Treating secondary malignant neoplasms: A burden of childhood cancer survivors

Abstract

Each year approximately 35,000 children and adolescents are diagnosed with cancer in Europe. Five-year survival rates have improved and now reach 80% in most European countries, thanks to a combination of chemotherapy, radiotherapy, and surgery. To date, there are more than 44,000 Italians still living several years after being diagnosed with cancer in developmental age. The risk of premature morbidity and mortality for cancer survivors is well known and documented. Approximately 60% of survivors of cancer in childhood and adolescence have at least one chronic health condition in later life, and more than one in four develop severe or life-threatening disorders. Among the various long-term iatrogenic sequelae of cancer treatments, the most worrisome are second malignant neoplasms. We reported on our mono-institutional experiences of screening and treating secondary breast cancer, secondary thyroid cancer and secondary osteosarcoma. Recommendations on the surveillance needed for cancer survivors because of the risk of late effects of their disease or its treatment suggest that discussing the potential problems early on can be crucial to a patient’s future health. These considerations and our consolidated experience strengthen our conviction that survivors of cancer in childhood and adolescence who develop second malignant neoplasms should be treated at highly-specialized centers. Multidisciplinary care requires close communications and high levels of up-to-date professional expertise. This challenging area of health care is also changing rapidly because cancer survivorship is a work in progress, but we cannot wait for definitive conclusions on many aspects because this will take decades, especially for pediatric patients.

Introduction

Approximately 35,000 children and adolescents are diagnosed with cancer in Europe every year. ¹ Five-year survival rates have improved and now reach 80% in most European countries (including Italy), thanks to a combination of chemotherapy, radiotherapy, and surgery. With more new technologies and innovative drug therapies being developed, there are also more and more survivors of cancer in childhood and adolescence, who currently amount to over 500,000 in Europe.^1–3 The outstanding improvement to the survival rates for pediatric and adolescent cancer is well recognized.

To date, there are more than 44,000 Italians still living many years after being diagnosed with cancer in developmental age, thanks to constantly-improving diagnostic and treatment protocols and personalized follow-up programs. ⁴

The Erice statement ⁵ underscores the need to follow up individuals cured of cancer to monitor them for potential long-term effects of their disease or its treatment. Referring to the evidence-based recommendations of the International Guidelines Harmonization Group (IGHG),^6,7 European and Italian national groups like PanCare (the Pan-European Network for Care of Survivors after Childhood and Adolescent Cancer) and AIEOP (Associazione Italiana Oncologia Ematologia Pediatrica), and to other expert opinions, a well-documented scientific literature promotes long-term follow-up programs, health care, and education for survivors, parents, and professionals.^8,9 Cancer in childhood and adolescence has been at the center of new research that, over the years, has focused on possible sequelae of the disease, not only physical, but also on the psychosocial level. The proposed programs could reduce the late medical and psychosocial burden on young cancer survivors by promoting the early detection and treatment of adverse events following antineoplastic treatments.^8,10

The risk of premature morbidity and mortality for cancer survivors, compared with the general population, is well known and documented. Many such health issues occur even 20-30 years after a diagnosis of cancer at a young age. Approximately 60% of survivors of cancer in childhood and adolescence have at least one chronic health condition in later life, and more than one in four develop severe or life-threatening disorders.^5-7,9 Among the various long-term iatrogenic sequelae of cancer treatments, the most worrisome are further tumors (second malignant neoplasms, SMN). The radiotherapy and chemotherapy regimens responsible for improving the survival rates for children and adolescents with cancer are not devoid of carcinogenic effects, and second malignancies are an important cause of death in long-term survivors.^11,12

The incidence of SMN is known to increase after radiotherapy, and the related risk persists for decades, long after the first tumor was diagnosed. ¹³ Many reports have been published, especially on Hodgkin lymphoma ¹⁴ and pediatric and adolescent cancer survivors, on the risk factors, the radiotherapy fields and doses, the type and dosage of chemotherapy, and the timing and type of follow up adopted in such patients. Those who develop a SMN are at greater risk of developing other tumors too: 20 years after the diagnosis of a SMN, the estimated cumulative incidence of further neoplasms is 47%. ¹⁵ Patients with a diagnosis of SMN should therefore have access to a cancer center with expertise on such late effects.

