Users Online: 96
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
ORIGINAL ARTICLE: GI CANCER
Year : 2019  |  Volume : 8  |  Issue : 2  |  Page : 92-97

Systemic chemotherapy and short-course radiation in metastatic rectal cancers: A feasible paradigm in unresectable and potentially resectable cancers


1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Medical Gastroenterology, Tata Memorial Hospital, Mumbai, Maharashtra, India
5 Department of Radiology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication15-Apr-2019

Correspondence Address:
Dr. Anant Ramaswamy
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sajc.sajc_174_18

Rights and Permissions
  Abstract 

Background: The optimal use and sequencing of short-course radiotherapy (SCRT) in metastatic rectal cancers (mRCs) are not well established. Materials and Methods: We retrospectively reviewed the records of mRC patients receiving SCRT followed by palliative chemotherapy between January 1, 2013, and December 31, 2016, in Tata Memorial Hospital. Patients were classified as having “potentially resectable” disease (local and metastatic) or “unresectable” disease at baseline based on prespecified criteria. Results: A total of 105 consecutive patients were available for analysis. The median age of patients was 48 years (range: 16–62 years), and 57.1% were male patients. Signet ring histology was seen in 13.3% of patients. The most common site of metastases was liver limited (29.5%), nonloco-regional nodes (12.4%), and lung limited metastases (9.5%). Chemotherapeutic regimens administered were capecitabine-oxaliplatin (70.5%), modified 5 fluorouracil (5 FU)-leucovorin-irinotecan-oxaliplatin (10.5%), and modified 5 FU-leucovorin-irinotecan (8.6%). Targeted therapy accompanying chemotherapy was administered in 27.6% of patients. About 42.1% of patients with potentially resectable disease and 11.1% with the unresectable disease at baseline underwent curative-intent resection of the primary and address of metastatic sites. With a median follow-up 18.2 months, median overall survival (OS) was 15.7 months (95% confidence interval: 10.42–20.99). Patients classified as potentially resectable had a median OS of 32.62 months while patients initially classified as unresectable had a median OS of 13.04 months (P = 0.016). The presence of signet ring morphology predicted for inferior mOS (P = 0.021). Conclusions: SCRT followed by systemic therapy in mRC is a feasible, efficacious paradigm for maximizing palliation, and achieving objective responses. The classification of patients based on resectability was predictive of actual resection rates as well as outcomes. Signet ring mRC show inferior outcomes in this cohort of patients.

Keywords: Chemotherapy, metastatectomy, metastatic rectal cancers, resectability, short-course radiotherapy


How to cite this article:
Ostwal V, Kapoor A, Engineer R, Saklani A, deSouza A, Patil P, Arya S, Ankathi SK, Chopra S, Patil M, Jain S, Ramaswamy A. Systemic chemotherapy and short-course radiation in metastatic rectal cancers: A feasible paradigm in unresectable and potentially resectable cancers. South Asian J Cancer 2019;8:92-7

How to cite this URL:
Ostwal V, Kapoor A, Engineer R, Saklani A, deSouza A, Patil P, Arya S, Ankathi SK, Chopra S, Patil M, Jain S, Ramaswamy A. Systemic chemotherapy and short-course radiation in metastatic rectal cancers: A feasible paradigm in unresectable and potentially resectable cancers. South Asian J Cancer [serial online] 2019 [cited 2019 May 24];8:92-7. Available from: http://journal.sajc.org/text.asp?2019/8/2/92/256067


  Introduction Top


Outcomes in metastatic colorectal cancers (mCRCs) have improved with the greater use of chemotherapy, monoclonal antibodies and recently, immunotherapy.[1],[2],[3],[4] Increasing resection rates for resectable liver metastases (LM) (up to 93%) and conversion rates for unresectable LM (up to 49%) to resectability by chemotherapy with or without monoclonal antibodies means that there is a need for addressing the rectal primary adequately as well.[5],[6],[7],[8] There also remains the unanswered question of potential benefit with surgical resection of the primary in patients with the unresectable metastatic disease with multiple retrospective studies suggesting a survival benefit for the strategy.[9],[10] There are also no firm guidelines regarding criteria for resectability of metastatic sites in CRC, though few exist for liver metastatectomy.

