# Choices made at the time of treatment that change the second cancer risk

Source: https://onco.cc/terms/rejuv-second-choices-made-at-treatment/  
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## TL;DR

Some of this risk is a decision rather than a fate. Where two treatments cure equally well and one carries less late risk, that is a conversation to have before treatment starts. Trials have settled several: a different partner drug in myeloma, a lower cyclophosphamide dose in breast cancer, brachytherapy rather than external beam.

## Summary

How to use this. These are decisions made with the treating team before or during treatment, not afterwards, and in every case the first question is whether the two options really do cure equally well for the particular disease in front of you. Curing the cancer is the priority and none of what follows changes that. Where there is a real choice, the question worth asking is: does this option change my risk of a second cancer, and by how much.

Myeloma: the partner drug. The individual-patient meta-analysis of 3,218 patients found that lenalidomide with oral melphalan raised the risk of a haematological second cancer against melphalan alone with a hazard ratio of 4.86 (95% CI 2.79 to 8.46, p < 0.0001), while lenalidomide with cyclophosphamide (1.26, 0.30 to 5.38) and lenalidomide with dexamethasone (0.86, 0.33 to 2.24) did not. The authors concluded that "alternatives, such as cyclophosphamide or alkylating-free combinations, should be considered instead of oral melphalan in combination with lenalidomide for myeloma". The same drug, a different partner, a fourfold difference in risk.

Breast cancer: the cyclophosphamide dose. In the pooled NSABP adjuvant trials, intensified cyclophosphamide at 2,400 mg/m2 with growth factor support gave a five-year cumulative incidence of acute myeloid leukaemia or myelodysplastic syndrome of 1.01 per cent (0.63 to 1.62) against 0.21 per cent (0.11 to 0.41) with standard doxorubicin and cyclophosphamide. Dose intensification did not become standard, and this is part of why.

Prostate cancer: the radiotherapy modality. In the meta-analysis of 21 studies, external beam radiotherapy was consistently associated with raised odds of a second bladder or bowel cancer while brachytherapy was not. Both are offered for appropriate localised disease, and the difference is one input into a choice that also turns on urinary, bowel and sexual function and on the stage.

Early Hodgkin lymphoma: whether to irradiate at all. The RAPID trial gave 602 patients with stage IA or IIA Hodgkin lymphoma three cycles of ABVD, then randomised the 420 who were PET-negative to involved-field radiotherapy or no further treatment. At a median 60 months, three-year progression-free survival was 94.6 per cent (95% CI 91.5 to 97.7) with radiotherapy and 90.8 per cent (86.9 to 94.8) without, an absolute difference of 3.8 percentage points (-8.8 to 1.3). The trial did not show non-inferiority of omitting radiotherapy on its own terms, and its conclusion was that these patients "had a very good prognosis either with or without consolidation radiotherapy". That is a real trade-off written down with both numbers: a few percentage points of early relapse risk against a radiation exposure whose cost is paid decades later.

And what the radiation actually costs, measured in the same trial. Individual dosimetry for the 144 PET-negative RAPID patients who received involved-field radiotherapy gave an average mean heart dose of 4.0 Gy (range 0.1 to 24.0) and an average bilateral common carotid artery dose of 21.5 Gy (0.6 to 38.1). The predicted 30-year radiation-related absolute excess cardiovascular mortality averaged 0.56 per cent (0.01 to 6.79), under 0.5 per cent in 67 per cent of patients and over 1 per cent in 15 per cent; the predicted excess incidence averaged 6.24 per cent (0.31 to 31.09), under 5 per cent in 58 per cent and over 10 per cent in 24 per cent. The authors' conclusion is the model for how this decision should be made: "Predicted excess cardiovascular risk is small for most patients, so radiotherapy may provide net benefit. However, for a minority of patients receiving high doses of radiation to cardiovascular structures, it may be preferable to consider advanced radiotherapy techniques to reduce doses or to omit radiotherapy and accept the increased relapse risk." Those figures are for cardiovascular disease, which has been modelled in more detail than second cancers have; the same logic and the same dosimetry apply.

Testicular cancer: surveillance instead of adjuvant treatment. The cohort of 40,576 testicular cancer survivors found raised second solid cancer risk after radiotherapy alone (relative risk 2.0, 1.9 to 2.2), chemotherapy alone (1.8, 1.3 to 2.5) and both (2.9, 1.9 to 4.2). For a man diagnosed with seminoma at 35, the cumulative risk of a solid cancer by 75 was 36 per cent, against 23 per cent in the general population. Those men were mostly treated with adjuvant radiotherapy, which has since been largely replaced by surveillance or single-dose carboplatin for stage I disease, precisely because the cure rate was already near complete and the late cost was the only thing left to reduce.

