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EURECCA consensus conference highlights about rectal cancer clinical management: The radiation oncologist’s expert review
Radiotherapy and Oncology xxx (2013) xxx–xxx
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Original article
EURECCA consensus conference highlights about rectal cancer clinical management: The radiation oncologist’s expert review Vincenzo Valentini a, Bengt Glimelius b, Karin Haustermans c, Corrie A.M. Marijnen d, Claus Rödel e, Maria Antonietta Gambacorta a,⇑, Petra G. Boelens f, Cynthia Aristei g, Cornelis J.H. van de Velde f a Department of Radiation Oncology, Cattedra di Radioterapia, Università Cattolica S. Cuore, Rome, Italy; b Department of Radiology, Oncology and Radiation Science, Uppsala University, Sweden; c Department of Radiation Oncology, University Hospitals Leuven Campus Gasthuisberg, Belgium; d Department of Clinical Oncology, Leiden University Medical Center, The Netherlands; e Radiation Oncology, University Hospital of Frankfurt, Germany; f Department of Surgery, Leiden University Medical Center, The Netherlands; g Radiation Oncology Section, Department of Surgery, Radiology and Dentistry, University of Perugia, Italy
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Article history: Received 18 September 2013 Accepted 20 October 2013 Available online xxxx Keywords: Rectal cancer Radiotherapy Combined modality therapy
a b s t r a c t Background and Purpose: Although rectal and colon cancer management has progressed greatly in the last few decades clinical outcomes still need to be optimized. Furthermore, consensus is required on several issues as some of the main international guidelines provide different recommendations. The European Registration of Cancer Care (EURECCA) drew up documents to standardize management and care in Europe and aid in decision-making. Material and Methods: In the present section the panel of experts reviews and discusses data from the literature on rectal cancer, focusing on recommendations for selecting between short-course radiotherapy (SCRT) and long-course radio-chemotherapy (LCRTCT) as preoperative treatment as well as on the controversies about adjuvant treatment in patients who had received a pre-operative treatment. Results: The starting-point of the present EURECCA document is that adding SCRT or LCRTCT to TME improved loco-regional control but did not increase overall survival in any single trial which, in any case, had improved with the introduction of total mesorectal excision (TME) into clinical practice. Moderate consensus was achieved for cT3 anyNM0 disease. In this frame, agreement was reached on either SCRT followed by immediate surgery or LCRTCT with delayed surgery for mesorectal fascia (MRF) negative tumors at presentation. LCRTCT was recommended for tumor shrinkage in MRF+ at presentations but if patients were not candidates for chemotherapy, SCRT with delayed surgery is an option/alternative. LCRTCT was recommended for cT4 anycNM0. SCRT offers the advantages of less acute toxicity and lower costs, and LCRTCT tumor shrinkage and down-staging, with 13–36% pathological complete response (pCR) rates. To improve the efficacy of preoperative treatment both SCRT and LCRTCT have been, or are being, associated with diverse schedules of chemotherapy and even new targeted therapies but without any definitive evidence of benefit. Nowadays, standard treatment is fluoropyrimidine alone since alternative agents and regimens have not been shown to be more active, only more toxic. Conclusions: The EURECCA panel summarized available evidence in an attempt to reduce variance in rectal cancer management. This is expected to benefit patients. Results from ongoing randomized trials will help clarify some of the issues that are still under debate. Ó 2013 Published by Elsevier Ireland Ltd. Radiotherapy and Oncology xxx (2013) xxx–xxx
Even though great progress has been made in rectal and colon cancer management over the past decades, clinical management and outcomes still need to be optimized. Consensus is required since some of the main international guidelines report few, albeit substantial differences in recommendations [1]. A step forward was taken with the publication of a consensus document on managing rectal cancer in 2009 [2]. It was followed by a position paper from the European Registration of Cancer Care (EURECCA) [3] ⇑ Corresponding author. E-mail address: [email protected] (M.A. Gambacorta).
which aimed at standardizing clinical management of colon and rectal cancer care in Europe, aiding doctors in multidisciplinary teams in decision-making and providing benchmarks to enhance the quality of treatment through audits and outcome analyses of population-based registries. The present review will focus on recommendations for patients with rectal cancer especially for selecting between short-course radiotherapy (SCRT) and long-course radio-chemotherapy (LCRTCT) as preoperative treatment as well as on the controversies about adjuvant treatment in patients who received either SCRT or LCRTCT.