The effect of radiotherapy (RT) in the local symptom and disease control of locally advanced rectal cancers (LARCs) has ensured that it is a part of the standard of care in the treatment of such cancers. While conventionally preoperative long-course chemoradiation (LCRT) was part of the treatment paradigm for LARC, there is growing evidence to suggest comparability and potential superiority of preoperative short-course RT (SCRT) and systemic chemotherapy as opposed to LCRT.[11],[12],[13] In patients with metastatic rectal cancer (mRC) at baseline, upfront SCRT provides palliation, potential stoma prevention besides avoiding undue delays in beginning systemic chemotherapy (with or without targeted therapy). It also overcomes the logistic constraints of combining RT for the primary rectal cancer and preparing the patient for potential surgery of the primary should there be adequate conversion/downstaging of primary and secondary sites post chemotherapy.[14],[15]


  Materials and Methods Top


Patient selection

The study is a retrospective analysis of mRC patients with metastases who were offered SCRT followed by chemotherapy, (with or without monoclonal antibodies based on feasibility) during January 1, 2013, to December 31, 2016, at the Department of Gastrointestinal Oncology, Tata Memorial Hospital (TMH) in Mumbai. The study was approved by the Institutional Review Board and Ethics Committee (IEC/0516/1664/001) and was conducted as per the Declaration of Helsinki guidelines. Patient data were extracted from a prospectively maintained rectal cancer database at TMH. Patients included in the study satisfied all the following criteria:

  1. Histologically confirmed adenocarcinoma of the rectum, either T3/T4 and or node (N) positive as per clinical diagnosis and contrast-enhanced magnetic resonance imaging (CE-MRI) of the rectum
  2. Evidence of metastases based on contrast-enhanced computed tomography (CT) scans or 18-fluorodeoxyglucose contrast-enhanced positron emission tomography scan.


Institution criteria for the potential liver-directed therapy of metastatic liver disease

  1. Technically R0 resection possible of all visible lesions
  2. Greater than 30% future liver remnant (FLR) post planned resection at baseline or >40% FLR postchemotherapy
  3. Size of hepatic lesions <5 cm and/or <4 LM
  4. Lesions in proximity to all hepatic veins or both branches of the portal vein, which may undergo potential downstaging and further resection.


Patients not satisfying the above criteria were classified as unresectable metastatic disease, though a surgical evaluation was considered at a later point for all patients if they had a good response at metastatic sites and controlled primary.

Resectability criteria of the primary rectal cancer

  1. Circumferential margin (CRM) negativity
  2. The absence of extension through the greater sciatic notch, encasement of external iliac vessels, paraaortic lymphadenopathy, or sacral invasion above S2–S3 junction
  3. R0 resection possible.


Patients with extensive side-wall involvement were considered for local resection based on a case-to-case scenario.

Short-course radiotherapy protocol

Patients received SCRT to a dose of 5 Gy per fraction for a total of five fractions given on 5 consecutive days.

Systemic chemotherapy protocol

Patients were planned for starting chemotherapy 5–10 days postcompletion of SCRT. Targeted therapy was added to chemotherapy backbone based on results of mutation testing. Regimens considered as first-line therapy in our institution include capecitabine-oxaliplatin (CAPOX), single-agent capecitabine, 5 fluorouracil (5 FU)-leucovorin-oxaliplatin (FOLFOX-7), modified 5 FU-leucovorin- irinotecan (mFOLFIRI without bolus 5 FU), and modified 5 FU-leucovorin-irinotecan-oxaliplatin (mFOLFIRINOX without bolus 5 FU). Dosages and schedules were as per standard schedules. Toxicity assessment during chemotherapy was done at every patient visit and recorded as per NCI-CTCAE (National Cancer Institute- Common Terminology Criteria for Adverse Events).