Tamoxifen, where the trade-off goes the other way. In NSABP B-14, the average annual hazard rate of endometrial cancer through all follow-up was 1.6 per 1,000 patient-years in the randomised tamoxifen group against 0.2 in the placebo group, a relative risk of 7.5; against population rates from SEER and from the B-06 trial the relative risks were 2.2 and 2.3. Twenty-one of the 24 originally reported endometrial cancers were FIGO stage 1, and four tamoxifen-treated women died of uterine cancer. In the same trial the five-year cumulative hazard for disease-free survival in the tamoxifen group was 38 per cent lower than in the placebo group, and the authors' conclusion was that "net benefit greatly outweighs risk". The published abstract also records that some data in the paper came from an investigator who submitted fraudulent data to the NSABP, affecting records on 24 of 182 randomly assigned patients and 8 of 37 registered patients reviewed, all involving pre-randomisation characteristics; the finding has since been confirmed in much larger datasets, but the caveat belongs with the citation.

The thing that makes all of this possible. A written treatment summary. Every choice above is invisible afterwards unless someone wrote down what was given, at what dose and to what part of the body. Asking for that document at the end of treatment, and keeping it, is the single most useful thing in this whole file.

## Fields

- Kind: Term
- Last checked: 2026-10-02
- Also known as: De-escalation and late effects; Treatment choice and second cancers; Omitting radiotherapy
- Tags: rejuvenation; survivorship; second-cancers; radiotherapy; chemotherapy

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Radiation-induced_cancer
- Palumbo et al., Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data (Lancet Oncol 2014): https://doi.org/10.1016/S1470-2045(13)70609-0
- Smith et al., Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the NSABP experience (JCO 2003): https://doi.org/10.1200/JCO.2003.03.114
- Wallis et al., Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis (BMJ 2016): https://doi.org/10.1136/bmj.i851
- Radford et al., Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma, the RAPID trial (NEJM 2015): https://doi.org/10.1056/NEJMoa1408648
- Cutter et al., Predicted risks of cardiovascular disease following chemotherapy and radiotherapy in the UK NCRI RAPID trial of PET-directed therapy for early-stage Hodgkin lymphoma (JCO 2021): https://doi.org/10.1200/JCO.21.00408
- Travis et al., Second cancers among 40,576 testicular cancer patients: focus on long-term survivors (JNCI 2005): https://doi.org/10.1093/jnci/dji278
- Fisher et al., Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the NSABP B-14 trial (JNCI 1994): https://doi.org/10.1093/jnci/86.7.527

## Connected records

- terms: [Alkylating agents and therapy-related myeloid neoplasms](https://onco.cc/terms/rejuv-second-alkylating-agents-and-myeloid-neoplasms/), [Bladder cancer after cyclophosphamide](https://onco.cc/terms/second-primary-bladder-after-cyclophosphamide/), [Bowel cancer after abdominal and pelvic radiotherapy](https://onco.cc/terms/second-primary-bowel-after-abdominal-radiotherapy/), [Deep inspiration breath-hold (DIBH)](https://onco.cc/terms/deep-inspiration-breath-hold/), [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Platinum drugs and PARP inhibitors: the newer leukaemia risk](https://onco.cc/terms/rejuv-second-platinum-and-parp-inhibitors/), [Radiotherapy and second cancers: field, dose and age at exposure](https://onco.cc/terms/rejuv-second-radiotherapy-dose-field-and-age/), [Second cancers after radiotherapy](https://onco.cc/terms/second-cancers-after-radiotherapy/), [Second cancers after treatment: what the risk is, and what is done about it](https://onco.cc/terms/rejuv-second-cancers-overview/), [Secondary malignancy (therapy-related cancer)](https://onco.cc/terms/secondary-malignancy/)
- cancers: [Breast cancer (all types)](https://onco.cc/cancers/breast-cancer/), [Endometrial cancer](https://onco.cc/cancers/endometrial/), [Hodgkin lymphoma](https://onco.cc/cancers/hodgkin-lymphoma/), [Multiple myeloma](https://onco.cc/cancers/multiple-myeloma/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Seminoma](https://onco.cc/cancers/seminoma/), [Testicular germ cell tumours](https://onco.cc/cancers/testicular/)
- fronts: [Recovery & Rejuvenation](https://onco.cc/fronts/rejuvenation/), [Supportive Care & Survivorship](https://onco.cc/fronts/supportive-care/)
- technologies: [Brachytherapy](https://onco.cc/technologies/brachytherapy/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Proton therapy](https://onco.cc/technologies/proton-therapy/), [Survivorship care and late-effects surveillance](https://onco.cc/technologies/survivorship-care-plan/)
- drugs: [Carboplatin](https://onco.cc/drugs/carboplatin/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Lenalidomide](https://onco.cc/drugs/lenalidomide/), [Melphalan (including hepatic delivery system)](https://onco.cc/drugs/melphalan/), [Tamoxifen](https://onco.cc/drugs/tamoxifen/)
- bottlenecks: [Surgery and radiotherapy cure most, get least](https://onco.cc/bottlenecks/b-surgery-radiation-innovation/), [Survivorship and late effects are neglected](https://onco.cc/bottlenecks/b-survivorship/), [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/), [Wrong doses](https://onco.cc/bottlenecks/b-dose-optimisation/)

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