Radiation Oncology/Toxicity/Second malignancies

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Risk of Second Malignancies

Ankylosing spondylitis

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Ewing's Sarcoma

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Optic Glioma

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Hodgkin's disease

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  • 2007: (Multinational) - PMID 17372278 — "Long-Term Solid Cancer Risk Among 5-Year Survivors of Hodgkin's Lymphoma." Hodgson DC et al. J Clin Oncol. 2007 Apr 20;25(12): 1489–1497.
    • >18,000 pts with survival >5 yrs.
    • 1490 second cancers, of which 850 estimated to be excess. 30 yr risk for solid cancer 18%(men)/26%(women) for pts diagnosed at age 30, vs 7%/9% general population.
    • Risk of SC associated with younger age at HD diagnosis. Largest risk for breast (RR=6), other supradiaphragmatic sites (RR=6), infradiaphragmatic (RR=3.7), malignant mesothelioma (RR=20).

Breast cancer:

  • McGill University / SEER; 2022 PMID 35668306 -- "Surgical Management and Contralateral Breast Cancer Risk in Women with History of Radiation Therapy for Hodgkin Lymphoma: Results from a Population-Based Cohort" (Eisenberg ER, Ann Surg Oncol. 2022 Jun 6. doi: 10.1245/s10434-022-11947-w. Online ahead of print.)
    • Retrospective SERR analysis. 295 women, prior RT for HL (age <30). All with subsequent breast cancer. Median age HL was 22, and BCA was 42
    • Outcome: Unilateral 89% vs synchronous bilateral 11%. For unilateral tumors, lumpectomy 19% vs mastectomy 81%
    • Contralateral breast cancer risk: 5-years 9%, 10-years 20%, 15 years 30%
    • Conclusion: High risk of contralateral breast cancer with prior chest RT for HL, consider prophylactic mastectomy
  • Child Cancer Survivor Study; 2014 PMID 24752044 -- "Breast cancer after chest radiation therapy for childhood cancer." (Moskowitz CS, J Clin Oncol. 2014 Jul 20;32(21):2217-23. doi: 10.1200/JCO.2013.54.4601. Epub 2014 Apr 21.)
    • Registry study. Childhood Cancer Survivor Study participants, 1230 female, chest irradiation
    • Outcome: Low dose radiation (median 14 Gy) to large volume (whole-lung) breast cancer risk standardized incidence ration 43.6 (SS); high dose of radiation to mantle field/Hodgkin, standardized incidence ratio 24. Cummulative incidence of breast cancer by age to was 30%, comparable between both groups. Breast cancer specific mortality at 5 years 12%, at 10 years 19%
    • Conclusion: Whole-lung irradiation confers greater risk of breast cancer than previously recognized; with substantial breast cancer mortality
  • Multicenter, 2011 (1980–2006) - PMID 21576642 -- "Characteristics and Outcomes of Breast Cancer in Women With and Without a History of Radiation for Hodgkin's Lymphoma: A Multi-Institutional, Matched Cohort Study." (Elkin BB, J Clin Oncol. 2011 Jun 20;29(18):2466-73.)
    • 8 centers. 253 women with breast cancer after RT for HL were matched to 741 women with sporadic breast cancer.
    • Median time from HL to breast cancer diagnosis was 18 yrs; median age at BC diagnosis, 42 y. Was more likely to be diagnosed by screening, more likely to be early stage, and more likely to be bilateral at diagnosis. Increased risk of metachronous contralateral breast cancer and increased risk of death from any cause. Breast cancer specific mortality was increased (but not S.S.)
    • Conclusion: "In women with a history of RT for HL, breast cancer is diagnosed at an earlier stage, but these women are at greater risk for bilateral disease and are more likely to die as a result of causes other than breast cancer. Our findings support close follow-up for contralateral tumors in these patients and ongoing primary care to manage comorbid conditions."
  • SEER; U. of Rochester, 2010 - PMID 20975072 -- "Long-Term Survival Among Patients With Hodgkin's Lymphoma Who Developed Breast Cancer: A Population-Based Study." (Milano MT, J Clin Oncol. 2010 Dec 1;28(34):5088-96.)
    • SEER study. Compared 298 HD survivors who developed breast cancer to 400,000+ women with first breast cancers.
    • OS survival inferior for HD pts with breast cancer, 15-yr OS 48% vs 69% (for localized BC) or 33% vs 43% (regional or distant BC). Increased 7-fold risk of death from other cancers. Increased heart disease mortality. 10-yr BC CSS was similar for pts with regional/distant disease but was inferior for HD pts with localized BC.
    • Conclusion: Women with HL may survive a subsequent diagnosis of BC, only to experience significant excesses of death from other primary cancers and cardiac disease. Greater awareness of screening for cardiac disease and subsequent primary cancers in patients with HL-BC is warranted.
  • Stanford
    • 1993 (1961–89) - PMID 8416252 — "Breast cancer after treatment of Hodgkin's disease." Hancock SL et al. J Natl Cancer Inst. 1993 Jan 6;85(1):25-31.
      • 885 women. Mean f/u 9.3 yrs. 672 treated with mantle field.
      • 25 developed breast cancer. RR=4.1. 136-fold increase for girls who received RT before age 15. No increased risk for women treated after age 30.


