Helical Tomotherapy Targeting Total Bone Marrow After Total Body

Radiotherapy and Oncology 98 (2011) 382–386

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Helical tomotherapy Helical tomotherapy targeting total bone marrow after total body irradiation for patients with relapsed acute leukemia undergoing an allogeneic stem cell transplant ⇑ Renzo Corvò a,c, , Michele Zeverino b, Stefano Vagge a,c, Stefano Agostinelli b, Salvina Barra c, Gianni Taccini b, Maria Teresa Van Lint d, Francesco Frassoni d, Andrea Bacigalupo d a University of Genoa, Italy; b Department of Medical Physics, National Cancer Research Institute, Genoa, Italy; c Department of Radiation Oncology, National Cancer Research Institute, Genoa, Italy; d Department of Hematology, BMT Unit, San Martino Hospital, Genoa, Italy article info abstract

Article history: Background and purpose: To report our clinical experience in planning and delivering total marrow irra- Received 31 August 2010 diation (TMI) after total body irradiation (TBI) in patients with relapsed acute leukemia undergoing an Received in revised form 1 December 2010 allogeneic stem-cell transplant (SCT). Accepted 4 January 2011 Materials and Methods: Patients received conventional TBI as 2 Gy BID/day for 3 days boosted the next Available online 19 February 2011 day by TMI (2 Gy in a single fraction) and followed by cyclophosphamide (Cy) 60 mg/kg for 2 days. While TBI was delivered with linear accelerator, TMI was performed with helical tomotherapy (HT). Keywords: Results: Fifteen patients were treated from July 2009 till May 2010, ten with acute myeloid leukemia, and Total marrow irradiation ﬁve with acute lymphoid leukemia. At the time of radiotherapy eight patients were in relapse and seven Helical tomotherapy Allogeneic stem-cell transplant in second or third complete remission (CR) after relapse. The donor was a matched sibling in 7 cases and Acute leukemia an unrelated donor in 8 cases. Median organ-at-risk dose reduction with TMI ranged from 30% to 65% with the largest reduction (-50%–65%) achieved for brain, larynx, liver, lungs and kidneys. Target areas (bone marrow sites and spleen in selected cases) were irradiated with an optimal conformity and an excellent homogeneity. Follow-up is short ranging from 180 to 510 days (median 310 days). However, tolerance was not different from a conventional TBI-Cy. All patients treated with TBI/TMI reached CR after SCT. Three patients have died (2 for severe GvHD, 1 for infection) and 2 patients showed relapsed leukemia. Twelve patients are alive with ten survivors in clinical remission of disease. Conclusions: This study conﬁrms the clinical feasibility of using HT to deliver TMI as selective dose boost modality after TBI. For patients with advanced leukemia targeted TMI after TBI may be a novel approach to increase radiation dose with low risk of severe toxicity. Ó 2011 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 98 (2011) 382–386

Total body irradiation (TBI) continues to play an important role tial TBI/TMI schedule in patients with acute leukemia in advanced in the conditioning regimens for patients undergoing stem-cell stage of disease undergoing an allogeneic SCT. transplant (SCT) for a wide variety of hematological malignancies [1,2]. However, increasing the total dose of TBI for patients with advanced acute leukemia may improve malignant clone killing Materials and methods but is associated with potential lethal toxicity [3]. Total marrow irradiation (TMI) delivered with helical tomotherapy (HT) may Patients overcome this problem [4–6]. Indeed, HT has the potential to con- Fifteen patients with poor-prognosis acute leukemia received form the radiation dose selectively to the body sites harboring leu- an allogeneic SCT between July 2009 and May 2010. The San Mar- kemia stem cells by reducing, meantime, the dose is delivered to tino Hospital Research Ethics Board, Genoa, approved the study. organs-at-risk of severe side effects [7,8]. Targeted TMI may be Patients enrolled into this study gave their consent to be treated delivered as selective dose boost modality after conventional TBI with the devised radiotherapy approach. Table 1 outlines clinical in the attempt to increase safely the total radiation dose. In this characteristics of the patients. Ten patients were with acute mye- study we investigated the clinical feasibility of an original sequen- loid leukemia, 5 in relapse status, and 5 in second clinical remission (CR) while ﬁve patients were with acute lymphoid leukemia,

⇑ Corresponding author at: Department of Radiation Oncology, National Cancer 3 in relapse status, one in second CR, and one in third CR. The med- Research Institute and University, Largo R. Benzi, 10, 16132 Genoa, Italy. ian blast count was 30% (7–100%) and the median peripheral blood E-mail address: [email protected] (R. Corvò). blast count was 2% (0–100%).

