Case study Strahlenther Onkol 2014 · 190:411–415 DOI 10.1007/s00066-013-0511-2 Received: 26 June 2013 Accepted: 8 November 2013 Published online: 7 February 2014 © Springer-Verlag Berlin Heidelberg 2014
F. Oskan1, 2 · U. Ganswindt1 · C. Belka1 · F. Manapov1 1 Department of Radiation Oncology, Ludwig-Maximilians-University Munich 2 Department of Radiation Oncology, University Hospital of Saarland, Homburg (Saar)
Primary non-small cell lung cancer in a transplanted lung treated with stereotactic body radiation therapy A case study
During the past two decades, there has been a gradual increase in the number of patients with lung transplant presenting with primary neoplasia [2, 21]. While high frequency of bronchogenic carcinoma in native lung after single-lung transplantation has been reported [13], lung cancer of donor origin is an extreme rare phenomenon. The first case of a primary lung cancer in transplanted lung was described in 2001. Since then, only five cases of lung cancer in donated lung have been reported. In this paper, we report on a case of early stage primary non-small cell lung cancer (NSCLC) lung cancer in a transplanted lung treated with stereotactic body radiation therapy (SBRT).
Case presentation A 59-year-old Caucasian woman with an alpha-1 antitrypsin deficiency and endstage emphysema received right singlelung transplantation in April 2004. Because of prolonged immunosuppression, the patient developed recurrent pulmonary infections. She was also diagnosed with chronic renal failure caused by immunosuppression drug use. In August 2008, an incidental nodule in the right upper lobe was detected in a routine chest Xray. A chest computer tomography (CT) demonstrated a 0.9×0.6 cm mass. One year later, a new chest CT showed an enlargement of this lesion that then sized 1.5×1 cm. She was admitted to the hospital in September 2009 for diagnostic evaluation.
At the time of hospitalization, she was free from any symptoms of chronic obstructive pulmonary disease (COPD) exacerbation and had no B-systematic complaints such as weight loss, night sweats, or general weakness. Laboratory findings revealed a white cell count of 6×109/l, 12.4 g/dl hemoglobin, and a platelet count of 290×109/l. Routine chemistry demonstrated a creatinine value of 2 mg/dl and urea of 83 mg/dl. Arterial blood gas analysis showed pO2 of 61 mmHg, pCO2 39 mmHg, and pH of 7.45. Serum levels of tacrolimus and mycophenolic acid were 6 μg/l (normal range 5–15 μg/l) and 1.9 μg/l (no normal range but 4–12 μg/l), respectively. Body plethysmography revealed a forced expiration volume at first second of FEV1 =1.2 l (49% of predicted). In the electrocardiogram, a left type AVblock I° was seen. Esophageal ultrasonography, gastroscopy, and coloscopy were unremarkable. In the chest CT, signs of emphysematous changes in the left lung fields were prominent, and a 1.6×1.2 cm sized, thus,
progressing mass in the right upper lobe was demonstrated (. Fig. 1). The combined positron emission tomography (PET) showed a pathological intensive glucose metabolism in the right upper lob with a maximum standardized uptake volume (SUV) of 13.6, and much lower metabolism in the lower and middle lobe with SUV max of 5.5, which were morphologically interpreted as atypical inflammatory process due to immunosuppression. No lymph node involvement or distant metastases were observed. Transthoracic fine needle aspiration was performed to confirm the malignancy of the upper lobe mass. Pathological examination was reported as moderately differentiated invasive SCC. The tumor was classified as cT1acN0 cM0 (Stage Ia) according to TNM classification (UICC). Because of medical co-morbidities, immunosuppression after lung transplantation, and compromised lung function, SBRT of the right upper lobe mass was deemed to be the most appropriate treatment option by the multidisciplinary tu-
Fig. 1 8 Transverse slice of matched PET-CT (left) and CT lung window (right) at initial diagnosis showing pathological metabolisms in the right upper lobe mass Strahlentherapie und Onkologie 4 · 2014
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Fig. 2 9 Sagital, coronal, and transversal slices representative of SBRT isodose distribution and beam arrangement
Volume [%] ITV PTV
80.00
Rib1+3 60.00
Rib2 Lung sum
40.00
Lung right Lung left
20.00
Spinal cord 0.00 0.00 Region of interest
20.00
40.00
60.00
Dose [Gy]
ITV
Min (Gy) Max (Gy) Median (Gy) Average (Gy) Std.Dev (Gy) Dose Volume (ccm) 68.9 76.7 73.8 73.8 1.6 7.23
PTV
56.9
76.7
70.5
70.2
5
25.56
Rib 1+3
34.9
70.9
58.3
56.9
11.3
3.95
Rib2
27.3
56.9
40.4
41.4
7.9
4.03
Lung sum
0.08
76.7
0.5
3.5
9.0
3285.7
Lung r.
