Part VIII · Therapeutic foundations · Chapter 43

Radiation oncology

What the medical oncologist needs from radiation, which is mostly the dose, the volume and the reason.

1 · Radiobiology and treatment planning

Two numbers govern every fractionation decision, and both are estimates rather than constants.

The first is fraction-size sensitivity, summarised by the ratio of the linear to the quadratic term in the standard dose-response model. A low ratio means a tissue is hurt disproportionately by larger fractions. Historically, tumours were assumed to have a high ratio and late-responding normal tissues a low one, which is the argument for many small fractions.

Breast cancer breaks that assumption, and the evidence is a direct measurement rather than an inference. In START A/B Trial A, 2236 women were randomised between 50 Gy in 25 fractions and two 13-fraction schedules designed to measure fraction sensitivity¹. The fitted ratio was 4.6 Gy for tumour control, with a 95% confidence interval of 1.1 to 8.1. For late change in breast appearance on photographic assessment it was 3.4 Gy, with an interval of 2.3 to 4.5. Because those two estimates sit close together, larger fractions do not buy tumour control at the cost of late normal tissue effect in this disease.

An earlier randomised trial had reached the same answer. It assigned 1410 women to 50 Gy in 25 fractions or to 39 Gy or 42.9 Gy in 13 fractions, all over five weeks². Ten-year ipsilateral relapse was 12.1%, 14.8% and 9.6%. The fitted fraction sensitivity for tumour was 4.0 Gy, similar to the estimate for late effects in healthy breast tissue.

The second number is the dose delivered to organs that are not the target. That is a planning property rather than a biological one, and it is discussed in Cardiac and pulmonary sparing and late effects.

Dose homogeneity within the breast is also a planning property, and randomised trials show that patients feel it. In 331 analysed patients, breast intensity-modulated radiotherapy reduced moist desquamation from 47.8% with a wedged technique to 31.2%³. In a second trial, simple intensity modulation reduced suboptimal overall cosmesis at five years, with an odds ratio of 0.68. It also reduced telangiectasia, with an odds ratio of 0.58⁴.

2 · Whole-breast, partial-breast, and chest wall irradiation

Radiation after breast-conserving surgery halves recurrence and reduces breast cancer death by about a sixth. The meta-analysis that established this covers 10,801 women in 17 randomised trials⁵. The 10-year risk of any first recurrence fell from 35.0% to 19.3%, an absolute reduction of 15.7 percentage points. The 15-year risk of breast cancer death fell from 25.2% to 21.4%, an absolute reduction of 3.8 percentage points.

The relationship between those two figures is the most useful number in this chapter. About one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and that ratio held across prognostic subgroups⁵. It converts a local control benefit into a mortality expectation, and it is what makes omission decisions calculable rather than intuitive.

A boost to the tumour bed adds a smaller increment, and its size depends on age. The EORTC boost trial randomised women with a microscopically complete excision, after 50 Gy to the whole breast, to a further 16 Gy or none⁶. Five-year local recurrence fell from 7.3% to 4.3%. In women aged 40 or younger it fell from 19.5% to 10.2%. The relative reduction was similar at every age, so the absolute gain shrinks as the baseline risk falls⁷. Young age and high-grade invasive ductal carcinoma were the strongest risk factors for local relapse, and margin status had no significant influence⁸. At 20 years, the boost reduced ipsilateral recurrence from 31% to 15% in women aged 50 or younger with adjacent ductal carcinoma in situ⁹.

The price is cosmetic. On panel assessment at three years, the boost was one of the factors associated with a worse cosmetic result¹⁰. Technique matters less than dose: in one institution's experience of 552 patients, electron, photon and interstitial implant boosts gave similar local control and cosmesis¹¹.

After mastectomy the benefit depends on nodal burden. A meta-analysis of 8135 women in 22 trials compared chest wall and nodal irradiation with no radiation after mastectomy and axillary dissection¹². In women with one to three positive nodes, overall recurrence and breast cancer mortality fell, with rate ratios of 0.68 and 0.80. In women with no positive nodes there was no effect on recurrence or mortality. In women with four or more positive nodes the rate ratios were 0.79 and 0.87.