Several studies have examined the prognosis, and the biological, clinical and pathological characteristics of specific types of SMN developing in survivors of cancer contracted in childhood and adolescence, comparing them with the same types of malignancy occurring in the general population.^16,17 Reports on SMN provide information on the relative risks, which vary with age, the characteristics of such second malignancies, and the radiation doses and fields, and chemotherapy regimens used to cure the first cancer. ¹⁶ Many articles have discussed the barriers for survivors encountered in efforts to deal with late effects, and the number of publications on the increased risk of SMN has risen in recent years.^16,18

On the other hand, few studies investigating SMN have compared cause-specific survival between patients who contracted a first cancer in childhood or adolescence and those whose first cancer developed in adulthood. ¹⁹ Even less information is available on the best options for treating the former patients effectively, and on the related outcomes. For many survivors of cancer in developmental age, it could be difficult to find the center best able to treat their particular type of SMN.

We reported on our mono-institutional experiences of screening and treating secondary breast cancer (SBC) in 2013 and 2015, ²⁰ secondary thyroid cancer (STC) in 2014, ²¹ and secondary osteosarcoma (SOS) more recently. ²² Below, we briefly report on our series.

Secondary breast cancer

We identified 78 women who developed SBC ²⁰ (invasive in 68 cases, 87%). They were a median 18 years of age when their first neoplasm was diagnosed, and 38 at the time of their SBC being discovered. Breast-conserving surgery was performed in 39 patients, and 32 underwent breast irradiation. Twenty (49%) of the 41 patients already given chemotherapy received an anthracycline-containing regimen. The five- and 11-year event-free survival and overall survival rates were 69% and 42%, respectively. Nine patients (12%) developed a third cancer, and 18 (23%) had a cardiovascular event.

In the 68 women with invasive SBC, the first event involved contralateral BC in 55% of cases. The five- and 11-year BC-specific survival rates were 84% and 68%, respectively. The survival rates after BC developing in women with a history of chest radiotherapy are not dissimilar to those seen for women with primary BC.

Secondary thyroid cancer

We considered 36 cases of STC ²¹ in patients treated for other malignancies in pediatric age seen at our institution in more than 30 years (between 1980 and 2012). In most cases, the primary cancer had been Hodgkin disease, and all patients had been given radiotherapy for their first malignancy. The treatment for STC was total thyroidectomy in 27 cases (including lymphadenectomy in six), and hemithyroidectomy in nine (with lymphadenectomy in one). Twelve patients also had radiometabolic therapy. All but two had TSH suppression therapy. Histology identified 31 papillary and five follicular carcinomas: at five and 10 years, the OS rate was 100% and 95%, respectively, and the Progression Free Survival rate was 96% and 83%. None of the patients died of their thyroid disease. Nodal involvement at onset was the only factor correlating with recurrence. Surgical sequelae only occurred in patients who underwent total thyroidectomy. These patients’ survival did not depend on the extent of surgery on the thyroid parenchyma. Our data confirm a good prognosis for STC, prompting us to encourage a minimalist approach to the treatment of these particular patients wherever possible.

