ANTICANCER RESEARCH 30: 4381-4388 (2010)

Cardiopulmonary Toxicity of Different Chemoradiotherapy Combined Regimens for Hodgkin’s Disease

ALESSANDRA BUSIA1, ALBERTO LAFFRANCHI2, SIMONETTA VIVIANI3, VALERIA BONFANTE3 and FABRIZIO VILLANI1

1Pneumology, 2Radiology, 3Medical , Fondazione IRCCS, Istituto Nazionale Dei Tumori, Milano, Italy

Abstract. The majority of patients with Hodgkin’s disease ventilation. The VEBEP regimens could be potentially more can be cured by combination of polychemotherapy and toxic for the heart, probably because of the higher radiotherapy (RT) that can produce late toxic pulmonary and cumulative dose of . cardiac effects which often remain at a subclinical level. The aim of the present investigation was to compare the late The majority of patients with Hodgkin’s disease can be cured pulmonary and cardiac toxicity of three chemotherapeutic with appropriate combination of active chemotherapeutic regimens combined with RT and particularly , agents and radiotherapy (RT). The more frequently used , and (ABVD), , chemotherapeutic regimens include doxorubicin, bleomycin, , , and prednisone vinblastine and dacarbazine (ABVD), ABVD with (VEBEP) and ABVD with mechloretamine, vincristine, mechloretamine, vincristine, and prednisone procarbazine and prednisone (MOPP). Patients and (MOPP) and vincristine, epirubicin, cyclophosphamide, Methods: We investigated 147 patients suffering from etoposide and prednisone (VEBEP). Considerable interest Hodgkin’s disease after a follow-up of at least 5 years from exists over the late cardiopulmonary toxic effects of these the completion of CT-RT. Seventy-eight patients were combined chemoradiotherapy regimens for Hodgkin’s submitted to ABVD-RT, 36 to VEBEP-RT and 33 to MOPP- disease because of the long survival of patients cured by ABVD-RT. Patients underwent spirometry, 2D-doppler these effective treatments (1-7). echocardiography at rest, cardiopulmonary exercise test on Mediastinal irradiation has been associated with both cycloergometer and determination of cardiac output by a non cardiac and pulmonary toxic effects that can develop months invasive method. Results: Patients of the three different to years after completion of therapy. Complications include treatment groups showed tolerance to exercise, and oxygen pericarditis, coronary artery fibrosis, myocardial infarction, consumption significantly lower than the predicted values but decreased ventricular function, electrocardiographic there were no statistically significant difference between the abnormalities and radiation pneumonitis and fibrosis (8-10). three groups. Nevertheless, patients treated with VEBEP and The incidence and severity of these toxic effects can be with MOPP-ABVD showed an ejection fraction at rest lower potentiated by the combination of chemotherapeutic agents than those observed in the ABVD group and patients treated with radiotherapy (6, 7, 11, 12). It is well known that with VEBEP showed a cardiac output for oxygen uptake bleomycin and and to a lesser extent, other lower than those observed in the ABVD and MOPP-ABVD antineoplastic drugs (such as cyclophosphamide and treatment groups. Conclusion: These data confirm that the etoposide) can cause dose-related pulmonary and cardiac combination of mediastinal RT with the more commonly used toxicity which can be potentiated by the addition of polychemotherapy regimens produce late toxic effects. The radiotherapy to the cardiomediastinic area (3, 5-7, 11-18). lower exercise capacity seems to be due to a combination of The majority of studies have focused on the evaluation of decreased cardiac performance and impairment of cardiopulmonary function at rest using conventional procedures (spirometry, determination of transfer factor for CO, echocardiography) but only few studies have evaluated cardiopulmonary function and reserve during Correspondence to: Dott.ssa A. Busia, U.O. Pneumologia e exercise (19-21). Therefore the aim of the present Fisiopatologia Respiratoria Fondazione IRCCS, Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milano, Italy. e-mail: investigation was to evaluate the cardiopulmonary response [email protected] to exercise in patients submitted to different chemotherapeutic regimens followed by mediastinal irradiation after a follow-up Key Words: Cardiopulmonary toxicity, Hodgkin’s disease. of at least 5 years from the achievement of complete