Table 1 For the second scan patients were positioned with feet first orien- Clinical and transplant characteristics and outcome. tation and scanned from the tip of the feet to the knees for the low- Characteristics n Status/cause of event er TMI planning. Ankles were positioned with the fixation device Median age (years) 35 (18–55) according to the first scan. CT data sets were sent for contouring Gender M/F 10/5 on the Eclipse treatment planning system (Varian Medical System, Diagnosis Palo Alto, USA) and then exported using DICOM-RT format to AML 10 Relapse (5), CR2 (5) tomotherapy planning System. For both CTs PTV resulted from ALL 5 Relapse (3, CR2 (1), CR3 (1) the isotropic expansion (4 mm) of the bone volumes; PTV repre- Transplant donor HLA id SIB 7 sents the bone targets that are active bone marrow sites such as HLA unrelated 8 the head (cranium and mandible), upper limb girdle (humerus, Acute GVHD scapulae, clavicles), sternum, ribs, vertebrae (cervical, thoracic, II 12 lumbar and sacrum), lower limb girdle (ox coxae, and femoral III 3 Chronic GVHD head), and lower extremities till tips of feet. Spleen was also in- Limited 13 cluded in the PTV when largely expanded in dimension. Normal Extensive 2 structures to be avoided included brain, eyes, parotid glands, oral Median follow-up (days) 310 (180–510) mucosa, larynx, thyroid, esophagus, lungs, heart, liver, kidneys, Leukemia relapse rate 2 (13%) small bowel, rectum, and bladder. Testes were considered as vol- Treatment-related mortality 3 (20%) cGVHD (2), infection (1) Disease-free survivors 10 (67%) umes-of-interest (VOI). The planning technique developed in our Overall survivors 12 (80%) Department in order to merge helical dose distributions along the entire patient axis is described elsewhere [11]. Briefly, for AML: acute myeloid leukemia, ALL: acute lymphoid leukemia; CR: clinical remission, CR2: second clinical remission; CR3: third clinical remission; GVHD: graft TMI plan parameters were set as follows: 5 cm for the field width, versus host disease, id SIB: identical siblings. pitch of 0.287, and modulation factor ranging from 1.5 to 2. Before TMI treatment all patients received at least three MVCT scans in order to check their alignment. The first scan was taken in the head/ Conditioning regimen neck region and included eyes and mandible, the second scan in- Major conditioning regimen was Total Body Irradiation (12 Gy cluded part of the lung volume and the third scan included the kid- in 6 fractionated doses, 2 Gy BID, 6 h apart) on days-7, -6, and -5 neys and part of the pelvic region. The average of any roto- followed by total marrow irradiation (2 Gy in single fraction) on translational shifts was applied to the final patient set-up before day -4 and by cyclophosphamide (Cy) 60 mg/kg/day per 2 days TMI. Dose point verification was carried out using a set of direct on days -3 and -2, being 0 day the time of allogeneic SCT. ion chambers (A1SL, Standard Imaging, Madison, USA) located in TBI was performed in AP/PA setting using the 6 MV beam of a the target at various anatomical regions (i.e. skull, sternum and Clinac 2100 CD linear accelerator (Varian, Palo Alto, USA). Every ribs) while GafChromic EBT2 (ISP Corporation, NJ, USA) were used patient was treated in a semi-standing position alternately facing for dose distribution verification of coronal planes encompassing and turning their back to the beam. In order to obtain a more either the brain or the lungs [11]. homogeneous dose distribution a plexiglas beam spoiler was used. Gantry rotation was 270° and the collimator was open to its max- Stem-cell transplant imum field size, 40 Â 40 cm2. The source axis distance was 500 cm. The dose prescription point was at navel level on the patient cen- Donor bone marrow was the stem cell (SC) source in all pa- tral axis. Personalized lung shields were used to compensate for tients. Seven patients received SC from HLA identical siblings and the different densities and to reduce the dose to the lungs by eight