Tumor response assessment

CT scans were reported as per RECIST 1.1 criteria.[16] In situations where response could not be quantified by RECIST, then the response was quantified based on collusion between treating physician and the gastrointestinal radiologist as follows: complete response (CR) – disappearance of all baseline lesions; partial response (PR) – significant regression of lesions at baseline; stable disease (SD) – no significant regression of baseline lesions and no new lesions; progressive disease (PD) – appearance of new lesions or significant increase in baseline lesions. Responses in the rectal primary were evaluated by CE-MRI and responses were recorded as CR, PR, SD, or PD based on changes in signal tumor intensity, regression in tumor and nodal size, regression in CRM status and the presence of fibrosis on T2-weighted sequences.[17],[18]

Prognostic factors

Predefined prognostic factors evaluated for correlation with overall survival (OS) were younger age at diagnosis (≤50 years vs. >50 years), degree of differentiation, signet ring histology CEA levels, Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0/1 vs. ≥2), and the presence of obstruction at baseline and resectability status potentially resectable versus unresectable metastatic disease at baseline.

Clinical data collection and statistics

All data were entered in IBM Statistical Package for the Social Sciences (SPSS) software version 21.0 and used for analysis. Descriptive statistics including median, frequency, and percentage for categorical variables is used to describe age, gender distribution, treatment, and response to treatment. Survival outcomes in terms of event-free survival (EFS) and OS were analyzed. Median EFS was calculated from the date of diagnosis to the date of clinical or radiological evidence of disease progression or the last follow-up date. Median OS was calculated from the date of diagnosis until the last follow-up or death. EFS and OS were calculated separately for the potentially resectable and unresectable cohorts. Survival analysis was performed using Kaplan–Meier estimates and log-rank test for bivariate comparisons. Variables achieving statistical significance (P ≤ 0.05) on univariate analysis were evaluated for multivariate analysis by the cox-regression.


  Results Top


Baseline characteristics

A total of 105 patients were included in the study in the specified time. Baseline demographic and clinical characteristics are detailed in [Table 1].
Table 1: Baseline demographic and clinical characteristics

Click here to view


Delivery of short-course radiotherapy and first line systemic therapy

SCRT was delivered as planned in all 105 patients, with no Grade 3 or Grade 4 toxicities. There were no unplanned delays in SCRT. The mean duration between completion of SCRT and beginning systemic therapy was 8 days (range: 2–22). The chemotherapy regimens used were as follows:

  • CAPOX (70.5%)
  • Modified FOLFIRINOX (10.5%)
  • Modified FOLFIRI (8.6%)
  • Modified FOLFOX (5.7%)
  • Capecitabine monotherapy (4.8%).


Common Grade 3 and Grade 4 toxicities as well as the requirement of dose reductions are provided in [Table 2].
Table 2: Characteristics of first line systemic therapy postshort course radiotherapy and response rates

Click here to view


Response rates, resection rates, and treatment of metastatic sites

Post-SCRT and chemotherapy, responses rates and disease control rates at primary and metastatic sites are shown in [Table 2].

In patients with potentially resectable disease (n = 38), 16 patients (42.1%) underwent curative-intent resection of the primary. In patients with baseline unresectable disease (n = 67), 8 patients (11.1%) underwent curative-intent resection of the primary. In these patients, details of surgery of the primary site as well as treatment of metastatic sites are described in [Supplementary Table 1][Additional file 1].



Overall survival and event-free survival

With a median follow-up 18.2 months, 59 patients had died of disease for a median OS of 15.7 months (95% confidence interval [CI]: 10.42–20.99). Patients classified as potentially resectable at baseline had a median OS of 32.62 months (95% CI: 17.7–47.5) whereas patients initially classified as unresectable had a median OS of 13.04 months (95% CI: 10.2–15.8) with a statistically significant difference in survival between the cohorts (P = 0.016). Patients who underwent resection of the primary rectal cancer from the entire cohort (n = 24) had a statistically superior survival compared to patients who did not undergo surgery of the primary (n = 81) (2-year survival 58% vs. 10.7%; P < 0.001).