0250-7005/2010 $2.00+.40 4381 ANTICANCER RESEARCH 30: 4381-4388 (2010) remission and the completion of the combined treatments, regions achieving complete remission or good partial remission after which is a time interval long enough to consider the . The median total radiotherapy dose was 30 Gy. pulmonary and cardiac damage as not being reversible. Radiotherapy started 4 weeks from chemotherapy completion and after a complete restaging for all the protocols given. All involved Patients and Methods nodal regions were mapped before chemotherapy started, but target volumes were defined on the basis of post-chemotherapy radiological examinations and delineation was obtained on X-rays during The study was conducted on 147 patients with Hodgkin’s disease in conventional simulation. At the time RT was carried out no CT complete remission after treatment with one of three different simulation or computerized treatment plans were performed. Daily chemotherapy regimens, ABVD, VEBEP or MOPP-ABVD, all fractionation was 90+90 cGy for 5 days per week, and was given followed by RT. through antero-posterior and postero-anterior equally weighted All patients had completed the combined treatment at least 5 portals, usually using a 6 MV linear accelerator for years prior to this study. supradiaphragmatic irradiation and 6 or 18 MV linear accelerator, The ABVD included the following drug depending on the thickness of the area, for infradiaphragmatic dosages: doxorubicin 25 mg/m2, bleomycin 10 mg/m2, vinblastine treatments. In order to give the scheduled total dose, physicists 6 mg/m2 and dacarbazine 375 mg/m2. All four drugs were administered prepared a dose distribution map for each patients. After set-up was with rapid intravenous (i.v.) injection on day 1 and 15, every 28 days. planned at a conventional simulator, customized shields were obtained Four weeks after the end of chemotherapy, high-voltage in all the patients with more than one site to be treated. Lung shields irradiation was started, encompassing only initial by involved were not modified during the treatment and no subcarinal bock was lymphonodal sites or having subtotal nodal extension according added; the spinal cord was shielded in the postero-anterior field at 30 randomization. All radiation fields were tailored using personalized Gy. Portal films were obtained on day 1 and repeated every week. shields. The dose was 36 Gy to involved and 30 to uninvolved nodes. Daily fractionation was 1.5-1.8 Gy. The VEBEP schedule consisted of the administration of Evaluation of pulmonary function. Standard spirometric parameters etoposide (VP-16) 120 mg/m2/i.v. and epirubicin 40 mg/m2 on days were determined using a model PFT Horizon Systems spirometer 1 and 2; bleomycin 10 mg/m2/i.v. on day 1 only; cyclophosphamide (Sensor Medics, Yorbalinda, CA, USA). Spirometry was performed 500 mg/m2 on days 1 and 2, while prednisone 50 mg/total dose per at least three times for each patient during each examination and at os (p.o.) was given from day 1 through 7. Cycles were repeated least two of the tests had to be within 5% of each other, as a every 21 days until clinical complete remission was documented, measure of reproducibility. Pulmonary function test data were followed by at least two consolidation cycles to a maximum of eight described as percentage of predicted values. Tranfer lung factor for cycles. Four