Organ preservation in rectal cancer: have all questions been answered?

Review

Organ preservation in rectal cancer: have all questions been answered? Corrie A M Marijnen

Improved treatment strategies have eliminated local control as the major problem in rectal cancer. With increasing awareness of long-term toxic effects in survivors of rectal cancer, organ-preservation strategies are becoming more popular. After chemoradiotherapy, both watchful waiting and local excision are used as possible alternatives for radical surgery. Although these seem attractive strategies, many issues about the safety of organ preservation remain. Additionally, radiotherapy strategies are mainly aimed at intermediate and high-risk rectal tumours, and adaptation of this standard practice for a completely new treatment indication has yet to start. This Review will discuss the options and problems of organ preservation, and address the research questions that need to be answered in the coming years, with a specific focus on radiotherapy.

Introduction Different viewpoints exist about the optimal (neo)-adjuvant treatment for rectal cancer. Preoperative radiotherapy provides significantly better local control than postoperative radiotherapy.1,2 However, there is no international consensus about the radiation schedule or patient selection for radiotherapy for rectal cancer. Results from two studies3,4 with total mesorectal excision have shown a significant reduction in local recurrences after short-course preoperative radiotherapy (5 × 5 Gy, followed by immediate surgery). In many countries patients are treated with preoperative radiotherapy (45–50 Gy) in combination with chemotherapy based on the results of the FFCD 92035 and EORTC 229216 studies. Results from two studies7,8 comparing the efficacy of short-course radiotherapy with chemoradiation showed no significant difference in local recurrences. Surgery is the mainstay of cure for rectal cancer, but is, unfortunately, associated with serious adverse events1,9,10 both for patients with and without a permanent colostomy.11 In the past few years, the awareness of the delicate balance between cure and quality of life has risen, and the role of radical surgery for all patients with rectal cancer is increasingly questioned. The introduction of population screening has led to improved survival and to a shift towards more early detection of rectal cancers, with 35% of tumours detected by screening being Dukes stage A versus 14% in a non-screened population.12 If this finding is taken into account, together with the negative effects of rectal cancer treatment on quality of life for cancer survivors, treatment initiatives aimed at organ preservation are very timely.

Organ preservation Local excision is increasingly used instead of total mesorectal excision in early rectal cancers (figure 1). Findings from two studies13,14 showed good outcomes in selected T1 tumours, but not in high-risk T1 or T2–3 tumours. Although different techniques are used for local excision (varying from a simple mucosectomy to an extensive local excision, which can occasionally include www.thelancet.com/oncology Vol 16 January 2015

regional lymph nodes), transanal endoscopic microscosurgery is thought to be the standard of care because improved outcomes can be achieved as a result of superior accessibility, visualisation, and precision of resection compared with conventional local excision. Interest in organ preservation for T2–3 tumours has risen because of a series of publications by Habr-Gama and colleagues,15,16 showing that, in patients with a clinical complete response after chemoradiotherapy, close observation instead of radical surgery led to acceptable outcomes. A review17 shows that the positive results achieved by this group can be reproduced in some studies but not in others. Analyses of a large populationbased database incorporating nearly 40 000 patients with stage I colorectal cancer showed that local excision of T1–2 rectal cancer after neoadjuvant therapy might be a safe approach.18 Inclusion of patients in studies for organ preservation strategies varies greatly, with some studies including cT1–2 tumours, whilst others incorporate cT3–4 tumours.16, 19–22 In a review including individual data from 2323 patients who underwent chemoradiotherapy, a clear association was shown between the clinical T-stage and the likelihood of achieving a pathological complete response. With pathological complete responses of 58%, 28%, 16%, and 12% for cT1, cT2, cT3 and cT4, respectively,23 the success of the watch and wait approach clearly depends on the initial tumour stages included.

