The role of induction chemotherapy in the treatment of locally recurrent rectal cancer D. M. G. I. van Zoggel
The role of induction chemotherapy in the treatment of locally recurrent rectal cancer Desley M. G. I. van Zoggel
Colofon The role of induction chemotherapy in the treatment of locally recurrent rectal cancer. Thesis, Maastricht University, the Netherlands 2022. DMGI van Zoggel, 2022, the Netherlands. ISBN 978-94-6458-599-5 Cover design and layour © evelienjagtman.com Printed by Ridderprint No parts of this thesis may be reproduced without prior permission of the author.
The role of induction chemotherapy in the treatment of locally recurrent rectal cancer PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit Maastricht, op gezag van Prof. dr. Pamela Habibović, Rector Magnificus, volgens het besluit van het College van Decanen, in het openbaar te verdedigen op dinsdag 11 oktober 2022 om 10:00 uur door Desley Maria Gijsberta Ingrid van Zoggel geboren op 14 juni 1991 te Veghel
PROMOTIECOMMISSIE Promotor Prof. dr. H.J.T. Rutten Copromotores Dr. G.A.P. Nieuwenhuijzen, Catharina Ziekenhuis, Eindhoven Dr. M. Kusters, Amsterdam Universitaire Medische Centra, Amsterdam Beoordelingscommissie Prof. dr. I.H.J.T. de Hingh (Voorzitter) Prof. dr. A.P. de Bruïne Prof dr. E.J. Schoon Dr. W. Setz-Pels, Catharina Ziekenhuis, Eindhoven Dr. R.G. Orsini, Elisabeth Tweesteden Ziekenhuis, Tilburg
Contents Chapter 1 General introduction and outline of the thesis 9 Chapter 2 Preliminary results of a cohort study of induction chemotherapy-based treatment for locally recurrent rectal cancer 19 DMGI vanZoggel, SJBosman,MKusters,GAPNieuwenhuijzen, JS Cnossen, GJ Creemers, G van Lijnschoten, HJT Rutten Br J Surg. 2018 Mar;105(4):447-452 Chapter 3 Improved outcomes for responders after treatment with induction chemotherapy and chemo(re)irradiation for locally recurrent rectal cancer 33 ELKVoogt, DMGI vanZoggel,MKusters, GAPNieuwenhuijzen, JG Bloemen, HMU Peulen, GJ Creemers, G van Lijnschoten, J Nederend, MJ Roef, JWA Burger, HJT Rutten Ann Surg Oncol. 2020 Sep;27(9):3503-3513 Chapter 4 Local recurrence in the lateral lymph node compartment: improved outcomes with induction chemotherapy combined with multimodality treatment 55 MKusters, SJBosman,DMGI vanZoggel,GAPNieuwenhuijzen, GJ Creemers, HA vd Berg, HJT Rutten Ann Surg Oncol. 2016 Jun;23(6):1883-9 Chapter 5 Impact of a history of metastases or synchronous metastases on survival in patients with locally recurrent rectal cancer 71 DMGI vanZoggel, ELKVoogt,MKusters, GAPNieuwenhuijzen, JS Cnossen, GJ Creemers, G van Lijnschoten, J Nederend, MJ Roef, JWA Burger, HJT Rutten Colorectal Dis. 2021 May;23(5):1120-1131 Chapter 6 MRI tumour regression grade in locally recurrent rectal cancer 99 ELK Voogt, S Noordkamp, DMGI van Zoggel, AW DaniëlsGooszen, GAP Nieuwenhuijzen, JG Bloemen, GJ Creemers, JS Cnossen, G van Lijnschoten, JWA Burger, HJT Rutten, J Nederend BJS Open. 2022 May;6(3):zrac033
Chapter 7 Metabolic positron emission tomography/CT response after induction chemotherapy and chemo(re)irradiation is associated with higher negative resection margin rate in patients with locally recurrent rectal cancer 119 DMGI van Zoggel, ELK Voogt, G van Lijnschoten, JS Cnossen, GJ Creemers, J Nederend, JG Bloemen, GAP Nieuwenhuijzen, JWA Burger, SGGF Lardenoije, HJT Rutten, MJ Roef Colorectal Dis. 2022 Jan;24(1):59-67 Chapter 8 Summary, discussion and future perspectives 139 Chapter 9 Scientific and societal impact 153 Appendix Curriculum vitae 161 Dankwoord 165
Chapter 1 General introduction and outline of the thesis
Introduction and outline 11 CHAPTER 1 Introduction Treatmentofrectalcancerhasundergonemajorchangesovertheyears.Themanagement of primary rectal cancer has evolved from only surgical options to a multidisciplinary treatment with improved chances of cure for every stage of the disease. For every stage treatment goals are set and clear and a paradigm shift from a surgical resection to organ preservation in selected cases has occurred.1 Despite better neoadjuvant and surgical treatment in primary rectal cancer, local recurrence still occurs in 5-10 percent of patients.2,3 For those patients with locally recurrent rectal cancer (LRRC), treatment options and oncological outcomes have not changed as drastically. Still, most of the patients who develop a local recurrence will die of progressive disease and cure is only possible for a minority.4 Surgery with clear resection margins is the single most important factor influencing survival. This often involves extended pelvic resections with significant loss of function.5 Treatment principles for primary rectal cancer cannot simply be extrapolated to LRRC and for a better understanding, it is important to realize the differences between these two conditions. A primary rectal cancer originates de-novo following the well accepted sequence from polyp to carcinoma-in-situ tomalignant tumour. A local recurrence does not follow this natural sequence but is rather an outgrowth of persisting tumour cells after resection of the primary tumour. Whereas in de-novo origination it takes a long time for mutations to lead to malignant cells, in local recurrence malignant cells are already present and can therefore progress to a solid tumour in a relatively short time span. Theoretically, these cells can be more treatment resistant as they already have survived the primary tumour treatment principles. The development of metastases is a late event in primary rectal cancer, leaving a wide windowtoperforma curative treatment beforemetastases occurs. Evenafter successful treatment of the local recurrence, themajority of patients with LRRCwill die because of early development of metastatic disease. A possible explanation could be that in these cases, development of metastases does not happen after invasion of cancer cells into lymphatic tissue and blood vessels, but instead this process may have already started at the time of the primary tumour. It evenmay be argued that LRRC could in some cases be a manifestation of metastatic disease. Locally recurrent rectal cancer is not a new tumour. The aetiology of LRRC can be explained as a failure to eradicate the primary tumour completely, therefore being a failure of treatment. The quality of the primary surgery contributes to the development of LRRC. In the past, recurrence rates approaching 40 percent have been reported.6