weeks after the end of chemotherapy, high-voltage CO (DLCO ) was measured with the single breath technique of irradiation started. Ogilvie et al. (22) as modified by Cotes (23). DLCO values The MOPP-ABVD regimen included the MOPP regimen measured while breathing room air were corrected for haemoglobin (meclorethamine 6 mg/m2 i.v. and vincristine 1.4 mg/m2 i.v. days 1-8, concentration using the method of Dinakara et al. (24) in order to procarbazine 40 mg/m2 p.o. and prednisone 40 mg/m2 on day 1-14) obtain a DLCO value under standard conditions. monthly alternated with the ABVD regimen. Irradiation using high-energy photons was planned to the sites of Radiology. Radiographic evidence of pulmonary toxicity was initial bulky nodal involvement once complete remission or maximal defined as the presence of pulmonary interstitial infiltrated or tumor shrinkage was achieved by primary chemotherapy. The daily fibrosis on chest ×-ray during or following radiochemotherapy in dose ranged between 1.5-1.8 Gy, with five fractions per week. the absence of infection. Parenchymal lung damage was graded as Radiation treatment encompassed only the sites of bulky disease in follows: Grade 0: no evidence of lesions; grade 1: interstitial the majority of patients; the involved nodal sites and the contiguous retracting sclerosis without paramediastinal retraction; grade 2: uninvolved nodal sites were submitted to RT in a minority of cases interstitial retracting sclerosis with cranial retraction of pulmonary according to the following radiotherapy protocols. hilus and verticalization of cardiovascular structure; grade 3: interstitial and alveolar retracting sclerosis with mediastinal traction ABVD followed by RT of involved fields or subtotal nodal and dislocation. irradiation. Patients were randomly assigned to receive involved fields or subtotal nodal irradiation. The total dose to previously Cardiac function evaluation. Each patient, before starting the involved nodal regions ranged from 36 Gy (in patients with treatment, underwent a routine cardiologic check up based on confirmed complete remission) to 40 Gy (in patients with clinical evaluation and resting ECG and was then submitted to unconfirmed complete remission or partial remission). In patients cardiac monitoring by means of 2D-echocardiography. The allocated to receive subtotal nodal irradiation, the planned dose to echocardiographic examination consisted of a complete 2D and uninvolved sites was 30 Gy. Doppler study by means of a complete Agilent Sonos 5500 device with a 3.5 MHz phased array transducer. Each exanination was VEBEP combined with RT. In patients achieving partial or complete recorded by a VHS video tape-recorder inserted into the remission after chemotherapy, all initially involved nodal regions echocardiographic device. The playback of the obtained images was were irradiated. Total dose to complete remission sites was 30 Gy examined by two different operators. The left ventricular dimension and to those in partial remission was 36 Gy. were obtained from 2D-guided M-Mode tracing according to the recommendations of the American Society of Echocardiography Alternating or hybrid MOPP-ABVD with RT to bulky sites. (25). The ejection fraction was the result of two different evaluations Radiation treatment was planned to treat initially bulky nodal based on the Teicholz formula (26).