0.15
76.7
0.9
7.1
14.2
1153.75
Lung le
0.08
18.3
0.4
1.5
2.9
2150.82
Spinal co
0.03
1.8
0.2
0.3
0.2
61.5
Fig. 3 8 Dose–volume histograms showing dosimetric parameters analyzed including targets and organs at risk
Fig. 4 9 Transversal slice of control chest-CT performed 9 months after SBRT procedure demonstrating residual tumor and lung fibrosis
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mor board. Prior to radiation treatment, a dynamic planning CT with three breath phases (mid-ventilation, end expiration, and end inspiration) was performed in stereotactic treatment position in a vacuum system with both arm raised above the head using an arm rest. The internal target volume (ITV) was constructed by union of all delineations of the gross tumor volume (GTV) of the right upper lobe mass in all breathing phases, and a margin of 5 mm in all directions was added to generate the planning target volume (PTV). A dose of 7.5 Gy in 8 fractions was prescribed to the 80% isodose line covering the PTV. Eight static beams (. Fig. 2, 3) with energies of 6 MV were used. The radiation was delivered with daily electronic imaging and megavoltage cone beam CT (MV-CBCT)based guidance to verify the treatment position. The total dose of 60 Gy (biologic effective dose, BED10 =105 Gy) was delivered during a 2 week period in October 2009 without complication or exacerbation of the known respiratory insufficiency. At follow-up in February 2010 (3 months after SBRT), a control chest CT showed partial remission in the right upper lobe mass, which at the time had a diameter of 0.6×1 cm, but also radiographic signs of radiation pneumonitis. The patient reported no clinical symptoms. In July 2010 (9 months after SBRT), a CT chest was performed and demonstrated scarcely impounded tumor residual in the right upper lobe combined with area of lung fibrosis (. Fig. 4). A FEV1 of 1.1 l was revealed by body plethysmography. Restaging PET-CT performed 14 months after SBRT in December 2010 showed resid-
Abstract · Zusammenfassung ual activity in the right upper lobe mass with SUV max 9, as well as multiple new lesions in the right lung (. Fig. 5). In February 2011, CT-guided puncture of two lesions were done. The pathological examination of obtained martial from the central localized lesion showed no signs of malignancy. The biopsy from the dorsal lesion confirmed malignancy and the patient did not receive further oncological therapy. The last follow-up contact was made in July 2011, namely 22 month after initial diagnosis.
Discussion Patients with lung transplantation are at an increased risk of developing malignancy with a prevalence of 2–4% for lung cancer after single or bilateral transplantation [9, 13, 23, 25]. Although prolonged immunosuppressive therapy and the underlying disease with inherent increased risk of malignancy might play a key role [2, 11, 21, 23], the causal mechanisms remain unclear because of very limited data. In most reported cases, the diagnosis of lung cancer was based on an incidental radiological finding of a new or an enlarging nodule or mass in asymptomatic patients [9, 11, 23]. However, the majority of pulmonary nodules are reported to be of infectious origin [18]. In several studies, the time interval between transplantation and manifestation of lung cancer ranged between 3 and 5 years [9, 13, 23, 25]. The majority of cases are diagnosed in native lungs of transplant patients. On the other hand, reports on primary lung cancer in the lung of donor origin are extremely rare. The first case of primary lung cancer of donor origin after bilateral lung transplantation was described in 2001 by De Soyza et al. [12]. Their patient was a 25-year-old who developed metastatic small cell carcinoma 13 month after bilateral lung transplant due to cystic fibrosis. The patient underwent standard chemotherapy with no clinical response and died 1 month after. Beyer et al. [5] reported a case of moderately differentiated adenocarcinoma diagnosed in the donor lung 33 months after bilateral pulmonary transplantation. The tumor was treated surgically.