patients SC from unrelated donors. Marrow from unrelated 17% (i.e. 10 Gy) compared to the prescription point nominal dose donors was provided by the Italian National Marrow Donor Regis- (12 Gy). Dose calculation was provided by our in-house algorithm try. Unrelated donor was matched according to the criteria at the which computes the central axis dose at four different levels: abdo- time of transplant. All patients received GvHD prophylaxis with men, thorax, lungs, and head. This allowed optimizing the dose methotrexate and cyclosporine. Patients were monitored for cyto- delivery in order to maintain the dose to each body district with- megalovirus antigenemia and received pre-emptive therapy with in ±5% of the prescription dose. This was confirmed by in vivo foscarnet or gangiclovir or combined treatment. High dose intrave- dosimetry which was performed for every patient by using a set nous IgG were given at doses ranging between 100 and 400 mg/kg/ of semiconductor diode detectors (PTW, Freiburg, Germany) for week until day 100. Fluconazole was used as standard fungal pro- the measurement of entrance and exit dose [9,10]. phylaxis until day 75 [12]. TMI was performed by Helical Tomotherapy (Tomotherapy Hi- Art, Madison, USA). HT can deliver an image-guided IMRT treatment of maximum size of 40 cm wide by 160 cm long resulting Clinical end-points the most appropriate technique to be adopted for TMI treatment The main end-point of the study was to evaluate the clinical [7]. Two CT scans with a slice thickness of 1 cm were collected feasibility of the sequential TBI/TMI approach. The investigation for every patient [11]. For the first scan patients were immobilized assessed the occurrence of acute and chronic GVHD and other by means of two thermoplastic masks (ORFIT Industries, Belgium) treatment-related events. Grading of acute and chronic GVHD fol- fixed to the all-in-one (AIO) solution base plate. The first mask lowed the commonly accepted criteria [13]. Secondary end-points immobilized the head and the neck while the second mask immo- were the achievements of engraftment and clinical remission after bilized the arms and the hands close to the thorax. Hands of the pa- SCT and the rate of early leukemia relapse. tients were positioned on the groins with the fingers closed to each other to ensure a good reproducibility. In addition, ankles were Results placed in an appropriate fixation device (Combifix, Civco Medical Solutions, USA) to minimize lower limbs motion. Scan volume runs TMI planning and delivery from the vertex to the knees for upper TMI planning. Fiducial markers were placed at the shoulder level and lasers were marked All the patients completed the 14 Gy TBI/TMI schedule in the on the thermoplastic masks for treatment position and alignment. planned overall time. The dose coverage to the bone marrow sites 384 Total marrow irradiation in acute leukemia

Fig. 1. Sectional views of TMI dose painting shown in a patient with relapsed acute leukemia. provided by TMI is shown in a color wash presentation in Fig. 1. Table 2 Mean PTV D95 (i.e. the dose received by the 95% of the target vol- Median organ dose reduction by TMI and median overall total doses received after ume) and mean D5 (i.e. the dose received by the 5% of the target TBI/TMI schedule. volume) equal to the 93.3% and the 102.9% of the prescribed dose Organ Median dose Range Median total dose respectively, conﬁrming an optimal plan quality. The median dose reduction (%) with TMI TBI plus TMI reduction for different OARs is reported in Table 2. As it is shown, Brain 48.1 41.0–60.0 1304 cGy dose sparing ranged approximately from 30% to 65% of prescribed Parotid gland 29.3 15.0–43.5 1342 cGy dose with the largest reduction (À50%, À65%) achieved for eyes, Eye 52.0 30.2–60.5 1296 cGy Oral mucosa 42.1 20.5–50.0 1316 cGy larynx, breast, liver, kidneys, bowel, and pelvic organs. Small or- Larynx 54.5 43.0–61.7 1292 cGy gans located in the head region as parotids and oral mucosa were Thyroid 48.4 27.5–51.0 