4382 Busia et al: Cardiopulmonary Toxicity of CRT Regimens in Hodgkin’s Disease

Table I. Characteristics of patients.

Pts (n) M/F (%) Age, years Stage (%) Histology, n (%) Mean±SE (range) I II III IV Bulky Nodular sclerosis Other

ABVD 78 42/58 37.6±1.1 9 85.9 2.6 2.6 15.4 35 (44.8) 43 (55.2) (23-65) VEBEP 36 47/53 36.9±1.7 2.8 63.9 19.4 13.9 33.3 19 (52.7) 17 (47.3) (24-64) MOPP-ABVD 33 45/55 41.2±1.5 6.1 63.6 12.1 18.2 42.4 20 (45.5) 13 (54.5) (30-60)

Cardiopulmonary exercise testing and determination of Table II. Mean cumulative dose of bleomycin, anthracyclines, hemodynamic parameters. A multistage test (10 W at 3-min cyclophosphamide and mediastinal RT. intervals) was performed on an upright cycle ergometer at a pedal frequency of 60 rpm with expired gases and minute ventilation Mean±SE (range) measured, breath by breath, using a mass spectrometer (Amis 2000, Innovision, Odense, Denmark). Patients breathed through a low ABVD VEBEP MOPP-ABVD resistance, low dead space. The following parameters were Bleomycin (mg/m2) 80.1±0.9 72.7±1.5 69.1±4.9 measured: oxygen consumption (VO2), CO2 production, minute ventilation, alveolar ventilation, physiologic dead space to tidal (62.9-120) (49-82) (29-81) 2 volume ratio and oxygen pulse. A 12-lead ECG was taken at rest Anthracyclines (mg/m ) Doxorubicin 198.1±2.2 157.5±5.4 and every minute throughout exercise. (102-300) (74-200) Patients exercised to exhaustion or to the occurrence of 4’Epirubicin 570.6±18.3 predefined criteria for termination of the test: systolic blood pressure (146-658) more than 250 mmHg, blood pressure drop more than 20 mmHg, SaO2 less than 80%, heart rate more than 100% of predicted, Cyclophosphamide (mg/m2) 7178.8±220 cardiac arrhythmia, angina pectoris, heart ischemia. (3624-9000) Cardiac output was determined by the noninvasive acetylene Mediastinal RT (Gy) 35.6±0.2 32.9±0.6 32.7±1.2 rebreathing technique using the same device. The precision and (30-43) (30-45) (23-45) reliability of this system have been validated in animals and humans (27-30). The rebreathing bag was filled with a gas mixture of 50% oxygen, 0.3% acetylene, 5% sulfur hexafluoride and balance N2 to a total volume corresponding to 40% of the patient vital capacity. Rebreathing started at normal end-tidal level with the patient completely emptying the bag and was performed for 30 s. more than 70% of cases in the three groups. Bulky Thereafter the cardiac output was calculated by an integrated mediastinal involvement was more frequent in the VEBEP computer from the disappearance curve of acetylene in the bag and MOPP-ABVD groups in comparison to group 1. The (27-30). The test was performed at rest and twice during median duration of radiotherapy was 27 (18-31) days. incremental bicycle exercise (30 W/min). Toxicity of radiotherapy was mainly represented by For all patients, simultaneous measurements of oxygen consumption and cardiac output was performed, this allowed the dysphagia, esophagitis and . No patient required radiotherapy or chemotherapy interruption. relationship between O2 consumption and cardiac output to be calculated for each patient. As shown in Tables I and II no statistically significant differences were found in age, cumulative dose of Results radiotherapy to the pericardial-mediastinic area and of bleomycin, even though it was found slightly higher in the The study was conducted on 147 patients with a follow-up ABVD group. Patients submitted to VEBEP chemotherapy from the completion of treatments longer than 5 years. The received a median cumulative dose of epirubicin of clinical characteristics of patients are listed in Table I. 570 mg/m2 which is equivalent in terms of cardiotoxic effect Seventy-eight patients were treated with the ABVD regimen, to 400 mg/m2 of doxorubicin. Cyclophosphamide was 36 with the VEBEP regimen and 33 with the MOPP-ABVD included only in the VEBEP regimen and its mean regimen. Most patients were under 40 years of age. cumulative dose was 7178 mg/m2. Nodular sclerosis accounted for more than 44% of cases Chest X-ray review allowed detection of radiographic in the three groups and stage I and II disease accounted for parenchymal lung damage in 61/78 of patients in the ABVD

4383 ANTICANCER RESEARCH 30: 4381-4388 (2010)

Table III. Radiological evaluation of pulmonary toxicity. Table IV. Pulmonary function parameters.

Grade ABVD VEBEP MOPP-ABVD ABVD VEBEP MOPP-ABVD

n % n % n % VC 102.1±1.66 102.4±2 99.3±2.9 FVC 103.6±1.64 103.8±2 100.8±2.9 0 17 21.8 4 11.1 6 18.1 FEV1 98.8±1.7 100.5±2.2 97±3 1 25 32.1 10 27.7 7 21.2 FEV1/FVC 81.8±0.8 82.3±0.9 81.5±1.2 2 25 32.1 16 44.4 11 33.3 FEF 25-75 84.1±2.7 85.1±3.4 83.9±4.5 3 11 12.4 6 16.7 9 27.3 TLC 98.8±1.9 98.7±1.3 96.7±2 RV 92.8±1.3 93.9±1.8 94.9±2.3 Total 78 36 33 RV/TLC 28.2±0.6 29±1.5 30.4±0.7 DLCO 80±1.3 86.2±3.64 84.3±3 DLCO/VA 70.7±1.3 73.9±2.9 75.8±2.6