In addition to these patients, the case of a patient who received bilateral lung transplantation as treatment for endstage usual interstitial pneumonia resulting in idiopathic lung fibrosis was reported by von Boehmer et al. [26]. Seven months later, the patient developed a large cell carcinoma in the right mediastinal lymph node and two small intrapulmonal nodules in the middle lobe. She underwent 3 cycles of neoadjuvante chemotherapy with pemetrexed and carboplatin with no clinical response and then underwent an extended right pneumonectomy with a pathological stage ypT4ypN2. At the 4-month follow-up, a PET-CT demonstrated diffuse metastatic lesions in the bone and a new lesion in the superior lingua of the left lung. She died 7 months after initial diagnosis. De Boer et al. [10] described a patient who developed primary metastatic NSCLC 5 years after bilateral lung transplantation. Due to expected complications caused by immunosuppressive therapy, it was decided not to treat the patient with chemotherapy. Chao et al. [8] reported on a patient harboring a large cell carcinoma in the left lower lob 24 months after bilateral lung transplantation. She underwent a left lower lobe wedge resection. Five month later, a PET-CT revealed multiple metastases in the liver and bones. The patient refused chemotherapy and died. Surgery remains the cornerstone treatment of early stage NSCLC in transplanted patients. Nevertheless, the outcomes of surgical treatment of malignant lung tumor in solid organ transplant recipients remain unsatisfied. Anyanwu et al. [1] reported on 17 cases of primary lung carcinoma diagnosed between 1990 and 2000 in patients who have previously undergone thoracic transplantation. Most of them (13/17) were asymptomatic at presentation and presented with an incidental abnormality noted on chest radiography. Of these, 8 patients underwent surgical resection, 5 received radiation therapy, 2 were treated with chemotherapy, and 2 with chemo- and radiotherapy. The 5-year survival of patients with stage I disease was 35%. Of the 8 patients who underwent surgical intervention, 1 patient died in the postoperative period, and 3 pa-
Strahlenther Onkol 2014 · 190:411–415 DOI 10.1007/s00066-013-0511-2 © Springer-Verlag Berlin Heidelberg 2014 F. Oskan · U. Ganswindt · C. Belka · F. Manapov
Primary non-small cell lung cancer in a transplanted lung treated with stereotactic body radiation therapy. A case study Abstract The first case of primary lung cancer in a transplanted lung was described in 2001. Since then, only 5 cases of lung cancer in donated lung have been reported. We present one more patient with non-small cell cancer in the transplanted lung treated with stereotactic body radiation therapy. In most cases of primary lung cancer in transplanted lung, rapid progression of the cancer was reported. Occurrence of the locoregional failure in our case could be explained by factors related to the treatment protocol and also to underlying immunosuppression. Keywords Lung neoplasms · Organ transplantation · Immunosuppression · Stereotactic body radiotherapy · Bronchial neoplasms
Primäres nicht-kleinzelliges Bronchialkarzinom in einer mit stereotaktischer Körperstrahlentherapie behandelten transplantierten Lunge. Eine Fallstudie Zusammenfassung Der erste Fall eines primären Bronchialkarzinoms in einer transplantierten Lunge wurde im Jahr 2000 beschrieben. Seither sind nur 5 Fälle von primärem Lungenkrebs in einer Spenderlunge berichtet worden. Wir präsentieren einen weiteren Patienten mit einem nicht-kleinzelligen Bronchialkarzinom in der transplantierten Lunge, der mit einer stereotaktischen Körperstrahlentherapie behandelt wurde. Bei den meisten Fällen eines primären Bronchialkarzinoms in einer Spen derlunge wurde ein rascher Progress berichtet. Das Auftreten eines lokoregionären Rezidivs bei unserem Fall könnte durch Faktoren bezüglich des Behandlungsprotokolls und auch durch die zugrundeliegende Immunsuppression erklärt werden. Schlüsselwörter Lungenneoplasien · Organtransplantation · Immunsuppression · Stereotaktische Körperstrahlentherapie · Bronchialneoplasien
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Fig. 5 8 Coronal slices of initial PET-CT (a) and restaging PET 14 months after SBRT (b) demonstrate obvious locoregional tumor progression. Axial slices of a restaging PET-CT showing new lesions (apical, central, and dorsal), residual metabolism in right upper lob mass (field margins), lung fibrosis (in radiation field), and pleura effusion. Histological examination of sampled tissues from the dorsal lesion (d) confirmed the malignancy and, thus, tumor progression, whereas no evidence of malignancy was reported from the central lesion (e)