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  • Toronto, 2007 PMID 17206473 -- "Radiation induced peripheral nerve tumors: case series and review of the literature." (Zadeh G, J Neurooncol. 2007 Jun;83(2):205-12.)
    • Retrospective. 6 cases of post-radiation peripheral nerve tumors. RT dose 24-40 Gy, at treatment 1.5–49 years. Majority neurofibromas (n=3) and schwannomas (n=3)


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  • The Netherlands; 2008 (1989–2003) PMID 18323547 -- "Risk of new primary nonbreast cancers after breast cancer treatment: a Dutch population-based study." (Schaapveld M, J Clin Oncol. 2008 Mar 10;26(8):1239-46.)
    • Population analysis. 58,068 Dutch patients diagnosed with invasive BCA. Median F/U 5.4 years. Second non-breast cancers (SNBC) evaluated, and standardized incidence ratio (SIR) computed
    • Outcome: SNBC 10-year cumulative incidence 5.4%, SIR 1.22 (SS).
      • If RT: young patients (<50) higher lung cancer HR 2.3 (SS); older patients (>50) higher STS HR 3.4 (SS)
      • If chemo: young patients lower all cancers HR 0.8 (SS); older patients higher melanoma, uterine CA, AML
      • If hormones: higher overall incidence HR 1.1 (SS), uterus specifically 1.8 (SS)
    • SNBC worsened overall survival HR 4.0 (SS)
    • Conclusion: Breast cancer patients experience a small but significant risk of developing second non-breast cancer
  • Indiana; 2004 PMID 15166670 -- "Cutaneous angiosarcoma following breast-conserving surgery and radiation: an analysis of 27 cases." (Billings SD, Am J Surg Pathol. 2004 Jun;28(6):781-8.)
    • Retrospective. 27 cases. Median time-to-diagnosis 5 years, some in <3 years. Lymphedema largely absent. Frequently (~50%) multifocal, and high grade (60%)
    • Outcome: treated with excision/mastectomy. Median F/U 3.7 years. Median OS 2.7 years; 52% LR, 40% DM
  • Florida; 2003 (Review) PMID 12673708 -- "Angiosarcoma after breast-conserving therapy." (Monroe AT, Cancer. 2003 Apr 15;97(8):1832-40.)
    • Review
  • Wayne State; 2002 (1973–1997) PMID 11955733 -- "Sarcoma as a second malignancy after treatment for breast cancer." (Yap J, Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1231-7.)
    • SEER review. 274,572 cases with primary breast cancer; 263 patients with subsequent sarcoma (87 RT, 176 no RT)
    • Outcome: 15-year sarcoma incidence RT 0.3% vs. no RT 0.2% (SS). Angiosarcoma was 57% of RT cases vs 6% if no RT. 5-year OS 27-35%
    • Conclusion: RT associated with increased risk of sarcoma, but magnitude of risk small. Angiosarcoma significantly more prevalent
  • Goustave Roussy; 1991 (France)(1954–1983) PMID 1648044 -- "Long-term risk of sarcoma following radiation treatment for breast cancer." (Taghian A, Int J Radiat Oncol Biol Phys. 1991 Jul;21(2):361-7.)
    • Retrospective. 7620 patients treated for breast CA. 11 sarcomas (0.1%) induced by RT (2 Steward-Treves Syndroma and 9 within RT field). Mean latent period 9.5 years. RT dose 45/18
    • Histology: MFH 5, fibrosarcoma 3, lymphangiosarcoma 2, osteochondrosarcoma 1
    • Survival: 2.4 years; 9/11 died of the sarcoma. Standardized incidence ratio 1.8 (SS)
    • Conclusion: Higher risk of developing sarcoma


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  • Chiba; 2007 (Japan)(1961–1986) PMID 17889265 -- "Long-term survival and risk of second cancers after radiotherapy for cervical cancer." (Ohno T, Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):740-5.)
    • Retrospective. 2,167 patients with cervical CA; 25,771 person-years of follow up. 49% survived >10 years
    • 2nd cancers: 210 (1%), 1.6% excess risk per person per decade, cumulative risk 24% at 30 years
    • Conclusion: small but significant risk; benefit of RT outweighs the risk