0167-8140/$ - see front matter Ó 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.radonc.2013.10.024
Please cite this article in press as: Valentini V et al. EURECCA consensus conference highlights about rectal cancer clinical management: The radiation oncologist’s expert review. Radiother Oncol (2013), http://dx.doi.org/10.1016/j.radonc.2013.10.024
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EURECCA consensus conference: Radiation Oncology perspective
Preoperative radiotherapy treatment schedule: short versus long course The EURECCA conference achieved moderate consensus for algorithms advocating preoperative RT for cT3 anyNM0 disease at presentation. In this frame, agreement was reached on SCRT followed by immediate surgery or LCRTCT with delayed surgery for a mesorectal fascia (MRF) negative presentation in any localization. LCRTCT was recommended, despite lack of definitive evidence that it improved outcomes [4], for MRF+ presentations (irrespective of localization and nodal involvement), in order to achieve tumor shrinkage. For this group of patients, SCRT with delayed surgery should be proposed only if patients were not candidates for the combination with chemotherapy. LCRTCT was recommended for cT4 anycNM0. Although North American guidelines describe LCRTCT as the option of choice for preoperative treatment of cT3-T4N+/ M0 [5], there is no European consensus on this issue [1]. The EURECCA document emphasized global reports of better survival for rectal cancer patients after the introduction of total mesorectal excision (TME) and increased use of preoperative RT [6]. Although an older study had reported a survival gain with SCRT [7], no single randomized trial has observed significantly increased overall survival (OS) after adding either SCRT or LCRTCT to TME. Both regimens improved loco-regional control to about the same extent and had similar effects on OS and long-term toxicity [3,8,9]. Compared with LCRTCT, SCRT is associated with less acute toxicity, and lower costs. LCRTCT has the potential for tumor shrinkage and downstaging, which led to pathological complete response (pCR) rates of 13–36% [10]. On the other hand downsizing, downstaging and even pCR, are seen when surgery is delayed after SCRT [11–13]. In the pre-operative RT setting, randomized trials evaluated administering SCRT followed by surgery vs surgery alone which was eventually followed by postoperative adjuvant RT ± chemotherapy for high-risk presentations [8,14]. The Dutch TME trial randomized 1861 patients to no pre-operative treatment or to SCRT (25 Gy in 5 fractions). At 11.6 years median follow-up, local control (LC) was significantly better in the SCRT group [15]. Even though postoperative RT was mandatory for patients who had received surgery alone and had circumferential resection margin (CRM) involvement of 61 mm (CRM+), only 47% were treated. The MRC C07 trial assigned patients to pre-operative SCRT versus primary surgery. Post-operative LCRTCT was administered to the surgeryalone group when CRMs were involved or threatened (<1 mm). Results showed local control and disease free survival (DFS) were significantly better in the SCRT group, OS did not differ between the groups (HR = 0.91; 0.73–1.13; p = 0.40) [14]. Randomized trials also compared pre- and post-operative LCRTCT administration. In 823 patients Sauer et al. (CAO/ARO/ AIO-94) delivered 50.4 Gy in 28 fractions with concomitant chemotherapy to increase radiosensitivity with a boost of 5.4 Gy in the postoperative arm. At 11 years follow-up the preoperative LCRTCT approach was associated with higher LC, less toxicity and increased sphincter preservation in a subgroup [9,16]. Two randomized trials directly compared SCRT and LCRTCT. In 316 patients with palpable cT3 lesions above the anorectal ring Bujko et al. [4,17] observed no significant differences in LC, DFS and 4-year OS. LC rates were, however, numerically higher (16% vs 11%) in the LCRTCT group. LCRTCT was associated with significantly higher rates of acute toxicity (grade III–IV: 18.2% LCRTCT vs 3.2% SCRT) and pCR (16.1%-LCRTCT vs 0.7%-SCRT), and a lower CRM+ rate (4.4%-LCRTCT vs 13%-SCRT). In the Australia and New Zealand trial Ngan et al. [18] randomized 366 patients with cT3 any N lesions of the middle and lower rectum to SCRT or LCRTCT. Adjuvant chemotherapy was planned for both groups (6 courses
in the SCRT cohort; 4 in the LCRTCT group, which was administered to 85% and 86% of patients, respectively). With a median 5.9 years follow-up, no significant differences were found in OS, late toxicity and distant recurrence rates. The 3-year local recurrence showed no significant difference between the groups (7.5 for SCRT vs 4.4% for LCRTCT; p = 0.24); for tumors at <5 cm from the anal verge there was a trend for reduced local recurrences with the LCRTCT approach (6/48 (12.5%) SCRT patients, and 1/31 (3.2%) LCRTCT; p = 0.21). Interestingly like Bujko et al. [17] pCR and downstaging rates were significantly higher in the LCRTCT group (15%- vs 1%-S CRT; p < 0.01; 45%- vs 28%-SCRT; p = 0.002 respectively). The authors concluded that ‘‘LCRTCT may be more effective in reducing local recurrence for distal tumors . . . and it may be reasonable to suggest a policy that distal . . . tumors be treated with LCRTCT.’’ This conclusion was hotly debated [19,20], as it derived from an unplanned analysis, the results of which were not statistically significant. There are some limitations in the trials conducted by Bujko et al. [19] and Ngan et al. [18]. OS was not the primary end-point, and relatively few patients were accrued. An on-going German study (the so-called ‘‘Berlin study’’), designed to compare SCRT followed by early surgery with LCRTCT, expects to enroll 760 patients with cT2N+/T3Nx disease. Adjuvant chemotherapy is mandatory for all to avoid potential bias [21]. Given the results to date, the EURECCA consensus document contains different viewpoints on preoperative schedules for low seated lesions. In summary, when compared, SCRT and LCRTCT seem to provide similar OS, LC and DFS in patients with intermediate advanced rectal cancer, chiefly cT3MRF . SCRT was associated with less acute toxicity. LCRTCT achieved more downstaging and better pCR and CRM-rates than SCRT with immediate surgery, which is the evidence for recommending LCRTCT for advanced-stage disease (cT3MRF+, cT4) where some degree of downsizing or downstaging is usually needed. Lack of definitive evidence precludes recommending one modality over the other in less advanced stages as consensus was moderate to minimum [3]. Two specific issues play a central role in the preoperative RT setting; pCR induction and CRM status. Response to preoperative treatment is widely debated. Some studies did not show any impact on outcomes [22]. Others reported that when pCR is achieved after preoperative treatment outcomes are greatly better with fewer local recurrences [23,24], and better OS and distant metastases rates, as highlighted by two recent meta-analyses [25,26]. Moreover, to aid the multidisciplinary team in decision-making when difficulties arise because of tumor heterogeneity, Valentini et al. [25] suggested pCR be incorporated as a response parameter into specific predictive nomograms. MRF status has an impact before and after preoperative therapy and may determine choice of schedule. Involved CRM (61 mm) after surgery are associated with high risk of metastases and low survival rates [27,28], as first shown by the Dutch trial results [8,28]. In the Polish trial LCRTCT decreased the CRM+ rates, however, this did not result in lower local recurrence rates, which is likely related to different time intervals to surgery [17]. The Australian and New Zealand trial did not focus on that issue [18]. The consensus conference agreed on the need to distinguish pathological (CRM) and imaging (MRF) findings. Recent studies highlighted the efficacy of Magnetic Resonance Imaging (MRI) in determining MRF involvement at clinical staging [29] which is useful information for selecting the recommended preoperative modality in different situations. Some studies are attempting to overcome some of the drawbacks of both preoperative approaches. In patients with locally advanced rectal cancer, the international phase III trial Rectal Cancer and Pre-operative Induction Therapy Followed by Diligent Operation (RAPIDO) is testing SCRT
Please cite this article in press as: Valentini V et al. EURECCA consensus conference highlights about rectal cancer clinical management: The radiation oncologist’s expert review. Radiother Oncol (2013), http://dx.doi.org/10.1016/j.radonc.2013.10.024
V. Valentini et al. / Radiotherapy and Oncology xxx (2013) xxx–xxx
followed by 6 cycles of capecitabine plus oxaliplatin and then TME vs LCRTCT followed by TME and adjuvant chemotherapy with 8 cycles of capecitabine plus oxaliplatin [30]. Primarily to assess R0 resection rates, the Polish Colorectal Cancer Study Group is randomizing patients to SCRT followed by 3 cycles of 5-fluoruracil, leucovorin and oxaliplatin (FOLFOX4) vs LCRTCT [19]. The Stockholm III trial is randomizing patients to LCRT (without concomitant chemotherapy), SCRT with immediate surgery or SCRT with surgery delayed for up to 8 weeks to determine which option most decreases LR rate, improves tumor regression and reduces toxicity. In a recent interim report on 657 patients, SCRT with immediate surgery was associated with significantly higher postoperative complication rates. Preliminary data on pCR rates showed 0.4% yp-Stage 0 (1/244) after SCRT with early surgery, 9.8% (24/246) after SCRT with delayed surgery and 2% (2/95) after LCRT alone [31,32]. Since not all patients were randomized to all three arms, the Stockholm III trial will probably define the potential of SCRT with delayed surgery rather than compare SCRT directly with LCRT. Concomitant chemotherapy clearly demonstrated to provide better outcomes than LCRT alone. The EORTC 22921 [33] and the FFCD 9203 are the two main studies that randomly evaluated LCRT with or without concomitant chemotherapy. In the EORTC 22921 patients were randomized in a 2 by 2 factorial design, leading to four arms: (1) RT alone without postoperative chemotherapy; (2) LCRTCT without postoperative chemotherapy (3) RT alone with postoperative chemotherapy; (4) LCRTCT with postoperative chemotherapy. The FFCD 9203 randomized patients to receive preoperative LCRT vs LCRTCT; postoperative chemotherapy was administered to all patients. In both studies no differences emerged in DFS or OS, while LC and pCR rates were significantly better in the preoperative LCRTCT arm in the FFCD 9203 trial [34] and in all three arms that received chemotherapy in the EORTC 22921 trial [33]. Adding chemotherapy clearly increased acute toxicity and worsened