At the time of median follow-up, 67 patients had an event for median EFS of 10.84 months (95% CI: 9.10–12.58). Patients classified initially as potentially resectable had a median EFS of 13.44 months (95% CI: 7.5–19.4) while patients classified as unresectable had a median EFS of 9.76 months (95% CI: 8.4–11.1), and this difference was statistically significant (P = 0.030). Patients who underwent resection had a median EFS of 22.9 months as compared to a median EFS of 7.8 months in patients who did not undergo resection of the primary (P < 0.001).

Prognostic factors for overall survival

Of the prognostic factors elevated, on univariate analysis, younger age (<50 years) (P = 0.021), and presence of signet ring histology (P = 0.010), predicted for a statistically significant inferior OS, while potential resectability status at baseline predicted for a superior OS (P = 0.016). On multivariate analysis, the presence of signet ring morphology (P = 0.021) and resectability status at baseline (0.027) retained their statistical significance for OS [Table 3].
Table 3: Univariate and multivariate analysis of prognostic factors for overall survival

Click here to view



  Discussion Top


The sequence of SCRT followed by palliative chemotherapy in mRC is suggested by the ESMO treatment guidelines and offers the paradigm of addressing the primary upfront regarding local control, and palliation, without delaying systemic chemotherapy.[19] If initial systemic treatment entails chemotherapy alone, downstaging to resectability is about 22% as opposed to about 49% with chemotherapy-targeted therapy combinations.[1],[5],[20],[21],[22],[23],[24]

The salient features of the studies we selected for evaluation and comparison with the current study.[14],[15],[25] The striking clinical features at baseline in patients in the current study are the younger age at diagnosis (median age –48 years), a high number of patients with ECOG PS ≥2 (64.7%), the high incidence of signet ring cancers (13.3%) and presence of obstruction requiring the creation of a stoma (58.1%). Such clinical factors suggest a different disease presentation, increased burden of disease and potentially, biology especially signet ring histology, as compared to published data from Western trials as well as the studies shown for comparison.[26],[27],[28]

SCRT in our cohort was tolerated well, with no delays in the initiation of systemic therapy. This is line with the philosophy of addressing the primary tumor early with no undue delay in the initiation of systemic therapy. A majority of patients were treated with CAPOX chemotherapy as the first line, which is in keeping with recommendations for the first line therapy for mCRC.[8],[19] A small number of patients were also treated with the mFOLFIRINOX regimen, considering the regimen's potentially greater cytoreductive capability.[7],[29],[30] While the hematological toxicities in our study were manageable, one-quarter of patients required dose-reductions, either upfront or during chemotherapy. Primary reasons were an attempt at the safe administration in patients with borderline (ECOG PS ≥2–64.7%) as well as nonhematological toxicities such as diarrhea (grade 3/4 – 16.2%) and HFS (Grade 2/3 – 10.5%). Besides baseline ECOG PS being a predictor for tolerance issues with chemotherapy, we have previously shown that homozygous DPD mutations may have a slightly higher prevalence in Indian patients – these reasons may account for the incidence of nonhematological toxicities seen.[31],[32],[33],[34] Targeted therapy was used in only 27% of patients, predominantly being bevacizumab. Use of targeted therapy is limited, especially in low middle-income countries.[35],[36],[37] As compared to the current study, the study by van Dijk et al. used targeted therapy in 100% of their patients, while the South Korean study used targeted therapy in a comparable 22% of patients.[14]

The prespecified criteria for resectability clearly predicted for significantly increased use of liver-directed therapy (LDT) (42.1% in potentially resectable group vs. 11.1% in unresectable group) and more importantly, statistically different survival outcomes (32.62 months vs. 13.04 months; P = 0.016). While there are no uniform criteria for selecting patients for LDT, our institution criteria is practical and easy to use a combination of pre- and post-therapy points of reference for selection of patients.[6],[7],[23],[24],[38] We acknowledge that our institution criteria need further validation prospectively, whereas at the same time pointing out that criteria for liver resection have differed across studies and institutions.