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  • Netherlands Cancer Institute; 2007 PMID 17906202 -- "Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer." (van den Belt-Dusebout AW, J Clin Oncol. 2007 Oct 1;25(28):4370-8.)
    • Cohort study. 2,707 patients with testicular cancer, surviving >5 years. Incidence of 2nd malignancies (SMN) and cardiovascular disease (CVD). Mean F/U 17.6 years
    • Outcome: 270 second malignancies (10%), risk 1.7x over general population
    • SMN by modality: subdiaphargmatic RT 2.6x, chemo 2.1 x over surgery alone
    • SMN+CVD by modality: RT 1.8x, chemo 1.9x over surgery alone. Smoking 1.7x. Median OS after SMN 1.4 years and after CVD 4.7 years
    • Conclusion: RT and chemo increase risk of SMN or CVD almost 2x, similar as smoking
  • National Institute of Health (NIH); 2005 PMID 16174857 -- "Second cancers among 40,576 testicular cancer patients: focus on long-term survivors." (Travis LB et al., J Natl Cancer Inst. 2005 Sep 21;97(18):1354-65)
    • Reviewed 14 tumor registries in Europe and North America (1943–2001) looking at risk of second solid cancers with RR = 2.0 after radiation, RR = 1.8 after chemotherapy, and RR = 2.9 after radiation and chemotherapy.
    • For patients diagnosed at age 35 years, cumulative risks of solid cancer to age 75 years were 36% (seminoma) and 31% (nonseminomas), compared with 23% for the general population.
      • Note: Separate study documents increased risk of liquid tumors PMID 18433667

RT-induced soft-tissue sarcoma

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  • Memorial Sloan Kettering
    • 2004 (1982–2001) PMID 15166970 -- "Long-term results with resection of radiation-induced soft tissue sarcomas." (Cha C, Ann Surg. 2004 Jun;239(6):903-9; discussion 909–10.)
      • Retrospective. 4884 adult patients with sarcoma, 123 (2.5%) with RT-induced soft tissue sarcoma
      • Demographics: median time-to-sarcoma 8.6 years (0.5 - 44.5); original malignancy breast 29%, lymphoma 16%, prostate 15%; sarcoma histology MFH 23%, fibrosarcoma 15%, angiosarcoma 15%
      • 5-year OS if curative resection: 41%; negative predictors: high grade, age >60, SM+
      • Conclusion: Long-term follow up necessary, surgery primary therapy
    • 2010 (1982–2007) PMID 20308666 -- "Do radiation-associated soft tissue sarcomas have the same prognosis as sporadic soft tissue sarcomas?" (Gladdy RA, J Clin Oncol. 2010 Apr 20;28(12):2064-9. Epub 2010 Mar 22.)
      • Retrospective. 7,649 soft tissue sarcomas, 130 radiation-associated sarcomas (RAS). Definition of RAS: h/o radiation exposure >6 months prior to sarcoma, in-field occurrence, and pathologic confirmation of different type than primary cancer.
      • Epidemiology: Median RT dose 54 Gy (20-160 Gy). Median time-to-development 10 years (1.3 – 74 years), varied by histologic type (liposarcoma 4.3 years shortest vs leiomyosarcoma 23 years longest). High grade 83%, deep 87%.
      • Outcome: 5-year DSS 58% (worse than sporadic STS, HR 1.7, SS). Predictors of DSS were histologic type, SM status, and tumor size
      • Conclusion: Radiation-induced sarcomas have significantly worse prognosis than sporadic STSs

From RT for heterotopic ossification:

Childhood Cancer Survivors

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  • CCSS; 2009 PMID 19255307 -- "Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study cohort." (Meadows AT, J Clin Oncol. 2009 May 10;27(14):2356-62. Epub 2009 Mar 2.)
    • Retrospective. 14,358 cohort members.
    • Outcome: Second malignancy rate 6%. 30-year cumulative incidence of SMN 9%, nonmelanoma skin cancer 7%. Risk elevated after >20 years. Risks differ by subtype
    • Conclusion: Childhood cancer survivors at substantial and increasing risk for SNs


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  • Kiev; 2009 (1987–1997) PMID 19688829 -- "Radiation-induced leukemia among children aged 0-5 years at the time of the chernobyl accident." (Noshchenko AG, Int J Cancer. 2009 Aug 17. [Epub ahead of print])
    • Retrospective, case control. 246 leukemia cases (ALL 74%), age 0–5 at the time of Chernobyl accident and 492 matched controls. Four dose groups <3 mGy, 3-10 mGy, 10-100 mGy, >100 mGy. Accumulated dose >10 mGy 8%
    • Outcome: Leukemia risk <3 mGy 1, 3-10 mGy OR 1.5 (NS), 10-100 mGy OR 5.5 (SS), >100 mGy 5.5 (SS). Association stronger in males. ALL diagnosed mostly age 5–9, AML age 5–17. Estimate 5% increased risk over baseline
    • Conclusion: There is an association between radiation and development of leukemia