 3 20 25 1 3 5 15 3 20 25 6 3
EQD2 (Gy3)
Median GTV (cc)
Median PTV (cc) 34 10 440 402 3 38 72 375 59 982 519 131 111
Number of patients
5 3 2 1 1 1 1 1 1 1 1 1 1
EQD2, equivalent dose in 2 Gy per fraction; GTV, gross tumor volume; PTV, planning target volume.
for central tumors 5 or 6 fractions [11,12]. An overview of the treatment schedules is given in Table 1. All doses were recalculated to an Equivalent Dose of 2 Gy per fraction (EQD2), with the formula: d ⁄ n ⁄ ((d + a/ß)/(2 + a/ß)), with d the dose per fraction (Gy) and n the number of fractions. For tumor dose and acute side effects an a/ß value of 10 Gy was used (Gy10) and for late effects an a/ß value of 3 Gy (Gy3). Patient, tumor and treatment characteristics are shown in Table 2. For the SBRT, the dose was prescribed to the 70–85% isodose line, covering at least 95% of the PTV. The maximum dose was defined by the 100% isodose line. The toxicity was scored using the Common Terminology Criteria for Adverse Events (CTCAE 4.0).
Dose addition The XIO dose distributions were calculated using the superposition-convolution algorithm. The CyberKnife treatment plans were calculated with the Monte Carlo algorithm or recalculated with the Monte Carlo algorithm if the dose calculation for treatment planning was performed using the equivalent-path length method to account for tissue heterogeneities [13]. Table 2 Patient, tumor and treatment characteristics. Gender Male Female
Number of patients 14 6
Primary tumor Lung carcinoma Colorectal carcinoma Sarcoma
Number of patients 17 2 1
Stage Stage I Stage II Stage IV
Number of patients 10 1 9
Histology Adenocarcinoma Squamous cell carcinoma Clear cell carcinoma Small cell lung carcinoma No pathology
Number of patients 1 2 1 2 14
Median radiation dose to the tumor First radiation Reirradiation
Gy10, (range) 133 (44–150) 83 (23–150)
Median age at time of reirradiation (years) Median interval between the radiation (months) Median follow up after reirradiation (months)
71 (50–80) 17 (2–33) 12 (2–52)
The lungs and the heart were contoured completely. The esophagus, spinal cord, and trachea were contoured in each treatment plan in such a way that the length of the contoured organ was equal on both CT scans. The length of the contoured organ was based on anatomical structures such as the carina and the vertebra and was based on the extents of radiation fields of both plans. CT scans, dose distributions and structure sets were sent to an in-house developed software platform for analysis. First, two CT scans were aligned rigidly by using an automatic bone match (translation and rotations). Then for each organ individually, a non-rigid registration was applied based on the contours of the organs at risk. Previously, this method was applied to sum dose distributions of external beam radiotherapy and brachytherapy for oropharyngeal cancer patients [14–16]. Using the obtained transformation, the dose distribution of the reirradiation was mapped to the dose grid of the first treatment and the dose values were summed after having converted both dose distributions to a biologically equivalent dose in 2 Gy fractions (EQD2) [16]. Finally, dose volume histograms (DVHs) of the organs at risk were calculated using the summed dose distribution. The organs at risk with an accumulated Dmax over 70 Gy3 were selected and related to the toxicity that was recorded. The percentage of the lungs receiving 20 Gy3 or more (V20) and mean lung dose (MLD) were calculated without subtraction of the GTV, CTV, or PTV. The target of the first irradiation was not always at the same location in the lung as the target of the second irradiation. Dose addition of the lung with subtraction of the target would have resulted in a dose addition of a deformed lung. This deformed lung was not present at the time of the treatment, and would result in a wrong calculation. Therefore, we calculated the lung parameters (V20,. . .) without subtracting the GTV, CTV or PTV, and these parameters are not exactly the same as normally used in the literature. The volume of overlap between the 2 irradiation plans was determined at the dose level of 50% and 80% of the prescribed dose. These dose levels were determined by summing the dose level of 50% and 80% in the primary plan and in the reirradiation plan in EQD2, resulting in the 50% or 80% summed dose. The amount of overlap was defined as the total volume of the lungs receiving equal or more than the 50% and 80% summed dose. Results The median Dmax of the lung in the summed plans was 363 Gy3 (range 123–590 Gy3; Table 3). The median volume of overlap in the lungs was 48 cc (range 0.9–704 cc) for the 50% dose level and 18 cc
