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Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 39-42

Contentious issues in the management of carcinoma of the rectum


Department of Surgical Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India

Date of Web Publication26-Nov-2019

Correspondence Address:
Chetan Kantharia
Department of Surgical Gastroenterology, Seth GS Medical College and KEM Hospital, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJCS.IJCS_5_19

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  Abstract 


The management of Carcinoma of the Rectum is fairly standardized and protocolized, based on universally followed guidelines, including the NCCN, ESMO, and ASCO guidelines. However, there are certain advances and practices recommended which are contentiously requiring further debates and studies. The present study addresses these issues in its right perspective based on literature evidence.

Keywords: Controversy, current management, rectal carcinoma


How to cite this article:
Kantharia C, Pujari S, Jain K, Prabhu R. Contentious issues in the management of carcinoma of the rectum. Indian J Colo-Rectal Surg 2018;1:39-42

How to cite this URL:
Kantharia C, Pujari S, Jain K, Prabhu R. Contentious issues in the management of carcinoma of the rectum. Indian J Colo-Rectal Surg [serial online] 2018 [cited 2019 Dec 12];1:39-42. Available from: http://www.ijcrsonweb.org/text.asp?2018/1/2/39/271749




  Introduction Top


The management of Carcinoma (Ca) of Rectum practiced is protocolized based on the TNM staging. The management protocol is largely dictated by the accepted guidelines, including the NCCN, ASCO, and ESMO guidelines. However, there are certain new advances recommended which are debatable and require further studies to make them universally acceptable. This article discusses the issues, its pros and cons, its present state, based on the available literature evidence.

The issues discussed are:

  1. Clinical complete response (cCR) following neoadjuvant chemoradiotherapy (nCRT)
  2. Total neoadjuvant therapy for locally advanced rectal carcinoma
  3. Selective elimination of radiotherapy (RT)
  4. Lateral pelvic lymph node dissection.



  Clinical Complete Response Following Neoadjuvant Chemoradiotherapy Top


cCR can be defined as the absence of any palpable tumor or irregularity on digital rectal examination, absence of lesion on colonoscopy, absence of any residual tumor in the primary site, and draining lymph nodes on imaging with magnetic resonance imaging (MRI) or endorectal ultrasound (ERUS), negative biopsies from the remnant scar. Besides this, there is a return to normal levels of initially raised CEA levels.[1] About 10%–40% of patients show a complete clinical response.[1]

Since the landmark publication by Habr-Gama et al.,[2] in 2004, advocating a “Wait and Watch” policy over surgery for patients with complete clinical response post-nCRT, many dedicated centers have been implementing the same. They have reported encouraging oncological and functional outcome results with standardized CRT and a nonoperative strategy. The Habr-Gama et al. study reported 71 patients with rectal cancer with a cCR, followed by a watch and wait policy. Their mean follow-up was 57 months. The 5-year survival and disease-free survival (DFS) reported was 100% and 92%, respectively, for “Wait and Watch policy” compared to 88% and 83%, respectively, for the nonresponders with salvage TME group.[2]

Renehan et al.,[3] in their study, reported 129 patients with Watch and Wait policy. Their median follow-up was 33 months. 44 (34%) patients showed local re-growth 3-year actuarial rate of 38%. Thirty-six (88%) of 41 patients with nonmetastatic local re-growth were salvaged surgically. In matched analyses, with 109 patients in each treatment group at 3 years there was no difference in both the groups. The DFS and overall survival (OS) in “Wait and Watch” group was 88% and 96%, respectively, and 78% and 87%, respectively, in the Surgical resection group.

The biggest drawback of “Wait and Watch Policy” is that they require rigorous and meticulous follow-up[4] and more frequent than routine surveillance. This is to ensure that surgical salvage is feasible and timely. This calls for a standardized protocol for surveillance It is also important that patients be counseled that the Wait and Watch Policy is not standard of care and that there is risk of recurrence and metastatic disease. Thus, more prospective randomized studies on this are required before “Wait and Watch Policy” become Standard of Care.


  Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer Top


Total neoadjuvant therapy includes the administration of induction or consolidation chemotherapy with chemo-RT before surgery for locally advanced rectal carcinoma (LARC). This is in contrast to the standard followed treatment, comprising preoperative chemo-RT followed by total mesorectal excision and postoperative adjuvant chemotherapy for clinical stage II or III locally advanced rectal cancer (LARC) (T3/4, N0, or node-positive). The rationale put forward by the proponents[5] of TNT are:

  1. Increased completion of planned therapy
  2. Increased rate of downstaging
  3. Taking care of micrometastasis very early in the course of the disease by early introduction of optimal systemic chemotherapy
  4. obviates the need for postoperative therapy and patient compliance
  5. reducing duration with a diverting ileostomy
  6. Besides the standard regimen, though it confers excellent local control, the problem of distant metastasis remains.


