The continuous development of chemotherapeutic agents has seen both a qualitative and quantitative rise in the recent few decades. However, drawbacks in clinical implementation are grounded on the vast array of toxic side effects that may accompany their use, especially of anthracyclines.
Depending on age, cumulative dose, and cardiovascular predispositions, their application may lead to cytostatic-induced cardiomyopathy (CCMP), perhaps one of the most feared complications.1
Unfortunately, despite ongoing research concerning novel antineoplastic medication, certain drug families such as anthracyclines remain indispensable in daily oncological practice, where securing cardiac function remains an unsolved challenge.
In cases of severe cardiac failure in the setting of cardiomyopathy, including CCMP, implementation of ventricular assist devices (VADs) as a bridge to transplant has become a common approach,2,3 while an orthotopic heart transplantation remains the gold-standard to date. Unfortunately, ongoing oncological disease is a contraindication to receiving a heart transplantation in patients acutely afflicted with severe heart failure.4
In light of this, discussing the notion that VADs may be a viable option to bridge the time to oncological remission and thus transplant eligibility is vital.
This case report portrays a young female patient suffering from anthracycline-induced cardiomyopathy secondary to chemotherapy for an osteosarcoma. Despite decremental prognostic factors, such as renal insufficiency and impending multiorgan failure, our patient was successfully treated with an orthotopic heart transplantation, enabled by bridging with a biventricular assist device.
A 15 year old female Dutch patient with a periosteal osteosarcoma of the left distal femur was transferred from the Netherlands to the Cardiac Surgery Department at the German Heart Center Berlin for emergent intervention after developing anthracycline-induced toxic cardiomyopathy. Her osteosarcoma had been surgically removed 6 months previously, subsequently receiving chemotherapy in accordance to the European Organisation for Research and Treatment of Cancer-Scheme, with a cumulative anthracycline dose of 450 mg/m2. Her initial presentation was cachectic with peripheral edemas, ascites, cisplatin-induced second-grade renal insufficiency (estimated GFR 62 ml/min) and catecholamine-dependent (Dobutamine 10–20 µg/kg/min). After persistent low-output syndrome and in light of the patient’s youthful age, we decided to implant a biventricular assist device (BVAD) (EXCOR, Berlin Heart GmbH) despite existing contraindications for an orthotopic heart transplantation.
Median sternotomy revealed a grossly enlarged heart with minimal visual contractility. Under extracorporeal circulation, the implantation of the BVAD was performed without complication. Postoperatively, a hemodynamically relevant secondary hemorrhage within the pericardial space necessitated a resternotomy to evacuate the hematoma a week after the BVAD implantation. Her further postoperative course remained uneventful, such that she could be discharged home, 2 months after the BVAD implantation.
Under BVAD support, the patient’s general condition improved drastically, having returned to a normal BMI (175 cm, 61.5 kg) within 3 months after her stay at our department. An intermittent derailment of her INR value to 5.1 under phenprocoumon therapy self-corrected overnight without necessitating a fresh-frozen-plasma transfusion. Two major incidences occurred approximately a year after her initial presentation, both requiring emergent surgical intervention. An infected epigastric hematoma, approximately 8 × 8 cm large, was evacuated without complication, and surgical palpation of the cavity revealed no cavitary connections. Shortly thereafter, routine echocardiographic diagnostics revealed a large right ventricular thrombus, warranting the indication for replacement of the right ventricular component of the BVAD. Both incidences were handled successfully and remained without consequences. During her time on BVAD support, our patient underwent a femoral reconstruction with homologous spongiosa. A computer tomography performed 10 months later confirmed that she was tumor free, enabling the registration for the waiting list of Eurotransplant.
Hence, after almost 419 days on BVAD support, a matching donor heart was found and the patient underwent assist device explantation and orthotopic heart transplantation (Figure 1). The surgery was performed successfully and without complication. Postoperative hemodynamic stability was achieved with the aid of calcium-sensitizers and catecholamines. A hypotensive tendency was counteracted and successfully normalized through medication adjustments. Despite ongoing second-grade renal insufficiency, her renal retention parameters remained stable and the immunosuppressive regimen with Cyclosporine A, mycophenolate-mofetil, and Prednisone was well tolerated. In addition to relying on echocardiographic diagnostics such as early diastolic relaxation time, fractional shortening, and wall thickness measurements of the posterior left ventricular wall and septum, a telemetric intramyocardial electrogram pacemaker was implanted to facilitate early detection of graft rejection and, if necessary, early intervention.
Routine follow ups showed a patient without complaints and with satisfying clinical and laboratory examination results, with no indications of impending rejection. However, 12 months after transplantation, routine cardiac catheterization for coronary vasculopathy revealed a 75% occlusion of the right circumflex coronary artery (RCX) and immediate percutaneous transluminal coronary angiography (PTCA) with stenting was performed. Due to intrainterventional difficulties regarding the localization of the stenosis, a reduction to only 50% occlusion could be safely ensured. A re-evaluation 3 months later revealed reocclusion of the RCX at 75% warranting a re-PTCA and stenting, which was performed successfully. Six years after receiving her heart transplant, our patient successfully underwent a kidney transplantation.