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T.R. Meijneke et al. / Radiotherapy and Oncology 107 (2013) 423–427 Table 3 Dmax of the lung (Gy3), Median V20, V13 and V5 (in %) of ipsilateral lung, contralateral lung and of both lungs for the summed and the single plans. Summed plan
First plan
Second plan
Dmax of the lungs (Gy3)
363 (123–590)
292 (47–384)
189 (29–417)
Median V20 Both lungs (%) Ipsilateral lung (%) Contralateral lung (%)
15 (3–47) 28 (6–73) 1 (0–47)
7 (0–37) 14 (0–66) 0 (0–19)
8 (0–15) 13 (0–31) 0 (0–30)
Median V13 Both lungs (%) Ipsilateral lung (%) Contralateral lung (%)
22 (4–55) 37 (7–77) 2 (0–55)
10 (1–41) 19 (1–70) 0 (0–32)
11 (1–37) 21 (2–68) 0 (0–6)
Median V5 Both lungs (%) Ipsilateral lung (%) Contralateral lung (%)
41 (8–72) 57 (14–83) 18 (0–68)
21 (1–61) 33 (3–77) 5 (0–44)
18 (0–39) 31 (0–59) 4 (0–22)
(range 0.2–279 cc) for the 80% dose level. Two patients did not have any overlap at the 80% dose level although the tumors were close to each other. An example of the dose summation is shown in Fig. 1. The median accumulated V20 of the lungs was 15.2%. The V20, V13 and V5 are shown in Table 3. The median accumulated MLD for the whole group was 15 Gy3 (range 4.2–27.6 Gy3). Seven patients had an accumulated dose P70 Gy3 in the heart and the trachea. The median Dmax of the heart in these 7 patients was 115 Gy3, and for the trachea 89 Gy3. The results for the first and second plan are shown in Table 4. Eight patients had an accumulated dose P70 Gy3 in the esophagus. The median accumulated dose of these patients was 85 Gy3 (range 71–123 Gy3). Other structures, like the spinal cord and the plexus brachialis did not receive P70 Gy3 in the summed plan. No acute and late grade 3–5 toxicity during or after the reirradiation was recorded. Four patients had dyspnea (one acute, three late), two patients complained of acute pain, one of late pain and two of acute dysphagia. The reirradiation showed no acute or chronic skin intoxications or nausea. Two patients had rib fractures, one patient was without any symptom, the other had chronic pain. Four patients received a MLD above 20 Gy3 and two of them had a V20 above 40%. No pulmonary complaints were recorded for these patients after the treatment. One patient died at nine months after the treatment due to peritonitis carcinomatosa, the other patient is now seven months in follow-up and has had no pulmonary complaints, the third patient is now 2 years in follow-up and has no pulmonary complaints and the last patient died at eleven months after the treatment due to cardiac failure.
The median overall survival was 15 months. The 1- and 2-year overall survivals were 67% and 33%, respectively. Nine patients died in total, 4 patients died due to tumor progression or related symptoms. Five patients died due to other causes: 2 due to cardiac causes, one due to cerebral hemorrhage, one due to a fall and the death of the last patient was unknown. The Dmax of the heart of the 2 patients with a cardiac cause of death was 8.4 Gy3 and 14.4 Gy3 in the summed plan. The median time to local failure was 22 months. The 1-year local control rate was 75% and the 2-year rate was 50%. The median disease free survival was 9.7 months and the 1-year disease free survival was 50%.
Discussion Dmax and organs at risk The median Dmax of the lung in the summed plans was 363 Gy3 (range 123–590 Gy3). Although this was high, no high toxicity score was present among the patients. In the search for more literature about Dmax and toxicity in lung cancer, no literature was found. For head and neck cancer acceptable toxicity was observed considering a median accumulated lifetime dose of 111 Gy [17]. Abusaris et al. concluded that reirradiation for the rectum, bowel and bladder using extra-cranial SBRT was feasible and resulted in a 96% symptomatic response with low toxicity [18]. She also reported that a second reirradiation with a median accumulated maximum dose of 133 Gy3 to these regions was safe [4]. Three patients showed a V20 over 40%. Two of these patients had no pulmonary toxicity, the third patient complained of acute
Fig. 1. An example of the accumulated dose distribution in a patient a: the dose distribution of the first irradiation in absolute dose; b: the dose distribution of the reirradiation in absolute dose; c: the accumulated dose distribution in EQD2.