A total of 24 patients (22.9%; n = 105) of patients in the entire cohort of the study underwent resection of the primary and treatment of the metastases as well. While prospective studies have shown conversion rates (to metastasectomy) of 33%–61% in patients with liver-limited disease,[7],[39],[40] a significant proportion of patients in this cohort had greater than one site of disease (40%), lung lesions (35.2%), and <5 liver lesions (55.9%; n = 59). Such a cohort is representative of an mRC cohort as against a truly oligometastatic disease cohort. The disease burden of patients in the current study (63.8% unresectable) cohort is closer to the patients in the study by Tyc-Szczepaniak et al. (100% unresectable) than the other studies shown for comparison. With the confines of such a flawed cross-study comparison, the resection rates of 22.9% are indicative of the feasibility of such sequencing of therapy. The studies by van Dijk et al. (100%) and Yoon et al. (70%) clearly had more patients with resectable metastatic disease, and this bears out in the final resectability rates [Table 4].
Table 4: Studies evaluating short-course radiotherapy and systemic chemotherapy in metastatic rectal cancers

Click here to view


The median EFS (10.84 months) and OS (15.7 months) of the entire cohort is a reflection of patients being treated predominantly with chemotherapy and having the majorly unresectable metastatic disease.[41],[42],[43] Going beyond OS, the combination of upfront SCRT and systemic therapy allowed for good local control rates (primary disease control rates – 68.6%), effective palliation of the primary as well avoidance of palliative surgery postbeginning of treatment.

Higher incidence of signet ring cancers and their inferior outcomes (10.22 months vs. 18.73 months) suggests the need for a different approach to treating these cancers as shown in previous studies as well.[44],[45]

The current study has multiple limitations, and caveats exist considering the retrospective nature of the study. The patients in this study are clearly a heterogeneous cohort with multiple sites of disease; metastasectomy of sites beyond the liver is not a uniform option in patients with mCRC. While the criteria for LDT used was uniform, this needs refinement and validation in a larger cohort of patients as only 42.1% of patients with potentially addressable secondary sites finally underwent resection of primary and secondaries. We are also unable to speculate as to the actual number of patients in whom a stoma was avoided, i.e., identification of a cohort of near obstructed patients.


  Conclusions Top


The study suggests that's SCRT followed by systemic therapy in mRCs is a feasible, efficacious paradigm for maximizing palliation and objective responses. The classification of patients based on resectability was predictive of actual resection rates as well as outcomes. Signet ring mRC show inferior outcomes in this cohort of mRC patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, et al. PEAK: A randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 2014;32:2240-7.  Back to cited text no. 1
    
2.
Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): A randomised, open-label, phase 3 trial. Lancet Oncol 2014;15:1065-75.  Back to cited text no. 2
    
3.
Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: A randomized clinical trial. JAMA 2017;317:2392-401.  Back to cited text no. 3
    
4.
Diaz LA, Marabelle A, Delord JP, Shapira-Frommer R, Geva R, Peled N, et al. Pembrolizumab therapy for microsatellite instability high (MSI-H) colorectal cancer (CRC) and non-CRC. J Clin Oncol 2017; 35 15 Suppl: 3071.  Back to cited text no. 4
    
5.
Gruenberger B, Tamandl D, Schueller J, Scheithauer W, Zielinski C, Herbst F, et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 2008;26:1830-5.  Back to cited text no. 5
    
6.
Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC intergroup trial 40983): A randomised controlled trial. Lancet 2008;371:1007-16.  Back to cited text no. 6
    
7.
Gruenberger T, Bridgewater J, Chau I, García Alfonso P, Rivoire M, Mudan S, et al. Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: The OLIVIA multinational randomised phase II trial. Ann Oncol 2015;26:702-8.  Back to cited text no. 7
    
8.
Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016;27:1386-422.  Back to cited text no. 8
    
