Table 3.
The burden of late mortality among adolescent and young adult cancer survivors by tumor group (n = 54).
| Reference | Cancer Type | Number of Aya Participants | Outcome Ascertainment | Results |
|---|---|---|---|---|
| Mixed-cancer cohort | ||||
| Garwicz S, 2012 [71] | Any primary malignancy | NR | Death certificates and Cause of Death Registers’ files | HR for all-cause mortality was 1.6 (95% CI 1.43–1.80) for survivors aged 15–19 at diagnosis compared to survivors aged 0–4. HR for mortality from first primary was 1.59 (95% CI 1.37–1.84), from second primary was 1.24 (95% CI 0.89–1.72), from non-cancer causes was 1.82 (95% CI 1.44–2.28). |
| Prasad P, 2012 [72] | Any solid tumor or hematological malignancy | 6297 | National Population Register, Statistics Finland | SMR for all causes of death: for ages 15–19 (9.2, 95% CI 7.8–10.6) and for ages 20–34 (5.8, 95% CI 5.4–6.2). SMR for death due to circulatory disease: for diagnosis of HL, 8.4 (95% CI 3.1–18.2) for ages 15–19 and 6.5 (95% CI 4.6–8.9) for ages 20–34. For diagnosis of NHL, 21.8 (95% CI 7.1–50.8) for ages 15–19 and 3.3 (95% CI 1.4–6.5) for ages 20–34. For CNS tumor, 1.2 (95% CI 0.03–6.6; non-significant) for ages 15–19 and 3.2 (95% CI 1.3–6.5) for ages 20–34. |
| Zhang, 2012 [18] | Any primary malignancy | 1248 | Ministry of Health Vital Statistics Agency, British Columbia Cancer Registry | Among 1248 YA cancer survivors, 11.1% died more than 5 years after diagnosis. The mortality rate was higher than the rate for the general British Columbian population (SMR 5.9, 95% CI 4.9–6.9; AER 5.3). |
| Haggar F, 2013 [70] | Any primary malignancy | 10,266 | Western Australia Cancer Registry, Western Australia Mortality Register, Australian National Death Index | Overall 5-year relative survival rates for AYAs diagnosed with any cancer in the most recent diagnostic period (2000–2004) were 0.84 (95% CI 0.82–0.86) in males and 0.86 (95% CI 0.85–0.88) in females. |
| Kero A, 2014 [49] | Any primary malignancy except carcinoma in situ lesion of the skin | 11,417 | National Death Certificate files, Statistics Finland | SMR among AYA cancer survivors was 4.2 (95% CI 4.0–4.3) for all causes of death. Cause-specific SMR was highest for infections (SMR = 4.0, 95% CI 2.1–5.8) and cancer (SMR = 10.9, 95% CI 10.4–11.2); lowest for diabetes (SMR: 0.8, 95% CI 0.2–1.4), “external” (SMR = 0.8, 95% CI 0.6–1.1), and alcohol-related (SMR = 0.8, 95% CI 0.6–1.1). |
| Chao C, 2016 [58] | Any primary malignancy | 5673 | Kaiser Permanente Southern California’s electronic health records, California state death records, United States Social Security death records | Higher all-cause mortality in cancer survivors who developed CVD compared to survivors without CVD (HR 10.9, 95% CI 8.1–14.8). Compared to those without CVD, survivors who developed CVD had lower 5- (0.67 with CVD vs. 0.92 without CVD) and 10-year (0.55 vs. 0.90) survival after diagnosis. |
| Henrique L, 2016 [73] | Neoplasia excluding primary tumors in the CNS | 889 | Sistema de Informações sobre Mortalidade (system database on mortality) | Adjusting for neoplasia and sex: Higher risk of dying for individuals with non-hematological neoplasia (solid tumors) compared with individuals diagnosed with leukemias and lymphomas (HR: 1.47, 95% CI: 1.12–1.93). Compared with individuals diagnosed with leukemias and lymphomas, individuals diagnosed with non-hematological neoplasia had greater risk of death (HR: 1.51, 95% CI: 1.15–1.99). |
| Henson K, 2016 [74] | Any primary malignancy | 200,945 | Office of National Statistics in England and the Welsh Cancer Registry, Health and Social Care Information Center | 2016 survivors died of cardiac disease. The SMR for all cardiac diseases was 1.4 (95% CI 1.3–1.4). Compared to the general population, higher SMR was observed for survivors of HL (SMR: 3.8; 95% CI, 3.5–4.2), AML (SMR: 2.7; 95% CI, 1.6–4.4), genitourinary cancers other than bladder cancer (SMR: 2.0; 95% CI, 1.6–2.5), NHL (SMR: 1.7, 95% CI, 1.5–2.1), lung cancer (SMR: 1.7; 95% CI, 1.2–2.4), leukemia other than acute myeloid (SMR: 1.6, 95% CI, 1.0–2.4), central nervous system tumor (SMR: 1.4; 95% CI, 1.1–1.6), cervical cancer (SMR:1.3; 95% CI, 1.1–1.5), and breast cancer (SMR: 1.2; 95% CI, 1.1–1.4). |