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Reirradiation for tumors in the lung Table 4 Organs with an accumulated Dmax P70 Gy3. Median (Gy3)
Range (Gy3)
Median volume P70 Gy3 (cc)
Range (cc)
Heart (n = 7) Summed plan First plan Second plan
114.5 71.3 95.6
74.2–271.4 4.2–223.4 16.2–232.7
1.4
0.01–53.4
Esophagus (n = 8) Summed plan First plan Second plan
85.2 60.7 37.1
70.5–123.2 1.5–76.9 2.1–82.4
3.4
0.03–10.3
Trachea (n = 7) Summed plan First plan Second plan
89.2 49.8 65.1
72.3–122.4 19.8–77.5 1.4–113.1
2.1
0.04–20.0
pain (grade 2). Four patients showed a MLD above 20 Gy3. Two of them died but not due to pulmonary problems, the other two patients are still alive. Peulen et al. did not report any statistical correlation between MLD and frequency of grade 3–5 lung toxicity after reirradiation [19]. Only three patients (15%) complained of dyspnea grade 1, and one patient (5%) of dyspnea grade 2. Both showed no sign of clinical radiation pneumonitis (RP). Okamoto et al. described that RP was more frequently experienced after reirradiation, but no cases of grade 4 or 5 RP occurred [9] and Montebello et al. described only one patient out of 30 with symptomatic RP [8]. This low percentage seems to correspond with our results. Two patients (10%) complained of acute dysphagia grade 1 after reirradiation. Both patients had an accumulated esophagus dose above 70 Gy3. Although there were no clinical signs of acute esophagitis among our patients, other authors did report esophagitis after reirradiation [10]. The low number of side effects can be explained by the median follow-up of only 12 months. A longer follow up may reveal a higher late toxicity rate. On the other hand, we previously published excellent quality of life after stereotactic radiotherapy [11,20]. This was probably so because we only did irradiate a small volume. Current data seem to support that a high maximum summed dose is feasible and safe because a small volume of recurrent disease was reirradiated to a very high dose. A dose volume effect could play a role in the appearance of side effects. However, due to the limited number of patients included in this study, we were not able to look at this dose volume effect.
Survival and outcome The median survival was 15 months. This is in accordance with the results shown by Jeremic´ et al, who reported a median survival time ranging from 5 to 14 months [21]. However, it is difficult to compare both studies as our study population has different stages. Nine patients died after reirradiation, but 5 patients died of non-tumor related causes. The large percentage of non-tumor related deaths was not unexpected as 14 of the 20 patients were no surgical candidates due to their comorbidities. The mean time of local control was 24 months. It is remarkable that in this small group 4 patients had a local recurrence after irradiation despite the high dose (>82 Gy3) which was given to the tumor.
Dose addition Dose addition of two treatment plans based on different CT scans requires a registration from one to the other coordinate system. A rigid registration leads to unsatisfactory results when organs are deformed at one time point with respect to the other time point. In those cases non-rigid registration is required. The
algorithm employed here matches the contoured boundaries of the organs. The deformation field is extrapolated to the inner part of the organ using the transformation function obtained. This method was validated for three-dimensional dose addition of external beam radiotherapy and brachytherapy for oropharyngeal patients by applying a robustness analysis. The non-rigid registration framework was also validated to quantify deformations of the prostate including seminal vesicles, for cervical cancer patients experiencing extreme deformations as a result of bladder filling variations, and to align vessel trees in largely deformed livers [14,15,22]. The results of these studies support the use of the non-rigid registration method to sum dose for lung cancer patients, as the degree of deformation in the current patient group is significantly less than e.g. observed in cervix patients. Still, inevitable anatomic inaccuracies in the non-rigid registration will propagate to the summed dose distributions, which will be mostly pronounced in the target region of the primary treatment plan. For selected patients, reirradiation to the lungs with median accumulated Dmax of 363 Gy3 appeared to be feasible and safe, because low toxicity was found. A median accumulated V203 of 15.2% and accumulated doses more than 70 Gy3 to the heart, trachea and esophagus did not result in severe toxicity.