9.
Verhoef C, de Wilt JH, Burger JW, Verheul HM, Koopman M. Surgery of the primary in stage IV colorectal cancer with unresectable metastases. Eur J Cancer 2011;47 Suppl 3:S61-6.  Back to cited text no. 9
    
10.
Venderbosch S, de Wilt JH, Teerenstra S, Loosveld OJ, van Bochove A, Sinnige HA, et al. Prognostic value of resection of primary tumor in patients with stage IV colorectal cancer: Retrospective analysis of two randomized studies and a review of the literature. Ann Surg Oncol 2011;18:3252-60.  Back to cited text no. 10
    
11.
Folkesson J, Birgisson H, Pahlman L, Cedermark B, Glimelius B, Gunnarsson U, et al. Swedish rectal cancer trial: Long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol 2005;23:5644-50.  Back to cited text no. 11
    
12.
Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M, et al. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 2006;93:1215-23.  Back to cited text no. 12
    
13.
Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Kryński J, et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: Results of a randomized phase III study. Ann Oncol 2016;27:834-42.  Back to cited text no. 13
    
14.
van Dijk TH, Tamas K, Beukema JC, Beets GL, Gelderblom AJ, de Jong KP, et al. Evaluation of short-course radiotherapy followed by neoadjuvant bevacizumab, capecitabine, and oxaliplatin and subsequent radical surgical treatment in primary stage IV rectal cancer. Ann Oncol 2013;24:1762-9.  Back to cited text no. 14
    
15.
Tyc-Szczepaniak D, Wyrwicz L, Kepka L, Michalski W, Olszyna-Serementa M, Palucki J, et al. Palliative radiotherapy and chemotherapy instead of surgery in symptomatic rectal cancer with synchronous unresectable metastases: A phase II study. Ann Oncol 2013;24:2829-34.  Back to cited text no. 15
    
16.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.  Back to cited text no. 16
    
17.
Patel UB, Blomqvist LK, Taylor F, George C, Guthrie A, Bees N, et al. MRI after treatment of locally advanced rectal cancer: How to report tumor response – The MERCURY experience. AJR Am J Roentgenol 2012;199:W486-95.  Back to cited text no. 17
    
18.
Arya S, Das D, Engineer R, Saklani A. Imaging in rectal cancer with emphasis on local staging with MRI. Indian J Radiol Imaging 2015;25:148-61.  Back to cited text no. 18
[PUBMED]  [Full text]  
19.
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. 19
    
20.
Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408-17.  Back to cited text no. 20
    
21.
Botrel TE, Clark LG, Paladini L, Clark OA. Efficacy and safety of bevacizumab plus chemotherapy compared to chemotherapy alone in previously untreated advanced or metastatic colorectal cancer: A systematic review and meta-analysis. BMC Cancer 2016;16:677.  Back to cited text no. 21
    
22.
Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. XELOX vs. FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer 2011;105:58-64.  Back to cited text no. 22
    
23.
Adam R, De Gramont A, Figueras J, Guthrie A, Kokudo N, Kunstlinger F, et al. The oncosurgery approach to managing liver metastases from colorectal cancer: A multidisciplinary international consensus. Oncologist 2012;17:1225-39.  Back to cited text no. 23
    
24.
Lam VW, Spiro C, Laurence JM, Johnston E, Hollands MJ, Pleass HC, et al. A systematic review of clinical response and survival outcomes of downsizing systemic chemotherapy and rescue liver surgery in patients with initially unresectable colorectal liver metastases. Ann Surg Oncol 2012;19:1292-301.  Back to cited text no. 24
    
25.
Yoon HI, Koom WS, Kim TH, Ahn JB, Jung M, Kim TI, et al. Upfront systemic chemotherapy and short-course radiotherapy with delayed surgery for locally advanced rectal cancer with distant metastases: Outcomes, compliance, and favorable prognostic factors. PLoS One 2016;11:e0161475.  Back to cited text no. 25
    
26.
Hyngstrom JR, Hu CY, Xing Y, You YN, Feig BW, Skibber JM, et al. Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: Analysis from the National Cancer Data Base. Ann Surg Oncol 2012;19:2814-21.  Back to cited text no. 26
    