1304 cGy less spared than others due to the choice of treatment parameters. Lung 48.8 41.0–53.0 1102 cGya The average total doses received by different OARs irradiated with Breast 61.0 45.1–68.2 1278 cGy 12 Gy TBI and 2 Gy TMI are reported in Table 2. Esophagus 48.0 40.0–58,2 1300 cGy Heart 46.7 43.0–52.5 1300 cGy The upper TMI beam on time ranged from 17.5 to 23 min with Liver 52.3 43.5–60.0 1296 cGy an average of approximately 20 min. The lower TMI beam on time Bowel 53.7 47.7–59.5 1292 cGy ranged from 6 min to 12 min with an average value of 9 min. No Kidneys 63.0 47.0–73.0 1274 cGy acute adverse effects as nausea or vomiting occurred during TMI Bladder 62.1 50.2–69.3 1276 cGy Rectum 58.4 48.2–65.2 1283 cGy delivery. Overall, tolerance to 14 Gy TBI/TMI plus Cy was not differ- Uterus 64.7 58.0–76. 1270 cGy ent from a conventional 12 Gy TBI plus Cy approach. a Average lung dose with TBI was kept below 1000 cGy in 6 fractions.

Transplant outcome Follow-up ranges from 180 to 510 days (average: 310 days). in 13 (87%) patients and severe cGvHD in the remaining 2 (13%) pa- Engraftment was achieved in all patients with timing ranging from tients. Three patients have died, respectively due to severe cGVH at 8 to 35 days from transplant. Acute grade II GvHD developed in 12 294 and 76 days and due to lethal infection at 112 days post-trans- patients and grade III in 3 patients. Limited chronic GvHD occurred plant. Two patients have relapsed at 120 and 160 days: the first pa- R. Corvò et al. / Radiotherapy and Oncology 98 (2011) 382–386 385 tient was affected by acute lymphoid leukemia in third clinical age dose reduction (>50%) was obtained for eyes, larynx, breast, li- remission; the second was with acute myeloid leukemia in relapse ver, kidneys, bowel, and pelvic organs (bladder, rectum and status at time of transplant. Twelve patients (80%) are alive with uterus). A minor average dose reduction (<50%) was observed for ten (67%) patients surviving in clinical remission of disease. brain, parotid glands, oral mucosa, thyroid, and heart. These dosimetric data well compare with data reported recently by other authors exploring fractionated TMI by HT for hematological malig- Discussion nancies [4,6,19]. As reported in Table 2, the average total doses delivered with TBI/TMI to critical organs as lungs, heart, kidneys, Recently, Total Marrow Irradiation delivered by Helical Tomo- and liver remained not superior to 1300 cGy without occurrence therapy has been proposed to deliver a more targeted conformal of clinical toxicities. Specifically, the average dose reduction by form of TBI [4]. Dosimetric studies with TMI demonstrated reduced TMI for lungs was approximately 48%. Considering that with TBI doses to critical organs which predicted for reduced toxicities [6]. lung dose was preserved by personalized shielding to an average TMI has been mainly explored as single radiation modality associ- maximum dose of 1000 cGy in 6 fractions, the average overall lung ated with different conditioning chemotherapeutic agents for pa- dose received after TMI was approximately 1100 cGy in 7 fractions tients with acute leukemia or multiple myeloma candidates to of radiotherapy. Since no interstitial pneumonitis occurred in our hemopoietic stem-cell transplant [7]. However, the clinical experi- patients at the median follow-up of 6 months we suggest that this ences on TMI are still limited with a low number of patients trea- TBI/TMI schedule was safe and further escalating doses of TMI ted so far [7,8,14]. Interestingly, conformal TMI may be an could be delivered without the risk of lung as a dose-limiting nor- attractive method to target specific body structures with leukemia mal tissue for radiotherapy [20]. Conversely, as reported from burden without the risk of severe radiation-induced side-effects other experiences [6,8], small organs located in the head region [15]. In this feasibility study we explored TMI as ‘‘selective boost’’ as eyes, parotids, and oral mucosa were less spared than