The efficacy of adjuvant chemotherapy on the overall outcome in the setting of nCRT is not clear. None of the randomized trials,[6],[7],[8],[9] including the European Organisation for Research and Treatment of Cancer 22921 trial[6] which is the largest study, has not shown a benefit. This study clearly established that adjuvant treatment did not improve disease-free or OS after nCRT or neoadjuvant RT.

Recently, a systematic review by Zaborowski et al.[10] on TNT has been published. It involves ten studies and included 648 patients, 612 of whom underwent induction chemotherapy and nCRT followed by interval resection for rectal cancer. This review has reported an overall weighted mean local recurrence of 3.5%, distant metastasis of 20.6%, and an OS of 80.3% and 74.4% at the end of three and 5 years, and DFS of 69.6% and 65.4%, respectively, at the end of three and 5 years.

However, there are disadvantages too associated with TNT. They are:

  1. Delay in performance of definitive surgery and deterioration of the performance status
  2. Full-dose of systemic therapy may affect fitness for surgery, thus delaying the surgery, and an increase in postoperative morbidity rates
  3. Delay in surgery may lead to local disease progression.


Besides there are lot of loopholes in TNT, including the lack of standardization of chemotherapy regimens used, both in the neoadjuvant and adjuvant setting. Besides what has been reported in all the studies are only short-term results. Long-term outcomes are yet to be seen, and only after that, we could make a definitive conclusion. There are many ongoing prospective trials, including the RAPIDO[11] and PROSPECT[12] trial, which may give a definite answer to the shortcomings of TNT. Thus, though total neoadjuvant treatment holds a lot of promise, whether it actually improves the overall and DFS needs to be seen and confirmed.

Selective elimination of radiotherapy

The decrease in local recurrence rate following rectal surgery has been largely attributed to incorporation of contemporary NACRT and following a standardized TME approach. However, there is a thought that a standardized TME approach alone with neoadjuvant chemotherapy in a select subgroup of patients with proximal rectal tumors, can lead to a comparable outcome as with contemporary NACRT, with a negative circumferential radial margin. Besides, this selective exclusion of RT also helps in avoiding the potential short- and long-term toxicities of pelvic RT. Currently, there is an ongoing clinical trial registered with the Clinical trial registry. This trial is being conducted by National Cancer Institute and the Canadian Cancer Trials Group. This is a multi-center, Phase II/III study. It is called as the PROSPECT trial[12] (PROSPECT: Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients with Locally Advanced Rectal Cancer Undergoing Surgery). The primary objective of the trial for Phase II component is to assure that neoadjuvant FOLFOX followed by selective use of 5FUCMT group (Group 1) maintains the current high rate of pelvic R0 resection and is consistent with noninferiority for time to local recurrence (TLR). In Phase III component the objective is to compare neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) to standard 5FUCMT (Group 2) with respect to the co-primary endpoints of the TLR and DFS. Patients are stratified according to ECOG performance status (0 or 1 vs. 2) and randomized to 1 of 2 treatment regimens.

In the experimental Group I patients will receive FOLFOX chemotherapy once every 2 weeks for six cycles total over a period of 12 weeks. After completing FOLFOX chemotherapy, the patient will have an MRI scan or ERUS to examine the tumor. If the tumor has not decreased in size by at least 20%, the patient will receive 5FUCMT (radiation with chemotherapy). If the tumor has decreased in size by 20%, then the patient will proceed directly to surgery. If all borders of the tumor are normal postsurgery, then the patient receives six additional cycles of FOLFOX chemotherapy. If all borders of the tumor are not normal then the patient receives chemoradiation therapy for 5.5 weeks after surgery. After chemoradiation, additional cycles of FOLFOX or similar chemotherapy will be recommended for four cycles or 8 weeks. Patient observation with follow-up evaluations and event monitoring will occur up to 8 years postrandomization.

In the comparator Group II, patients receive 5FUCMT, including chemotherapy and radiation therapy, for 5.5 weeks. Patients will be given either 5-fluorouracil or capecitabine and radiation therapy. After the chemoradiation therapy is completed, patients will proceed directly to surgery. Postsurgery, patients will receive FOLFOX chemotherapy once every 2 weeks for 8 cycles total over a period of 16 weeks. Patient observation with follow-up evaluations and event monitoring will occur up to 8 years postrandomization.

The results of this study will serve as a definite guideline whether it would be possible to selectively eliminate RT in a select subgroup of patients of rectal carcinoma.