Values are expressed as a percentage of predicted values (mean±SE). VC: Vital capacity; FVC: forced vital capacity; FEV1: forced expiratory group (78.2%), 32/36 patients of the VEBEP group (88.9%) volume in one second; FEF 25-75: forced expiratory flow between 25- and 27/33 patients of the MOPP/ABVD group (81.9%). Grade 75% of FVC; TLC: total lung capacity; RV: residual volume; DLCO: 3 damage was present in 11/78 patients of the ABVD group diffusion lung capacity for carbon monoxide; VA: alveolar volume. (12.4%), 6/36 patients of the VEBEP group (16.7%) and 9/33 patients of the MOPP/ABVD group (27.3%) (Table III). As shown in Table IV, no statistically significant differences were found between the three groups in relation to spirometric parameters and DLCO. As indicated in Table V, the percentage of patients with a DCLO less than 80% of that predicted was not found to be significantly different in the three treatment groups. 2D-Echocardiographic evaluation showed statistically significant lower ejection fraction and minor axis shortening in patients submitted to the VEBEP and MOPP-ABVD treatments in comparison to those observed in patients submitted to the ABVD regimen (Table II). All patients were submitted to cardiopulmonary exercise test. The cause of exercise test cessation was mainly represented by muscular exhaustion. Other causes of cessation were dyspnea, which occurred in a few patients of the ABVD group, and heart rate exceeding the maximum Figure 1. The relationship between cardiac index and oxygen consumption predicted value, mainly observed in the VEBEP group (See of patients treated with radiotherapy and doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD), vinblastine, epirubicin, Table VII). cyclophosphamide, etoposide and prednisone (VEBEP), and ABVD with The physiological response to incremental exercise is mechloretamine, vincristine, procarbazine and prednisone (MOPP-ABVD). reported in Table VIII. No statistically significant differences were found in heart rate and blood pressure. Lower oxygen pulse and lower work load attained were found in the MOPP-ABVD (see Table IX). Oxygen consumption at peak Discussion and at anaerobic threshold was found to be slightly reduced in the MOPP-ABVD group in comparison to the ABVD and It is well known that mantle field irradiation can produce VEBEP groups, but the difference was not found statistically pulmonary and cardiac toxicity due to RT to the pericardial significant. mediastinal area, with an incidence and grade variable and The relationship between cardiac index and oxygen dependent on the irradiation techniques employed, as well as consumption is reported in Figure 1 and shows a slight the volume of lung irradiated and the daily dose of displacement of the curve obtained from the ABVD-and radiotherapy (8). In the last decade, a significant decrease in VEBEP-treated patients from left to right, more evident in the frequency and severity of these sequelae were reported as the VEBEP group, in comparison to the curves obtained a result of refinement of RT techniques (8). Nevertheless from patients treated with MOPP-ABVD, but the difference pulmonary and cardiac toxicity, may respectively be enhanced was not statistically significant. by combination with bleomycin, cyclophosphamide, or by

4384 Busia et al: Cardiopulmonary Toxicity of CRT Regimens in Hodgkin’s Disease

Table V. Functional evaluation of pulmonary toxicity.