long-term quality of life [35,36]. Braendengen et al. randomized 207 patients with cT4 or recurrent lesions to induction LCRT alone or with concomitant chemotherapy. The latter group also received adjuvant chemotherapy for 16 weeks. LCRTCT improved LC (82% vs 67% at 5 years, p = 0.03), R0 resection rates (84% vs 68%, p = 0.009), pCR (16% vs 7%, p = 0.04) and cancer-specific survival (72% vs 55% at 5 years, p = 0.02), but not OS (66% vs 53%, p = 0.09) [37]. Again, the gain comes at the price of more acute toxicity and, unfortunately, probably also more late toxicity [35,37]. To improve LCRTCT efficacy new combinations of chemotherapy agents are under evaluation. Fluorouracil associated with oxaliplatin provided conflicting, albeit mostly negative results. Two major randomized trials showed no increase in pCR rates: the STAR-01 (on 747 patients) found 16% of pCR with or without oxaliplatin [38]; the ACCORD 12/0405 PRODIGE 2 (on 598 patients) found a non-significant improvement (13.9% vs 19.2%; p = 0.09) [39]. Toxicity rates were increased in the oxaliplatin arms. On the other hand, the German CAO/ARO/AIO-04 (on 1265 patients) showed a significant improvement in pCR rates (13% vs 17%; p = 0.038) with no significant differences in toxicity profiles [40]. The number of patients in the French study may have impacted upon statistical significance. Finally, the preliminary results of the European PETACC-6 study with 1094 patients did not detect any improvement in outcome, and once again reported more toxicity [41]. The conclusion to be made from these four randomized phase III trials is that the addition of oxaliplatin does not improve pCR rates. New molecular targeted antibodies like cetuximab or bevacizumab may also be combined with SCRT and sequential chemotherapy [42] or with LCRTCT, and are under evaluation but definitive evidence that they improve efficacy is lacking [43,44].
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Another strategy to strengthen LCRTCT is to increase the dose with an external beam concomitant RT boost or with a sequential brachytherapy boost [45,46]. At present the INTERACT study is determining whether this approach, and consequent shortening of the overall duration of preoperative RT, increases tumor response [47]. In summary, adding chemotherapy to LCRT improves LC at the expense of more toxicity. Gains might be greater in locally advanced rather than intermediate rectal cancer. At present, standard treatment is fluoropyrimidine alone since alternative agents and regimens have not been shown to be more active, only more toxic.
Adjuvant postoperative treatment The EURECCA document concluded with minimum or moderate consensus on the use of adjuvant chemotherapy (ADCT) for malignancies with high-risk features (e.g. poor grade, blood or lymphatic vessel invasion, unclear margins), nodal involvement, or a positive CRM. No consensus was reached on adjuvant therapy for confirmed ypT3pN0 CRM following preoperative RT or RTCT. It is recommended that the final choice about ADCT should be made by the multidisciplinary team because trials have not shown that it offers any clear clinical advantage, whereas a common belief is that it does, similar to the situation after colon cancer surgery. In fact, neither of the two main randomized trials found a survival advantage for patients who received ADCT [33,34] and, although a recent pooled analysis confirmed better LC, it also failed to find any improvement in OS [48]. Remarkably, the global rates of patients that actually received full dose ADCT in the EORTC and FFCD trials were low which may account for the obtained results. Furthermore, in daily clinical practice, up to 20% of patients did not receive ADCT because of comorbidities, physician refusal or other reasons [49]. As the EURECCA consensus document indicates, nomograms are suggested to aid the multidisciplinary team in decision-making about different presentations in daily practice. Valentini et al. [25] recently proposed a nomogram with data and features that had been extrapolated from a pooled analysis of randomized trials and externally validated on a different database. Balancing the weight of each feature (including ADCT) according to its global relevance for outcome, it was able to predict events in terms of OS, LC and distant progression [25]. Anyway, the EURECCA panel of expert did not find a consensus in recommending its use in all situations, taking into account the patient selection in the randomized studies pooled for the analysis. There was no wide consensus on administration of postoperative LCRT if disease had been confirmed as pT3pN /+. Particularly for CRM+, minimum consensus was reached for the recommendation to administer LCRTCT postoperatively. The problem was already raised by the Dutch and MRC CR07 trials [8,14] which highlighted that using postoperative RT/RTCT in attempts to improve prognosis associated with involved or threatened margins still resulted in poor outcomes. Indeed, this was also the main finding of the old Uppsala trial.
Conclusion The EURECCA panel summarized available evidence in an attempt to aid decision-making in clinical practice by reducing variance in rectal (and colon) cancer management in European countries. This is expected to benefit patients. Results from ongoing randomized trials will help clarify at least some of the issues that are still under debate.