Chapter 1 12 Significant improvements have been implemented in the surgical technique and total mesorectal excision has become the gold standard. Better surgical treatment, and the introduction of preoperative radiotherapy has led to a decrease in recurrence rates to 5-10 percent.3 Irradical resection, leaving tumour cells in the circumferential or distal resection margins, as well as incomplete resection of the mesorectum, have been identified as poor quality markers.7 Japanese studies have focused on the presence of positive lymph nodes in the lateral obturator and iliac fossae as a potential reason for local recurrence. It has been shown that most of these lymph nodes will be sterilized by pelvic external beam irradiation or chemoradiation.8 However, there is a renewed interest in these lymph nodes and their role in the aetiology of LRRC. Recent studies have shown that a substantial portion is not being eradicatedwith preoperative treatment, thus possibly needing surgical resection to lower the risk of lateral sidewall recurrences.9–11 Another pathway of development of local recurrence is exfoliation of tumour cells into the lumen.12 Migration of exfoliated tumour cells in peri-anastomotic abscesses or entrapment of these cells in the anastomosis can cause regrowth.13 Spillage of tumour cells in the operative field can be caused by advanced tumours breaking through the peritoneal surface, or by improper handling of the specimen during surgery.14 This type of recurrence follows the lining of abscesses or fistulas, or behaves in a multifocal pattern and can present as pelvic peritoneal carcinomatosis. Rarely, a recurrence is limited to the anastomosis itself, and more often the bulk of the recurrence lies perianastomotically. Regarding the treatment of LRRC, achieving a resectionwith clear margins is the single most important prognostic factor influencing survival. Achieving clear margins often presents a large challenge for the surgeon, and not achieving this can be considered as treatment failure. From an anatomical point of view, the pelvis is a dense structure comprising different compartments holding organs and structures.15 Modern rectal cancer surgery is based on removal of the rectal compartment with its mesorectal fascial lining and complete mesorectum by a so called total mesorectal excision (TME). After this kind of surgery for the primary tumour, the borders of these pelvic compartments have been distorted and even a solitary recurrence is likely to involve multiple compartments. To still achieve clear margins, resection will require extended procedures, and often an exenteration including resection of neural or bony structures is necessary. En-bloc resection and subsequent reconstruction can involve different specialties with extensive experience in this field.
Introduction and outline 13 CHAPTER 1 Inorder tomaximize the ability toachieve clearmargins, neoadjuvant treatment options inLRRCare explored. In locally advanced primary rectal cancer, the role of preoperative chemoradiotherapy to downsize and downstage the tumour is already established. In most LRRC patients who are radiotherapy naive, full course of chemoradiotherapy will also be applied. In LRRC patients who have already received chemoradiotherapy for their primary tumour, the discussion is still ongoingwith regard to reirradiation.16 These local recurrences originate fromcancer cellswho have persisted after radiotherapy and may be considered more radiotherapy resistant. Previously irradiated healthy pelvic tissuewill impose dose limitations on reirradiation. The administration of reirradiation doses ranging from 30-40 Gy has proved to be feasible.17,18 However, these doses are considered too low to eradicate potentially radioresistant cancer cells. Some centres have opted not to use reirradiation to avoid the potential side effects of possibly even ineffective reirradiation, and go straight to surgery.19 Other centres seek to overcome the dose limitations combining limited external beam reirradiation with a relatively high intraoperative boost, while shielding sensitive tissues.20 The radiobiological equivalent of a single high boost is three times as high as a comparable fractionated dose. The combined external and intraoperative local dose at the area of risk can reach between 70-90 Gy. An intraoperative boost can be delivered with a dedicated electron beam accelerator or by means of high dose rate brachytherapy equipment. Evaluation of the tumour by MRI is pivotal for the surgical treatment planning in primary rectal cancer. It enables delineation of the tumour extension in relation to the mesorectal fascia,whichwill beremovedduringTMEsurgery. Incaseof closeor involved margins chemoradiotherapy will be used to downsize and downstage the tumour in order to be able to achieve clear resection margins. In LRRC interpretation of the MRI is hindered by postoperative changes, possible infectious complications or alterations in tissue after radiotherapy, all leading to more extensive fibrosis. Furthermore, the growth patternmay bemore spiculated rather than solid in this fibrotic tissue. A straight delineation of the mesorectal fascia like in primary cancer is absent and therefore the radiologist cannot simply state if the circumferential resectionmarginwill be involved. Radiologists and surgeons have to join forces in order to plan the extent of surgery required to achieve clear resection margins. In locally advanced primary rectal cancer a new concept of usage of chemotherapy has been developed in order to treat micrometastases more effectively. The classic treatment with chemoradiotherapy and surgery followed by chemotherapy was compared to chemoradiotherapy followed by chemotherapy and then proceeding to surgery. A much higher pathological complete response rate was found in the experimental arm of 36 percent versus 21 percent in the classic treatment arm,
Chapter 1 14 showing that local response of the tumour may also be amplified with this approach.21 The RAPIDO study, which randomized between short course radiotherapy followed by chemotherapy versus chemoradiotherapy, both followed by surgery, confirmed the increased local response rates, and also a reduction of development of metastases.22 Both studies did not show a survival benefit. The recent publication of the PRODIGE 23 study confirmed prior findings and noted a trend towards improved overall survival.23 All these studies showed that this total neoadjuvant approach was feasible in locally advanced primary rectal cancer without significant increase of morbidity, and might lead to an improved oncological outcome. In this thesis the principle of introducing total neoadjuvant treatment in the management of LRRC is investigated.