tients subsequently died because of local recurrence. In a more recent retrospective study published by Yserbty et al. [27], 13 of 494 patients (2.6%) developed lung carcinoma after lung transplantation. Four patients had early stage, whereas all others had locally advanced or metastatic disease. One patient underwent radical radiotherapy for stage IB lung cancer and died 2 years later due to pneumonia without evidence of recurrence. Two of the 5 patients who underwent radical surgery had recurrence within the first year after surgical resection. There was a significant difference in median survival between patients with early stage and advanced lung cancer (21 months vs. 6 months, p=0.037). These data indicate that patients with posttransplant lung cancer may have benefit from screening and early detection. In other surgical series, outcomes for lung cancer in transplant patients seemed to be similar to that of general population [7, 24]. However, the postoperative mortality and morbidity are high in transplant patients. In a study on heart transplant patients who underwent surgical resection for primary lung cancer, high rates of postoperative morbidity (7 patients) and mortality (3 patients) were reported by Bagan et al. [3]. Postoperative complications in 7 of 10 patients resulted mainly
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from infectious origin. The 5-year survival rate was 40.9% with a median survival of 45 months. In a further series on five solid organs transplanted patients who underwent surgical resection for malignant lung tumors postoperative infectious complications were also described [28]. The striking feature is that the lung transplant patients might be per se medically inoperable, since they have limited functional capacity and low cardiopulmonary reserve due to the underlying disease, which could be further complicated by prolonged immunosuppressive therapy [20]. Stereotactic body radiation therapy (SBRT) is emerging as the new standard of care of patients with medically inoperable stage I NSCLC [4]. Furthermore, there are some data showing that the utilization of modern technologies might improve local tumor control even in locally advanced stages [6, 16]. On the other hand, observation alone as a strategy for medically inoperable patients is not justified. In studies comparing outcomes of treatment with observation alone, much shorter survival times and higher mortality have been reported for patients who were observed only [22]. Occurrence of the locoregional failure in the presented case could also be explained by factors related to treatment protocol and due to underlying prolonged immunosuppression. In a translational
study, Lee et al. [19] demonstrated that high-dose radiotherapy increases T-cells leading to eradication of the primary tumor or distant metastasis in a CD8 + Tcell dependent fashion and that immunotherapy could amplify radiation-initiated immunity to eradicate local and disseminated disease. Interaction between high dose radiation therapy, tumor cells, and the immune system has been also excellently reviewed [15]. This model implies that radiation-initiated immunity and antitumor efficacy of SBRT could be compromised by immunosuppressive therapy. Although Duncker-Rohr et al. [14] demonstrated favorable local tumor control in 45 lung lesions treated with a moderate dose stereotactic radiotherapy (35 Gy in 5 fractions), a BED greater than 106 Gy is required for optimal local control in stage I non-small cell lung cancer [17, 29]. Whether patients with immunosuppressive therapy might require BED greater than 106 Gy remains unclear, especially considering that very high BED, more than 146 Gy, seems to be associated with poorer outcomes [29].
Conclusion Although comparable tumor control rates as in the nontransplant population could not be achieved, treatment decision making for lung cancer of donor or-
igin does not fundamentally differ from that for lung cancer in a native lung. However, the context is more complicated by underlying multiple medical problems and prolonged immunosuppression therapy, which is more intense than the case of other solid organ transplantation. Efficacy of SBRT might be compromised by immunosuppressive therapy.
Corresponding address F. Oskan Department of Radiation Oncology, University Hospital of Saarland Kirrbergerstr. 100, 66421 Homburg (Saar) Germany [email protected]
Compliance with ethical considerations Conflict of interest. F. Oskan, U. Ganswindt, C. Belka, and F. Manapov state there are no conflicts of interest. The accompanying manuscript does not include studies on humans or animals.
References 1. Anyanwu AC, Townsend ER, Banner NR et al (2002) Primary lung carcinoma after heart or lung transplantation: management and outcome. J Thorac Cardiovasc Surg 124:1190–1197 2. Aparicio MB, Martinez CM (2009) Neoplasia in lung transplant. Arch Bronconeumol 45:363–365 3. Bagan P, Assouad J, Berna P et al (2005) Immediate and long-term survival after surgery for lung cancer in heart transplant recipients. Ann Thorac Surg 79:438–442 4. Baumann P, Nyman J, Hoyer M et al (2009) Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 27:3290–3296 5. Beyer EA, DeCamp MM, Smedira NG et al (2003) Primary adenocarcinoma in a donor lung: evaluation and surgical management. J Heart Lung Transplant 22:1174–1177 6. Boda-Heggemann J, Lohr F, Wenz F et al (2011) kV Cone-beam CT-based IGRT: a clinical review. Strahlenther Onkol 187:284–291 7. Bruschi G, Conforti S, Torre M et al (2009) Longterm results of lung cancer after heart transplantation: single center 20-year experience. Lung Cancer 63:146–150 8. Chao FY, Force S, Gal A et al (2012) Metastatic non-small cell lung cancer of donor origin post bilateral lung transplant. Chest 142(4_ MeetingAbstracts):572A–572A 9. Collins J, Kazerooni EA, Lacomis J et al (2002) Bronchogenic carcinoma after lung transplantation: frequency, clinical characteristics, and imaging findings. Radiology 224:131–138