Please cite this article in press as: Valentini V et al. EURECCA consensus conference highlights about rectal cancer clinical management: The radiation oncologist’s expert review. Radiother Oncol (2013), http://dx.doi.org/10.1016/j.radonc.2013.10.024
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EURECCA consensus conference: Radiation Oncology perspective
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Please cite this article in press as: Valentini V et al. EURECCA consensus conference highlights about rectal cancer clinical management: The radiation oncologist’s expert review. Radiother Oncol (2013), http://dx.doi.org/10.1016/j.radonc.2013.10.024
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
EURECCA consensus conference highlights about rectal cancer clinical management: The radiation oncologist’s expert review Vincenzo Valentini a, Bengt Glimelius b, Karin Haustermans c, Corrie A.M. Marijnen d, Claus Rödel e, Maria Antonietta Gambacorta a,⇑, Petra G. Boelens f, Cynthia Aristei g, Cornelis J.H. van de Velde f a Department of Radiation Oncology, Cattedra di Radioterapia, Università Cattolica S. Cuore, Rome, Italy; b Department of Radiology, Oncology and Radiation Science, Uppsala University, Sweden; c Department of Radiation Oncology, University Hospitals Leuven Campus Gasthuisberg, Belgium; d Department of Clinical Oncology, Leiden University Medical Center, The Netherlands; e Radiation Oncology, University Hospital of Frankfurt, Germany; f Department of Surgery, Leiden University Medical Center, The Netherlands; g Radiation Oncology Section, Department of Surgery, Radiology and Dentistry, University of Perugia, Italy
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Article history: Received 18 September 2013 Accepted 20 October 2013 Available online xxxx Keywords: Rectal cancer Radiotherapy Combined modality therapy
a b s t r a c t Background and Purpose: Although rectal and colon cancer management has progressed greatly in the last few decades clinical outcomes still need to be optimized. Furthermore, consensus is required on several issues as some of the main international guidelines provide different recommendations. The European Registration of Cancer Care (EURECCA) drew up documents to standardize management and care in Europe and aid in decision-making. Material and Methods: In the present section the panel of experts reviews and discusses data from the literature on rectal cancer, focusing on recommendations for selecting between short-course radiotherapy (SCRT) and long-course radio-chemotherapy (LCRTCT) as preoperative treatment as well as on the controversies about adjuvant treatment in patients who had received a pre-operative treatment. Results: The starting-point of the present EURECCA document is that adding SCRT or LCRTCT to TME improved loco-regional control but did not increase overall survival in any single trial which, in any case, had improved with the introduction of total mesorectal excision (TME) into clinical practice. Moderate consensus was achieved for cT3 anyNM0 disease. In this frame, agreement was reached on either SCRT followed by immediate surgery or LCRTCT with delayed surgery for mesorectal fascia (MRF) negative tumors at presentation. LCRTCT was recommended for tumor shrinkage in MRF+ at presentations but if patients were not candidates for chemotherapy, SCRT with delayed surgery is an option/alternative. LCRTCT was recommended for cT4 anycNM0. SCRT offers the advantages of less acute toxicity and lower costs, and LCRTCT tumor shrinkage and down-staging, with 13–36% pathological complete response (pCR) rates. To improve the efficacy of preoperative treatment both SCRT and LCRTCT have been, or are being, associated with diverse schedules of chemotherapy and even new targeted therapies but without any definitive evidence of benefit. Nowadays, standard treatment is fluoropyrimidine alone since alternative agents and regimens have not been shown to be more active, only more toxic. Conclusions: The EURECCA panel summarized available evidence in an attempt to reduce variance in rectal cancer management. This is expected to benefit patients. Results from ongoing randomized trials will help clarify some of the issues that are still under debate. Ó 2013 Published by Elsevier Ireland Ltd. Radiotherapy and Oncology xxx (2013) xxx–xxx
Even though great progress has been made in rectal and colon cancer management over the past decades, clinical management and outcomes still need to be optimized. Consensus is required since some of the main international guidelines report few, albeit substantial differences in recommendations [1]. A step forward was taken with the publication of a consensus document on managing rectal cancer in 2009 [2]. It was followed by a position paper from the European Registration of Cancer Care (EURECCA) [3] ⇑ Corresponding author. E-mail address: [email protected] (M.A. Gambacorta).
which aimed at standardizing clinical management of colon and rectal cancer care in Europe, aiding doctors in multidisciplinary teams in decision-making and providing benchmarks to enhance the quality of treatment through audits and outcome analyses of population-based registries. The present review will focus on recommendations for patients with rectal cancer especially for selecting between short-course radiotherapy (SCRT) and long-course radio-chemotherapy (LCRTCT) as preoperative treatment as well as on the controversies about adjuvant treatment in patients who received either SCRT or LCRTCT.
