The potential of neoadjuvant short-course radiotherapy in rectal carcinoma

The purpose of this review is to compare neoadjuvant long-course chemoradiotherapy and short-course radiotherapy treatment regimens in order to assess the possibility of a transition from long-course chemoradiotherapy to short-course radiotherapy in the Irish setting in patients who require pre-operative treatment.

We reviewed randomised controlled trials assessing neoadjuvant treatment regimens of rectal cancer published between 1996-2012. These include the Swedish Rectal Cancer Trial, the Dutch trial, trials conducted by the Polish Colorectal Study Group, the German Rectal Cancer Study Group, the EORTC 22921, the FFCD 9203 and TROG 01.04 trials. 

Different endpoints were compared. No advantage in local control, overall survival or disease-free survival was established with the use of short-course radiotherapy, which may also have greater late toxicity. Although chemoradiotherapy may have greater acute toxicity, it may downstage and downsize tumours. There is no clear difference in sphincter preservation or incontinence between modalities. Variable pre-operative staging, anatomical locations, surgical techniques, and radiotherapy/chemotherapy protocols make comparisons difficult and a randomised controlled trial in the Irish setting is suggested.

Introduction 

Colorectal cancer is the second most common cause of cancer death in Ireland with 1,900 new cases annually. One-third of those are rectal tumours where surgery alone results in high recurrence rates and significant morbidity and mortality. Adjuvant chemoradiotherapy and neoadjuvant radiotherapy have been established as standards of care in treating rectal cancer but debate exists over neoadjuvant courses: Ireland and North America use long-course chemoradiotherapy while short-course radiotherapy is preferred in Europe. 

Methods

We reviewed recent literature regarding both regimens with emphasis on seven randomised studies (see Table 1).^1-7 We compared local recurrence rates, survival, quality of life and toxicities to highlight the advantages and disadvantages of each modality. Only the Polish and Trans-Tasman Radiation Oncology Group (TROG) trials directly compared the two treatment modalities. Short-course radiotherapy was delivered in the Swedish, Dutch, Polish and TROG trials as five fractions of 5Gy over one week with immediate surgery. In the EORTC 2291 and FFCD 9203 trials, patients received 25 fractions of 1.8Gy over five weeks with delayed surgery. Adjuvant chemotherapy protocols also varied across studies.

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Results

Local recurrence

Rates of local recurrence are associated with primary tumour location, TNM staging and treatment protocols. Local control has been improved by total mesorectal excision (TME), in which the mesorectal fascia, blood vessel and its lymph nodes are resected.² Negative resection margins are crucial to reduce local recurrence (6% versus 17% with positive margins).⁸

The Swedish trial, predating the TME era, confirmed lower recurrence rates with neoadjuvant radiotherapy and surgery.¹ The Dutch trial, using TME, noted two-year local recurrence rates of 2.4% with neoadjuvant radiotherapy versus 8.2% with surgery alone (p < 0.001).² Twelve-year recurrence rates were 5% versus 11% (p < 0.0001).⁹ The benefit increased with the distance from the anal verge and radiotherapy could not compensate for positive margins. 

The EORTC 22921 trial demonstrated a benefit with chemoradiotherapy regardless of the location of the tumour with five-year local recurrence rates of 8.7% versus 17.1% with radiotherapy alone (p = 0.002).⁵ The FFCD 9203 trial had similar five-year local recurrence rates of 8.1% in the chemoradiotherapy arm and 16.5% in the radiotherapy arm (p = 0.004).⁶ The Polish study reported no differences in local recurrence between short-course radiotherapy and long-course chemoradiotherapy.³

Similarly, the TROG trial showed no statistical difference between local recurrence rates in short-course radiotherapy compared to long-course chemoradiation (7.5% versus 4.4% [p = 0.24] three-year local recurrence rate). However, this study also suggested that long-course chemoradiation may be more effective in reducing local recurrence for distal tumours, as a subset analysis of 79 patients with distal tumours highlighted an incidence of 12.5% local recurrence for short-course radiation versus 0% with long-course chemoradiotherapy. 