Lancet Oncol 2015; 16: e13–22 Department of Clinical Oncology, Leiden University Medical Center, Leiden, Netherlands (Prof C A M Marijnen PhD) Correspondence to: Prof Corrie A M Marijnen, Department of Clinical Oncology, Leiden University Medical Center, 2300 RC Leiden, Netherlands [email protected]

Assessment of clinical response Assessment of clinical complete response is difficult and probably the most limiting factor for safe introduction of the watch and wait strategy. Recommendations about assessment of clinical response are mainly eminence-based, and vary between different authors.19,24 As a result, the concordance between clinical and pathological complete response has proven to be challenging in many studies, as reviewed by Glynne-Jones and colleagues.25 26 A retrospective study in operated patients used the criteria for clinical complete response as defined by e13

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Figure 1: Difference between total mesorectal excision specimen (A), including all mesorectal fat and anal sphincter and total mesorectal excision specimen (B), not including any lymph nodes

Habr-Gama and colleagues and identified a disappointing sensitivity of 26% with a specificity of 97% and a false positive rate of 27%. Additionally, twothirds of patients with ypT0 (ie, pathological T0 after neoadjuvant therapy) had residual mucosal abnormalities, and could not be regarded as having a complete clinical response according to the used definition. However, because only histological data were used in this study, the results might have been better if digital rectal examination had also been used. The ACOSOG Z6041 trial defined clinical complete response as the complete disappearance of a tumour on proctoscopic examination and reported a sensitivity of 85% and a specificity of 67% as a predictor of pathological complete response.27 The false positive rate was 33%. These results strengthen the idea that assessment of mucosal abnormalities is insufficient, and alternative ways to confirm pathological complete response need to be identified. Endoscopic biopsy is by far the easiest way to obtain tissue for histopathological examination, but retrospective series show poor accuracy in predicting a pathological complete response after neoadjuvant treatment (<25%),28,29 possibly because of sampling errors and variation in a priori likelihood of pathological complete response. Increased accuracy can be achieved when several diagnostic modalities are combined, but generally at the cost of poor sensitivity.29 In view of these uncertainties, centralisation of the watch and wait approach, done within the framework of prospective studies, is a prerequisite to safely abandon surgery. A carefully designed follow-up protocol is needed to guarantee that tumour residues or recurrences will be detected in time. Local excision has been suggested to be more suitable than watchful waiting as an organ preservation strategy because histological confirmation is acquired. However, lymph nodes are not routinely included in the local excision specimen, and the assessment of pathological completed response after neoadjuvant treatment will thus only be based on the pathologically confirmed T stage, with the risk of understaging nodal status. e14

Transanal endoscopic microsurgery as a diagnostic and treatment modality For T1 rectal tumours, transanal endoscopic microsurgery can be used as the primary treatment. Although local recurrences are more common compared with total mesorectal excision surgery, overall survival is generally similar with less treatment-associated morbidity and mortality.30 However, transanal endoscopic microsurgery as the only treatment modality in high-risk T1 or T2–3 tumours is thought to be unacceptable because of higher risks of local recurrence.14 Although some retrospective studies31–33 suggest a good outcome with postoperative chemoradiotherapy for T2 or T3 tumours, preoperative chemoradiotherapy seems more successful. For patients who responded well but who have residual mucosal abnormalities, full thickness local excision of the original tumour bed will allow adequate T staging, which can be used to estimate the risk of lymph node involvement. Results from several reports34–36 show a clear correlation between the pathological T-stage after neoadjuvant therapy stage and the risk of involved pelvic lymph nodes, with a very low risk (<5%) for patients with ypT0, 20% for those with ypT2, and even higher risks for ypT3 or ypT4. As a result, patients with tumours that are ypT2 or higher after neoadjuvant treatment are generally not regarded as suitable candidates for organ preservation. Estimated risks for patients with ypT1 range between 5% and 20%, hampering general advice on the safety of organ preservation for this group. Because the a-priori chance of nodal involvement will have an effect on the estimated risk, a local excision in clinically node-negative patients with ypT1 after chemoradiotherapy seems safe to do. Unfortunately, reliable identification of nodenegative patients is a major problem. Nonetheless, because of the low risk of nodal involvement in cT1–2 tumours, these patients might qualify for organ preservation when suspected lymph nodes are absent. However, for patients with a T3–4 tumour with a higher chance of nodal involvement, remaining nodal disease after chemoradiotherapy is much more probable, even when ypT1 is achieved after neoadjuvant treatment. For these patients, therefore, organ preservation strategies should not be recommended. www.thelancet.com/oncology Vol 16 January 2015