References [1] Hung JJ, Hsu WH, Hsieh CC, et al. Post-recurrence survival in completely resected stage I non-small cell lung cancer with local recurrence. Thorax 2009;64:192–6. [2] Zimmermann FB, Molls M, Jeremic B. Treatment of recurrent disease in lung cancer. Semin Surg Oncol 2003;21:122–7. [3] Jackson MA, Ball DL. Palliative retreatment of locally-recurrent lung cancer after radical radiotherapy. Med J Aust 1987;147:391–4. [4] Abusaris H, Storchi PR, Brandwijk RP, Nuyttens JJ. Second re-irradiation: efficacy, dose and toxicity in patients who received three courses of radiotherapy with overlapping fields. Radiother Oncol 2011;99:235–9. [5] Rades D, Rudat V, Veninga T, Stalpers LJ, Hoskin PJ, Schild SE. Prognostic factors for functional outcome and survival after reirradiation for in-field recurrences of metastatic spinal cord compression. Cancer 2008;113:1090–6. [6] Cetingoz R, Arican-Alicikus Z, Nur-Demiral A, Durmak-Isman B, Bakis-Altas B, Kinay M. Is re-irradiation effective in symptomatic local recurrence of non small cell lung cancer patients? A single institution experience and review of the literature. J BUON 2009;14:33–40. [7] Ebara T, Tanio N, Etoh T, Shichi I, Honda A, Nakajima N. Palliative re-irradiation for in-field recurrence after definitive radiotherapy in patients with primary lung cancer. Anticancer Res 2007;27:531–4. [8] Montebello JF, Aron BS, Manatunga AK, Horvath JL, Peyton FW. The reirradiation of recurrent bronchogenic carcinoma with external beam irradiation. Am J Clin Oncol 1993;16:482–8. [9] Okamoto Y, Murakami M, Yoden E, et al. Reirradiation for locally recurrent lung cancer previously treated with radiation therapy. Int J Radiat Oncol Biol Phys 2002;52:390–6. [10] Poltinnikov IM, Fallon K, Xiao Y, Reiff JE, Curran Jr WJ, Werner-Wasik M. Combination of longitudinal and circumferential three-dimensional esophageal dose distribution predicts acute esophagitis in hypofractionated reirradiation of patients with non-small-cell lung cancer treated in stereotactic body frame. Int J Radiat Oncol Biol Phys 2005;62:652–8.
T.R. Meijneke et al. / Radiotherapy and Oncology 107 (2013) 423–427 [11] van der Voort van Zyp NC, Prevost JB, van der Holt B, et al. Quality of life after stereotactic radiotherapy for stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2010;77:31–7. [12] Nuyttens JJ, van der Voort van Zyp NC, Praag J. Outcome of four-dimensional stereotactic radiotherapy for centrally located lung tumors. Radiother Oncol 2012;102:383–7. [13] van der Voort van Zyp NC, Hoogeman MS, van de Water S, et al. Clinical introduction of Monte Carlo treatment planning: a different prescription dose for non-small cell lung cancer according to tumor location and size. Radiother Oncol 2010;96:55–60. [14] Bondar L, Hoogeman MS, Vasquez Osorio EM, Heijmen BJ. A symmetric nonrigid registration method to handle large organ deformations in cervical cancer patients. Med Phys 2010;37:3760–72. [15] Vasquez Osorio EM, Hoogeman MS, Bondar L, Levendag PC, Heijmen BJ. A novel flexible framework with automatic feature correspondence optimization for nonrigid registration in radiotherapy. Med Phys 2009;36:2848–59. [16] Vasquez Osorio EM, Hoogeman MS, Teguh DN, et al. Three-dimensional dose addition of external beam radiotherapy and brachytherapy for oropharyngeal patients using nonrigid registration. Int J Radiat Oncol Biol Phys 2011;80:1268–77.
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[17] Zwicker F, Roeder F, Hauswald H, et al. Reirradiation with intensity-modulated radiotherapy in recurrent head and neck cancer. Head Neck 2011;33:1695–702. [18] Abusaris H, Hoogeman M, Nuyttens JJ. Re-irradiation: outcome, cumulative dose and toxicity in patients retreated with stereotactic radiotherapy in the abdominal or pelvic region. Technol Cancer Res Treat 2012;11:591–7. [19] Peulen H, Karlsson K, Lindberg K, et al. Toxicity after reirradiation of pulmonary tumours with stereotactic body radiotherapy. Radiother Oncol 2011;101:260–6. [20] van der Voort van Zyp NC, van der Holt B, van Klaveren RJ, Pattynama P, Maat A, Nuyttens JJ. Stereotactic body radiotherapy using real-time tumor tracking in octogenarians with non-small cell lung cancer. Lung Cancer 2010;69:296–301. [21] Jeremic B, Videtic GM. Chest reirradiation with external beam radiotherapy for locally recurrent non-small-cell lung cancer: a review. Int J Radiat Oncol Biol Phys 2011;80:969–77. [22] Vasquez Osorio EM, Hoogeman MS, Mendez Romero A, Wielopolski P, Zolnay A, Heijmen BJ. Accurate CTMR vessel-guided nonrigid registration of largely deformed livers. Med Phys 2012;39:2463–77.