The trials behind that meta-analysis reported survival benefits a decade earlier. In the Danish 82b trial, 1708 premenopausal women with stage II or III disease received CMF with or without chest wall and nodal irradiation after mastectomy¹³. Ten-year overall survival was 54% with radiotherapy and 45% without it. The companion 82c trial, in postmenopausal women taking tamoxifen, found 45% against 36%¹⁴. The British Columbia trial showed the same direction at 20 years, with breast cancer-specific survival of 53% against 38%¹⁵.

Radiotherapy changed the pattern of failure in the Danish trials. Fewer patients had a locoregional recurrence as the first event, and fewer developed distant metastases overall¹⁶. An editorial accompanying the 82b report read this as local control stopping metastases at their source¹⁷. ASCO's guideline on post-mastectomy radiotherapy then graded each indication by the level of evidence behind it¹⁸. The failure pattern without radiotherapy made the case. Among 1,031 patients treated by mastectomy and doxorubicin-based chemotherapy alone, 10-year isolated locoregional recurrence was 4%, 10%, 21% and 22% with none, one to three, four to nine, and ten or more involved nodes, and the chest wall was the commonest site¹⁹.

After neoadjuvant chemotherapy, the evidence for post-mastectomy radiotherapy is retrospective, and it points to presentation as well as response. In one institutional analysis, radiotherapy improved locoregional control and survival for clinical T3 tumours, stage III disease and four or more positive nodes, whatever the response to chemotherapy²⁰. Among 106 patients with a pathological complete response treated by mastectomy, 10-year locoregional recurrence in clinical stage III disease was 7.3% with radiotherapy and 33.3% without it²¹. A small phase II protocol of neoadjuvant MVAC for locally advanced disease had shown locoregional relapse of 7% with chest wall radiation and 31% without it²². After breast-conserving surgery, in 751 patients, locoregional control after neoadjuvant chemotherapy depended on subtype and on whether a complete response was achieved²³. Whether nodal response can now remove the indication is the question NSABP B-51 asked, in Regional nodal irradiation.

Partial-breast irradiation restricts the target to the tumour bed. Two large trials reached different verdicts on almost the same absolute difference, and the reason is instructive. IMPORT LOW randomised 2018 women and found five-year local relapse of 1.1% with whole-breast radiotherapy, 0.2% with a reduced-dose approach and 0.5% with partial-breast radiotherapy²⁴. Both experimental arms met the non-inferiority criterion. NSABP B-39/RTOG 0413 randomised 4216 women and found a 10-year cumulative incidence of ipsilateral recurrence of 4.6% with accelerated partial breast irradiation and 3.9% with whole-breast irradiation²⁵. The hazard ratio of 1.22 did not meet the prespecified equivalence criterion.

Technique and schedule decide the toxicity of partial-breast irradiation. The RAPID trial randomised 2135 women to external-beam partial-breast irradiation of 38.5 Gy in ten twice-daily fractions, or to whole-breast irradiation²⁶. Eight-year ipsilateral recurrence was 3.0% and 2.8%, which met non-inferiority. Adverse cosmesis was already more frequent with the partial-breast schedule at three years, at 29% against 17% on nurse assessment²⁷.

The Florence trial gave 30 Gy in five once-daily fractions with intensity modulation to 520 women²⁸. Ten-year ipsilateral recurrence was 3.7% against 2.5% after whole-breast irradiation, with less acute and late toxicity and a better cosmetic result. A trial of 258 women treated by multicatheter brachytherapy or electrons reported 20-year ipsilateral recurrence of 9.6% against 7.9%²⁹. Its brachytherapy arm had better cosmetic results than whole-breast irradiation. In IMPORT LOW, patients reported fewer adverse effects over five years after partial-breast and reduced-dose radiotherapy than after whole-breast radiotherapy³⁰.