10. De Boer M, Vink A, Graaf EA van de (2012) Nonsmall cell lung carcinoma of donor origin after bilateral lung transplantation. Lung Cancer 76:259– 261 (Epub) 11. De Perrot M, Wigle DA, Pierre AF et al (2012) Bronchogenic carcinoma after solid organ transplantation. Ann Thorac Surg 75:367–371 12. De Soyza AG, Dark JH, Parums DV et al (2001) Donor-acquired small cell lung cancer following pulmonary transplantation. Chest 120:1030–1031 13. Dickson RP, Davis RD, Rea JB et al (2006) High frequency of bronchogenic carcinoma after single-lung transplantation. J Heart Lung Transplant 25:1297–1301 14. Duncker-Rohr V, Nestle U, Momm F et al (2013) Stereotactic ablative radiotherapy for small lung tumors with amoderate dose: favourable results and low toxicity. Strahlenther Onkol 189:33–40 15. Finkelstein SE, Timmerman R, McBride WH et al (2011) The confluence of stereotactic ablative radiotherapy and tumor immunology. Clin Dev Immunol 2011:439752 (Epub) 16. Guckenberger M, Kavanagh A, Partridge M et al (2012) Combining advanced radiotherapy technologies to maximize safety and tumor control probability in stage III non-small cell lung cancer. Strahlenther Onkol 188:894–900 17. Guckenberger M, Allgaeur M, Apold S et al (2013) Safety and efficacy of stereotactic body radiotherapy for stage i non-small-cell lung cancer in routine clinical practice: a patterns-of-care and outcome analysis. J Thorac Oncol 8:1050–1058 18. Lee P, Minai OA, Mehta AC et al (2004) Pulmonary nodules in lung transplant recipients: etiology and outcome. Chest 125:165–172 19. Lee Y, Auh LS, Wang Y et al (2009) Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114:589–595 20. Lyu DM, Zamora MR (2009) Medical complications of lung transplantation. Proc Am Thorac Soc 6:101–107 21. Mathew J, Kratzyka A (2009) Lung cancer and lung transplantation: a review. J Thorac Oncol 4:753– 760 22. McGarry RC, Song G, Rosiers P des et al (2002) Observation-only management of early stage, medically inoperable lung cancer: poor outcome. Chest 121:1155–1158 23. Minai OA, Shah S, Mazzone P et al (2008) Bronchogenic carcinoma after lung transplantation: characteristics and outcomes. J Thorac Oncol 3:1404– 1409 24. Mohammadi S, Bonnet N, Leprince P et al (2007) Long-term survival of heart transplant recipients with lung cancer: the role of chest computed tomography screening. Thorac Cardiovasc Surg 55:438–441 25. Raviv Y, Shitrit D, Amital A et al (2011) Lung cancer in lung transplant recipients: experience of a tertiary hospital and literature review. Lung Cancer 74:280–283 26. Von Boehmer L, Draenert A, Jungraithmayr W et al (2012) Immunosuppression and lung cancer of donor origin after bilateral lung transplantation. Lung Cancer 76:118–122 27. Yserbty J, Verleden G, Dupont L et al (2012) Bronchial carcinoma after lung transplantation: a single-center experience. J Heart Lung Transplant 31:585–590 28. Wojtyś M, Janowski H, Wójcik J et al (2012) Surgical treatment of malignant lung tumors in solid organ recipients. Pneumonol Alergol Pol 80:343–348
29. Zhang J, Yang F, Li B et al (2011) Which is the optimal biologically effective dose of stereotactic body radiotherapy for stage I non-small-cell lung cancer? A meta-analysis. Int J Radiat Oncol Biol Phys 81:e305–e316
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F. Oskan1, 2 · U. Ganswindt1 · C. Belka1 · F. Manapov1 1 Department of Radiation Oncology, Ludwig-Maximilians-University Munich 2 Department of Radiation Oncology, University Hospital of Saarland, Homburg (Saar)
Primary non-small cell lung cancer in a transplanted lung treated with stereotactic body radiation therapy A case study
During the past two decades, there has been a gradual increase in the number of patients with lung transplant presenting with primary neoplasia [2, 21]. While high frequency of bronchogenic carcinoma in native lung after single-lung transplantation has been reported [13], lung cancer of donor origin is an extreme rare phenomenon. The first case of a primary lung cancer in transplanted lung was described in 2001. Since then, only five cases of lung cancer in donated lung have been reported. In this paper, we report on a case of early stage primary non-small cell lung cancer (NSCLC) lung cancer in a transplanted lung treated with stereotactic body radiation therapy (SBRT).
Case presentation A 59-year-old Caucasian woman with an alpha-1 antitrypsin deficiency and endstage emphysema received right singlelung transplantation in April 2004. Because of prolonged immunosuppression, the patient developed recurrent pulmonary infections. She was also diagnosed with chronic renal failure caused by immunosuppression drug use. In August 2008, an incidental nodule in the right upper lobe was detected in a routine chest Xray. A chest computer tomography (CT) demonstrated a 0.9×0.6 cm mass. One year later, a new chest CT showed an enlargement of this lesion that then sized 1.5×1 cm. She was admitted to the hospital in September 2009 for diagnostic evaluation.