| Berkman A, 2017 [75] | Any primary malignancy | 135,705 | SEER | Survivors of germ cell cancer (HR 2.03, 95% CI 1.66, 2.48), melanoma (HR 1.89, 95% CI 1.14, 3.14), and HL (HR 1.63, 95% CI 1.44, 1.84) had the highest risk at 20 years. For CVD deaths, specifically, Black survivors of AYA leukemias (HR 1.68, 95% CI: 1.06, 2.65), NHL (HR 3.25, 95% CI 1.56, 6.77), thyroid (HR 14.31, 95% CI 3.44, 59.45), melanoma (HR 2.42, 95% CI 1.89, 3.10), and other cancers (HR 2.54, 95% CI 2.13, 3.05) had a higher risk at 20 years. |
| Anderson C, 2018 [76] | Any primary malignancy except Kaposi sarcoma | 205,954 | SEER | At 7 years, relative survival of AYA cancer survivors exceeded 95% compared with the general population. Greater relative survival for patients diagnosed in 1988–2009 compared to those diagnosed in 1973–1987. Survival improvements over time were noted for most cancers. |
| Fidler M, 2018 [77] | Any primary malignancy | 200,945 | Office for National Statistics and Welsh Cancer Registry, National Death Registration systems | At the end of follow-up, 17% of TYAC survivors had died, of which, 3.2% were due to respiratory causes. Compared to the general population, TYA survivors were more likely to die from a respiratory cause (SMR: 1.7; 95% CI 1.6 to 1.8). |
| Hayek S, 2018 [23] | Any primary malignancy | 1765 | Israel national population register | 95 deaths were reported in the AYA age group, corresponding with a HR of 1.54 (95% CI 1.13–2.09). |
| Keegan T, 2018 [46] | 14 first primary AYA cancers | 79,176 | California Cancer Registry and linkages to state and national vital status databases | In total, 2249 of 79,176 patients developed CVD (2.8%). 9285 patients died over the follow-up period (11.7%). |
| Anderson C, 2019 [78] | Any primary malignancy except Kaposi sarcoma | 401,287 | SEER | The 10-year cumulative incidence of noncancer-related death after AYA cancer was 2% and 5% among women and men, respectively. The 20-year cumulative incidence of noncancer-related deaths was 4% and 6%, respectively. |
| Bagnasco F, 2019 [79] | Any primary malignancy | 753 | National health system registries | Compared to children ages 0–4 at diagnosis, adolescent survivors had a higher risk of death from recurrence (RR-AER = 2.6, 95% CI 1.8–3.8), but not other causes (RR-AER = 1.1, 95% CI 0.6–1.9). SMR for death from all causes except recurrence was 0.59 (95% CI 0.37–0.92) compared to those aged 0–4. |
| Chao C, 2019 [25] | Any primary malignancy | 10,574 | SEER | Higher risk of dying in AYA after developing SMN compared to those in comparison group who developed first cancer (HR = 1.90 (95% CI, 1.61–2.24)). AYA cancer survivors’ 5-year overall mortality after SMN diagnosis was 31.9% (128 of 401). |
| Moke D, 2019 [80] | Any primary malignancy | 225,493 | SEER | The 7- and 10-year overall survival probability was higher among those diagnosed in 2001–2017 compared to 1988–2000 (78.1% vs. 66.7%) and (75.3% vs. 64.4%), respectively. |
| Armenian S, 2020 [81] | Any primary malignancy | 10,574 | SEER | Survival rate of AYA cancer survivors was 78.5% at 25 years after diagnosis, but was at a 10.4-fold increased risk of death compared to noncancer controls (IRR = 10.4, 95% CI 9.7–11.2). Absolute excess risk for death from any cause was 12.7 per 1000 person-years (95% CI, 11.9–13.4 per 1000 person-years). Fifteen years post-diagnosis, incidence of second cancer mortality exceeded the rate of recurrence-related mortality. Lowest long-term survival in breast cancer survivors (25 years: 59.8%) and the highest long-term survival in thyroid cancer survivors (25 years: 95.3%). |