DLCO and TLC >80% of pred DLCO<80% pred and TLC>80% pred DLCO and TLC <80% pred

n % n % n %

ABVD 42 53.8 32 41 4 5.1 VEBEP 21 58.3 14 38.9 1 2.8 MOPP-ABVD 20 60.6 11 33.3 2 6.1

antracyclines that can produce cardiotoxic effects generally Table VI. Heart rate, blood pressure and echocardiographic parameters. dose-related (12-18). It is in particular well known that the use of anthracyclines in long-term treatment is limited by ABVD VEBEP MOPP-ABVD dose-related cardiac toxicity (13-15) that can produce Heart rate (b/min) 94±1.9 98.3±2.9 93.4±2.5 irreversible cardiomyopathy. A relatively large number of Blood pressure (mmHg) retrospective studies have reported lung and cardiac function Max 123.9±1.5 122.9±2.1 126.4±2.8 impairment induced by chemotherapy associated with RT. Min 83.6±1 83±1.2 85.6±2.1 Concerning the problem of lung toxicity, the most important End diastolic dimension (cm) 4.6±0.04 4.22±0.25 3.91±0.32 signs observed in many studies are abnormal radiological End systolic dimension (cm) 2.96±0.04 2.82±0.17 2.42±0.21 Ejection fraction % 64.8±0.5 54.9±3.2* 53.9±4.5* findings, by the occurrence of a restrictive lung syndrome and Minor axis shortening 35.8±0.45 29.7±1.84* 29.3±0.71* mainly by decrease of transfer lung function for CO. Our results confirm that the three chemoradiotherapic Values are expressed as mean±SE. *p<0.05 vs. ABVD. regimens are able to produce subclinical pulmonary toxicity which is evidenced by radiological findings and values of DLCO less than 80% of those predicted, which were recorded in more than 40% of patients. However no ventilation limitation (31-32). In cardiac disease or statistically significant differences were observed between deconditioning, similar decreases result from inadequate the three treatments. oxygen utilization by or delivery to exercising muscles. Echocardiographic parameters recorded at rest The present data suggest that exercise is limited not only documented a significant decrease of ejection fraction in the by ventilation factors because of the reduction of DLCO but groups of patients treated with the VEBEP and MOPP- also by exercise-associated cardiac dysfunction. In normal ABVD regimens in comparison with the ABVD group; this individuals, exercise is accompanied by recruitment of small observation could indicate a higher cardiotoxic potential of pulmonary vessels arterioles and capillaries that allow these regimens. cardiac output to increase without significantly altering Maximun work load attained was found to be non pulmonary vascular resistance or pulmonary artery pressure. statistically different in the three treatment groups and did One possible explanation is that in our patients exercise may not exceed 75% of the predicted value. be associated with an increase of pulmonary vascular Peak oxygen consumption was found to be similar in the resistance and pulmonary artery pressure: these factors could three treatment groups and did not exceed the median of reduce the volume of blood flowing from the right to the left 63% of the predicted value when expressed as ml/kg/min and ventricle (reduced left ventricular preload). In addition, as 74% of predicted values when expressed as l/min. Moreover the right ventricle becomes overloaded, the intraventricular oxygen consumption at the anaerobic threshold was found to septum shifts, altering the geometry of the left ventricle and be at the lower limit of the normal range and the relationship further restricting left ventricular filling. between oxygen consumption and cardiac index was found On the other hand, the occurrence of ventricular to be lower than that normally observed in healthy dysfunction among factors able to reduce exercise individuals of matched age. performance cannot be excluded. In fact it must be These results indicate a reduced tolerance to exercise in remembered that all the patients in this study were treated these patients. The problem is to establish whether this effect with anthracyclines, which can cause cardiac toxicity, and is due to pulmonary or cardiac dysfunction, or both. Oxygen were submitted to mediastinal irradiation which have been uptake at peak exercise is usually reduced in patients associated with late cardiac toxic effects (8, 12-15). In suffering from interstitial lung disease as is demonstrated by particular, it must be stressed that patients in the VEBEP exercise terminating at a lower work level because of regimen were treated with epirubicin at a mean cumulative

4385 ANTICANCER RESEARCH 30: 4381-4388 (2010)

Table VII. Causes of cessation of exercise test (values are expressed as %).

Muscular exhaustion Dyspnea Hypertension Heart rate exceeding in Maximum predicted Other or combination

ABVD 52 11 5.5 9 22.5 VEBEP 60.6 - 3.6 25 10.8 MOPP-ABVD 57 - 4 9 34

Table VIII. Heart rate, blood pressure and oxygen pulse recorded at cumulative doses of drugs that can produce irreversible peak. pulmonary and cardiac damage and of RT should reduce toxicity while maintaining a high by curative activity. At the Heart rate Blood pressure O -pulse 2 same time, cardiopulmonary function in patients treated with (% of predicted) (mmHg) ml/beat chemotherapeutic regimens followed by mediastinal ABVD 100.4±0.9 185.5±3 9±0.4 irradiation needs to be constantly evaluated from the 97.1±1.8 achievement of complete remission and during the follow-up. VEBEP 91.2±1.1* 182.1±4.8 9.4±0.7 96.8±2.2 References MOPP-ABVD 84.5±1.6* 190.7±4.5 8.3±0.4 98.3±2.5 1 Aleman BM, van den Belt-Dusebout AW, De Bruin ML, van’t Veer MB, Baaijens MH, de Boer JP, Hart AA, Klokman WJ, *p<0.05 vs. group ABVD. Kuenen MA, Ouwens GM, Bartelink H and van Leeuwen FE: Late cardiotoxicity after treatment for Hodgkin . Table IX. Maximal workload attained, oxygen consumption at peak and Blood 109(5): 1878-1886, 2007. at anaerobic threshold (AT). 2 Ng AK: Late complications after treatment for . Curr Hematol Malig Rep 3(3): 119-125, 2008.