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Analysis of a national database identified the following additional risk factors for local recurrence after local excision: depth of tumour invasion, tumour diameter, lymphovascular invasion, and poor differentiation.14 Most surgeons will do radical surgery after local excision if any of these risk factors are present. There is concern that the completion of total mesorectal excision might be hampered by previous local excision extending in the mesorectal fat, with a high risk of a compromised mesorectal fascia, leading to a higher risk of local recurrence compared with immediate radical surgery. Most studies report no local recurrences in the group of patients with ypT1 or ypT2 with poor histopathological features undergoing transanal endoscopic microsurgery followed by immediate completion total mesorectal excision;13,14,37,38 however, some studies report local recurrence rates of up to 10%.39

Trial results In a randomised Italian study,40 100 patients with a low lying cT2N0 tumour received neoadjuvant chemoradiotherapy, and were randomised between total mesorectal excision and transanal endoscopic microsurgery. Long-term local recurrence rates were 6% and 8%, respectively; however, taking into account the inclusion of solely cT2N0 disease, the local recurrence rate was relatively high after chemoradiotherapy followed by total mesorectal excision. Several prospective phase 2 studies27,37,41 have been published in which local excision is used both as a therapeutic and diagnostic modality. In these studies, tumour response after chemoradiotherapy was used as guidance about whether local treatment is oncologically safe. An Italian trial41 included a group of patients with low lying cT2 and cT3N0–1 tumours and recommended treatment of chemoradiotherapy with a radiotherapy dose of at least 50·4 Gy and fluorouracil-based chemotherapy. After local excision, follow-up was allowed for patients with ypT0 or ypT1 after neoadjuvant therapy with negative margins, no lymphovascular invasion, and sufficient tumour regression. Of the 63 patients included, 68% fulfilled these criteria, and were closely observed. For the other 20 patients, radical surgery was advised, but seven patients refused and in two patients a re-local excision was performed. No local recurrences occurred in the patients that adhered to the protocol, but two local recurrences occurred in those nine patients, showing the risk of organ preservation in high-risk patients. A multicentre Polish trial37 included 89 patients with unfavourable cT1N0, cT2N0, or borderline cT2N0 orcT3N0 tumours. Neoadjuvant treatment consisted of either a radiotherapy dose of 5 × 5 Gy plus a 4 Gy boost or chemoradiotherapy (55·8 Gy with fluorouracil-based chemotherapy), followed by local excision 6–8 weeks thereafter. For good responders (defined as ypT0 or ypT1 without unfavourable characteristics), this was the definitive treatment, whereas immediate surgery was www.thelancet.com/oncology Vol 16 January 2015

recommended for all other patients. The 2-year local recurrence rate was 10% in the group of patients that responded well. For poor responders, eight patients underwent radical surgery and no recurrences were reported in this group. However, another 18 patients did not undergo surgery, resulting in a 2-year local recurrence rate of 37%. This result again underlines the point that local excision after chemoradiotherapy is an inadequate treatment in high-risk patients. In the ACOSOG Z6041 trial,27 90 patients with cT2N0 rectal cancer have been treated with chemoradiotherapy (50·4–54·0 Gy with capecitabine and oxaliplatin) followed by local excision 6 weeks later. For patients with ypT2 or less, local excision is deemed the definitive treatment, whereas for patients with ypT3, positive nodes, or positive resection margins, further treatment was left at the discretion of the supervising physician. In view of previous results it will be interesting to see whether the decision to follow these highly selected patients with ypT2 is oncologically safe. 30% of patients had no response and still had a ypT2 tumour, but no data for oncological outcomes are available yet. The toxic effects of the treatment were substantial with 33 (39%) of 84 patients having grade 3 or higher toxic effects during chemoradiotherapy and 45 (58%) of 77 having perioperative complications, of which 12 (16%) of 77 were grade 3 or higher.