| Cuglievan B, 2020 [82] | Brain tumor, HL, Leukemia, non-HL, thyroid cancer, sarcomas (bone or soft-tissue) | 201 | Electronic medical records | Ten-year overall survival for AYAs was about 78%. |
| Suh E, 2020 [42] | Leukemia, CNS malignancy, HL, NHL, Wilms tumor, neuroblastoma, soft-tissue sarcoma, and bone cancer | 5804 | United States National Death Index | SMR among all AYA patients for death from all causes was 5.9 (95% CI 5.5–6.2). SMR was 4.8 (95% CI 4.4–5.1) for non-recurrent, health-related causes, 7.8 (95% CI 7.0–8.7) for SMN, 4.4 (95% CI 3.7–5.2) for cardiac causes, 7.4 (95% CI 5.7–9.5) for pulmonary causes, 2.8 (95% CI 2.4–3.2) for other medical causes, 1.1 (95% CI 0.9–1.3) for external causes. Health-related causes of late mortality (SMNs, CVD, pulmonary disease, other median causes) accounted for 52% of deaths among survivors, followed by 36% for recurrence or progression of primary cancer. Cumulative mortality at 30 years was 23% compared to 16% for childhood cancer survivors. |
| Lymphoma cohort | ||||
| Anton–Culver, 2010 [83] | NHL | 3489 | Death certificates | Overall, 1081 of 3489 people died in the study cohort. The most common causes of death were due to lymphoma-related causes and human immunodeficiency virus. |
| Castellino, 2011 [84] | HL | 1273 | United States National Death Index | The HR for risk of death from any cause for the 15–21 age group was 1.1 (95% CI 0.6–2.0), relative to the <10 age group. |
| Xavier A, 2015 [31] | HL | 5156 | SEER | 5-year survival was better among patients treated with RT relative to those who were not (96.1% vs. 94.6%, respectively, p = 0.002). |
| Hossain J, 2015 [85] | AML | 2290 | SEER | The risk of mortality was 30% greater for males compared to females in the 20–24 age group (HR 1.30, 95% CI 1.12–1.52). |
| Bhuller K, 2016 [32] | First primary malignancy: HL. SMN: Any secondary malignancy | 442 | Canadian Vital Statistics Agency | 60 deaths reported; half of them within 20 years post diagnosis. Standardized mortality ratio for HL survivors was 8.8 (95% CI: 6.7–11.3). Increased risk of death: 18-fold from SMN, 3-fold from non-malignant disease, and 19-fold from circulatory disease. The risk of death remained persistently elevated up to 35 years from diagnosis due to non-relapse mortality. |
| Keegan T, 2016 [86] | HL | 9353 | California Cancer Registry, death certificates | Among 9353 patients, 8108 were still alive at the end of follow-up. The highest number of observed deaths was from HL (7.2%), NHL (1.2) and other cancer (1.1%). |
| Keegan T, 2018 [67] | HL | 5085 | State and national vital statistics databases | All medical conditions examined in this study reduced overall and HL-specific survival. Respiratory conditions reduced overall survival the most of any condition (HR 6.17, 95% CI 4.5, 8.5). |
| Patel C, 2018 [87] | HL | 511 | National Death Index | The 10-, 15-, 20-, and 25-years post-treatment overall survival probabilities were 92.0%, 87.4%, 83.5%, and 75.4%, respectively. |
| Leukemia cohort | ||||
| Goldman, 2010 [88] | Chronic myeloid leukemia | 1373 | Center for International Blood and Marrow Transplant Research, Bone Marrow Transplant Registry, National Marrow Donor Project | The relative risk of death, treatment failure, or both among those 20–29 and 30–39 years of age at transplantation did not differ from those of patients age <20 years at HCT transplantation |
| Chen Y, 2012 [89] | Acute promyelocytic leukemia | 372 | SEER | Ten-year relative survival (RS) was 0.24 (95% CI 0.16–0.33) for the 1975–1990 period, and 0.60 (95% CI 0.50–0.68) for the 1991–1999 period. Ten-year RS for the most recent period (2000–2008) was not reported. |
| Hunger S, 2012 [90] | ALL | 1515 | COG ALL clinical trials | Eight percent of adolescent ALL survivors in the cohort died between 5–9.99 years after the start of the study. Less than one percent died at 10 or more years. |