Contents lists available at SciVerse ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
SBRT of lung cancer
Reirradiation and stereotactic radiotherapy for tumors in the lung: Dose summation and toxicity Thomas R. Meijneke, Steven F. Petit, Davy Wentzler, Mischa Hoogeman, Joost J. Nuyttens ⇑ Department of Radiation Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 31 December 2012 Received in revised form 20 March 2013 Accepted 24 March 2013 Available online 3 May 2013 Keywords: Reirradiation Lung cancer Toxicity Dose accumulation
a b s t r a c t Purpose: To assess the accumulated dose and the toxicity after reirradiation for tumors in the lung using non-rigid registration. Material and methods: Twenty patients with a tumor in the lung were reirradiated with or after stereotactic radiotherapy. The summed dose distribution was calculated using non-rigid registration. All doses were recalculated to an equivalent dose of 2 Gy per fraction (EQD2). The median follow-up time was 12 months (range 2–52). Results: The median Dmax of the lung in the summed plans was 363 Gy3 (range 123–590). The median accumulated V20 of the lungs was 15.2%. Seven patients had in the heart and the trachea an accumulated dose P70 Gy3, with a median Dmax of the heart of 115 Gy3 and 89 Gy3 for the trachea. Eight patients had in the esophagus an accumulated dose P70 Gy3, with a median accumulated dose of 85 Gy3. No grade 3– 5 toxicity was observed. Conclusion: Reirradiation of the lung with or after stereotactic radiotherapy is feasible to a median Dmax of 363 Gy3 to the lung, as low toxicity was observed. Ó 2013 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 107 (2013) 423–427
Although recent biological and technological advances in lung cancer management have been made, disease recurrence is still the dominant cause of death after initial treatment of lung cancer [1]. When surgery or chemotherapy is not an option as treatment of a local recurrence, radiotherapy can be considered [2]. For patients who previously received irradiation, an additional radiotherapy treatment (or reirradiation) is often limited by the radiation tolerance of the anatomic structures surrounding the tumor. The potential toxicity to the surrounding tissues, like the spinal cord, the esophagus and other critical structures, limits the high dose needed to treat the tumor [3]. Throughout the years, various studies have tried to report the maximum doses that are acceptable for surrounding tissues for reirradiation [4,5]. Several authors did retreat small groups of patients with primary lung tumors and reported their results. Reirradiation to a median cumulative absolute dose of 80–110 Gy was feasible, however with a short median survival of 3–8 months because most treatments were given as palliative treatment [3,6–10]. These authors did report the toxicity, but the volume of field overlap and the accumulated dose to the tumor region and to the organs at risk were never reported. Therefore, the goal of the present study was to determine the accumulated dose–volume parameters
⇑ Corresponding author. Address: Department of Radiotherapy, Erasmus MCDaniel den Hoed Cancer Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail address: [email protected] (J.J. Nuyttens). 0167-8140/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.radonc.2013.03.015
to organs at risk after two irradiations in a group of 20 patients with cancer in the lung.
Methods and materials Patients and treatment From 2005 to 2012, 48 patients were reirradiated to the lung. Twenty patients were included in this study as they fulfilled the following criteria: (1) stereotactic body radiotherapy (SBRT) as first or second treatment, (2) an overlap of the two separate dose distributions (3) a treatment plan made by Xio (version 4.64.00, Elekta, Stockholm, Sweden) or Multiplan (version 2.2.0 or 3.5.3, Accuray, Sunnyvale, USA). All 20 patients received a curative treatment as the first treatment, 14 patients were first treated with curative SBRT and 6 patients with conventional chemoradiotherapy (1 concurrent, 5 sequential). The reirradiation consisted of 18 stereotactic treatments with curative intention, one curative conventional treatment and one palliative irradiation. Two patients received chemotherapy prior to the SBRT. SBRT was only used if the patient had only one PET-positive tumor in his body. All 6 patients who first got a conventional, curative irradiation were then treated using SBRT. The choice of the treatment schedule did depend on the proximity of the organs at risk as esophagus, trachea, mainstem bronchus and spinal cord and on the previous dose these organs at risk received. For peripheral tumors, 3 fractions were used,
424
Reirradiation for tumors in the lung
Table 1 An overview of the treatment schedules. Reirradiation
First radiation EQD2 (Gy3)
Median GTV (cc)
Total dose Number of (Gy) fractions
EQD2 (Gy10)
50-60 51–60 51–60 51 51 45 48 48 32 36 36 30 20
83-110 130–180 20 115–150 204–276 4 115–150 204–276 6 115 204 6 115 204 0.2 71 108 82 72 106 47 72 106 43 48 70 103 48 65 110 48 65 9 33 36 270 23 28 589
5 3 3 3 3 5 6 6 4 6 6 10 5
Median PTV (cc)
Total dose Number of (Gy) fractions
EQD2 (Gy10)
46 14 19 20 4 147 93 102 197 189 28 822 1734
60 51–60 60 50 30 60 60 45 60 50 45 48 60
150 276 12 115–150 204–276 2 65 72 73 50 50 106 100 198 0.2 150 276 15 110 180 32 49 54 109 150 276 21 52 55 240 44 43 84 72 106 70 150 276 53
3 3 20 25 1 3 5 15 3 20 25 6 3
EQD2 (Gy3)
Median GTV (cc)
Median PTV (cc) 34 10 440 402 3 38 72 375 59 982 519 131 111
Number of patients
5 3 2 1 1 1 1 1 1 1 1 1 1
EQD2, equivalent dose in 2 Gy per fraction; GTV, gross tumor volume; PTV, planning target volume.