Introduction and outline 15 CHAPTER 1 Outline of the thesis In chapter 1 the typical features of LRRC are explained in comparison with locally advanced primary rectal cancer. The importance of achieving resection with clear margins is highlighted. Treatment options are discussed and the concept of total neoadjuvant treatment is introduced. In chapter 2 the concept of induction chemotherapy is investigated by comparing a cohort of LRRCpatientswhohave received inductionchemotherapybefore reirradiation to a cohort which only received preoperative reirradiation before surgery for their local recurrence. In chapter 3 the impact of introducing this treatment with induction chemotherapy in LRRC on clear resection margin rate and pathological response is further analysed. Lateral sidewall recurrences are notoriously difficult to treat due to their possible fixation to the muscular sidewall, iliac vessels and neuroplexus. Preliminary data on the effect of induction chemotherapy on resectability and downstaging in these cases are presented in chapter 4. Chapter 5 evaluates the impact of having hadmetastases in the past or havingmetastases at the time of LRRCdiagnosis, in comparison to LRRC patients who never hadmetastases. If response to neoadjuvant treatment becomes a treatment goal, evaluation of response is also necessary. In primary rectal cancer response evaluation has become important not only for surgical treatment planning, but also for selection of patients for organ preservation approach. The combination of endoscopy and MRI is a reliable to evaluate response in rectal cancer. The situation in LRRC is different as endoscopy is not always possible after prior abdominoperineal resection, and even if endoscopy would be possible, the bulk or complete local recurrence is not visible intraluminally. Imaging in LRRC becomes more important, but is hampered by postoperative changes and fibrosis. In chapter 6 mrTRG after induction chemotherapy and chemo(re)irradiation is correlated with final pathology. In chapter 7 the contribution of PET/CT in response evaluation after induction chemotherapy is analysed. Chapter 8 is the closing chapter with discussion of the findings and speculation on future perspectives. A short summary of all chapters is also provided in chapter 8.
Chapter 1 16 References 1. van der Valk MJM, Hilling DE, Bastiaannet E, et al. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet. 2018;391:2537–2545. 2. Kapiteijn E, Marijnen CAM, Nagtegaal ID, et al. Preoperative Radiotherapy Combined with Total Mesorectal Excision for Resectable Rectal Cancer. N Engl J Med. 2001;345:638–646. 3. van Gijn W, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of themulticentre, randomised controlles TME trial. Lancet Oncol. 2011;12:575–582. 4. Detering R, Karthaus EG, Borstlap WAA, et al. Treatment and survival of locally recurrent rectal cancer: A cross-sectional population study 15 years after the Dutch TME trial. Eur J Surg Oncol. 2019;45:2059–2069. 5. MatsuyamaT, Yamauchi S,MasudaT, et al. Treatment and subsequent prognosis in locally recurrent rectal cancer: a multicenter retrospective study of 498 patients. Int J Colorectal Dis. 2021;36:1243– 1250. 6. Kapiteijn E, Van de Velde CJH. The role of total mesorectal excision in the management of rectal cancer. Surg Clin North Am. 2002;82:995–1007. 7. Nagtegaal ID, Velde CJH van de, Worp E van der, et al. Macroscopic Evaluation of Rectal Cancer Resection Specimen: Clinical Significance of the Pathologist in Quality Control. https://doi. org/101200/JCO200207010. 2016;20:1729–1734. 8. Kusters M, Beets GL, Van De Velde CJH, et al. A comparison between the treatment of low rectal cancer in japan and the netherlands, focusing on the patterns of local recurrence. Ann Surg. 2009;249:229–235. 9. Kusters M, Uehara K, Velde CJHV De, et al. Is There Any Reason to Still Consider Lateral Lymph Node Dissection in Rectal Cancer? Rationale and Technique. Clin Colon Rectal Surg. 2017;30:346– 356. 10. Ogura A, Konishi T, CunninghamC, et al. Neoadjuvant (chemo)radiotherapy with total mesorectal excision only is not sufficient to prevent lateral local recurrence in enlarged nodes: Results of the multicenter lateral node study of patients with low ct3/4 rectal cancer. J Clin Oncol. 2019;37:33–43. 11. Ogura A, Konishi T, Beets GL, et al. Lateral Nodal Features on Restaging Magnetic Resonance Imaging Associated with Lateral Local Recurrence in Low Rectal Cancer after Neoadjuvant Chemoradiotherapy or Radiotherapy. JAMA Surg. 2019;154:1–8. 12. K O, S S, Y K, et al. A prospective clinical study assessing the presence of exfoliated cancer cells and rectal washout including tumors in patients who receive neoadjuvant chemoradiotherapy for rectal cancer. Surg Today. 2020;50:352–359. 13. SW, J L, SW, et al. Adverse Effects of Anastomotic Leakage on Local Recurrence and Survival After Curative Anterior Resection for Rectal Cancer: A Systematic Review and Meta-analysis. World J Surg. 2017;41:277–284. 14. Nagtegaal ID, Quirke P. What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol. 2008;26:303–312. 15. Rokan Z, Simillis C, Kontovounisios C, et al. Systematic review of classification systems for locally recurrent rectal cancer. BJS open.;5 . Epub ahead of print 2021. DOI: 10.1093/bjsopen/zrab024. 16. SuskoM, Lee J, Salama J, et al. TheUse of Re-irradiation inLocallyRecurrent, Non-metastaticRectal Cancer. Ann Surg Oncol. 2016;23:3609–3615.
Introduction and outline 17 CHAPTER 1 17. Bosman SJ, Holman FA, Nieuwenhuijzen GAP, et al. Feasibility of reirradiation in the treatment of locally recurrent rectal cancer. Br J Surg. 2014;101:1280–1289. 18. Van Der Meij W, Rombouts AJM, Rutten H, et al. Treatment of Locally Recurrent Rectal Carcinoma in Previously (Chemo)Irradiated Patients: A Review. Dis Colon Rectum. 2016;59:148–156. 19. Lee DJK, Sagar PM, Sadadcharam G, et al. Advances in surgical management for locally recurrent rectal cancer: How far have we come? World J Gastroenterol. 2017;23:4170–4180. 20. Calvo FA, Sole C V., Rutten HJ, et al. ESTRO/ACROP IORT recommendations for intraoperative radiation therapy in locally recurrent rectal cancer. Clin Transl Radiat Oncol. 2020;24:41–48. 21. Cercek A, Roxburgh CSD, Strombom P, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMAOncol.;4 . Epub aheadof print 2018. DOI: 10.1001/jamaoncol.2018.0071. 22. Bahadoer RR, Dijkstra EA, van Etten B, et al. Short-course radiotherapy followed by chemotherapy before totalmesorectal excision (TME) versus preoperative chemoradiotherapy, TME, andoptional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22:29–42. 23. Conroy T, Bosset JF, Etienne PL, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCERPRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22:702–715.