In summary, neoadjuvant radiotherapy reduces the incidence of local recurrence compared to surgery alone, but there is no clear evidence of enhanced local control between short-course radiotherapy and long-course chemoradiotherapy, unless tumour location is taken into account. 

Survival

The Swedish trial demonstrated improved overall survival with neoadjuvant radiotherapy versus surgery alone (five-year 58% versus 48%, and 13-year 38% versus 30%).^1,10 However, the Dutch trial showed no difference in overall survival between short-course neoadjuvant radiotherapy versus surgery alone (82% versus 81.8%, respectively).² The German study found no benefit of neoadjuvant chemoradiotherapy over adjuvant chemoradiotherapy in five-year overall (76% versus 74%, respectively) or disease-free survival (68% versus 65%).⁴

The FFCD 9203 trial demonstrated no five-year overall survival benefit of neoadjuvant chemoradiotherapy compared to neoadjuvant radiotherapy (67.9% versus 67.4%).⁶

The Polish study indicated no difference between short-course radiotherapy and long-course chemoradiotherapy in overall survival rates (67.2% versus 66.2%) or disease-free status (58.4% versus 55.6%).³

The EORTC 22921 trial reported no difference in five-year overall or disease-free survival in the two neoadjuvant radiotherapy arms versus the two neoadjuvant chemoradiotherapy arms.⁵

The TROG trial also did not establish any significant increase in five-year survival rates between short-course and long-course treatments (74% versus 70%, p = 0.62).⁷ On the whole, no significant difference in overall or disease-free survival has been established between neoadjuvant short-course radiotherapy and long-course chemoradiotherapy. 

Sphincter preservation

Randomised controlled trials have examined whether neoadjuvant therapy facilitates sphincter preservation with low-lying tumours. In the German study, among patients determined prior to randomisation to require abdominoperineal resection (n = 194), greater sphincter preservation was achieved in the neoadjuvant chemoradiotherapy group (39 versus 19% with adjuvant therapy; p = 0.04).⁴  The FFCD 9203 trial demonstrated no difference in sphincter preservation between the two treatment regimens,⁶ while EORTC 22921 found a 3% increase in sphincter-sparing resection with neoadjuvant chemoradiotherapy.⁵ In the Polish trial, patients deemed to require abdominoperineal resection, who received combined therapy, showed downstaging of tumour but sphincter preservation did not differ.³

Variations in tumour location, individual anatomy, surgeon’s skills and willingness to carry out the operation make comparisons between trials difficult. At present, sphincter preservation may not be increased by chemoradiotherapy, as clinical tumour response is often not sufficient to modify the surgeon’s decision.⁶

Quality of life

Studies examining the quality of life (QoL) of rectal cancer patients have found that radiotherapy negatively affects urinary, anorectal and sexual function. Bowel incontinence proved to have the greatest impact on QoL. The Dutch study established no differences in urinary function between neoadjuvant radiotherapy and TME surgery alone, but increased rates of faecal incontinence (62% versus 38%, respectively; p < 0.001) and increased sexual dysfunction in males and females post short-course radiotherapy were reported.^11,12 

The Polish study examined anorectal and sexual functions after neoadjuvant chemoradiotherapy versus radiotherapy alone in 316 randomised patients and concluded that two-thirds of patients reported anorectal dysfunction impacting QoL in 20%, but this was independent of the treatment received.¹³ Overall, short-course radiotherapy showed no advantage over long-course chemoradiotherapy with regards to incontinence.

Toxicity

The benefits of neoadjuvant radiotherapy may be overshadowed by the toxicity of therapy, especially in patients with a low risk of local recurrence when treated with surgery alone. 

Acute toxicity, consisting mainly of poor wound healing, gastrointestinal, genitourinary and neurological complaints, is higher when neoadjuvant radiotherapy is supplemented with chemotherapy. 