0167-8140/$ - see front matter Ó 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.radonc.2013.10.024
Please cite this article in press as: Valentini V et al. EURECCA consensus conference highlights about rectal cancer clinical management: The radiation oncologist’s expert review. Radiother Oncol (2013), http://dx.doi.org/10.1016/j.radonc.2013.10.024
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EURECCA consensus conference: Radiation Oncology perspective
Preoperative radiotherapy treatment schedule: short versus long course The EURECCA conference achieved moderate consensus for algorithms advocating preoperative RT for cT3 anyNM0 disease at presentation. In this frame, agreement was reached on SCRT followed by immediate surgery or LCRTCT with delayed surgery for a mesorectal fascia (MRF) negative presentation in any localization. LCRTCT was recommended, despite lack of definitive evidence that it improved outcomes [4], for MRF+ presentations (irrespective of localization and nodal involvement), in order to achieve tumor shrinkage. For this group of patients, SCRT with delayed surgery should be proposed only if patients were not candidates for the combination with chemotherapy. LCRTCT was recommended for cT4 anycNM0. Although North American guidelines describe LCRTCT as the option of choice for preoperative treatment of cT3-T4N+/ M0 [5], there is no European consensus on this issue [1]. The EURECCA document emphasized global reports of better survival for rectal cancer patients after the introduction of total mesorectal excision (TME) and increased use of preoperative RT [6]. Although an older study had reported a survival gain with SCRT [7], no single randomized trial has observed significantly increased overall survival (OS) after adding either SCRT or LCRTCT to TME. Both regimens improved loco-regional control to about the same extent and had similar effects on OS and long-term toxicity [3,8,9]. Compared with LCRTCT, SCRT is associated with less acute toxicity, and lower costs. LCRTCT has the potential for tumor shrinkage and downstaging, which led to pathological complete response (pCR) rates of 13–36% [10]. On the other hand downsizing, downstaging and even pCR, are seen when surgery is delayed after SCRT [11–13]. In the pre-operative RT setting, randomized trials evaluated administering SCRT followed by surgery vs surgery alone which was eventually followed by postoperative adjuvant RT ± chemotherapy for high-risk presentations [8,14]. The Dutch TME trial randomized 1861 patients to no pre-operative treatment or to SCRT (25 Gy in 5 fractions). At 11.6 years median follow-up, local control (LC) was significantly better in the SCRT group [15]. Even though postoperative RT was mandatory for patients who had received surgery alone and had circumferential resection margin (CRM) involvement of 61 mm (CRM+), only 47% were treated. The MRC C07 trial assigned patients to pre-operative SCRT versus primary surgery. Post-operative LCRTCT was administered to the surgeryalone group when CRMs were involved or threatened (<1 mm). Results showed local control and disease free survival (DFS) were significantly better in the SCRT group, OS did not differ between the groups (HR = 0.91; 0.73–1.13; p = 0.40) [14]. Randomized trials also compared pre- and post-operative LCRTCT administration. In 823 patients Sauer et al. (CAO/ARO/ AIO-94) delivered 50.4 Gy in 28 fractions with concomitant chemotherapy to increase radiosensitivity with a boost of 5.4 Gy in the postoperative arm. At 11 years follow-up the preoperative LCRTCT approach was associated with higher LC, less toxicity and increased sphincter preservation in a subgroup [9,16]. Two randomized trials directly compared SCRT and LCRTCT. In 316 patients with palpable cT3 lesions above the anorectal ring Bujko et al. [4,17] observed no significant differences in LC, DFS and 4-year OS. LC rates were, however, numerically higher (16% vs 11%) in the LCRTCT group. LCRTCT was associated with significantly higher rates of acute toxicity (grade III–IV: 18.2% LCRTCT vs 3.2% SCRT) and pCR (16.1%-LCRTCT vs 0.7%-SCRT), and a lower CRM+ rate (4.4%-LCRTCT vs 13%-SCRT). In the Australia and New Zealand trial Ngan et al. [18] randomized 366 patients with cT3 any N lesions of the middle and lower rectum to SCRT or LCRTCT. Adjuvant chemotherapy was planned for both groups (6 courses
in the SCRT cohort; 4 in the LCRTCT group, which was administered to 85% and 86% of patients, respectively). With a median 5.9 years follow-up, no significant differences were found in OS, late toxicity and distant recurrence rates. The 3-year local recurrence showed no significant difference between the groups (7.5 for SCRT vs 4.4% for LCRTCT; p = 0.24); for tumors at <5 cm from the anal verge there was a trend for reduced local recurrences with the LCRTCT approach (6/48 (12.5%) SCRT patients, and 1/31 (3.2%) LCRTCT; p = 0.21). Interestingly like Bujko et al. [17] pCR and downstaging rates were significantly higher in the LCRTCT group (15%- vs 1%-S CRT; p < 0.01; 45%- vs 28%-SCRT; p = 0.002 respectively). The authors concluded that ‘‘LCRTCT may be more effective in reducing local recurrence for distal tumors . . . and it may be reasonable to suggest a policy that distal . . . tumors be treated with LCRTCT.’’ This conclusion was hotly debated [19,20], as it derived from an unplanned analysis, the results of which were not statistically significant. There are some limitations in the trials conducted by Bujko et al. [19] and Ngan et al. [18]. OS was not the primary end-point, and relatively few patients were accrued. An on-going German study (the so-called ‘‘Berlin study’’), designed to compare SCRT followed by early surgery with LCRTCT, expects to enroll 760 patients with cT2N+/T3Nx disease. Adjuvant chemotherapy is mandatory for all to avoid potential bias [21]. Given the results to date, the EURECCA consensus document contains different viewpoints on preoperative schedules for low seated lesions. In summary, when compared, SCRT and LCRTCT seem to provide similar OS, LC and DFS in patients with intermediate advanced rectal cancer, chiefly cT3MRF . SCRT was associated with less acute toxicity. LCRTCT achieved more downstaging and better pCR and CRM-rates than SCRT with immediate surgery, which is the evidence for recommending LCRTCT for advanced-stage disease (cT3MRF+, cT4) where some degree of downsizing or downstaging is usually needed. Lack of definitive evidence precludes recommending one modality over the other in less advanced stages as consensus was moderate to minimum [3]. Two specific issues play a central role in the preoperative RT setting; pCR induction and CRM status. Response to preoperative treatment is widely debated. Some studies did not show any impact on outcomes [22]. Others reported that when pCR is achieved after preoperative treatment outcomes are greatly better with fewer local recurrences [23,24], and better OS and distant metastases rates, as highlighted by two recent meta-analyses [25,26]. Moreover, to aid the multidisciplinary team in decision-making when difficulties arise because of tumor heterogeneity, Valentini et al. [25] suggested pCR be incorporated as a response parameter into specific predictive nomograms. MRF status has an impact before and after preoperative therapy and may determine choice of schedule. Involved CRM (61 mm) after surgery are associated with high risk of metastases and low survival rates [27,28], as first shown by the Dutch trial results [8,28]. In the Polish trial LCRTCT decreased the CRM+ rates, however, this did not result in lower local recurrence rates, which is likely related to different time intervals to surgery [17]. The Australian and New Zealand trial did not focus on that issue [18]. The consensus conference agreed on the need to distinguish pathological (CRM) and imaging (MRF) findings. Recent studies highlighted the efficacy of Magnetic Resonance Imaging (MRI) in determining MRF involvement at clinical staging [29] which is useful information for selecting the recommended preoperative modality in different situations. Some studies are attempting to overcome some of the drawbacks of both preoperative approaches. In patients with locally advanced rectal cancer, the international phase III trial Rectal Cancer and Pre-operative Induction Therapy Followed by Diligent Operation (RAPIDO) is testing SCRT
Please cite this article in press as: Valentini V et al. EURECCA consensus conference highlights about rectal cancer clinical management: The radiation oncologist’s expert review. Radiother Oncol (2013), http://dx.doi.org/10.1016/j.radonc.2013.10.024
V. Valentini et al. / Radiotherapy and Oncology xxx (2013) xxx–xxx
followed by 6 cycles of capecitabine plus oxaliplatin and then TME vs LCRTCT followed by TME and adjuvant chemotherapy with 8 cycles of capecitabine plus oxaliplatin [30]. Primarily to assess R0 resection rates, the Polish Colorectal Cancer Study Group is randomizing patients to SCRT followed by 3 cycles of 5-fluoruracil, leucovorin and oxaliplatin (FOLFOX4) vs LCRTCT [19]. The Stockholm III trial is randomizing patients to LCRT (without concomitant chemotherapy), SCRT with immediate surgery or SCRT with surgery delayed for up to 8 weeks to determine which option most decreases LR rate, improves tumor regression and reduces toxicity. In a recent interim report on 657 patients, SCRT with immediate surgery was associated with significantly higher postoperative complication rates. Preliminary data on pCR rates showed 0.4% yp-Stage 0 (1/244) after SCRT with early surgery, 9.8% (24/246) after SCRT with delayed surgery and 2% (2/95) after LCRT alone [31,32]. Since not all patients were randomized to all three arms, the Stockholm III trial will probably define the potential of SCRT with delayed surgery rather than compare SCRT directly with LCRT. Concomitant chemotherapy clearly demonstrated to provide better outcomes than LCRT alone. The EORTC 22921 [33] and the FFCD 9203 are the two main studies that randomly evaluated LCRT with or without concomitant chemotherapy. In the EORTC 22921 patients were randomized in a 2 by 2 factorial design, leading to four arms: (1) RT alone without postoperative chemotherapy; (2) LCRTCT without postoperative chemotherapy (3) RT alone with postoperative chemotherapy; (4) LCRTCT with postoperative chemotherapy. The FFCD 9203 randomized patients to receive preoperative LCRT vs LCRTCT; postoperative chemotherapy was administered to all patients. In both studies no differences emerged in DFS or OS, while LC and pCR rates were significantly better in the preoperative LCRTCT arm in the FFCD 9203 trial [34] and in all three arms that received chemotherapy in the EORTC 22921 trial [33]. Adding chemotherapy clearly increased acute toxicity and worsened long-term quality of life [35,36]. Braendengen et al. randomized 207 patients with cT4 or recurrent lesions to induction LCRT alone or with concomitant chemotherapy. The latter group also received adjuvant chemotherapy for 16 weeks. LCRTCT improved LC (82% vs 67% at 5 years, p = 0.03), R0 resection rates (84% vs 68%, p = 0.009), pCR (16% vs 7%, p = 0.04) and cancer-specific survival (72% vs 55% at 5 years, p = 0.02), but not OS (66% vs 53%, p = 0.09) [37]. Again, the gain comes at the price of more acute toxicity and, unfortunately, probably also more late toxicity [35,37]. To improve LCRTCT efficacy new combinations of chemotherapy agents are under evaluation. Fluorouracil associated with oxaliplatin provided conflicting, albeit mostly negative results. Two major randomized trials showed no increase in pCR rates: the STAR-01 (on 747 patients) found 16% of pCR with or without oxaliplatin [38]; the ACCORD 12/0405 PRODIGE 2 (on 598 patients) found a non-significant improvement (13.9% vs 19.2%; p = 0.09) [39]. Toxicity rates were increased in the oxaliplatin arms. On the other hand, the German CAO/ARO/AIO-04 (on 1265 patients) showed a significant improvement in pCR rates (13% vs 17%; p = 0.038) with no significant differences in toxicity profiles [40]. The number of patients in the French study may have impacted upon statistical significance. Finally, the preliminary results of the European PETACC-6 study with 1094 patients did not detect any improvement in outcome, and once again reported more toxicity [41]. The conclusion to be made from these four randomized phase III trials is that the addition of oxaliplatin does not improve pCR rates. New molecular targeted antibodies like cetuximab or bevacizumab may also be combined with SCRT and sequential chemotherapy [42] or with LCRTCT, and are under evaluation but definitive evidence that they improve efficacy is lacking [43,44].
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Another strategy to strengthen LCRTCT is to increase the dose with an external beam concomitant RT boost or with a sequential brachytherapy boost [45,46]. At present the INTERACT study is determining whether this approach, and consequent shortening of the overall duration of preoperative RT, increases tumor response [47]. In summary, adding chemotherapy to LCRT improves LC at the expense of more toxicity. Gains might be greater in locally advanced rather than intermediate rectal cancer. At present, standard treatment is fluoropyrimidine alone since alternative agents and regimens have not been shown to be more active, only more toxic.
Adjuvant postoperative treatment The EURECCA document concluded with minimum or moderate consensus on the use of adjuvant chemotherapy (ADCT) for malignancies with high-risk features (e.g. poor grade, blood or lymphatic vessel invasion, unclear margins), nodal involvement, or a positive CRM. No consensus was reached on adjuvant therapy for confirmed ypT3pN0 CRM following preoperative RT or RTCT. It is recommended that the final choice about ADCT should be made by the multidisciplinary team because trials have not shown that it offers any clear clinical advantage, whereas a common belief is that it does, similar to the situation after colon cancer surgery. In fact, neither of the two main randomized trials found a survival advantage for patients who received ADCT [33,34] and, although a recent pooled analysis confirmed better LC, it also failed to find any improvement in OS [48]. Remarkably, the global rates of patients that actually received full dose ADCT in the EORTC and FFCD trials were low which may account for the obtained results. Furthermore, in daily clinical practice, up to 20% of patients did not receive ADCT because of comorbidities, physician refusal or other reasons [49]. As the EURECCA consensus document indicates, nomograms are suggested to aid the multidisciplinary team in decision-making about different presentations in daily practice. Valentini et al. [25] recently proposed a nomogram with data and features that had been extrapolated from a pooled analysis of randomized trials and externally validated on a different database. Balancing the weight of each feature (including ADCT) according to its global relevance for outcome, it was able to predict events in terms of OS, LC and distant progression [25]. Anyway, the EURECCA panel of expert did not find a consensus in recommending its use in all situations, taking into account the patient selection in the randomized studies pooled for the analysis. There was no wide consensus on administration of postoperative LCRT if disease had been confirmed as pT3pN /+. Particularly for CRM+, minimum consensus was reached for the recommendation to administer LCRTCT postoperatively. The problem was already raised by the Dutch and MRC CR07 trials [8,14] which highlighted that using postoperative RT/RTCT in attempts to improve prognosis associated with involved or threatened margins still resulted in poor outcomes. Indeed, this was also the main finding of the old Uppsala trial.
Conclusion The EURECCA panel summarized available evidence in an attempt to aid decision-making in clinical practice by reducing variance in rectal (and colon) cancer management in European countries. This is expected to benefit patients. Results from ongoing randomized trials will help clarify at least some of the issues that are still under debate.
Please cite this article in press as: Valentini V et al. EURECCA consensus conference highlights about rectal cancer clinical management: The radiation oncologist’s expert review. Radiother Oncol (2013), http://dx.doi.org/10.1016/j.radonc.2013.10.024
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EURECCA consensus conference: Radiation Oncology perspective
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Please cite this article in press as: Valentini V et al. EURECCA consensus conference highlights about rectal cancer clinical management: The radiation oncologist’s expert review. Radiother Oncol (2013), http://dx.doi.org/10.1016/j.radonc.2013.10.024