Chapter 2 Preliminary results of a cohort study of induction chemotherapy-based treatment for locally recurrent rectal cancer DMGI van Zoggel, SJ Bosman, M Kusters, GAP Nieuwenhuijzen, JS Cnossen, GJ Creemers, G van Lijnschoten, HJT Rutten Br J Surg. 2018 Mar;105(4):447-452
Abstract Background A significant number of patients treated for locally recurrent rectal cancer have local or systemic failure, especially after incomplete surgical resection. Neoadjuvant treatment regimens in patients who have already undergone preoperative (chemo)radiotherapy for the primary tumour are limited. The objective of the present study was to evaluate the influence of a neoadjuvant regimen incorporating induction chemotherapy (ICT) in patientswith locally recurrent rectal cancerwhohadpreoperative (chemo)radiotherapy for the primary cancer or an earlier local recurrence. Methods Patients were treated with a sequential neoadjuvant regimen including three or four cycles of 5-fluorouracil and oxaliplatin-containing chemotherapy.When no progressive disease was found at evaluation, neoadjuvant treatment was continued with chemoradiation therapy (CRRT) using 30 Gy with concomitant capecitabine. If there was a response to ICT, the patient was advised to continuewith systemic chemotherapy after CRRT as consolidation chemotherapy while waiting for resection. These patients were compared with patients who received CRRT alone in the same time interval. Results Of 58 patients who had ICT, 32 (55 percent) had surgery with clear resection margins, of whom ten (17 percent) exhibited a pathological complete response (pCR). The remaining 26 patients had 23 R1 and three R2 resections. In 71 patients who received CRRT, a similar rate of R0 (35 patients) and R1 (36) resection was found (P = 0.506), but only three patients (4 percent) had a pCR (P = 0.015). Conclusion The incorporation of ICT in neoadjuvant regimens for locally recurrent rectal cancer is a promising strategy.
Induction chemotherapy in locally recurrent rectal cancer 21 CHAPTER 2 Introduction Despite better preoperative and surgical treatment of rectal cancer, the incidence of locally recurrent rectal cancer remains approximately 5–10 percent.1 Unlike primary rectal cancer, local recurrence is not confined to a well-defined surgical compartment, and multicompartment exenterative procedures are often required to achieve clear resection margins.2–4 Preoperative treatment is used to downsize the tumour and facilitate surgical resection. However, because most patients have received preoperative (chemo)radiotherapy for their primary rectal cancer, the possible modalities in recurrent disease are limited. Whether these patients can be reirradiated safely is still debated.5 Despite the fact that chemoradiation therapy (CRRT) cannot be considered standard therapy in the management of patientswith previously irradiated locally recurrent rectal cancer, it has beendemonstrated6–9 that reirradiationwitha limiteddoseof 30–39Gyandconcomitant chemotherapy can be applied safely and effectively in locally recurrent disease. Even after reirradiation, incomplete resection remains a problem in a significant number of patients. The most important positive prognostic factor for recurrent rectal cancer appears to be radical resection with clear margins (R0).4,10,11 Early development of metastatic disease is quite commonwhen local recurrence has occurred.12 Even after successful treatment of local recurrence, development of systemic disease remains the principal cause of death.13 This finding indicates the importance of administering systemic chemotherapy early in the treatment. The use of induction chemotherapy (ICT) as part of the preoperative management of patients with locally recurrent rectal cancer may offer several advantages. First, systemic treatment might improve resectability by a significant downsizing and downstaging effect, as shown in primary colorectal cancer.14,15 Second, ICT may lead to an increased rate of pathological complete response (pCR) and thus possibly better overall survival. Finally, it might prevent early metastatic disease or offer the best palliative treatment in the meantime, and prevent extensive surgical morbidity.
Chapter 2 22 Methods Details of all patients with locally recurrent rectal cancer who underwent a resection at CatharinaHospital, a national tertiary referral centre for locally recurrent rectal cancer, between January 2010 and December 2016 were collected in a prospective database and reviewed retrospectively. A cohort of patients who had undergone reirradiation were selected, including thosewhohad full-course radiotherapy for either their primary tumour or a previous local recurrence. Patients with unresectable distant metastatic disease at presentation were excluded. At the start, these patients were deemed unresectable with regard to achieving clear margins; later, more ‘regular’ patients with locally recurrent disease were also selected. Patients who did not receive ICT but only concurrent CRRT, were used to compare the primary endpoints of pCR, clear margin (R0) rate, overall survival (OS), local recurrence-free survival (LRFS) and metastasisfree survival (MFS). Treatment and imaging regimen The general treatment regimen for the ICT group (Figure 1) consisted of three cycles of CAPOX (capecitabine and oxaliplatin) or four cycles of FOLFOX (leucovorin, fluorouracil and oxaliplatin), after which tumour response was evaluated by MRI and/or PET–CT. The presence of systemic disease was evaluated with CT or PET-CT. Referring hospitals were advised to administer three cycles before CRRT. When a good response was noted, continuation of chemotherapy with three cycles of consolidation chemotherapy in the waiting time after CRRT was advised. Some patients received six cycles of chemotherapy before CRRT. If no response to the first three cycles was noted, consolidation chemotherapywas considered not to be useful when administered in the waiting period. CRRT consisted of 30–30.4 Gy in fractions of 2–1.8 Gy with concomitant capecitabine (825mg/m2 twice daily) in all patients. Resectability and timing of surgery The waiting period between radiotherapy and surgery was generally 8–10 weeks. The tumour was restaged with MRI one month after the last radiotherapy administration to determine response and local resectability, and metastatic disease was excluded by CT or PET–CT. All patients were discussed in a multidisciplinary board meeting, and two senior surgeons with 20 years of experience in recurrent rectal cancer surgery performed all resections, as described previously.16
Induction chemotherapy in locally recurrent rectal cancer 23 CHAPTER 2 Figure 1. Treatment flow chart for induction chemotherapy (ICT) Staging with MRI and PET/CT or CT 3 cycles of CAPOX ICT or 4 cycles of FOLFOX ICT Restaging with MRI and PET/CT or CT Locally unresectable or unresectable distant metastases Palliation No response CRRT Response Another 3-4 cycles of ICT CRRT CRRT 3-4 cycles for consolidation Restaging with MRI and PET/CT or CT Surgery Thirteen patients had ICT and consolidation therapy, 15 had all (full-course) chemotherapy cycles before chemoradiation therapy (CRRT) and 30 had only ICT and no consolidation therapy (for exact type of chemotherapy see Table S1, supporting information). Fourteen patients entered the palliative path. CAPOX capecitabine and oxaliplatin; FOLFOX leucovorin, fluorouracil and oxaliplatin.