others modality to increase radiation dose to the marrow after the deliv- due to the choice of treatment parameters: thus we cannot exclude ery of a conventional 12 Gy TBI schedule. The rationale we fol- that severe oral mucositis could occur also by using TMI after TBI. lowed to explore this novel sequential TBI/TMI approach was In the current series one patient suffered grade 3 oral mucositis based on several convincing reasons. First, TBI should remain in even if other transplant-related factors such immunosuppression the standard radiation schedule in the conditioning regimen of pa- could have played a major role. It is important to stress that by tients with advanced leukemia since it has been successfully used HT planning individualized doses to specific body sites, such as at our institution for over three decades, providing good clinical sanctuary organs as testes or brain, can be varied for single patient outcome especially in patients receiving an HLA-matched alloge- on the basis of previous disease history or co-morbidities. The neic stem-cell transplant from an unrelated donor [16,17]. Other understanding of the influence of each individual physical param- experiences and a recent meta-analysis seem to confirm our sug- eter (field width, pitch and modulation factor) is essential to im- gestions [1,2,18]. TBI assures a good coverage of entire body by prove target dose coverage as well as critical tissue dose and avoiding the risk of leukemia relapse in sites such as skin. Second, delivery time [21]. since increasing the dose of TBI is not advisable due to the high risk In conclusion, the current report describes the clinical feasibility of increased toxicity mainly to the lungs, liver, and kidneys, addi- of using HT to deliver TMI as selective dose boost modality after tional radiation dose should be elapsed only by advanced tech- conventional TBI in the attempt to increase safely the total radia- nique as TMI having the potential to target only bone marrow; tion dose. Further assessment of this novel modality appears justi- moreover, it is possible to increase the dose of TMI with a multi- fied. A dose escalation trial to determine the maximum tolerated step process by adding 1 or 2 Gy per step up to 18–20 Gy with dose of TMI given as multi-step boost irradiation after TBI is now the potential of a reduced risk of radiation-related toxicity. ongoing at our institution for the treatment of patients with acute Although 16 Gy has been recently suggested as the maximum tol- leukemia relapsed after previous SCT. erated dose for twenty patients with multiple myeloma treated with fractionated TMI [14], the top level of TMI dose achievable in allogeneic SCT for advanced leukemia has not been yet assessed Conflicts of interest statement [18]. As previously observed [16] in allogeneic SCT, a higher dose of radiation might be correlated with a higher probability of develop- None. ing chronic GVHD, considered as the clinical expression of Graft- vs-Leukemia [17]. In this investigation we present the preliminary Acknowledgments data obtained exploring the clinical feasibility of adding 2 Gy TMI to 12 Gy TBI. Preliminary results showed that in a selected group This study was partly supported by Fondazione CARIGE, Genoa, of poor-prognosis patients with advanced acute leukemia trans- Italy. planted in relapse status or in second or third remission the tolerance was not different from the conventional TBI-Cy conventional References regimen. No patient suffered from severe acute toxicity during radiation course. Even if the main end-point of the investigation [1] Shi-Xia X, Xian-Hua T, Hai-Qin X, et al. Total body irradiation plus was a clinical feasibility of this novel approach we observed that cyclophosphamide versus busulphan with cyclophosphamide as conditioning at the median follow-up of 310 days (range: 180–510 days) only regimen for patients with leukemia undergoing allogeneic stem cell 2 patients have relapsed. 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