Ever since her heart transplantation after a 491 day VAD support, our patient has been able to enjoy life in all its facets. She has continued on to become a swimming world champion multiple times (Figure 1), found a loving partner, and to date, 19 years later, remains physically active, fully employed, and socially engaging, inspiring many with her case. We are humbled to have played a role in facilitating her development and proud to have witnessed her success.
Despite treatment success, our case raises multiple fundamental questions that have to be addressed not only to forward and optimize the field of cardiac transplantation but of all transplant medicine.
The viability of VADs for overcoming waiting times in patients with heart failure of different etiologies has been widely discussed and established.5,6 However, discussions on the use of VADs to bridge severe heart failure in the setting of ongoing oncological disease are scarce. It is, therefore, crucial to acknowledge and incorporate various deleterious outcomes when considering their implantation in the aforementioned setting.
A VAD approach, despite providing immediate cardiovascular relief, is not connected to the maintenance of oncological remission or the prevention of malignant recurrence. Therefore, a specialized oncological assessment of complete absence of malignancy before implantation and the definition of support duration up to which remission may be regarded as consolidated, respective of the type of oncological disease, may be considered. Preparation for possible failure to maintain remission is vital, as this disqualifies the patient for transplantation. Thus, alternative plans must be formulated pre-emptively, emphasizing importance on pharmacological and weaning strategies and perhaps, lighting the stage for the notion of possible myocardial recovery. In our case, a timely diagnosis, early surgical removal, and immediate aggressive chemotherapy have induced remission, unfortunately at the cost of cardiac toxicity. Additionally, her prospective time on VAD support and possible alternative strategies remained uncertain, relying on the clinical experience and expertise of the physicians in charge. It is therefore imperative for transplant medicine to address the matter surrounding transplant eligibility in oncological patients on VAD support and formulate defining criteria upon which cardiosurgical and oncological patients may benefit.
Unlike VADs, orthotopic heart transplantations are valued as the unequivocal solution for patients with heart failure, taking their place as the gold-standard treatment.7 However, discussing the possibility that rigorous posttransplant immunosuppression may drive malignant processes, whether recurrences or de novo, is vital.8
However, some studies have shown that the risk in developing posttransplant malignancy is comparable and the difference of no great significance between those suffering from pretransplant malignancy and those free of a malignant disease.2
Similar results have been extrapolated by a long-term retrospective single-center study, underlining no significant differences in posttransplant infections, rejection episodes, or the rate of posttransplant malignancies between patients with and without pretransplant oncological disease.3
A different study has shown similar posttransplant survival rates between cancer survivors (92.5%, 90.6%, 80.3%, and 65% at 0.4, 1, 5, and 10 years, respectively) and those without prior malignancy in children (90.1%, 84.4%, 73.8%, and 57.7%).9 However, they demonstrated a significantly higher rate of posttransplant malignancy in those with prior oncological disease, recording a rate of 13% as opposed to 5.4% in those without.
Another study revealed a positive correlation between pre- and posttransplant malignancies, determining pretransplant solid malignancy as a risk factor for the development of posttransplant skin malignancy but not of solid malignancies.
A differentiation must be made between solid and hematological malignancies, as hemato-oncological diseases such as lymphoma, leukemia, and myeloma may carry an increased risk after heart or lung transplantation.
A history of malignancy has been considered as a contraindication for heart transplantation. The number of patients with prior malignancy needing transplantation is increasing due to improved survival and to cardiotoxic cancer treatment. The primary concern in these patients is the potential for recurrent, or de novo, malignancy due to the associated immunosuppression necessary to prevent allograft failure. However, this reluctance for transplantation can be challenged by the already available results.2
Based on the findings of cases and small series, several reports have indicated that heart transplantation in end-stage heart failure patients with previous malignancy or chemotherapy-induced cardiomyopathy may be feasible and assume a positive trajectory in selected patients.10–12
Pretransplant malignancy is thus becoming less of a contraindication to orthotopic heart transplantations worldwide. It is imperative, however, that more clinical experience be gained and spread regarding long-term outcomes of transplant recipients with an oncological history, such that safe inclusion and exclusion criteria may be defined and rigorous posttransplant oncological evaluations be implemented.