Chapter 2 24 Pathology All specimens were revised by a single pathologist trained as a total mesorectal excision pathologist, andwith particular expertise in evaluating recurrent rectal cancer specimens using theMandard classification.17 pCRwas defined as the absence of tumour residue (Mandard score 1). Margin status was classified as either microscopic (R1) or macroscopic (R2) tumour present in the resection margin, or a tumour-free resection margin (R0). Patients with a pCR were classified as R0, but were analysed as a separate group to determine differences from R0 resections with and without pCR in survival curves. Statistical analysis To compare individual variables, t tests and χ2 tests were used when appropriate. OS for resected patients was calculated as the time interval between the date of resection of the recurrence and the date of last follow-up or death. LRFS was calculated as the time interval between the date of recurrence resection and the date of histological or evident radiological presence of a local rerecurrence. MFS was calculated as the time interval between the date of recurrence resection and the date of histological or evident radiological presence of distantmetastasis. OS, LRFS andMFSwere estimated using the Kaplan–Meier method, with differences assessed with the log rank test. Statistical analysis was performed using SPSS® version 23 forWindows® (IBM, Armonk, NewYork, USA). Sample size calculationswere donewith Power and Precision™ release 4.1 2012 (Biostat, Englewood, New Jersey, USA).
Induction chemotherapy in locally recurrent rectal cancer 25 CHAPTER 2 Results During the selected time frame, ICT was incorporated into the multimodality management of 58patients, and71 patients receivedconcurrent CRRTalone. Patient and neoadjuvant treatment characteristics are shown inTable 1. Apart fromsex differences, there were no significantly different characteristics between the two groups. Table 1. Patient and neoadjuvant treatment characteristics for all resected patients ICT + CRRT CRRT alone P-value N = 58 N = 71 Age (years)* 64 (33-76) 65 (30-84 0.297 Sex ratio (M:F) 46:12 40:31 0.006 Stage of primary tumour† 0 1 (2) 1 (1) 0.080 I 3 (5) 13 (19) II 13 (22) 19 (27) III 35 (60) 35 (50) IV 6 (10) 2 (3) (Neo)adjuvant treatment for primary tumour None/chemotherapy alone‡ 4 (7) 5 (7) 0.697 Radiotherapy (5x5 Gy) 22 (38) 32 (45) Chemoradiotherapy 32 (55) 34 (48) History of metastases§ No 40 (69) 55(78) 0.276 Yes 18 (31) 16 (23) Type of primary surgery Hartmann procedure 3 (5) 2 (3) 0.073 Rectosigmoid resection 2 (3) 0 (0) Low anterior resection 27 (47) 38 (54) Abdominoperineal/ abdominosacral resection 23 (40) 22 (31) Total exenteration 3 (5) 2 (3) Other/unknown 0 (0) 7 (10) Local recurrence First 51 (88) 65 (92) 0.570 Second 6 (10) 4 (6) Third 1 (2) 2 (3) Values in parentheses are percentages unless indicated otherwise; *values are median (range). †Information on the primary tumour could not be retrieved for one patient in the chemoradiation therapy (CRRT) group. ‡These patients did receive full-course radiotherapy for a previous recurrence. § Metachronous or synchronous resectable metastases. ‡χ2 test, except §t test ICT induction chemotherapy.
Chapter 2 26 In general, local recurrences occurred within the first 3 years after resection of the primary tumour, with amedian interval of 32 (range 5–201)months for first recurrences and of 17 (range 8–52) months between previous recurrence surgery and index surgery for second and third recurrences. Of the 58 patients in the ICT group, ten required a dose reduction during ICT and six during their CRRT. Four patients in this group were hospitalized during ICT, and one patient during CRRT. In the CCRT-only group, one patient required dose reduction, and four had to be hospitalized. Postoperative complications (Clavien–Dindo grade III–IV) were comparable between groups: 13 (22 percent) in the ICT group and 19 (27 percent) in the CRRT group (P = 0.715). Clear margin and pathological complete response rates Patients who received ICT had a similar R0 resection rate to those who had CRRT alone (55 versus 49 percent respectively; P = 0.506), but exhibited a significantly increased pCR rate (17 versus 4 percent; P = 0.015) (Table 2). The remaining 26 patients in the ICT arm had 23 R1 and three R2 resections, and the 36 remaining in the CRRT-alone arm all had an R1 resection. Table 2. Pathological responses of patients in induction chemotherapy and chemoradiation therapyalone groups ICT + CRRT CRRT alone P-value Total N = 58 N = 71 N = 129 R0 32 (55) 35 (49) 0.506 67 (51.9) pCR 10 (17) 3 (4) 0.015 13 (10.1) Values in parentheses are percentages. ICT induction chemotherapy; CRRTchemoradiation therapy; R0 complete resection; pCRpathological complete response. Overall survival The 3-year OS rate for the 129 patients was 44 percent (median survival 27months), 92 percent in patients who had a pCR, 54 percent in thosewith an R0 resection but no pCR, and 32 percent in patients who had an R1/R2 resection (P = 0.012) (Figure 2). In the ICT group, patients who had a pCR were all alive at the end of follow-up, whereas those with R0 but no pCR or margin-positive patients had a median survival of 23 months (P = 0.039). There were only three R2 resections in the ICT group, and none in the CRRT group; therefore, no separate analyses for resection state were performed. In the CRRT group, only three patients achieved a pCR, so the numbers were too small to perform statistical comparisons; however, one patient with a pCR died from another cause at 10 months.