VO2 Max VO2 at AT VO2 at AT Workload 3 Sénécal D, Jais JP, Desablens B, Berthou C, Casassus P, Moles (% predicted) (% predicted) %VO2max attained,% MP, Delwail V, Gastinne T, Colonna P and Andrieu JM: Twenty- of predicted year disease and treatment-associated mortality rates of patients with Hodgkin lymphoma of clinical stages IIIB and IV ABVD 63.21±1.8 59.81±1.94 33.42±1.04 72.1±2.3 prospectively treated with 3-month anthracycline-based VEBEP 62.9±2.9 69.91±5.1 35.26±1.55 73.1±3 chemotherapy followed by extended high-dose radiation. Cancer MOPP-ABVD 60.4±2.3 58.34±2.85 33.70±2.28 68±2.5 112(4): 846-855, 2008. 4 Koontz BF, Kirkpatrick JP, Clough RW, Prosnitz RG, Gockerman JP, Moore JO and Prosnitz LR: Combined-modality therapy versus radiotherapy alone for treatment of early-stage Hodgkin’s disease: cure balanced against complications. J Clin dose of 570 mg/m2, which correspond to about 380 mg/m2 Oncol 24(4): 605-611, 2006. of doxorubicin, and the patients in the ABVD and MOPP- 5 Brusamolino E, Baio A, Orlandi E, Arcaini L, Passamonti F, ABVD regimens were treated with doxorubicin at a mean Griva V, Casagrande W, Pascutto C, Franchini P and Lazzarino cumulative dose of 198 mg/m2 and 157.5 mg/m2, M: Long-term events in adults patients with clinical stage IA- respectively. This could explain the displacement of the IIA nonbulky Hodgkin’s lymphoma treated with four cycles of curve of cardiac index as a function of oxygen consumption doxorubicin, bleomycin, vinblastine and dacarbazine and towards the right which was observed in the VEBEP group adjuvant radiotherapy: a single institution 15-year follow-up. Clin Cancer Res 12(21): 6487-6493, 2006. and, to a lesser extent, in the ABVD group in comparison to 6 Villani F, Fede Catania A, Laffranchi A, Maffioli L, Viviani S that observed for the MOPP-ABVD group, suggesting a and Bonfante V: Effect of an intensive chemotherapy followed possibly more cardiotoxic effect of these regimens. by mediastinal irradiation on pulmonary and cardiac function in advanced Hodgkin’s disease. Cancer Invest 21: 185-192, Conclusion 2003. 7 Gobbi PG, Broglia C, Levis A, La Sala A, Valentino F, Chisesi T, In conclusion, the majority of patients with Hodgkin’s disease Sacchi S, Corbella F, Cavanna L, Iannito E, Pavone V, Molica S, can be cured with an appropriate combination of active Corazza GR and Federico M: MOPPEBVCAD Chemotherapy with limited and conditioned radiotherapy in advanced chemotherapeutic agents and RT and this patient population Hodgkin’s lymphoma: 10 years results, late toxicity and second generally consists of young people. Therefore, the acute and tumors. Clin Cancer Res 12(2): 529-535, 2006. long-term toxicity it is of great concern and the results of the 8 Movses B, Raffin TA, Epstein AM and Link CJ: Pulmonary present investigation have shown that the strategy to reduce radiation injury. Chest 111: 1061-1076, 1997.