Patient selection for partial-breast irradiation is set out in consensus statements. The ASTRO consensus statement, first published in 2009, was updated to lower the age of its "suitable" group from 60 to 50 years³¹. The update placed low-risk ductal carcinoma in situ meeting RTOG 9804 criteria in that group. It advised telling patients that intraoperative radiotherapy carries a higher risk of ipsilateral recurrence than whole-breast irradiation, and restricted it to invasive cancers considered suitable.

3 · Regional nodal irradiation

Two randomised trials define what regional nodal irradiation adds, and they agree more than their headline conclusions suggest.

MA.20 randomised 1832 women with node-positive or high-risk node-negative disease treated by breast-conserving surgery³². At 10 years, overall survival was 82.8% with nodal irradiation and 81.8% without it, with a hazard ratio of 0.91 and an interval of 0.72 to 1.13. Disease-free survival was 82.0% against 77.0%, with a hazard ratio of 0.76. Grade 2 or higher acute pneumonitis occurred in 1.2% against 0.2%, and lymphoedema in 8.4% against 4.5%.

EORTC 22922 randomised 4004 patients to internal mammary and medial supraclavicular irradiation or not³³. At 10 years, overall survival was 82.3% against 80.7%, with a hazard ratio of 0.87 and an interval of 0.76 to 1.00. Disease-free survival was 72.1% against 69.1%. Breast cancer mortality was 12.5% against 14.4%, with a hazard ratio of 0.82. At 15 years, breast cancer mortality and any breast cancer recurrence remained lower with nodal irradiation, but overall survival was 73.1% against 70.9%, with a hazard ratio of 0.95³⁴.

Read together, nodal irradiation improves disease outcomes by a few percentage points and does not clearly improve overall survival. The decision is therefore a trade against lymphoedema, pneumonitis and cardiac dose rather than a straightforward benefit.

The internal mammary chain is the most contested part of that target. A Danish cohort allocated internal mammary irradiation by laterality, treating right-sided cancers and sparing the heart in left-sided ones³⁵. Among 3089 women, 15-year overall survival was 60.1% with it and 55.4% without it, with an adjusted hazard ratio of 0.86. A Korean randomised trial of 735 women found no significant disease-free survival gain from adding it to nodal irradiation, with a hazard ratio of 0.80³⁶. An ad hoc subgroup with medial or central tumours did better with it.

Which nodes are in the target is also a planning decision. Consensus guidelines define the volumes for elective nodal irradiation³⁷. When the RTOG breast atlas was tested against the location of involved nodes, it could miss axillary disease in patients with clinically involved nodes³⁸.

The target is now being redefined by response rather than by anatomy. NSABP B-51 randomised 1641 patients whose biopsy-proven nodal disease had cleared to ypN0 after neoadjuvant chemotherapy, and 1556 of them entered the primary-event analysis³⁹. Regional nodal irradiation gained them nothing measurable. The hazard ratio for invasive recurrence or breast cancer death was 0.88, with a 95% confidence interval of 0.60 to 1.28. The axillary surgical counterpart of this shift is in Axillary management after neoadjuvant therapy.

4 · Fractionation, hypofractionation, and acceleration

Three generations of trials shortened the same treatment, and each generation was validated before the next began.

A Canadian trial randomised 1234 women to 50 Gy in 25 fractions or 42.5 Gy in 16 fractions⁴⁰. Ten-year local recurrence was 6.7% and 6.2%, an absolute difference of 0.5 percentage points with a 95% confidence interval of minus 2.5 to 3.5. Good or excellent cosmetic outcome was 71.3% and 69.8%.