Secondary osteosarcoma

We identified 26 patients (13 females, 13 males) who developed SOS ²² a median 7.3 years after being diagnosed with primary neoplasms in childhood and adolescence (5/7 of the patients tested for Li-Fraumeni, resulted positive). The median age of the sample when their primary neoplasms and SOS were diagnosed was 8.0 and 15.0 years, respectively. To treat their primary neoplasms, 24 of the 26 patients had been given radiotherapy, and 19 had received chemotherapy including doxorubicin. More than half of the SOS occurred at unfavorable sites (nine hip bone, six skull). All but one patient had chemotherapy with tailored schedules, omitting doxorubicin in 19 cases. Eighteen of the 26 patients underwent surgery, achieving wide margins in 14/18. Pathological response to neoadjuvant chemotherapy was evaluable in 9/18 surgically-treated patients: the median proportion of necrosis was 60% (50-95%). The five- and 10-year overall survival and probabilities after SOS was diagnosed (with 95% confidence intervals) were 50% (32.7-76.5%) and 38.9% (22.4-67.4%); the five- and 10-year progression-free survival rate was 47% (29.9-73.7%) and 35.2% (19.3-64.4%), respectively. Although these survival rates after SOS are lower than in patients with primary osteosarcoma, they are not negligible, so it is mandatory to discuss the best treatment for such patients at a referral center, in terms of their chances of cure and quality of life.

Details of the characteristics, treatment and survival of the patients who developed the above-mentioned three types of SMN after surviving cancer in childhood and adolescence cancers are reported in the three cited studies.^20-22

Recommendations on the surveillance needed for cancer survivors because of the risk of late effects of their disease or its treatment suggest that discussing the potential problems early on can be crucial to a patient’s future health. This is only the starting point, however. It seems unthinkable to merely provide information about this risk and the related screening programs. When SMN are diagnosed, patients and families need to be accompanied along a properly-encoded path, and national referral centers with the necessary expertise should be recommended. For example, at our institute we use our expertise and skills to help our patients manage the impact of the recent diagnosis, organize their treatment plan and to cope with their disease. Working at a cancer institute makes us responsible for filling the gaps in our knowledge in this particular area of patient care and drawing more attention to the growing importance of this type of expertise. The DCOG-LATER study ¹⁷ examined three case series of SMN (41 SBC, 45 bone and soft tissue sarcomas, and 17 melanoma) matched with patients with corresponding primary tumors in the population-based cancer registry, comparing survival, and cause of death. The study confirmed a similar overall survival for SBC and secondary melanoma, and a worse survival for secondary sarcoma. Limitations of the study consisted in the small numbers of site-specific SMN, and fact that data on several important clinical characteristics were often missing.

Milano et al. ²³ found that many Hodgkin lymphoma survivors who developed SBC died of another tumor, cardiovascular events or other causes, whereas SBC was the cause of death in the vast majority of the childhood cancer survivors who developed SBC in the DCOG-LATER cohort. Because women who survived cancer earlier in life and then develop SBC will have already been exposed to radiation, they would be at greater risk of side-effects and toxicity if they are given further radiotherapy following breast-conserving surgery. This means that they are sometimes not considered candidates for breast-conserving treatment. Similarly, because many of these women may also have received chemotherapy for their primary cancer, this is believed to limit the options for systemic adjuvant chemotherapy when SBC is diagnosed. The problem in such cases lies in how to strike the best balance between the risks and benefits of treatments for their SBC. A multidisciplinary approach (adequate loco-regional treatment followed by adjuvant medical treatment in patients at moderate-to-high risk of recurrent disease) was generally able to achieve much the same survival rates as in women diagnosed with sporadic BC showing similar pathological features. Given the years in which our patients were treated, we did not consider the possibility of triple-negative SBC. Teepen et al. ¹⁷ reported a lower percentage (7.7%) of triple-negative SBC than the one reported in a retrospective French study ²⁴ (29.2%), and they found that it developed in breast tissues receiving >20 Gy.