At the time of hospitalization, she was free from any symptoms of chronic obstructive pulmonary disease (COPD) exacerbation and had no B-systematic complaints such as weight loss, night sweats, or general weakness. Laboratory findings revealed a white cell count of 6×109/l, 12.4 g/dl hemoglobin, and a platelet count of 290×109/l. Routine chemistry demonstrated a creatinine value of 2 mg/dl and urea of 83 mg/dl. Arterial blood gas analysis showed pO2 of 61 mmHg, pCO2 39 mmHg, and pH of 7.45. Serum levels of tacrolimus and mycophenolic acid were 6 μg/l (normal range 5–15 μg/l) and 1.9 μg/l (no normal range but 4–12 μg/l), respectively. Body plethysmography revealed a forced expiration volume at first second of FEV1 =1.2 l (49% of predicted). In the electrocardiogram, a left type AVblock I° was seen. Esophageal ultrasonography, gastroscopy, and coloscopy were unremarkable. In the chest CT, signs of emphysematous changes in the left lung fields were prominent, and a 1.6×1.2 cm sized, thus,
progressing mass in the right upper lobe was demonstrated (. Fig. 1). The combined positron emission tomography (PET) showed a pathological intensive glucose metabolism in the right upper lob with a maximum standardized uptake volume (SUV) of 13.6, and much lower metabolism in the lower and middle lobe with SUV max of 5.5, which were morphologically interpreted as atypical inflammatory process due to immunosuppression. No lymph node involvement or distant metastases were observed. Transthoracic fine needle aspiration was performed to confirm the malignancy of the upper lobe mass. Pathological examination was reported as moderately differentiated invasive SCC. The tumor was classified as cT1acN0 cM0 (Stage Ia) according to TNM classification (UICC). Because of medical co-morbidities, immunosuppression after lung transplantation, and compromised lung function, SBRT of the right upper lobe mass was deemed to be the most appropriate treatment option by the multidisciplinary tu-
Fig. 1 8 Transverse slice of matched PET-CT (left) and CT lung window (right) at initial diagnosis showing pathological metabolisms in the right upper lobe mass Strahlentherapie und Onkologie 4 · 2014
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Fig. 2 9 Sagital, coronal, and transversal slices representative of SBRT isodose distribution and beam arrangement
Volume [%] ITV PTV
80.00
Rib1+3 60.00
Rib2 Lung sum
40.00
Lung right Lung left
20.00
Spinal cord 0.00 0.00 Region of interest
20.00
40.00
60.00
Dose [Gy]
ITV
Min (Gy) Max (Gy) Median (Gy) Average (Gy) Std.Dev (Gy) Dose Volume (ccm) 68.9 76.7 73.8 73.8 1.6 7.23
PTV
56.9
76.7
70.5
70.2
5
25.56
Rib 1+3
34.9
70.9
58.3
56.9
11.3
3.95
Rib2
27.3
56.9
40.4
41.4
7.9
4.03
Lung sum
0.08
76.7
0.5
3.5
9.0
3285.7
Lung r.
0.15
76.7
0.9
7.1
14.2
1153.75
Lung le
0.08
18.3
0.4
1.5
2.9
2150.82
Spinal co
0.03
1.8
0.2
0.3
0.2
61.5
Fig. 3 8 Dose–volume histograms showing dosimetric parameters analyzed including targets and organs at risk
Fig. 4 9 Transversal slice of control chest-CT performed 9 months after SBRT procedure demonstrating residual tumor and lung fibrosis
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mor board. Prior to radiation treatment, a dynamic planning CT with three breath phases (mid-ventilation, end expiration, and end inspiration) was performed in stereotactic treatment position in a vacuum system with both arm raised above the head using an arm rest. The internal target volume (ITV) was constructed by union of all delineations of the gross tumor volume (GTV) of the right upper lobe mass in all breathing phases, and a margin of 5 mm in all directions was added to generate the planning target volume (PTV). A dose of 7.5 Gy in 8 fractions was prescribed to the 80% isodose line covering the PTV. Eight static beams (. Fig. 2, 3) with energies of 6 MV were used. The radiation was delivered with daily electronic imaging and megavoltage cone beam CT (MV-CBCT)based guidance to verify the treatment position. The total dose of 60 Gy (biologic effective dose, BED10 =105 Gy) was delivered during a 2 week period in October 2009 without complication or exacerbation of the known respiratory insufficiency. At follow-up in February 2010 (3 months after SBRT), a control chest CT showed partial remission in the right upper lobe mass, which at the time had a diameter of 0.6×1 cm, but also radiographic signs of radiation pneumonitis. The patient reported no clinical symptoms. In July 2010 (9 months after SBRT), a CT chest was performed and demonstrated scarcely impounded tumor residual in the right upper lobe combined with area of lung fibrosis (. Fig. 4). A FEV1 of 1.1 l was revealed by body plethysmography. Restaging PET-CT performed 14 months after SBRT in December 2010 showed resid-
Abstract · Zusammenfassung ual activity in the right upper lobe mass with SUV max 9, as well as multiple new lesions in the right lung (. Fig. 5). In February 2011, CT-guided puncture of two lesions were done. The pathological examination of obtained martial from the central localized lesion showed no signs of malignancy. The biopsy from the dorsal lesion confirmed malignancy and the patient did not receive further oncological therapy. The last follow-up contact was made in July 2011, namely 22 month after initial diagnosis.