Toxic effects and functional outcomes The results of the ACOSOG trial highlight one of the criticisms about organ preservation—ie, the early nature of these cancers does not justify neoadjuvant treatment if patients can undergo radical surgery. The toxic effects of chemoradiotherapy can be substantial and treatmentrelated mortality from chemoradiotherapy might even occur in 0·5–1% of the patients.42 Additionally, concerns have been raised about impaired wound healing after chemoradiotherapy. Although data about the incidence of suture wound dehiscence are not consistent and range between 7% and 26%, most reports suggest that reintervention is seldom necessary.43–45 At present, information about the functional outcome is based on reports with a small number of patients, often with non-validated questionnaires. A comparison between patients with early rectal cancer undergoing total endoscopic microsurgery or total mesorectal excision showed no difference in perceived quality of life, but defecation disorders were more frequently encountered after total mesorectal excision.46 However, whether functional outcomes remain better after chemoradiotherapy, possibly with a full dose to the anal sphincters, is not yet clear. In a study assessment of 44 patients who underwent (chemo)radiotherapy and local excision, incontinence for loose stools was reported in 46% of patients and urgency in 49%.47 These figures did not differ from the results in historical controls that underwent an anterior resection without neoadjuvant therapy. However, e15

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Figure 2: Routine dose distribution (A and C) and suggested dose distribution for early rectal cancer (B and D) Yellow=47·5 Gy. Aqua=40 Gy. Blue=30 Gy. White=15 Gy. Red line=routine PTV. Blue line=suggested PTV.

a comparison between patients undergoing total endoscopic microsurgery only or total endoscopic microsurgery after chemoradiotherapy showed no difference in faecal incontinence.45 The addition of chemoradiotherapy to treatment for organ preservation is associated with increased toxic effects; this is especially important for patients who responded poorly, who will endure the downsides of multimodality treatment without having any benefit. Careful selection is, therefore, needed to limit overtreatment in patients responding poorly. Furthermore, better information about functional outcomes are needed based on validated questionnaires, preferably obtained in randomised comparisons.

Salvage surgery after organ preservation Whether assessment of organ preservation strategies should be based on initial local recurrence rates is questionable. In view of the fact that radical resection might still be possible in many recurring patients, e16

disease-free survival after salvage treatment might be a better outcome measure. Habr-Gama and colleagues16 showed a 5-year disease-free survival of 68% for patients on a watch-and-wait strategy, improving to a very good 94% if the first recurrence was not taken into account.16 For salvage surgery after local excision, data are scarce, and difficult to interpret. In retrospective series, medically unfit patients are often included, making radical salvage surgery impossible. In most studies, the majority are local recurrences only, although 20–40% might be distant metastases or a combination of both.37,41,48 The question of whether this is an indication of the behaviour of an aggressive biological tumour or a result of inadequate treatment at tumour presentation is not easily answered. Additionally, the promising results reported by HabrGama and colleagues can be partly explained by the fact that most recurrences were intraluminal, whereas little data are available about the site of recurrence after local excision. More extensive growth in the original local excision bed might complicate easy salvage. www.thelancet.com/oncology Vol 16 January 2015

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To finally decide whether the benefits of organ preservation balance the increased oncological risk, trials randomising organ preservation against radical surgery are needed to compare long-term outcomes, both for oncological endpoints and for quality of life.