4386 Busia et al: Cardiopulmonary Toxicity of CRT Regimens in Hodgkin’s Disease

9 Hull MC, Morris CG, Pepine CJ and Mendenhall NP: Valvolar 21 Villani F, Busia A, Villani M, Laffranchi A, Viviani S and disfunction and carotid, subclavial and coronary artery disease Bonfante V: Cardiopulmonary response to exercise in patients in survivors of Hodgkin’s lymphoma treated with radiation with different degrees of lung toxicity after radio-chemotherapy therapy. JAMA 290: 2831-2837, 2003. for Hodgkin’s disease. Anticancer Res 29: 777-784, 2009. 10 Adams MJ, Hardenbergh PH, Constine LS and Lipshultz SE: 22 Ogilvie CM, Forster RE, Blakemore WS and Morton JW: A Radiation associated cardiovascular disease. Critical reviews in standardized breath-holding technique for the clinical Oncology/Haematology 45: 55-75, 2003. measurement of the diffusing capacity of the lung for carbon 11 Hirsch A, Vander Els N, Strauss DJ, Gomez EG, Leung D, monoxide. J Clin Invest 36: 1-17, 1957. Portlock CS and Yahalom J: Effect of ABVD chemotherapy with 23 Cotes JE: Measurement of the transfer factor (diffusing capacity) and without mantle or mediastinal irradiation on pulmonary for the lung and its subdivision. In: Lung Function, 4th ed. function and symptoms in early-stage Hodgkin’s disease. J Clin Boston: Blackwell Scientific Publication pp. 230-250, 1979. Oncol 14: 1297-1305, 1996. 24 Dinakara P, Blumenthal WS, Johnston RF, Kauffman LA and 12 Aviles A, Neri N, Nambo MJ, Huerta-Guzman J, Talavera A and Slnick PB: The effect of anaemia on pulmonary diffusing Cleto S: Late cardiac toxicity secondary to treatment in capacity with derivation of a correct equation. Am Rev Respir Hodgkin’s disease. A study comparing doxorubicin, epirubicin Dis 102: 965-969, 1970. and in combined therapy. Leuk Lymphoma 46: 25 Sahn DJ, DeMaria A, Kisslo J and Weyman A: Recommendations 1023-1028, 2005. regarding quantitation in M-mode echocardiography: results of a 13 Hershman DL, McBride RB, Eisenberger A, Tsai WY, Grann VR survey of echocardiographic measurements. Circulation 58(6): and Jacobson JS: doxorubicin, cardiac risk factors and cardiac 1072-1083, 1978. toxicity in elderly patients with diffuse B-cell non-Hodgkin’s 26 Teichholz LE, Kreulen T, Herman MV and Gorlin R: Problems lymphoma. J Clin Oncol 26(19): 3159-65, 2008. in echocardiographic volume determinations: echocardiographic 14 Hequet O, Le QH, Moullet I, Pauli E, Salles G, Espinouse D, angiographic correlations in the presence or absence of asynergy. Dumontet C, Thieblemont C, Arnaud P, Antal D, Bouafia F and Am J Cardiol 37(1): 7-11, 1976. Coiffier B: Subclinical late cardiomyopathy after doxorubicin 27 Connie CW: Recruitment of lung diffusing capacity: update of therapy for lymphoma in adults. J Clin Oncol 22(10): 1864-71, 2004. concept and application. Chest 122: 1774-1783, 2002. 15 Nousiainen T, Jantunen E, Vanninen E and Hartikainen J: Early 28 Nystrom J, Celsing F, Carlens P, Ekblom H and Ring F: decline in left ventricular ejection fraction predicts doxorubicin Evaluation of a modified acetylene rebreathing method for the cardiotoxicity in lymphoma patients. Br J Cancer 86(11): 1697- determination of cardiac output. Clin Physiol 63: 201-210, 1987. 700, 2002. 29 Kallay MC, Hyde RW, Smith RJ, Rothbard RL and Schreiner 16 Sleijfer S: Bleomycin-induced pneumonitis. Chest 120: 617-624, BF: Cardiac output by rebreathing in patients with 2001. cardiopulmonary diseases. J Appl Physiol 63: 201-210, 1987. 17 Malik SW, Myers JL, DeRemee RA and Specks U: Lung 30 Liu Y, Menold E, Dullenkopf A, Reissnecker S, Lormes W, toxicity associated with cyclophosphamide use. Haematological Lehmann M and Steinacker JM: Validation of the acetylene 85: 1032-1039, 2000. rebreathing method for measurement of cardiac output at rest 18 Malik SW, Myers JL, DeRemee RA and Specks U: Lung and during exercise. Clin Physiol 17: 171-182, 1997. toxicity associated with cyclophosphamide use. Two distinct 31 Javaheri S and Sicilian L: Lung function, breathing pattern, and patterns. Am J Respir Crit Care Med 154: 1851-1856, 1996. gas exchange in interstitial lung disease. Thorax 47: 93-97, 1992. 19 Elbl L, Vasova I, Tomaskova I, Jedlicka F, Navratil M, Pospisil 32 Hansen JE and Wasserman K: Pathophysiology of activity Z and Vorlicek J: Cardiac function and cardiopulmonary limitation in patients with interstitial lung disease. Chest 109: performance in patients after treatment for non-Hodgkin’s 1566-1576, 1996. lymphoma. Neoplasma 53: 174-181, 2006. 20 Elbl L, Vasova I, Jedlika F, Kral Z, Navratil M, Smardova L, Wagnerova B and Vorlicek J: Cardiopulmonary capacity after Received February 23, 2010 treatment of in adults. Leuk Lymphoma 47: 843- Revised August 25, 2010 851, 2006. Accepted September 3, 2010

4387