START A/B tested 13-fraction and 15-fraction schedules against 25 fractions⁴¹. At 10 years, locoregional relapse in Trial A was 6.3% with 41.6 Gy, 8.8% with 39 Gy and 7.4% with 50 Gy. In Trial B it was 4.3% with 40 Gy in 15 fractions against 5.5% with 50 Gy in 25 fractions. Breast induration, telangiectasia and oedema were less common in the lower-dose arms. The first report of Trial B, at five years, had shown locoregional relapse of 2.2% after 40 Gy and 3.3% after 50 Gy, with fewer late effects on photographs and in patients' own assessments⁴².

A Danish trial tested 40 Gy in 15 fractions in 1854 women with node-negative cancer or ductal carcinoma in situ⁴³. Three-year breast induration was 9.0% against 11.8% with 50 Gy, and nine-year locoregional recurrence was 3.0% against 3.3%.

The earlier FAST trial gave five fractions once a week to 915 women⁴⁴. At ten years, normal tissue effects after 28.5 Gy did not differ significantly from those after 50 Gy in 25 fractions. After 30 Gy they were more frequent.

FAST-Forward compressed treatment to one week⁴⁵. Among 4096 patients, the five-year incidence of ipsilateral breast tumour relapse after 40 Gy in 15 fractions was 2.1%, and both five-fraction schedules met the non-inferiority criterion. The two five-fraction arms differed from each other in normal tissue effects rather than in tumour control. Moderate or marked clinician-assessed effects at five years were reported in 9.9% after 40 Gy, 15.4% after 27 Gy and 11.9% after 26 Gy. At ten years, the cumulative incidence of ipsilateral breast recurrence was 3.6% after 40 Gy, 2.9% after 27 Gy and 2.1% after 26 Gy. Moderate or marked clinician-reported breast or chest wall effects at ten years remained most frequent after 27 Gy⁴⁶.

That last comparison is the useful one. Total dose separated the two five-fraction arms, and fraction number did not. Acceleration is not intrinsically toxic. The dose chosen to accompany it is what determines late effect.

5 · Integration with systemic therapy and reconstruction

Most of the accepted sequencing rules rest on toxicity reasoning and consensus rather than on randomised comparison, and saying so is more useful than repeating them as though they were proven.

Concurrent anthracycline and radiation is avoided because both damage the heart and the skin. Taxanes are generally completed before radiation starts. Trastuzumab is continued through radiation. Endocrine therapy is commonly given concurrently. The evidence for each of these differs in strength, and the first is better supported than the last.

The order of chemotherapy and radiation after breast-conserving surgery has been randomised. Giving a 12-week chemotherapy course first produced more local and fewer distant or regional first recurrences at five years, a difference of borderline significance⁴⁷. With longer follow-up there was no significant difference in any event, distant metastasis or death, although the trial could not rule out a clinically important difference⁴⁸. For tamoxifen, three non-randomised comparisons found no difference in local recurrence or survival between concurrent and sequential use^49,50,51. A meta-analysis of 11 studies compared 1291 women treated concurrently with 1179 treated sequentially⁵². It found no difference in skin toxicity, pneumonitis, pulmonary fibrosis, local or distant recurrence, or survival, with tamoxifen or an aromatase inhibitor. For HER2-directed therapy, a systematic review found no serious adverse events reported with concurrent radiation, most of the data concerning trastuzumab⁵³. It also judged the data too heterogeneous for reliable conclusions.

Newer agents raise questions that have not been answered. CDK4/6 inhibitors and PARP inhibitors both suppress the marrow, and both are increasingly given in the adjuvant setting alongside or adjacent to radiation Targeted therapy. Overlapping myelosuppression is the practical constraint, and the trials that established these agents were not designed to answer the sequencing question.

Reconstruction and radiation interact in one direction. Among patients receiving post-mastectomy radiation, autologous reconstruction carried lower odds of a breast complication at two years than implant reconstruction, at 0.47 with an interval of 0.27 to 0.82⁵⁴. Unirradiated patients showed no difference between the approaches. The reconstructive decision therefore needs the radiation decision to have been made first, which is the point made in Reconstruction options and aesthetic outcomes.