for central tumors 5 or 6 fractions [11,12]. An overview of the treatment schedules is given in Table 1. All doses were recalculated to an Equivalent Dose of 2 Gy per fraction (EQD2), with the formula: d ⁄ n ⁄ ((d + a/ß)/(2 + a/ß)), with d the dose per fraction (Gy) and n the number of fractions. For tumor dose and acute side effects an a/ß value of 10 Gy was used (Gy10) and for late effects an a/ß value of 3 Gy (Gy3). Patient, tumor and treatment characteristics are shown in Table 2. For the SBRT, the dose was prescribed to the 70–85% isodose line, covering at least 95% of the PTV. The maximum dose was defined by the 100% isodose line. The toxicity was scored using the Common Terminology Criteria for Adverse Events (CTCAE 4.0).
Dose addition The XIO dose distributions were calculated using the superposition-convolution algorithm. The CyberKnife treatment plans were calculated with the Monte Carlo algorithm or recalculated with the Monte Carlo algorithm if the dose calculation for treatment planning was performed using the equivalent-path length method to account for tissue heterogeneities [13]. Table 2 Patient, tumor and treatment characteristics. Gender Male Female
Number of patients 14 6
Primary tumor Lung carcinoma Colorectal carcinoma Sarcoma
Number of patients 17 2 1
Stage Stage I Stage II Stage IV
Number of patients 10 1 9
Histology Adenocarcinoma Squamous cell carcinoma Clear cell carcinoma Small cell lung carcinoma No pathology
Number of patients 1 2 1 2 14
Median radiation dose to the tumor First radiation Reirradiation
Gy10, (range) 133 (44–150) 83 (23–150)
Median age at time of reirradiation (years) Median interval between the radiation (months) Median follow up after reirradiation (months)
71 (50–80) 17 (2–33) 12 (2–52)
The lungs and the heart were contoured completely. The esophagus, spinal cord, and trachea were contoured in each treatment plan in such a way that the length of the contoured organ was equal on both CT scans. The length of the contoured organ was based on anatomical structures such as the carina and the vertebra and was based on the extents of radiation fields of both plans. CT scans, dose distributions and structure sets were sent to an in-house developed software platform for analysis. First, two CT scans were aligned rigidly by using an automatic bone match (translation and rotations). Then for each organ individually, a non-rigid registration was applied based on the contours of the organs at risk. Previously, this method was applied to sum dose distributions of external beam radiotherapy and brachytherapy for oropharyngeal cancer patients [14–16]. Using the obtained transformation, the dose distribution of the reirradiation was mapped to the dose grid of the first treatment and the dose values were summed after having converted both dose distributions to a biologically equivalent dose in 2 Gy fractions (EQD2) [16]. Finally, dose volume histograms (DVHs) of the organs at risk were calculated using the summed dose distribution. The organs at risk with an accumulated Dmax over 70 Gy3 were selected and related to the toxicity that was recorded. The percentage of the lungs receiving 20 Gy3 or more (V20) and mean lung dose (MLD) were calculated without subtraction of the GTV, CTV, or PTV. The target of the first irradiation was not always at the same location in the lung as the target of the second irradiation. Dose addition of the lung with subtraction of the target would have resulted in a dose addition of a deformed lung. This deformed lung was not present at the time of the treatment, and would result in a wrong calculation. Therefore, we calculated the lung parameters (V20,. . .) without subtracting the GTV, CTV or PTV, and these parameters are not exactly the same as normally used in the literature. The volume of overlap between the 2 irradiation plans was determined at the dose level of 50% and 80% of the prescribed dose. These dose levels were determined by summing the dose level of 50% and 80% in the primary plan and in the reirradiation plan in EQD2, resulting in the 50% or 80% summed dose. The amount of overlap was defined as the total volume of the lungs receiving equal or more than the 50% and 80% summed dose. Results The median Dmax of the lung in the summed plans was 363 Gy3 (range 123–590 Gy3; Table 3). The median volume of overlap in the lungs was 48 cc (range 0.9–704 cc) for the 50% dose level and 18 cc