Nevertheless, some points must be addressed. An important aspect is the disease-free interval, which inversely correlates to posttransplant tumor recurrence, tumor, and overall mortality.13 An optimal disease-free interval is not known14 while some guidelines suggest complete remission times from pretransplant malignancy for at least 2 and probably 5 years.15,16 However, recommendations may differ across the scientific societies and the types and stages of malignancy.17 The decision should then be clinical, where the remission period for a given patient may be set as 1 year if the expected 5 year survival is at least 70%,14,18 but no arbitrary period should be used.19 Some issues remain for patients with chemotherapy-related cardiomyopathy who are dying unnecessarily of end-stage heart failure. Most transplant centers are either hesitant or prejudiced in performing transplantation because of concerns about potentially deficient intrinsic immunomodulation and fear of cancer recurrence or development of secondary cancers from therapeutic immunosuppression. Likewise, prudence in performing heart transplantation in patients with pretransplant malignancy, especially if donor hearts are scarce, arises as an issue.11
We acted beyond the guidelines and issues. Patients with prior malignancy may be eligible for heart transplantation when the risk of tumor recurrence is low, preferably after a reasonable time of complete remission, response to therapy, and negative metastatic workup. A life-saving algorithm was our primary goal- and that was implanting a BVAD. The central idea was to “wait and see” or rather aptly named a bridge to decision. It was difficult to predict the likelihood of possible outcomes, including myocardial recovery or permanent MCS necessity, as tumor behavior can be volatile. After a stringent follow up, heart transplantation became possible.
This is a fascinating case of a 15 year old girl, already afflicted by a femoral sarcoma and eventually beset with a biventricular failure secondary to an anthracycline-induced cardiomyopathy. As she was at the time ineligible for heart transplantation, a VAD support for 419 days affected a tumor-free state until heart transplantation became possible. Nineteen years to this date, she enjoys the luxuries in life.
1. Narezkina A, Nasim K: Anthracycline cardiotoxicity. Circ Heart Fail. 12: e005910, 2019.
2. Mistiaen WP: Heart transplantation
in patients with previous malignancy. An overview. Acta Cardiol. 70: 123–130, 2015.
3. Fernández-Vivancos C, Paniagua-Martín MJ, Marzoa-Rivas R, et al.: Long-term outcome in heart transplant patients with pretransplant malignancies. Transplant Proc. 42: 3006–3010, 2010.
4. Crespo-Leiro MG, Metra M, Lund LH, et al.: Advanced heart failure: a position statement of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 20: 1505–1535, 2018.
5. Hetzer R, Kaufmann F, Delmo Walter EM: Paediatric mechanical circulatory support with Berlin Heart EXCOR: development and outcome of a 23-year experience. Eur J Cardiothorac Surg. 50: 203–210, 2016.
6. Javier Delmo EM, Javier MFDM, Hetzer R: The role of ventricular assist device in children. Cardiovasc Diagn Ther. 11: 193–201, 2021.
7. Hetzer R, Weng Y, Delmo Walter EM: State of the art in paediatric heart transplantation
: the Berlin experience. Eur J Cardiothorac Surg. 43: 258–267, 2013.
8. Buell JF, Gross TG, Thomas MJ, et al.: Malignancy in pediatric transplant recipients. Semin Pediatr Surg. 15: 179–187, 2006.
9. Shah N, Aggarwal S, L’ecuyer T: Outcome of heart transplantation
in pediatric cancer survivors. Pediatr Transplant. 17: 423–428, 2013.
10. Dillon TA, Sullivan M, Schätzlein MH, et al.: Cardiac transplantation in patients with preexisting malignancies. Transplantation. 52: 82–85, 1991.
11. Grande AM, Rinaldi M, Sinelli S, D’Armini AM, Viganŏ M: Heart transplantation
in chemotherapeutic dilated cardiomyopathy. Transplant Proc. 35: 1516–1518, 2003.
12. Edwards BS, Hunt SA, Fowler MB, Valantine HA, Stinson EB, Schroeder JS: Cardiac transplantation in patients with preexisting neoplastic diseases. Am J Cardiol. 65: 501–504, 1990.
13. Sigurdardottir V, Bjortuft O, Eiskjær H, et al.: Long-term follow-up of lung and heart transplant recipients with pre-transplant malignancies. J Heart Lung Transplant. 31: 1276–1280, 2012.
14. Lenneman AJ, Wang L, Wigger M, et al.: Heart transplant survival outcomes for adriamycin-dilated cardiomyopathy. Am J Cardiol. 111: 609–612, 2013.
15. Ladowski SD, Abel M, Beatty L, Scatena M, Ladowski JS: Long-term follow-up of heart transplant recipients with pre-transplant malignancies. Texas Heart Inst J. 33: 27–30, 2006.
16. Handa N, McGregor CGA, Daly RC, et al.: Heart transplantation
for radiation-associated. end-stage heart failure. Transplant Int. 13: 162–165, 2000.
17. Penn I: The effect of immunosuppression on pre-existing cancers. Transplantation. 55: 742–747, 1993.
18. Koerner MM, Tenderich G, Minami K, et al.: Results of heart transplantation
in patients with preexisting malignancies. Am J Cardiol. 79: 988–991, 1997.
19. Mehra MR, Kobashigawa J, Starling R, et al.: Listing criteria for heart transplantation
: international Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates–2006. J Heart Lung Transplant. 25: 1024–1042, 2006.