Radiotherapy for organ preservation Radiotherapy target volume One of the most challenging factors in radiation therapy is delineation of treatment volumes. Despite all discussions about tailor-made treatment, treatment volumes in radiotherapy are not always adapted to the primary tumour status or the aim of the treatment. Target volumes for early or locally advanced tumours are often very similar, and generally contain the primary tumour, the mesorectal fat, and the presacral and internal iliac nodes (figure 2A and C).49 For early rectal tumours, the necessity of these large volumes is questionable because most patients will be clinically node-negative. Radiotherapy for organ preservation is primarily aimed at tumour downstaging and can therefore be restricted to the peritumoral area, which includes the primary tumour and the mesorectum only (figure 2B and D). A volume reduction can be achieved in the cranial-caudal direction and with respect to obturator nodes. Use of a smaller volume in organ preservation seems a safe approach, even in the case of unexpected nodal involvment, as shown in a series of 121 patients50 with locally advanced rectal cancer who underwent chemoradiotherapy. Most lymph nodes were identified along the major supplying vessels, but 83 (77%) of 108 involved lymph nodes were identified in the mesorectum. Restricting the target volume to the primary tumour and the nearby mesorectum will decrease treatmentrelated toxic effects without compromising outcomes.

Timing of surgery Increasing the interval between the end of radiotherapy and surgery has been used in an attempt to increase downstaging and downsizing, facilitate surgical resection, and possibly enhance sphincter preservation. Nowadays, prolonging the interval between neoadjuvant treatment and surgery is also used to achieve higher proportions of patients achieving pathological complete responses after neoadjuvant treatment, and subsequently increasing the number of patients suitable for organ preservation. However, most data about increased pathological complete responses are derived from locally advanced rectal cancers and results might not automatically translate towards early rectal cancers. Additionally, the assumption that pathological complete responses after neoadjuvant treatment are associated with good prognosis is mainly based on studies with conventional intervals.23 The question of whether this good prognosis also holds for pathological complete responses based on prolonged intervals, dose escalation, www.thelancet.com/oncology Vol 16 January 2015

or chemotherapy intensification cannot be answered yet. Because of the importance of pathological complete responses in organ preservation, these questions need to be addressed in early rectal cancer. The Lyon R90–01 trial randomly assigned 210 patients with cT2–3Nx rectal cancer with neoadjuvant radiotherapy (13 × 3 Gy) followed by surgery within 2 weeks or after 6–8 weeks.51 No significant difference in pathological complete response was reported, but ypT0 or ypT1 was more common in the longer interval group (15% vs 29%). No difference in survival or local recurrence rates was noted.52 Most data about chemoradiotherapy originate from retrospective series, with many various studies reporting neoadjuvant treatments, differences in assessment timepoints, and used outcome parameters.53–58 However, most data suggest that an interval of more than 8 weeks between the end of chemoradiotherapy and surgery results in more patients achieving a response. Results from a large population-based study59 showed that an interval of 15–16 weeks from the start of chemoradiotherapy leads to the most optimal response. To exceed the interval beyond these 16 weeks seemed to have a detrimental effect on the response rate. By contrast, a single centre study assessing clinical complete response in patients not operated on showed that the median time to complete response after radiotherapy was 4 months.60 Several retrospective series suggest that a prolonged interval after short-course radiotherapy also facilitates downstaging and downsizing.61–63 The interim results of the Stockholm III trial support this and show no residual tumour in 15 (13%) of 120 the patients receiving a radiotherapy schedule of 5 × 5 Gy followed by delayed surgery (4–8 weeks delay) versus 1 (1%) of 118 patients in the group receiving a radiotherapy schedule of 5 × 5 Gy and immediate surgery.64 So far, only one small randomised study65 has compared 37 patients receiving 5 × 5 Gy with delayed surgery, with 46 patients undergoing chemoradiotherapy (50 Gy with fluorouracil), with ypT0 noted in 3% and 13% of patients, respectively. Unfortunately, with an interval of 6 weeks after the end of radiotherapy in both groups, the design of this study is suboptimal. Because of the longer duration of chemoradiotherapy compared with the short course of radiotherapy, the overall treatment time from start of radiotherapy to surgery was much longer in the conventional arm, probably resulting in the increased downstaging in this group. For new trial designs, attention should be paid to the imbalance in overall treatment time when different fractionation schedules are used. In the discussion below, the overall time to surgery will be given for all treatment schedules, calculated from the first day of treatment to surgery. The relatively low number of pathological complete responses after 5 × 5 Gy radiotherapy and delayed surgery suggest that this is not an optimal schedule in organ preservation. However, taking into account that the interval can be further prolonged, and that patients for e17

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organ preservation will usually have smaller tumours, better results might be possible. In view of the less toxic profile of short-course radiotherapy compared with chemoradiotherapy, further exploration of the possibilities of short-course radiotherapy in organ preservation is certainly warranted.