| Canner J, 2013 [91] | AML | 238 | Children’s Cancer Group and COG | Overall survival for AYAs 8 years after study entry was approximately 48%, compared to approximately 58% for younger patients (<16 years old). |
| Woods W, 2014 [92] | AML | 517 | COG, Cancer and Leukemia Group B, and Southwest Oncology Group trials | Ten-year overall survival was 45.6% and 34% among the COG and CALG/SWOG cohorts, respectively. Ten-year overall survival was higher for patients aged 16–18 compared to aged 19–21 (43% vs. 32%, p = 0.034). |
| Wolfson J, 2018 [93] | ALL, AML | 761 | Los Angeles County Cancer Surveillance Program | Seven-year survival probabilities for 15–39-year-old ALL survivors were approximately 38% and 56% for patients treated at non-CCC/COG (other) and CCC/COG (Comprehensive Cancer Centers/ COG) facilities, respectively. Seven-year survival probabilities for 15–39 year old AML survivors were approximately 48% and 49% for patients treated at non-CCC/COG (other) and CCC/COG facilities, respectively. |
| Zheng C, 2018 [94] | Chronic myeloid leukemia | 74 | Data from Anhui Provincial Hospital | The seven-year overall and leukemia-specific survival for cord blood transplant patients was 55% and 48%, respectively, compared to sibling-allo-HCT, which was 63% and 61%, respectively. |
| Baron F, 2020 [95] | Primary or secondary AML | 661 | EORTC/GIMEMA AML-10 trial | No difference in survival by randomization group type (MXR/IDA vs. DNR) for AYA 15–25 (HR: 0.85, 95% CI: 0.56–1.27) or AYA 26–35 (HR: 1.11, 95% CI: 0.78–1.58). Similarly, no difference in survival was found by donor type (i.e., no donor vs. donor) for AYA 15–25 (HR: 0.66, 95% CI: 0.4–1.1) or 26–35 (HR: 0.65, 95% CI: 0.4–1.03) |
| Venkitachalam R, 2020 [96] | Acute Promyelocytic Leukemia | 246 | SEER | The 7-year survival probability was approximately 75.6% among AYA 16–20 |
| Melanoma cohort | ||||
| Fossa S, 2011 [97] | Testicular cancer | 20,411 | SEER | Ten-year cumulative testicular cancer-specific mortality rate for seminoma and nonseminoma was 1.4% (95% CI 1.2% to 1.7%) and 6.1% (95% CI 5.7% to 6.7%), respectively. Significantly decreased mortality was observed for participants aged 40 at diagnosis for seminoma HR: 2.0 (95% CI 1.5 to 2.6) and nonseminoma HR: 2.1 (95% CI, 1.7 to 2.6). |
| Pollack L, 2011 [98] | Melanoma excluding melanoma in situ | 13,383 | SEER | 10-year melanoma-specific survival was 91.9%. AYAs had better 10-year survival probability than those diagnosed at 40–64 (86.7%) or 65+ (77.0%). |
| Green A, 2012 [99] | Thin melanomas (< = 1.00 mm) | 1381 | Queensland Registrar of Births, Deaths, and Marriages | Ten-, 15-, and 20-year thin melanoma survival probabilities were 98.5%, 98.2%, and 97.9%, respectively. Better overall survival from thin melanomas for 15–24 years compared to those 45 or older at diagnosis. |
| Reed K, 2012 [100] | Cutaneous melanoma | 256 | Medical records | Ten-year overall survival probabilities by decade of diagnosis were approximately 82.7% for 1970–1979, 89.1% for 1980–1989, 94.3% for 1990–199, and 99.7% for 2000–2009. |
| Gamba C, 2013 [101] | Invasive melanoma of the skin | 8853 | National Center for Health Statistics | The results reported are for participants in the 1989–1999 diagnosis period. Overall, males were at high risk of mortality compared to females (HR: 1.45, 95% CI 1.25–1.67). |
| Plym A, 2014 [102] | Invasive malignant melanoma | 584 | National Population Register | Eight- and 10-year cumulative relative survival was approximately 92.1% and 90.9%, respectively |
| Other tumor-specific cohort | ||||
| Smoll N, 2013 [103] | Chordoma | 205 | SEER | Relative survival rates for AYAs were 69% (95% CI 60–76), 59% (95% CI 49–68), and 56% (95% CI 44–66) at 10, 15, and 20 years, respectively. |
| Youn P, 2014 [104] | Bone and soft tissue sarcoma | 28,844 | SEER | All-cause mortality in survivors was 76% higher compared to that of the general population (SMR 1.76, 95% CI 1.60–1.92; AER 19). At 20 years, this trend persisted (SMR 1.39, 95% CI 1.04–1.82; AER 20). |