As regards STC, there is an abundance of literature on the risk of its occurrence in survivors of cancer in childhood and adolescence, depending on the doses of radiotherapy they received for their primary cancer, and subsequent surveillance. Much has also been written about patient counselling, and about whether and when screening can be done using a method as simple and harmless as ultrasound. ²⁵ On the other hand, little has been written about how to treat this group of fragile patients, and the risk-benefit ratio of total thyroidectomy with versus without metabolic radiotherapy in a population definitely at high risk of developing third or further tumors. At our institute, it is customary to perform the least demolishing surgery - hemithyroidectomy - whenever possible, with lymphadenectomy of the levels involved, but this is based on the assumption that patients will attend an appropriate follow-up and remain in touch with our reference center. Other authors have suggested taking the same approach as for primary thyroid cancer because STC does not seem to have clinical features that should prompt physician not to be more aggressive to avoid treatment morbidity as the prognosis is as good as for sporadic STC. ²⁶ Shaha et al. reported on 116 patients with a history of radiotherapy to the head and neck, and compared them with 3509 patients with differentiated thyroid cancer and no prior exposure to radiation: no differences emerged in five-year disease-specific survival, and the recurrence-free survival rate was also similar in the two groups (97.8% vs 94.9%). ²⁷

A recent paper described a trend towards a higher incidence of surgical morbidity in patients with STC. ²⁸ The series was small, but our experience also suggests that patients treated with radiotherapy in the 1970s have hard necks with fibrotic tissues, and are therefore much more difficult to manage surgically.

There has been much debate on the increased risk of developing hematological malignancies after receiving metabolic radiotherapy. If this is true for patients generally, it will apply even more to cancer survivors. It is therefore important to select patients at low and intermediate risk who can really benefit from the administration of radiometabolic treatment. ²⁹ Here again, these considerations should encourage the treatment of patients with SMN at highly specialized centers. Such a “conservative” attitude may not be shared by all physicians dealing with thyroid cancer, especially outside institutions like ours, who might take a more aggressive approach due to a lack of awareness that patients who have survived cancer in childhood and adolescence may have not only a burden of previous treatments but also a hitherto unidentified genetic susceptibility.

The clinical management and treatment of patients with SOS is particularly complicated. Chemotherapy is essential, but seems to be less effective for SOS than for primary osteosarcoma. We need to bear in mind, however, that patients with SOS will have often been treated with less intensive chemotherapy regimens than those deemed appropriate nowadays.^30,31 Many patients with SOS cannot be given full doses of anthracyclines or methotrexate because of all their past systemic treatments. On the whole, the treatment plans adopted for the DCOG-LATER ¹⁷ cohort were the same for SOS as for a first OS, though the agents administered were not reported in detail. Surgery with wide margins is crucial for the local control and cure of any OS, but is often not feasible for SOS because many of them grow at unfavorable sites, such as the pelvis, sacrum, head or neck. ³² Radiotherapy may be the only viable local treatment option in such cases. Bjerkehagen ³³ found that the worse prognosis of SOS could be explained by these already-reported unfavorable factors. The chances of surviving after being diagnosed with SOS are certainly lower than for patients with primary OS, but they are not negligible, so every effort must be made to manage patients in the best possible way. This includes discussing the choice of treatment at referral centers to improve the chances of cure and quality of life.

With better treatments nowadays, the population of survivors of pediatric cancer is continuing to expand. It is important to monitor those survivors at higher risk of developing second malignancies. In this setting, surveillance activities should take into account the treatments previously administered (especially for sarcoma), i.e. radiotherapy and alkylators/anthracyclines, and the patient’s family history (or evidence of genetic conditions predisposing to cancer), to ensure the early detection of SMN.

These considerations and our consolidated experience^20–22 strengthen our conviction that survivors of cancer in childhood and adolescence who develop SMN should be treated at highly-specialized centers. Such cases demand a multidisciplinary discussion between pediatric oncologists, geneticists, adult cancer experts, surgeons and radiotherapists capable of deciding whether and how the patient can be treated again. Unlike pediatric oncologists working at cancer centers, those who work in pediatric hospitals do not usually have the chance of a daily exchange with experts on adult cancer and cannot follow up their pediatric cancer survivors at every step.