In the Polish trial, the incidence of grade 3/4 toxicity was 3.2% for short-course radiotherapy and 18.2% for chemoradiotherapy (p < 0.001).³ Short-course radiotherapy patients were more compliant, 97.2% completed treatment versus 69.2% of chemoradiotherapy patients. The EORTC 22921 trial reported grade 3 or higher acute toxicity in 7.4% of patients receiving neoadjuvant radiotherapy versus 13.9% of chemoradiotherapy patients (p < 0.001).⁵ In the FFCD 9203 trial, grade 3-4 acute toxicity occurred more frequently with neoadjuvant chemoradiotherapy compared to radiotherapy alone (14.6% versus 2.7%).⁶ The TROG trial found no statistical difference between the rates for grade 3-4, small or large intestine toxicity for short-course and long-course therapy (3.2% versus 5.1%, p = 0.53).⁷

In the Dutch trial, patients who received short-course radiation compared with TME surgery alone had slightly more blood loss during surgery (median 1,000ml versus 900ml; p < 0.001) and more perineal complications after abdominoperineal resection (29% versus 18%; p = 0.008). There was no difference in abdominal wound complications.¹⁴

Few studies have analysed late toxicity after long-term follow-up. The Swedish trial reported increased late hospital admissions of irradiated patients for gastrointestinal disorders including small bowel obstruction, nausea and abdominal pain.¹⁵ However, the target volume was larger than generally used in recent trials and newer multiple-beam techniques may also lower small bowel irradiation.

Pollack investigated late adverse effects in the Stockholm I and II trials after 15 years and concluded that neoadjuvant short-course high-dose radiotherapy may also increase the risk of cardiovascular morbidity (35% versus 19% after surgery alone; p = 0.032).¹⁶

The Polish trial reported no significant difference in late toxicity between short-course radiotherapy and long-course chemoradiotherapy (10.1% versus 7.1%, respectively; p = 0.360).³ The EORTC 22921 trial reported no significant difference in the incidence of late side-effects among their four treatment groups, but did note a lower rate of faecal incontinence after conservative surgery than the rates reported in the Swedish and Dutch trials. This may be related to different radiotherapy protocols and methods of assessment (faecal incontinence scored by treating physician versus self-reported), in addition to the exclusion of the anal canal from the irradiated volume for mid-rectum tumours.⁵

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Discussion

On the basis of this review, it is unclear whether short-course radiotherapy confers a significant advantage over long-course chemoradiotherapy. There is insufficient data to demonstrate differences in local control, survival rates or quality of life between the two regimens. Outcomes of treatment modalities are influenced by factors other than the choice of neoadjuvant regimen, such as the achievement of negative surgical margins, tumour location and surgeon’s skill and preference.

Neoadjuvant chemoradiotherapy is useful in downstaging and/or downsizing tumours, however, it may not alter the surgeon’s willingness to perform sphincter-sparing surgery. Acute toxicity seems greater after long-course chemoradiotherapy, but short-course radiotherapy may have greater late toxic effects, although this may only reflect the longer-term follow-up in this group. 

The absence of standardisation among studies confounded this review. Pre-operative staging was inconsistent between studies, anatomical location of tumours and surgical techniques differed, and radiotherapy and chemotherapy protocols varied. Moreover, the studies used different end points (eg. local recurrence rates, toxicity, QoL, etc). In order to evaluate the possibility of transitioning to short-course radiotherapy, this treatment option should be examined in a randomised controlled trial in the Irish setting. 

Note that not all cases of rectal carcinoma require pre-operative treatment as some present at an early stage and are directly referred for surgery, thereby highlighting practical challenges such as number of potential recruits and time for completion of the study. Other barriers may include the unfeasibility of immediate surgery after radiotherapy treatment, surgeons’ preferences or training, and cost.

Acknowledgements

We thank Dr Moya Cunningham, consultant radiation oncologist at St Luke’s Hospital, Tallaght Hospital and St James’s Hospital, for her feedback and expertise.

References

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