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T.R. Meijneke et al. / Radiotherapy and Oncology 107 (2013) 423–427 Table 3 Dmax of the lung (Gy3), Median V20, V13 and V5 (in %) of ipsilateral lung, contralateral lung and of both lungs for the summed and the single plans. Summed plan
First plan
Second plan
Dmax of the lungs (Gy3)
363 (123–590)
292 (47–384)
189 (29–417)
Median V20 Both lungs (%) Ipsilateral lung (%) Contralateral lung (%)
15 (3–47) 28 (6–73) 1 (0–47)
7 (0–37) 14 (0–66) 0 (0–19)
8 (0–15) 13 (0–31) 0 (0–30)
Median V13 Both lungs (%) Ipsilateral lung (%) Contralateral lung (%)
22 (4–55) 37 (7–77) 2 (0–55)
10 (1–41) 19 (1–70) 0 (0–32)
11 (1–37) 21 (2–68) 0 (0–6)
Median V5 Both lungs (%) Ipsilateral lung (%) Contralateral lung (%)
41 (8–72) 57 (14–83) 18 (0–68)
21 (1–61) 33 (3–77) 5 (0–44)
18 (0–39) 31 (0–59) 4 (0–22)
(range 0.2–279 cc) for the 80% dose level. Two patients did not have any overlap at the 80% dose level although the tumors were close to each other. An example of the dose summation is shown in Fig. 1. The median accumulated V20 of the lungs was 15.2%. The V20, V13 and V5 are shown in Table 3. The median accumulated MLD for the whole group was 15 Gy3 (range 4.2–27.6 Gy3). Seven patients had an accumulated dose P70 Gy3 in the heart and the trachea. The median Dmax of the heart in these 7 patients was 115 Gy3, and for the trachea 89 Gy3. The results for the first and second plan are shown in Table 4. Eight patients had an accumulated dose P70 Gy3 in the esophagus. The median accumulated dose of these patients was 85 Gy3 (range 71–123 Gy3). Other structures, like the spinal cord and the plexus brachialis did not receive P70 Gy3 in the summed plan. No acute and late grade 3–5 toxicity during or after the reirradiation was recorded. Four patients had dyspnea (one acute, three late), two patients complained of acute pain, one of late pain and two of acute dysphagia. The reirradiation showed no acute or chronic skin intoxications or nausea. Two patients had rib fractures, one patient was without any symptom, the other had chronic pain. Four patients received a MLD above 20 Gy3 and two of them had a V20 above 40%. No pulmonary complaints were recorded for these patients after the treatment. One patient died at nine months after the treatment due to peritonitis carcinomatosa, the other patient is now seven months in follow-up and has had no pulmonary complaints, the third patient is now 2 years in follow-up and has no pulmonary complaints and the last patient died at eleven months after the treatment due to cardiac failure.
The median overall survival was 15 months. The 1- and 2-year overall survivals were 67% and 33%, respectively. Nine patients died in total, 4 patients died due to tumor progression or related symptoms. Five patients died due to other causes: 2 due to cardiac causes, one due to cerebral hemorrhage, one due to a fall and the death of the last patient was unknown. The Dmax of the heart of the 2 patients with a cardiac cause of death was 8.4 Gy3 and 14.4 Gy3 in the summed plan. The median time to local failure was 22 months. The 1-year local control rate was 75% and the 2-year rate was 50%. The median disease free survival was 9.7 months and the 1-year disease free survival was 50%.
Discussion Dmax and organs at risk The median Dmax of the lung in the summed plans was 363 Gy3 (range 123–590 Gy3). Although this was high, no high toxicity score was present among the patients. In the search for more literature about Dmax and toxicity in lung cancer, no literature was found. For head and neck cancer acceptable toxicity was observed considering a median accumulated lifetime dose of 111 Gy [17]. Abusaris et al. concluded that reirradiation for the rectum, bowel and bladder using extra-cranial SBRT was feasible and resulted in a 96% symptomatic response with low toxicity [18]. She also reported that a second reirradiation with a median accumulated maximum dose of 133 Gy3 to these regions was safe [4]. Three patients showed a V20 over 40%. Two of these patients had no pulmonary toxicity, the third patient complained of acute
Fig. 1. An example of the accumulated dose distribution in a patient a: the dose distribution of the first irradiation in absolute dose; b: the dose distribution of the reirradiation in absolute dose; c: the accumulated dose distribution in EQD2.