The other interaction worth naming is delay. Every additional component in the sequence lengthens the interval from surgery to the completion of local therapy. Whether that interval matters is not well characterised, and treating it as harmless is an assumption rather than a finding.

6 · Omission in low-risk and older patients

Omission is the most developed de-escalation in this book, and the trials share a structure. Each accepts a defined increase in local recurrence in exchange for avoided toxicity, on the argument that local recurrence in these populations is salvageable and that mortality is dominated by competing causes.

CALGB 9343 randomised 636 women aged 70 or older with clinical stage I, oestrogen receptor positive disease treated by lumpectomy and tamoxifen⁵⁵. At 10 years, 98% of the irradiated group and 90% of the tamoxifen-only group were free from local and regional recurrence. There was no difference in mastectomy rate, time to distant metastasis, breast cancer specific survival or overall survival. Ten-year overall survival was 67% and 66%. The five-year report had shown locoregional recurrence of 1% with irradiation and 4% without it⁵⁶.

A second trial asked the question from age 50, in 769 women with node-negative tumours of 5 cm or less⁵⁷. Five-year local relapse was 0.6% with radiotherapy and tamoxifen and 7.7% with tamoxifen alone, with no significant difference in distant relapse or overall survival.

PRIME II randomised 1326 women aged 65 or older with node-negative, hormone receptor positive tumours of 3 cm or less, all receiving endocrine therapy⁵⁸. The 10-year cumulative incidence of local recurrence was 9.5% without radiotherapy and 0.9% with it, a hazard ratio of 10.4 with an interval of 4.1 to 26.1. Distant recurrence as a first event was 1.6% and 3.0%. Overall survival at 10 years was 80.8% and 80.7%. At five years, ipsilateral recurrence had been 4.1% without radiotherapy and 1.3% with it⁵⁹.

LUMINA selected by biology rather than by age alone⁶⁰. Five hundred women aged 55 or older with T1N0, grade 1 or 2, luminal A disease defined by a centrally assessed Ki-67 index of 13.25% or less received endocrine therapy without radiotherapy. Local recurrence at five years was 2.3%, with a 90% confidence interval of 1.3% to 3.8%, against a prespecified acceptability boundary of 5%.

Molecular selection is the next step and is not yet in routine use. A 16-gene signature developed for this purpose identified patients whose 10-year locoregional recurrence without radiation was 6% in one validation cohort and 7% in another⁶¹. Radiation gave that group no significant benefit, while the high-risk group did benefit. The interaction test between the signature and radiation in the combined validation cohort gave a p value of 0.066, which is the honest summary of where the evidence stands. Selection for omission in early hormone receptor positive disease is taken up in Adjuvant chemotherapy and the genomic assay decision and in older adults in Older adults and complex comorbidity.

7 · Reirradiation and metastatic applications

Reirradiation after a second lumpectomy is now an alternative to mastectomy for in-breast recurrence in selected patients. NRG Oncology/RTOG 1014 enrolled 58 evaluable patients with a unifocal recurrence smaller than 3 cm, arising more than a year after breast-conserving therapy⁶². Each received partial breast reirradiation to 45 Gy in 30 twice-daily fractions. The five-year cumulative incidence of further in-breast recurrence was 5%, with an interval of 1% to 13%. The five-year cumulative incidence of mastectomy was 10%. Grade 3 late adverse events occurred in 4 of 58 patients, and no higher grade late events were reported. The wider management of locoregional recurrence is in Locoregional recurrence.

In metastatic disease radiation does three separable jobs. It relieves symptoms, it prevents structural catastrophe in bone and spinal cord, and it treats the central nervous system. Those applications belong to Organ-specific metastases and complications and are not repeated here.

The fourth application is ablative intent in oligometastatic disease, and its evidence base is thinner than its adoption. SABR-COMET randomised 99 patients with one to five metastases across several primary tumour types, 18 of them breast, in a 1:2 ratio to standard care or standard care plus stereotactic ablative radiotherapy⁶³. Five-year overall survival was 17.7% and 42.3%.