Lateral pelvic lymph node dissection

The involvement of lateral pelvic lymph node remains a major cause of local recurrence in lower rectal carcinoma even when treated with nCRT. However, whether it should be routinely dissected or not remains a matter of controversy between the east and west. While the Japanese group considers TME and lateral pelvic lymph node dissection surgery even without nRT/CRT as a standard procedure, the surgeons from west, condemn the dissection of pelvic lymph nodes, as they argue that its involvement qualifies it as a systemic disease. The JCOG0212 trial[13] by The Japan Clinical Oncology Group (JCOG), comparing Mesorectal excision with dissection of lateral pelvic lymph node (Standard arm) with Mesorectal excision alone (experimental arm) have shown significantly high local recurrence rate in the Mesorectal excision-alone group (P = 0.024). The local recurrence and 5-year survival-free relapse rate were, 12.6% and 73.3%, respectively, in Mesorectal excision-alone group as compared to 7.4% and 73.4% in the Mesorectal excision with dissection of the lateral pelvic lymph node group. Akiyoshi et al.[14] have shown in their study that mesorectal excision with dissection of lateral pelvic lymph nodes improves the local control and survival of patients with pelvic LN metastasis in low rectal cancer treated with nCRT.

In general, the decision whether pelvic lymph nodes should be dissected or not is dictated by the response of pelvic LN to nCRT.[15] Persistent LLN >5 mm observed following post-nCRT MRI was found to be significantly associated with residual tumor metastasis, unlike responsive LLN after nCRT.


  Conclusion Top


These are the Contentious Issues in the Management of Ca of the Rectum with regard to which there is no consensus as yet, and results of further studies on them are awaited to make a conclusive statement on them.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Glynne-Jones R, Wyrwicz L, Tiret E, Brown G, Rödel C, Cervantes A, et al. Rectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv22-40.  Back to cited text no. 1
    
2.
Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro U Jr., Silva e Sousa AH Jr., et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: Long-term results. Ann Surg 2004;240:711-7.  Back to cited text no. 2
    
3.
Renehan AG, Malcomson L, Emsley R, Gollins S, Maw A, Myint AS, et al. Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): A propensity-score matched cohort analysis. Lancet Oncol 2016;17:174-83.  Back to cited text no. 3
    
4.
Martens MH, Maas M, Heijnen LA, Lambregts DM, Leijtens JW, Stassen LP, et al. Long-term outcome of an organ preservation program after neoadjuvant treatment for rectal cancer. J Natl Cancer Inst 2016;108. pii: djw171.  Back to cited text no. 4
    
5.
Cercek A, Roxburgh CS, Strombom P, Smith JJ, Temple LK, Nash GM, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol 2018;4:e180071.  Back to cited text no. 5
    
6.
Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: Long-term results of the EORTC 22921 randomised study. Lancet Oncol 2014;15:184-90.  Back to cited text no. 6
    
7.
Breugom AJ, van Gijn W, Muller EW, Berglund Š, van den Broek CB, Fokstuen T, et al. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo) radiotherapy and total mesorectal excision: A Dutch colorectal cancer group (DCCG) randomized phase III trial. Ann Oncol 2015;26:696-701.  Back to cited text no. 7
    
8.
Glynne-Jones R, Counsell N, Quirke P, Mortensen N, Maraveyas A, Meadows HM, et al. Chronicle: Results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Ann Oncol 2014;25:1356-62.  Back to cited text no. 8
    
9.
Sainato A, Cernusco Luna Nunzia V, Valentini V, De Paoli A, Maurizi ER, Lupattelli M, et al. No benefit of adjuvant fluorouracil leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR-RT). Radiother Oncol 2014;113:223-9.  Back to cited text no. 9
    
10.
Zaborowski A, Stakelum A, Winter DC. Systematic review of outcomes after total neoadjuvant therapy for locally advanced rectal cancer. Br J Surg 2019;106:979-87.  Back to cited text no. 10
    
11.
Nilsson PJ, van Etten B, Hospers GA, Påhlman L, van de Velde CJ, Beets-Tan RG, et al. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer – The RAPIDO trial. BMC Cancer 2013;13:279.  Back to cited text no. 11
    
12.
PROSPECT: Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients with Locally Advanced Rectal Cancer Undergoing Surgery; 2012. Available from: https://clinicaltrials.gov/ct2/show/NCT01515787. [Last accessed on 2018 Sep 01].  Back to cited text no. 12
    
13.
Fujita S, Mizusawa J, Kanemitsu Y, Ito M, Kinugasa Y, Komori K, et al. Mesorectal excision with or without lateral lymph node dissection for clinical stage II/III lower rectal cancer (JCOG0212): A multicenter, randomized controlled, noninferiority trial. Ann Surg 2017;266:201-7.  Back to cited text no. 13
    
14.
Akiyoshi T, Ueno M, Matsueda K, Konishi T, Fujimoto Y, Nagayama S, et al. Selective lateral pelvic lymph node dissection in patients with advanced low rectal cancer treated with preoperative chemoradiotherapy based on pretreatment imaging. Ann Surg Oncol 2014;21:189-96.  Back to cited text no. 14
    
15.
Oh HK, Kang SB, Lee SM, Lee SY, Ihn MH, Kim DW, et al. Neoadjuvant chemoradiotherapy affects the indications for lateral pelvic node dissection in mid/low rectal cancer with clinically suspected lateral node involvement: A multicenter retrospective cohort study. Ann Surg Oncol 2014;21:2280-7.  Back to cited text no. 15
    




 

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