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Reirradiation for tumors in the lung Table 4 Organs with an accumulated Dmax P70 Gy3. Median (Gy3)
Range (Gy3)
Median volume P70 Gy3 (cc)
Range (cc)
Heart (n = 7) Summed plan First plan Second plan
114.5 71.3 95.6
74.2–271.4 4.2–223.4 16.2–232.7
1.4
0.01–53.4
Esophagus (n = 8) Summed plan First plan Second plan
85.2 60.7 37.1
70.5–123.2 1.5–76.9 2.1–82.4
3.4
0.03–10.3
Trachea (n = 7) Summed plan First plan Second plan
89.2 49.8 65.1
72.3–122.4 19.8–77.5 1.4–113.1
2.1
0.04–20.0
pain (grade 2). Four patients showed a MLD above 20 Gy3. Two of them died but not due to pulmonary problems, the other two patients are still alive. Peulen et al. did not report any statistical correlation between MLD and frequency of grade 3–5 lung toxicity after reirradiation [19]. Only three patients (15%) complained of dyspnea grade 1, and one patient (5%) of dyspnea grade 2. Both showed no sign of clinical radiation pneumonitis (RP). Okamoto et al. described that RP was more frequently experienced after reirradiation, but no cases of grade 4 or 5 RP occurred [9] and Montebello et al. described only one patient out of 30 with symptomatic RP [8]. This low percentage seems to correspond with our results. Two patients (10%) complained of acute dysphagia grade 1 after reirradiation. Both patients had an accumulated esophagus dose above 70 Gy3. Although there were no clinical signs of acute esophagitis among our patients, other authors did report esophagitis after reirradiation [10]. The low number of side effects can be explained by the median follow-up of only 12 months. A longer follow up may reveal a higher late toxicity rate. On the other hand, we previously published excellent quality of life after stereotactic radiotherapy [11,20]. This was probably so because we only did irradiate a small volume. Current data seem to support that a high maximum summed dose is feasible and safe because a small volume of recurrent disease was reirradiated to a very high dose. A dose volume effect could play a role in the appearance of side effects. However, due to the limited number of patients included in this study, we were not able to look at this dose volume effect.
Survival and outcome The median survival was 15 months. This is in accordance with the results shown by Jeremic´ et al, who reported a median survival time ranging from 5 to 14 months [21]. However, it is difficult to compare both studies as our study population has different stages. Nine patients died after reirradiation, but 5 patients died of non-tumor related causes. The large percentage of non-tumor related deaths was not unexpected as 14 of the 20 patients were no surgical candidates due to their comorbidities. The mean time of local control was 24 months. It is remarkable that in this small group 4 patients had a local recurrence after irradiation despite the high dose (>82 Gy3) which was given to the tumor.
Dose addition Dose addition of two treatment plans based on different CT scans requires a registration from one to the other coordinate system. A rigid registration leads to unsatisfactory results when organs are deformed at one time point with respect to the other time point. In those cases non-rigid registration is required. The
algorithm employed here matches the contoured boundaries of the organs. The deformation field is extrapolated to the inner part of the organ using the transformation function obtained. This method was validated for three-dimensional dose addition of external beam radiotherapy and brachytherapy for oropharyngeal patients by applying a robustness analysis. The non-rigid registration framework was also validated to quantify deformations of the prostate including seminal vesicles, for cervical cancer patients experiencing extreme deformations as a result of bladder filling variations, and to align vessel trees in largely deformed livers [14,15,22]. The results of these studies support the use of the non-rigid registration method to sum dose for lung cancer patients, as the degree of deformation in the current patient group is significantly less than e.g. observed in cervix patients. Still, inevitable anatomic inaccuracies in the non-rigid registration will propagate to the summed dose distributions, which will be mostly pronounced in the target region of the primary treatment plan. For selected patients, reirradiation to the lungs with median accumulated Dmax of 363 Gy3 appeared to be feasible and safe, because low toxicity was found. A median accumulated V203 of 15.2% and accumulated doses more than 70 Gy3 to the heart, trachea and esophagus did not result in severe toxicity.
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