Induction chemotherapy in locally recurrent rectal cancer 27 CHAPTER 2 Figure 2. Kaplan–Meier curve for overall survival in all resected patients based on pathological outcome. D. M. G. I. van Zoggel, S. J. Bosman, M. Kusters, G. A. P. Nieuwenhuijzen, J. S. Cnossen, G. J. Creemerset al. mine differences from R0 resections with and within survival curves. al analysis are individual variables, t tests and χ2 tests were en appropriate. OS for resected patients was cals the time interval between the date of resection currence and the date of last follow-up or death. as calculated as the time interval between the date ence resection and the date of histological or eviological presence of a local rerecurrence. MFS was d as the time interval between the date of recurection and the date of histological or evident radipresence of distant metastasis. OS, LRFS andMFS mated using the Kaplan–Meier method, with difassessed with the log rank test. cal analysis was performed using SPSS ® version indows ® (IBM, Armonk, New York, USA). Samalculations were done with Power and Precision™ 1 2012 (Biostat, Englewood, New Jersey, USA). he selected time frame, ICT was incorporated multimodality management of 58 patients, and nts received concurrent CRRT alone. Patient and ant treatment characteristics are shown inTable 1. om sex differences, there were no significantly characteristics between the two groups. eral, local recurrences occurred within the first fter resection of the primary tumour, with a interval of 32 (range 5–201) months for first ces and of 17 (range 8–52) months between preurrence surgery and index surgery for second and urrences. Of the 58 patients in the ICT group, red a dose reduction during ICT and six during RRT. Four patients in this group were hospitalng ICT, and one patient during CRRT. In the nly group, one patient required dose reduction, had to be hospitalized. Postoperative compliClavien–Dindo grade III–IV) were comparable groups: 13 (22 per cent) in the ICT group and 19 ent) in the CRRT group (P=0⋅715). argin and pathological complete response who received ICT had a similar R0 resection rate who had CRRT alone (55versus 49 per cent respec- =0⋅506), but exhibited a significantly increased e (17 versus 4 per cent; P=0⋅015) (Table 2). The 0·2 0 0·4 Overall survival 0·6 0·8 1·0 6 12 18 Time after surgery (months) No. at risk 24 30 36 pCR 13 12 6 5 4 2 1 R0, no pCR 54 47 34 28 20 14 13 R1/R2 62 45 35 28 20 15 10 pCR R0, no pCR R1/R2 Fig. 2 Kaplan–Meier curve for overall survival in all resected patients based on pathological outcome. pCR, pathological complete response; RO, complete resection; R1/R2, microscopic/macroscopic tumour present in the resection margin. P=0⋅012 (log rank test) remaining 26 patients in the ICT arm had 23 R1 and three R2 resections, and the 36 remaining in the CRRT-alone arm all had an R1 resection. Overall survival The 3-year OS rate for the 129 patients was 44 per cent (median survival 27months), 92 per cent in patients who had a pCR, 54 per cent in those with an R0 resection but no pCR, and 32 per cent in patients who had an R1/R2 resection (P=0⋅012) (Fig. 2). In the ICT group, patients who had a pCR were all alive at the end of follow-up, whereas those with R0 but no pCR or margin-positive patients had a median survival of 23months (P=0⋅039). There were only three R2 resections in the ICT group, and none in the CRRT group; therefore, no separate analyses for resection state were performed. In the CRRT group, only three patients achieved a pCR, so the numbers were too small to perform statistical comparisons; however, one patient with a pCR died from another cause at 10months. Local and distant recurrence The 3-year LRFS rate was 41 per cent (median survival 20months), 89 per cent at 24months in patients who had a pCR, 65 per cent in those with R0 but no pCR, and 25 per cent for patients with an R1/R2 resection (P<0⋅001). The 3-year MFS rate was 45 per cent (median survival 28months), 60 per cent in patients who had a pCR, 60 per Society Ltd www.bjs.co.uk BJS2018; 105: 447–452 y John Wiley & Sons Ltd pCRpathological complete response; R0 complete r section; R1/R2microscopic/macroscopic tumour pr sent in the resection margin. P = 0.012 (log rank test). Local and distant recur ence The 3-year LRFS rate was 41 percent (median survival 20 months), 89 percent at 24 months in patients who had a pCR, 65 percent in those with R0 but no pCR, and 25 p rcent for patients with an R1/R2 resection (P < 0.001). The 3-year MFS rate was 45 percent (median survival 28 months), 60 percent for R0 but no pCR, and 25 percent for patients with an R1/R2 resection (P = 0.010). Supplemental file Table S1. Types of chemotherapy and treatment regimens for induction chemotherapy Type of chemotherapy Induction + consolidation Induction Full-course chemotherapy before CRRT Total CAPOX 10 19 8 37 (64) FOLFOX 0 2 4 6 (10) CAPOX + Avastin 2 3 1 6 (10) FOLFIRI 1 1 0 2 (3) CAPOX switch to FOLFOX 0 0 1 (2) Other 0 4 2 6 (10) Total 13 (22) 30 (52) 15 (26) 58 Values in parentheses are percentages.