8 · Cardiac and pulmonary sparing and late effects

Cardiac dose is the late effect that has changed practice most, because it is measurable before treatment starts and can be modified.

One population-based case-control study covered 2168 women treated between 1958 and 2001, of whom 963 had a major coronary event and 1205 were controls⁶⁴. The rate of major coronary events rose by 7.4% per gray of mean heart dose, with a 95% confidence interval of 2.9% to 14.5%. The relationship was linear with no apparent threshold. The excess began within five years of treatment and continued into the third decade. The average of the mean heart doses in that cohort was 4.9 Gy.

Three consequences follow. Mean heart dose is a number that can be reported, so it can be asked for. Any technique that lowers it, including breath-hold, prone positioning and restriction of the target volume, is a treatment decision rather than a technical detail. And the absence of a threshold means there is no dose below which cardiac sparing stops being worth pursuing.

Position is one of those techniques. In women with large breasts, a randomised comparison of prone with supine hypofractionated treatment found less acute skin toxicity in the prone position⁶⁵. Ipsilateral lung dose and mean left anterior descending artery dose were also lower.

Second cancers are the other durable late effect. A meta-analysis of 13 cohort studies included 762,468 patients⁶⁶. More than five years after diagnosis, radiotherapy was associated with an increased risk of second non-breast cancer, with a relative risk of 1.12. The relative risk was 1.39 for lung cancer, 1.53 for oesophageal cancer and 2.53 for sarcoma. Lung cancer risk was highest at 15 years or more, at 1.66. No association was found with thyroid cancer.

Those are relative risks against unirradiated breast cancer patients, drawn from cohorts treated largely with older techniques and larger fields. They describe the direction of the hazard reliably and the current magnitude poorly.

Pulmonary toxicity is mostly a function of the volume of lung in the field, which is why it rises with nodal irradiation. MA.20 reported grade 2 or higher acute pneumonitis in 1.2% against 0.2%³². Late cardiac and pulmonary surveillance in survivors is developed in Cardio-oncology, surveillance and prevention and Pulmonary, neurologic, and hematologic complications.

9 · Immune effects of radiation and candidate radiosensitivity biomarkers

Radiation kills by damaging DNA, and the same damage is an immune stimulus. Cytosolic DNA generated by irradiation is sensed by cGAS, activates STING, and drives type I interferon production. That pathway is the bridge between genomic instability and immune recognition developed in Genomic instability, cGAS-STING, and the bridge to immune recognition.

The dose relationship is counterintuitive and worth knowing. In cancer cell lines, the exonuclease Trex1 is induced by doses above roughly 12 to 18 Gy per fraction and degrades the cytosolic DNA that would otherwise trigger sensing⁶⁷. Repeated irradiation at doses below that induction threshold amplified interferon beta, recruited Batf3-dependent dendritic cells, and was required for the CD8 T cell priming that produced systemic tumour rejection with checkpoint blockade. Larger fractions were immunologically worse rather than better.

Those are preclinical data in mouse models and cell lines, and they should be labelled as such. Abscopal responses in patients are rare, and no randomised trial in breast cancer has shown that adding radiation to checkpoint blockade improves survival. The immunotherapy context is in Immunotherapy and the luminal immune deficit that constrains it is in Immune contexture by subtype and the luminal deficit.

Radiosensitivity biomarkers remain investigational, and the two with the most support point in opposite directions. One genomic model converts physical dose into a predicted biological effect. Across 1615 patients in 11 pooled cohorts it was associated with time to first recurrence and with overall survival, with hazard ratios of 0.98 and 0.97⁶⁸. Physical dose alone was associated with neither. The 16-gene signature discussed in Omission in low-risk and older patients identifies patients unlikely to benefit from radiation at all⁶¹.

The honest summary is narrow. No radiosensitivity assay is in routine clinical use. The candidates with the strongest data predict who can safely receive less rather than who should receive more, which is the same direction of travel as the rest of this chapter.

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