Radiotherapy dose escalation To increase the radiotherapy dose might be helpful to increase the tumour response—and as a result, facilitate more organ preservation. Several retrospective studies showed that with a minimum preoperative dose of 50 Gy better local control could be achieved than with lower doses.66,67 To further escalate the dose without exceeding normal tissue tolerance, local boosts to the tumour can be applied by various radiotherapy techniques. The attraction of intracavitary irradiation, either by contact therapy or by endoluminal brachytherapy, lies in the ability to deliver a localised high dose with a rapid fall-off and sparing of adjacent normal tissues.68 A randomised trial69 escalating the dose with an endocavitary contact x-ray, compared 13 × 3 Gy (overall time to surgery of 8 weeks) with endocavitary boost (85 Gy in three fractions) followed by 13 × 3 Gy (overall time to surgery of 10 weeks). The proportion of patients with a clinical complete response improved substantially from one (2%) of 43 patients to 11 (24%) of 45 patients, without any increase in acute or postoperative toxic effects. An exact estimate of the proportion of patients achieving pathological complete response cannot be given because six patients with a clinical complete response did not undergo surgery. A randomised trial70 compared fluorouracil-based chemoradiotherapy (50·4 Gy, overall time to surgery of 14 weeks) with the same chemoradiotherapy with two high-dose rate brachytherapy fractions of 5 Gy each (60·4 Gy, overall time to surgery of 14 weeks). In T3 tumours, the R0 resection rate was significantly better in the brachytherapy group (99% vs 90%, p=0·03) as was the major response defined as tumour regression grade 1 and 2 (44% vs 28%, p=0·04). By contrast, the pathological complete response (defined as ypT0N0) was 18% in both groups. These results underline an important issue in local dose escalation for organ preservation strategies. Although a better tumour response can be achieved, lymph nodes possibly involved will not receive a higher dose. Nowadays, the accepted risk of lymph node involvement in a patient with ypT0 or ypT1 is based on a homogeneous dose distribution. Increasing the dose on the tumour only will lead to a higher percentage of nodal involvement in this group. As a result, higher risk of local recurrence might occur after localised dose escalation and organ preservation. Intensity modulated radiotherapy with an integrated, simultaneously given boost has been tested in several small series, and might have the advantage that e18

suspicious lymph nodes can be included in the boost volume. A prospective trial in which 57 patients with a threatened mesorectal fascia received daily a simultaneously given boost of 0·4 Gy in the primary tumour (total dose 55·2 Gy), on top of the standard 46 Gy chemoradiotherapy to the whole pelvic area, showed that this is feasible without significantly increased toxic effects.71 So far, reliable data to assess the effect on pathological complete responses are not available.

Chemoradiotherapy with chemotherapy intensification In an attempt to improve local control and disease-free survival, several randomised phase 3 trials assessed the effect of adding oxaliplatin to fluorouarcil-based chemoradiotherapy in patients with locally advanced rectal cancer.72–76 Results for pathological complete response have been disappointing, with only one study showing a significantly increased proportion of patients with a ypT0N0 with the addition of oxaliplatin (17% vs 13%, p=0·04).73 In view of these results and the shown increased toxic effects, adding oxaliplatin in early rectal cancers cannot be recommended.

New neoadjuvant treatment strategies To overcome the risk of disease progression during the interval between radiotherapy and surgery, the addition of neoadjuvant chemotherapy is an attractive option in locally advanced tumours for several reasons. Apart from addressing possible distant (micro)metastases, the additional chemotherapy might result in an increase of primary tumour downstaging. However, some studies with treatment escalation showed increased T downstaging, but no difference in N stage after chemoradiotherapy for locally advanced rectal cancer.73,77 When comparing different treatment strategies by adding neoadjuvant chemotherapy, the time to surgery will, by definition, be prolonged. As such, reported improvements in pathological response rates can be attributed to either the addition of chemotherapy or the prolonged interval. The results summarised below should therefore be interpreted with caution.