Chapter 2 28 Discussion This study has demonstrated high pCR rates in patients with locally recurrent rectal carcinoma after a new sequential neoadjuvant regimen consisting of ICT followed by CRRT. This is comparable to pCR rates described after chemoradiotherapy in locally advancedprimary rectal cancer.18,19 Furthermore, pCRexhibiteda strong relationshipwith OS, LRFS and MFS. This is an important finding as the treatment options for this group of patients are limited. Thus, new treatment options should focus on increasing the pCR rate. To date, only case reports 20–22 have described pCR in locally recurrent rectal cancer. In subgroupanalyses of the ICTandCRRTgroups, thebenefit of apCRwas apparent only in the ICT group. This findingmight reflect a systemic effect, reducing the development of systemic micrometastasis and improving not only local, but also distant recurrence rates. These are, however, speculations, as these trends could not be demonstrated by survival differences in the two groups. This lack of statistical significance might be due to a power problem; hence, these data need to be interpreted with caution. Similar R0 margin rates were observed in patients who underwent ICT and those who had CRRT alone. However, there is a need to clarify why the ICT was initiated. ICT was formerly administered exclusively to patients with unresectable locally recurrent rectal cancer. In several cases, remarkable resultswere observed: many lesions became resectable, and some patients even had a pCR. After observing favourable results in this poor category of patients, this regimenwas expanded to patients with locally recurrent rectal cancer and better prognostic features. The ICT group thus consisted of surgically unfavourable recurrent cases and could hamper any comparison. However, the finding that ICT results inmore pCRs and similar R0 resection rates in these unfavourable cases demonstrates that it has a definite role in intensifying the response of neoadjuvant treatment in previously irradiated patients with locally recurrent rectal cancer. Studies of ICT in recurrent rectal cancer are not available, but the findings here are in line with the results of studies on primary locally advanced rectal cancer, which demonstrated a higher response rate after ICT before chemoradiotherapy and also seemed to translate into a better outcome.23,24 Further radiological guidelines are required to enable categorization of ‘resectable’ versus ‘irresectable’ disease, such that similar groups of patients can be compared to demonstrate a difference in R0 resection rate. Amajor advantage of a neoadjuvant treatment regimen including ICT is the avoidance of possible overtreatment in patients with progressive systemic disease. This regimen enables the possibility of observing oncobiological behaviour of the recurrent disease, and unnecessary surgery might be prevented in patients with progressive distant
Induction chemotherapy in locally recurrent rectal cancer 29 CHAPTER 2 disease. Response to this treatment could also be used as a selection criterion for further procedures. Good responders not developing metastases may be better candidates for this extensive surgery, whereas those who exhibit local progression or even developmetastases during chemotherapy could be spared unnecessarymorbidity and mortality, and undergo the best palliative treatment in the meantime. One of the major drawbacks of this study is that it was not designed as a prospective study to achieve a complete response. Negative selection bias on the basis of more or less unfavourable conditions may have influenced the results. The accidental finding that most of these patients could undergo an R0 resection and unexpectedly showed a high pCR rate is hypothesis-generating, and requires further validation in future studies. To show an increase in the pCR rate following ICT from5 to 15 percent (two-tailed α = 0.05 and power of 80 percent), the number of patients in each arm would need to be 140. A difference of 15 percent in the R0 resection rate, which is the strongest predictor of oncological outcome, would also require 140 patients per arm. To demonstrate a 10 percent increase in theDFS rate at 3 years, more than 700 patients would be required in each study arm, which is an unrealistic number for a study with such a heterogeneous group as patients with locally recurrent rectal cancer. Alternative study designs, such as a matched case–control study, would require a relatively small cohort of patients to undergo the intervention.
Chapter 2 30 References 1. van Gijn W, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of themulticentre, randomised controlles TME trial. Lancet Oncol. 2011;12:575–582. 2. Sasikumar A, Bhan C, Jenkins JT, et al. Systematic Review of Pelvic Exenteration With En Bloc Sacrectomy for Recurrent Rectal Adenocarcinoma: R0 Resection Predicts Disease-free Survival. Dis Colon Rectum. 2017;60:346–352. 3. Harris CA, Solomon MJ, Heriot AG, et al. The Outcomes and Patterns of Treatment Failure After Surgery for Locally Recurrent Rectal Cancer. Ann Surg. 2016;264:323–329. 4. Alberda WJ, Verhoef C, Schipper MEI, et al. The Importance of a Minimal Tumor-Free Resection Margin in Locally Recurrent Rectal Cancer. Dis Colon Rectum. 2015;58:677–685. 5. Bhangu A, Beynon J, Brown G, et al. Consensus statement on the multidisciplinary management of patients with recurrent and primary rectal cancer beyond total mesorectal excision planes. Br J Surg.;100 . Epub ahead of print 2013. DOI: 10.1002/BJS.9192_1. 6. Bosman SJ, Holman FA, Nieuwenhuijzen GAP, et al. Feasibility of reirradiation in the treatment of locally recurrent rectal cancer. Br J Surg. 2014;101:1280–1289. 7. MohiuddinM, MarksG, Marks J. Long-termresults of reirradiation for patientswith recurrent rectal carcinoma. Cancer. 2002;95:1144–1150. 8. Glimelius B. Recurrent rectal cancer. The pre-irradiated primary tumour: can more radiotherapy be given? Colorectal Dis. 2003;5:501–503. 9. Van Der Meij W, Rombouts AJM, Rutten H, et al. Treatment of Locally Recurrent Rectal Carcinoma in Previously (Chemo)Irradiated Patients: A Review. Dis Colon Rectum. 2016;59:148–156. 10. Dresen RC, Gosens MJ, Martijn H, et al. Radical Resection After IORT-Containing Multimodality Treatment is the Most Important Determinant for Outcome in Patients Treated for Locally Recurrent Rectal Cancer. Ann Surg Oncol. . Epub ahead of print 2008. DOI: 10.1245/s10434-0089896-z. 11. Holman FA, Bosman SJ, Haddock MG, et al. Results of a pooled analysis of IOERT containing multimodality treatment for locally recurrent rectal cancer: Results of 565 patients of two major treatment centres. Eur J Surg Oncol. 2017;43:107–117. 12. van den Brink M, Stiggelbout AM, van den Hout WB, et al. Clinical nature and prognosis of locally recurrent rectal cancer after total mesorectal excision with or without preoperative radiotherapy. J Clin Oncol. 2004;22:3958–3964. 13. Tanis PJ, Doeksen A, Van Lanschot JJB. Intentionally curative treatment of locally recurrent rectal cancer: a systematic review. Can J Surg. 2013;56:135. 14. BakarA, BhattiH,WaheedA, et al. Can InductionChemotherapybeforeConcurrent Chemoradiation Impact Circumferential Resection Margin Positivity and Survival in Low Rectal Cancers ? 2015;16:2993–2998. 15. Fernandez-Martos C, Garcia Fadrique A, Glynne-Jones R. Optimal sequencing of neoadjuvant therapy (NAT) in rectal cancer: upfront chemotherapy vs. upfront chemoradiation. Curr Color Cancer Rep. 2017;13:154–165. 16. Dresen RC, Kusters M, Daniels-Gooszen AW, et al. Absence of tumor invasion into pelvic structures in locally recurrent rectal cancer: prediction with preoperative MR imaging. Radiology. 2010;256:143–150.