Discussion Patients with lung transplantation are at an increased risk of developing malignancy with a prevalence of 2–4% for lung cancer after single or bilateral transplantation [9, 13, 23, 25]. Although prolonged immunosuppressive therapy and the underlying disease with inherent increased risk of malignancy might play a key role [2, 11, 21, 23], the causal mechanisms remain unclear because of very limited data. In most reported cases, the diagnosis of lung cancer was based on an incidental radiological finding of a new or an enlarging nodule or mass in asymptomatic patients [9, 11, 23]. However, the majority of pulmonary nodules are reported to be of infectious origin [18]. In several studies, the time interval between transplantation and manifestation of lung cancer ranged between 3 and 5 years [9, 13, 23, 25]. The majority of cases are diagnosed in native lungs of transplant patients. On the other hand, reports on primary lung cancer in the lung of donor origin are extremely rare. The first case of primary lung cancer of donor origin after bilateral lung transplantation was described in 2001 by De Soyza et al. [12]. Their patient was a 25-year-old who developed metastatic small cell carcinoma 13 month after bilateral lung transplant due to cystic fibrosis. The patient underwent standard chemotherapy with no clinical response and died 1 month after. Beyer et al. [5] reported a case of moderately differentiated adenocarcinoma diagnosed in the donor lung 33 months after bilateral pulmonary transplantation. The tumor was treated surgically.
In addition to these patients, the case of a patient who received bilateral lung transplantation as treatment for endstage usual interstitial pneumonia resulting in idiopathic lung fibrosis was reported by von Boehmer et al. [26]. Seven months later, the patient developed a large cell carcinoma in the right mediastinal lymph node and two small intrapulmonal nodules in the middle lobe. She underwent 3 cycles of neoadjuvante chemotherapy with pemetrexed and carboplatin with no clinical response and then underwent an extended right pneumonectomy with a pathological stage ypT4ypN2. At the 4-month follow-up, a PET-CT demonstrated diffuse metastatic lesions in the bone and a new lesion in the superior lingua of the left lung. She died 7 months after initial diagnosis. De Boer et al. [10] described a patient who developed primary metastatic NSCLC 5 years after bilateral lung transplantation. Due to expected complications caused by immunosuppressive therapy, it was decided not to treat the patient with chemotherapy. Chao et al. [8] reported on a patient harboring a large cell carcinoma in the left lower lob 24 months after bilateral lung transplantation. She underwent a left lower lobe wedge resection. Five month later, a PET-CT revealed multiple metastases in the liver and bones. The patient refused chemotherapy and died. Surgery remains the cornerstone treatment of early stage NSCLC in transplanted patients. Nevertheless, the outcomes of surgical treatment of malignant lung tumor in solid organ transplant recipients remain unsatisfied. Anyanwu et al. [1] reported on 17 cases of primary lung carcinoma diagnosed between 1990 and 2000 in patients who have previously undergone thoracic transplantation. Most of them (13/17) were asymptomatic at presentation and presented with an incidental abnormality noted on chest radiography. Of these, 8 patients underwent surgical resection, 5 received radiation therapy, 2 were treated with chemotherapy, and 2 with chemo- and radiotherapy. The 5-year survival of patients with stage I disease was 35%. Of the 8 patients who underwent surgical intervention, 1 patient died in the postoperative period, and 3 pa-
Strahlenther Onkol 2014 · 190:411–415 DOI 10.1007/s00066-013-0511-2 © Springer-Verlag Berlin Heidelberg 2014 F. Oskan · U. Ganswindt · C. Belka · F. Manapov
Primary non-small cell lung cancer in a transplanted lung treated with stereotactic body radiation therapy. A case study Abstract The first case of primary lung cancer in a transplanted lung was described in 2001. Since then, only 5 cases of lung cancer in donated lung have been reported. We present one more patient with non-small cell cancer in the transplanted lung treated with stereotactic body radiation therapy. In most cases of primary lung cancer in transplanted lung, rapid progression of the cancer was reported. Occurrence of the locoregional failure in our case could be explained by factors related to the treatment protocol and also to underlying immunosuppression. Keywords Lung neoplasms · Organ transplantation · Immunosuppression · Stereotactic body radiotherapy · Bronchial neoplasms
Primäres nicht-kleinzelliges Bronchialkarzinom in einer mit stereotaktischer Körperstrahlentherapie behandelten transplantierten Lunge. Eine Fallstudie Zusammenfassung Der erste Fall eines primären Bronchialkarzinoms in einer transplantierten Lunge wurde im Jahr 2000 beschrieben. Seither sind nur 5 Fälle von primärem Lungenkrebs in einer Spenderlunge berichtet worden. Wir präsentieren einen weiteren Patienten mit einem nicht-kleinzelligen Bronchialkarzinom in der transplantierten Lunge, der mit einer stereotaktischen Körperstrahlentherapie behandelt wurde. Bei den meisten Fällen eines primären Bronchialkarzinoms in einer Spen derlunge wurde ein rascher Progress berichtet. Das Auftreten eines lokoregionären Rezidivs bei unserem Fall könnte durch Faktoren bezüglich des Behandlungsprotokolls und auch durch die zugrundeliegende Immunsuppression erklärt werden. Schlüsselwörter Lungenneoplasien · Organtransplantation · Immunsuppression · Stereotaktische Körperstrahlentherapie · Bronchialneoplasien