Chemoradiotherapy followed by chemotherapy followed by surgery In a randomised trial77 for clinical stage II or III disease, 144 patients were randomly assigned to either chemoradiotherapy (50·4–54 Gy with fluorouarcil; overall time to surgery of 12 weeks) or chemoradiotherapy (same regimen) followed by two cycles of mFOLFOX-6 (overall time to surgery of 19 weeks). Although the overall pathological response was improved in the experimental group (p=0·02), the difference in the proportion of patients with a ypT0N0 after neoadjuvant treatment was not significant (18% vs 25%). The observed increase in patients with a ypT0 (23% vs 31%) was not accompanied by a decrease in nodal involvement (25% in both groups). www.thelancet.com/oncology Vol 16 January 2015

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Chemotherapy followed by chemoradiotherapy followed by surgery

Chemotherapy followed by short-course radiotherapy followed by surgery

A single-centre phase 2 trial investigated an approach of chemotherapy followed by chemoradiotherapy followed by surgery in 105 patients with 50 (48%) cT3 tumours and 39 (37%) cN2 disease.78 Treatment consisted of 12 weeks of CAPOX followed by chemoradiotherapy (54 Gy with capecitabine) and surgery 6 weeks thereafter (overall time to surgery of 24 weeks). The number of patients achieving a complete response, as assessed by MRI was 3 (3%) after chemotherapy and 15 (14%) after chemoradiotherapy; ypT0N0 was reported in 21 (20%) of the patients. A randomised phase 2 trial79 included 108 patients with MRI-defined locally advanced rectal cancer. Treatment consisted either of chemoradiotherapy (50·4 Gy with CAPOX) followed by surgery and four cycles of adjuvant CAPOX (overall time to surgery of 11 weeks) or four cycles of induction CAPOX followed by chemoradiotherapy (same regimen) and surgery (overall time to surgery of 23 weeks). Although more downstaging was noted in the experimental group, the proportion of patients with a ypT0N0 after neoadjuvant treatment was similar in both groups: 13% for the conventional group and 14% for the experimental group.

Alternatively, the sequence of four courses of neoadjuvant chemotherapy (FOLFOX-6) followed by short-course radiotherapy (20 Gy in five fractions) and immediate surgery (overall time to surgery 9 weeks) has been tested in an observational study, including 67 patients with cT3–4 tumours.84 Although downstaging was seen in half of the included patients, no pathological complete responses were reported, suggesting that any radiotherapy with an adequate interval to surgery is a prerequisite to achieve complete responses.

Short-course radiotherapy followed by chemotherapy followed by surgery The potential downstaging effects of the short-course radiotherapy have opened a new window of opportunity for intensification of neoadjuvant treatment by administering chemotherapy preoperatively, directly after the end of radiotherapy. One of the attractive features of this schedule is the relatively short overall time to surgery in which both optimum treatment for the primary tumour and full dose neoadjuvant chemotherapy can be given. Several prospective phase 2 studies tested the feasibility of short-course radiotherapy followed by systemic therapy for four to six courses, and surgery afterwards for either metastatic disease80 or locally advanced resectable81 disease. Results so far show acceptable toxic effects and promising proportions of patients achieving pathological complete response, varying between 21% and 26%. In a study82 for very advanced or recurrent rectal cancer, patients were randomly assigned to either 5 × 5 Gy radiation treatment followed by three courses of FOLFOX (overall time to surgery 12 weeks) or conventional chemoradiotherapy (50·4 Gy with FOLFOX, overall time to surgery 12 weeks). An interim analysis after inclusion of 97 patients showed a higher proportion of patients achieving a pathological complete response in the experimental group (21% vs 9%). The ongoing RAPIDO study randomises patients with very locally advanced tumours between 5 × 5 Gy followed by six courses of CAPOX versus conventional chemoradiotherapy (50 Gy with capecitabine) and will answer the question of which strategy results in more complete responses and better survival.83 www.thelancet.com/oncology Vol 16 January 2015