17. Mandard A -M, Dalibard F, Mandard J -C, et al. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer. 1994;73:2680–2686. 18. Cercek A, GoodmanKA, Hajj C, et al. Neoadjuvant chemotherapy first, followed by chemoradiation and then surgery, in the management of locally advanced rectal cancer. J Natl Compr Canc Netw. 2014;12:513–519. 19. De Campos-Lobato LF, Stocchi L, Da Luz Moreira A, et al. Pathologic complete response after neoadjuvant treatment for rectal cancer decreases distant recurrence and could eradicate local recurrence. Ann Surg Oncol. 2011;18:1590–1598. 20. Ishiba T, Ohtsukasa S, Kato S, et al. [A case of pathologically complete response of local recurrence in the mesorectum after multidisciplinary therapy.]. Gan To Kagaku Ryoho. 2013;40:1993–1995. 21. Iwata N, Ishikawa T, Takahashi H, et al. [A case of recurrent rectal cancer successfully treated for a long periodwith capecitabine plus oxaliplatin andbevacizumab therapy.]. GanToKagakuRyoho.;40. 22. Yatsuoka T, Nishimura Y, SakamotoH, et al. [Acase of recurrent rectal cancer with paraaortic lymph nodemetastasis treated by FOLFIRI therapy leading to complete response.]. Gan To Kagaku Ryoho. 2011;38:2057–2059. 23. Denost Q, Kontovounisios C, Rasheed S, et al. Individualizing surgical treatment based on tumour response following neoadjuvant therapy in T4 primary rectal cancer. Eur J Surg Oncol. 2017;43:92– 99. 24. Rouanet P, Rullier E, Lelong B, et al. Tailored Treatment Strategy for Locally Advanced Rectal Carcinoma Based on the Tumor Response to Induction Chemotherapy: Preliminary Results of the French Phase II Multicenter GRECCAR4 Trial. Dis Colon Rectum. 2017;60:653–663.
Chapter 3 Improved outcomes for responders after treatment with induction chemotherapy and chemo(re)irradiation for locally recurrent rectal cancer ELK Voogt, DMGI van Zoggel, M Kusters, GAP Nieuwenhuijzen, JG Bloemen, HMU Peulen, GJM Creemers, G van Lijnschoten, J Nederend, MJ Roef, JWA Burger, HJT Rutten Ann Surg Oncol. 2020 Sep;27(9):3503-3513
Abstract Background Despite improvements in themultimodality treatment for patientswith locally recurrent rectal cancer (LRRC), oncological outcomes remainpoor. This study evaluated the effect of induction chemotherapy and subsequent chemo(re)irradiation on the pathologic response and the rate of resections with clear margins (R0 resection) in relation to long-term oncological outcomes. Methods All consecutive patients with LRRC treated in the Catharina Hospital Eindhoven who underwent a resection after treatment with induction chemotherapy and subsequent chemo(re)irradiation between January 2010 and December 2018 were retrospectively reviewed. Induction chemotherapy consisted of CAPOX/FOLFOX. Endpoints were pathologic response, resection margin and overall survival (OS), disease free survival (DFS), local recurrence free survival (LRFS), and metastasis free survival (MFS). Results A pathologic complete response was observed in 22 patients (17 percent), a ‘good’ response (Mandard 2–3) in 74 patients (56 percent), and a ‘poor’ response (Mandard 4–5) in36patients (27percent). AnR0 resectionwasobtained in83patients (63percent). The degree of pathologic response was linearly correlated with the R0 resection rate (P = 0.026). In patients without synchronous metastases, pathologic response was an independent predictor for LRFS, MFS, and DFS (P = 0.004, P = 0.003, and P = 0.024, respectively), whereas R0 resection was an independent predictor for LRFS and OS (P = 0.020 and P = 0.028, respectively). Conclusions Induction chemotherapy inaddition toneoadjuvant chemo(re)irradiation is apromising treatment strategy for patients with LRRC with high pathologic response rates that translate into improved oncological outcomes, especially when an R0 resection has been achieved.
Improved outcomes for responders to induction chemotherapy 35 CHAPTER 3 Introduction Over the past decades, there have been significant improvements in the treatment of patients with rectal cancer. Due to the introduction of total mesorectal excision (TME) and the development of neoadjuvant (chemo)radiotherapy, the rate of locally recurrent rectal cancer (LRRC) has decreased from 20–30 to 6–10 percent.1–3 However, patients who develop LRRC remain to have a limited prognosis with 5-year overall survival rates of approximately 30 percent.4–7 The most important prognostic factor influencing survival after surgery is a clear resectionmargin (R0 resection).1,2,8–11 Achieving an R0 resection is challenging because of distorted anatomy due to previous TME surgery, the difficult distinction between fibrosis and malignant tissue after radiotherapy, and the ingrowth of the recurrent neoplasm into other structures, such as the adjacent organs, pelvic side wall, and the sacrum. To achieve downsizing of the local recurrence and consequently more R0 resections, neoadjuvant treatment with chemoradiotherapy is recommended.12 However, a proportion of patients with locally recurrent rectal cancer have already received (chemo)radiotherapy for their primary tumour. Previous studies have shown that in these patients reirradiation with a dose of 30 Gy combined with capecitabine is safe and effective.2,8 Alongside an R0 resection, a pathologic complete response (pCR) may be of prognostic value in predicting long-term outcomes for LRRC patients.13,14 Despite neoadjuvant treatment with chemo(re)irradiation, R0 resections are achieved in only 60 percent of cases and pCR rates are low (± 8 percent).7,15 The addition of induction chemotherapy to neoadjuvant chemo(re)irradiation may improve local downsizing and thereby improve the R0 resection and pCR rates. Furthermore, induction chemotherapy may eradicate occult micrometastases. Ultimately, this may improve long-termoncological outcomes. Our preliminary results showed a promising pCR rate with this treatment regimen.16 The current study evaluated the effect of induction chemotherapy administered prior to neoadjuvant chemo(re)irradiation on the pathologic response and the R0 resection rate in an extended cohort and the predictive value of the pathological response on oncological outcomes.
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