| Keegan T, 2015 [105] | First invasive thyroid carcinoma excluding Hürthle cell carcinomas | 16,827 | California Cancer Registry (hospital database linkages including the Social Security Administration) | Compared to women of the same age, AYA men were more likely to die from any cause after a diagnosis of thyroid cancer (HR 2.68, 95% CI 2.14–3.34). Higher risk of death for AYAs diagnosed at 30–34 (HR:1.53, 95% CI 1.16–2.01) and 35–39 (HR: 2.01, 95% CI 1.54–2.62) years of age compared to those diagnosed at 15–29 survival than younger AYAs (HR 1.5–2.0) |
| DeRouen M, 2016 [106] | Testicular cancer | 14,249 | SEER | Among AYAs with testicular cancer, there were 753, 41, 46, 504, and 14 all-cause deaths among Whites, Blacks, Asian/PI, Hispanic, and Other survivors, respectively. Approximately half of these deaths were due to testicular cancer. |
| Lau B, 2016 [107] | Thyroid SMN after any primary non-thyroid malignancy | 357 | SEER | Compared to those diagnosed with a first primary at 0–14 years of age, AYA diagnosed with first primary at age 15–39 had significant lower OS at 10 (AYA: 83.6% vs. Pediatric: 96.4%), 20 (56.3% vs. 88.0%), and 30 (50.9% vs.88.0%) years post-diagnosis. |
| Novetsky Friedman D, 2017 [108] | Ewing sarcoma | 97 | Memorial Sloan Kettering institutional cancer registry | HR for all-cause mortality was 3.0 (95% CI 1.4–6.4) for 20–29 year olds and 4.5 (95% CI, 2.0–10.6) for 30–39 year olds, compared to 0–9 year olds. |
| Bownes L, 2018 [109] | Malignant ovarian germ cell tumors | 3125 | National Cancer Data Base | Decreased survival was observed for those from a lower income quartile without insurance and with lower education background. The adjusted cumulative survivals at 100 months from diagnosis by education measured as percentage with no high school were approximately 97.9%, 95.2%, 96.1%, and 95.6% among those with > = 21%, 13.0 to 20.9%, 7.0–12.9%, and <7.0% without high school degree, respectively (p = 0.017). |
| Challapalli S, 2018 [110] | Head and neck squamous cell carcinoma | 1777 | SEER | The survival rate after 8 years of follow-up was 73%. |
| Chen I, 2018 [111] | Extracranial solid tumors | 4128 | SEER | Ten- and 20-year overall survivals for AYA patients were, respectively, 42% and 38% for Ewing sarcoma, 30% and 29% for neuroblastoma, 56% and 53% for osteosarcoma, 41% and 39% for rhabdomyosarcoma, and 59% and 57% for Wilms tumor. Compared to pediatric age group (0–15), AYAs are at higher risk of dying from all of the cancers studied except for osteosarcoma |
| Chu Q, 2020 [112] | Breast Cancer-women stage I to III | 1492 | Louisiana Tumor Registry | Taking AYA 18–39 years of age as referent category, the overall survival was similar to those 40–49 (HR:1.01, 95%, 95% CI:0.87–1.17) and 50–59 (HR:1.147, 95% CI: 0.99–1.32). However, those diagnosed at ages 60–69 and 70+ had higher risk of mortality than AYA 18–39 (HR: 1.68, 95% CI: 1.46–1.94) vs. HR: 3.93, 95% CI: 3.40–4.53), respectively. |
| Perisa M, 2020 [69] | Ewing Sarcoma | 45 | Nationwide Children’s Hospital Columbus, Ohio | Higher risk of mortality in AYA compared to pediatric patients (HR: 3.10, 95% CI:1.45–6.63).Ten-year overall survival was approximately 45% for AYA and 64% for pediatric patients. |
Abbreviations: AER, absolute excess risk; ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; AYA, adolescent and young adult; CI, confidence interval; CNS, central nervous system; CVD, cardiovascular disease; HL, Hodgkin lymphoma; HR, hazard ratio; IRR, incidence rate ratio; NHL, non-Hodgkin lymphoma; RR, rate ratio; SBDR, standardized bed day ratio; SEER, National Cancer Institute’s Surveillance, Epidemiology and End Results Program; SHR, standardized hospitalization ratio; SIR, standardized incidence ratio; SMN, subsequent malignant neoplasm; SPN, second primary neoplasm; YA, young adult.