It is important to consider certain problems peculiar to survivors of cancer in childhood and adolescence. The cumulative prevalence of serious or life-threatening chronic health conditions developing by the time they are 45 years old is 80%. ⁹ This figure suggests premature aging as a consequence of the therapies used to cure their cancers. Administering radiotherapy or further anthracyclines, or any other chemotherapy for SMN may exacerbate the well-known risk of long-term iatrogenic sequelae. The best treatment options (if available) should be discussed with patients, also bearing their life expectancy in mind. To give an example, modern reconstruction surgery after mastectomy (to avoid further RT) has reached a high level of aesthetic quality – sometimes better than conservative surgery – even in previously-irradiated tissues. On the other hand, radiotherapy remains the only option available in cases of SOS impossible to manage surgically. Cancer survivors may have a long-life expectancy nowadays, and it is important to develop methods for estimating the risk of late complications, and to propose appropriate interventions, whenever possible.

Genetic counseling is becoming more and more important in the setting of pediatric cancers for the best management of the disease itself, and the toxicity of treatments, for screening siblings, and in view of future pregnancies. In cases of SMN, it is recognized that the best treatment options may involve prophylactic measures, such as mastectomy or ovarectomy, and specific surveillance for patients and their siblings. Genetic counseling could shed light on the risk of hereditary cancer syndromes, and fertility professionals could help with any related decisions.

Fung and Travis ³⁴ identified four areas needing attention in order to move forward on cancer survivorship: i) precision medicine approaches to individualize treatment and enable a better risk stratification for a first primary neoplasm; ii) research on how genetic variants predispose survivors to long-term toxicities; iii) investigations into how aging interacts with long term morbidity; and iv) longitudinal cohort studies to follow survivors for life.

A strength of the present commentary lies in the identification of a fifth need, i.e. teams of experts on the treatment of such particular patients. This need is often overlooked, partly because the clinical expertise required to address all the problems involved means that different specialists are needed to cover all aspects of SMN: prevention and early detection, patients’ personalized treatment and quality of life; and more research. Given the priority of care, patients should be involved in discussions on the pros and cons of any reasonable treatment option for their SMN, including the risks of various subsequent cancers, and of severe late toxicity such as cardiovascular events, in order to arrive at a shared final decision. Surgical management options must be evaluated with caution. For example, necks that have become “complicated” and “hard” due to tissue fibrosis caused by previous radiotherapy should be assessed by a team with the expertise of a plastic surgeon. Sometimes, for a patient with heart disease and pulmonary fibrosis, a radiation-induced thyroid tumor may not be the main problem. In short, such patients need a team with all the necessary knowledge and capable of establishing the priorities for a given patient.

Pediatric oncologists have to summarize a patient’s history of previous treatments (as recorded in the “survivor’s passport”). Radiation oncologists need to identify the feasibility of radiotherapy for treating a second cancer. Then it is up to the whole team of different professionals to decide how and when it is best to treat a given patient. For all these aspects to be handled adequately, it is fundamentally important to have a motivated team of specialists with good communications, and capable of working together towards a shared goal, which is ultimately to give patients the best chances of being cured of their cancer with the fewest possible iatrogenic sequelae. It is also important to emphasize that a second cancer diagnosis can have a devastating psychological impact so patients should receive adequate psychological support when faced with this new challenge. Having the opportunity to be assisted by the team that treated their first cancer can help patients manage this emotional burden. Such teams do not spring up spontaneously. They have to be nurtured and motivated, primarily by the physicians involved. Multidisciplinary care requires close communication and high levels of up-to-date professional expertise. It is also time-consuming because every single patient needs to be considered from every angle and discussed in depth. This challenging area of health care is also changing rapidly because cancer survivorship is a work in progress, but we cannot wait for definitive conclusions on many aspects because this will take decades, especially for pediatric patients.