Neoadjuvant chemotherapy without (chemo) radiotherapy A study that omitted radiotherapy and added bevacizumab to four of the six neoadjuvant-modified FOLFOX6 courses (overall time to surgery 15–18 weeks) showed a promising 25% of patients had a ypT0 or ypT1.85 The concept of this approach is now being tested in the PROSPECT trial, randomising patients with rectal cancer (T2N1, T3N0–1) treated with FOLFOX between the selective use of the same neoadjuvant chemotherapy followed by low anterior resection and fluorouarcil-based chemoradiotherapy followed by low anterior resection.86 No results on the pathological complete responses are available yet.

Hypofractionated chemotherapy A combination of hypofractionated chemoradiotherapy has been tested in mainly T3N+ patients in the KROG 11–02 trial.87 Treatment consisted of ten fractions of 3·3 Gy, combined with daily capecitabine, followed by surgery 6–8 weeks after chemoradiotherapy (overall time to surgery of 9 weeks). In 11 of 80 patients, a ypT0 or ypT1 was reported, and grade 3 adverse effects were reported in five patients.

Hypofractionated chemotherapy In an attempt to limit late toxic effects, several small studies have assessed the feasibility of hyperfractionated accelerated radiotherapy combined with or without concomitant chemotherapy. Doi and colleagues88 combined ten fractions of 2·5 Gy, given twice daily with S-1, an oral prodrug of fluorouarcil, in 56 patients with cT3N1 rectal cancer (overall time to surgery of 4–5 weeks). The 3·6% pathological complete response was disappointing for this relatively early tumour.

Can we incorporate these new initiatives in organ preservation? Although previous studies contain interesting strategies, none of them can be thought to be a realistic option for early rectal cancers at present. Increased toxic effects are described in most strategies without a clinically relevant increase in pathological complete responses rates or tumour downstaging. Therefore, conventional e19

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fluorouarcil-based (either given infusionally or orally) chemoradiotherapy must still be regarded as the standard for neoadjuvant treatment in organ preservation.

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So far, little evidence from randomly controlled trials supports general acceptance of organ preserving strategies in rectal cancer and several radiotherapy issues for early tumours are unsolved. There is no consensus about target volumes, timing of response assessment, or the optimum treatment schedule. Attempts to improve the proportions of patients achieving pathological complete responses or tumour downstaging have been disappointing so far, although there is some evidence that radiotherapy dose escalation will lead to increased tumour downstaging, although it will not affect possibly involved lymph nodes. Questions about optimal patient selection, appropriate response assessment, and adequate follow-up have not been answered yet. Therefore, centralisation of patients undergoing organ preservation is warranted. Ideally, organ preservation should, at present, only be done within clinical trials, preferably randomised with a radical surgery group included. Declaration of interests I declare no competing interests. Acknowlegments Figure 1A was provided by Nagtegaal ID, Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands and figure 1B was provided by Bach S, Department of Colorectal Surgery, University of Birmingham, Queen Elizabeth Hospital Edgbaston, Birmingham, UK, personal communication. References 1 Frykholm GJ, Glimelius B, Påhlman L. Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results of a randomized trial and an evaluation of late secondary effects. Dis Colon Rectum 1993; 36: 564–72. 2 Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 2012; 30: 1926–33. 3 Sebag-Montefiore D, Stephens RJ, Steele R, et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 2009; 373: 811–20. 4 van Gijn W, Marijnen CA, Nagtegaal ID, et al, and the Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year followup of the multicentre, randomised controlled TME trial. Lancet Oncol 2011; 12: 575–82. 5 Gérard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006; 24: 4620–25. 6 Bosset JF, Calais G, Mineur L, et al, and the EORTC Radiation Oncology Group. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol 2014; 15: 184–90. 7 Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 2006; 93: 1215–23.

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