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Case study
Fig. 5 8 Coronal slices of initial PET-CT (a) and restaging PET 14 months after SBRT (b) demonstrate obvious locoregional tumor progression. Axial slices of a restaging PET-CT showing new lesions (apical, central, and dorsal), residual metabolism in right upper lob mass (field margins), lung fibrosis (in radiation field), and pleura effusion. Histological examination of sampled tissues from the dorsal lesion (d) confirmed the malignancy and, thus, tumor progression, whereas no evidence of malignancy was reported from the central lesion (e)
tients subsequently died because of local recurrence. In a more recent retrospective study published by Yserbty et al. [27], 13 of 494 patients (2.6%) developed lung carcinoma after lung transplantation. Four patients had early stage, whereas all others had locally advanced or metastatic disease. One patient underwent radical radiotherapy for stage IB lung cancer and died 2 years later due to pneumonia without evidence of recurrence. Two of the 5 patients who underwent radical surgery had recurrence within the first year after surgical resection. There was a significant difference in median survival between patients with early stage and advanced lung cancer (21 months vs. 6 months, p=0.037). These data indicate that patients with posttransplant lung cancer may have benefit from screening and early detection. In other surgical series, outcomes for lung cancer in transplant patients seemed to be similar to that of general population [7, 24]. However, the postoperative mortality and morbidity are high in transplant patients. In a study on heart transplant patients who underwent surgical resection for primary lung cancer, high rates of postoperative morbidity (7 patients) and mortality (3 patients) were reported by Bagan et al. [3]. Postoperative complications in 7 of 10 patients resulted mainly
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from infectious origin. The 5-year survival rate was 40.9% with a median survival of 45 months. In a further series on five solid organs transplanted patients who underwent surgical resection for malignant lung tumors postoperative infectious complications were also described [28]. The striking feature is that the lung transplant patients might be per se medically inoperable, since they have limited functional capacity and low cardiopulmonary reserve due to the underlying disease, which could be further complicated by prolonged immunosuppressive therapy [20]. Stereotactic body radiation therapy (SBRT) is emerging as the new standard of care of patients with medically inoperable stage I NSCLC [4]. Furthermore, there are some data showing that the utilization of modern technologies might improve local tumor control even in locally advanced stages [6, 16]. On the other hand, observation alone as a strategy for medically inoperable patients is not justified. In studies comparing outcomes of treatment with observation alone, much shorter survival times and higher mortality have been reported for patients who were observed only [22]. Occurrence of the locoregional failure in the presented case could also be explained by factors related to treatment protocol and due to underlying prolonged immunosuppression. In a translational
study, Lee et al. [19] demonstrated that high-dose radiotherapy increases T-cells leading to eradication of the primary tumor or distant metastasis in a CD8 + Tcell dependent fashion and that immunotherapy could amplify radiation-initiated immunity to eradicate local and disseminated disease. Interaction between high dose radiation therapy, tumor cells, and the immune system has been also excellently reviewed [15]. This model implies that radiation-initiated immunity and antitumor efficacy of SBRT could be compromised by immunosuppressive therapy. Although Duncker-Rohr et al. [14] demonstrated favorable local tumor control in 45 lung lesions treated with a moderate dose stereotactic radiotherapy (35 Gy in 5 fractions), a BED greater than 106 Gy is required for optimal local control in stage I non-small cell lung cancer [17, 29]. Whether patients with immunosuppressive therapy might require BED greater than 106 Gy remains unclear, especially considering that very high BED, more than 146 Gy, seems to be associated with poorer outcomes [29].
Conclusion Although comparable tumor control rates as in the nontransplant population could not be achieved, treatment decision making for lung cancer of donor or-
igin does not fundamentally differ from that for lung cancer in a native lung. However, the context is more complicated by underlying multiple medical problems and prolonged immunosuppression therapy, which is more intense than the case of other solid organ transplantation. Efficacy of SBRT might be compromised by immunosuppressive therapy.
Corresponding address F. Oskan Department of Radiation Oncology, University Hospital of Saarland Kirrbergerstr. 100, 66421 Homburg (Saar) Germany [email protected]
Compliance with ethical considerations Conflict of interest. F. Oskan, U. Ganswindt, C. Belka, and F. Manapov state there are no conflicts of interest. The accompanying manuscript does not include studies on humans or animals.
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