27.
Tan Y, Fu J, Li X, Yang J, Jiang M, Ding K, et al. A minor (<50%) signet-ring cell component associated with poor prognosis in colorectal cancer patients: A 26-year retrospective study in China. PLoS One 2015;10:e0121944.  Back to cited text no. 27
    
28.
Chew MH, Yeo SA, Ng ZP, Lim KH, Koh PK, Ng KH, et al. Critical analysis of mucin and signet ring cell as prognostic factors in an Asian population of 2,764 sporadic colorectal cancers. Int J Colorectal Dis 2010;25:1221-9.  Back to cited text no. 28
    
29.
Glynne-Jones R, Hava N, Goh V, Bosompem S, Bridgewater J, Chau I, et al. Bevacizumab and combination chemotherapy in rectal cancer until surgery (BACCHUS): A phase II, multicentre, open-label, randomised study of neoadjuvant chemotherapy alone in patients with high-risk cancer of the rectum. BMC Cancer 2015;15:764.  Back to cited text no. 29
    
30.
Bachet JB, Lucidarme O, Taïeb J, Maillard E, Levache CB, Raoul JL, et al. FOLFIRINOX as induction treatment in rectal cancer patients with synchronous metastases (RCSM): Results of the FFCD 1102 phase II trial. J Clin Oncol 2016;34 15 Suppl: 3513.  Back to cited text no. 30
    
31.
Sahu A, Ramaswamy A, Ostwal V. Dihydro pyrimidine dehydrogenase deficiency in patients treated with capecitabine based regimens: A tertiary care centre experience. J Gastrointest Oncol 2016;7:380-6.  Back to cited text no. 31
    
32.
Crosara Teixeira M, Marques DF, Ferrari AC, Alves MF, Alex AK, Sabbaga J, et al. The effects of palliative chemotherapy in metastatic colorectal cancer patients with an ECOG performance status of 3 and 4. Clin Colorectal Cancer 2015;14:52-7.  Back to cited text no. 32
    
33.
Prigerson HG, Bao Y, Shah MA, Paulk ME, LeBlanc TW, Schneider BJ, et al. Chemotherapy use, performance status, and quality of life at the end of life. JAMA Oncol 2015;1:778-84.  Back to cited text no. 33
    
34.
Watanabe A, Yang C, Cheung WY. ECOG performance status as a predictor of adjuvant chemotherapy (AC) toxicities in stage III colorectal cancer (CRC) patients. J Clin Oncol 2017;35 4 Suppl: 789.  Back to cited text no. 34
    
35.
Ghosh J, Gupta S, Desai S, Shet T, Radhakrishnan S, Suryavanshi P, et al. Estrogen, progesterone and HER2 receptor expression in breast tumors of patients, and their usage of HER2-targeted therapy, in a tertiary care centre in India. Indian J Cancer 2011;48:391-6.  Back to cited text no. 35
[PUBMED]  [Full text]  
36.
Parikh RC, Du XL, Morgan RO, Lairson DR. Patterns of treatment sequences in chemotherapy and targeted biologics for metastatic colorectal cancer: Findings from a large community-based cohort of elderly patients. Drugs Real World Outcomes 2016;3:69-82.  Back to cited text no. 36
    
37.
Ignacio DN, Griffin JJ, Daniel MG, Serlemitsos-Day MT, Lombardo FA, Alleyne TA, et al. An evaluation of treatment strategies for head and neck cancer in an African American population. West Indian Med J 2013;62:504-9.  Back to cited text no. 37
    
38.
Maor Y, Malnick S. Liver injury induced by anticancer chemotherapy and radiation therapy. Int J Hepatol 2013;2013:815105.  Back to cited text no. 38
    
39.
Garufi C, Torsello A, Tumolo S, Ettorre GM, Zeuli M, Campanella C, et al. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. Br J Cancer 2010;103:1542-7.  Back to cited text no. 39
    
40.
Folprecht G, Gruenberger T, Bechstein W, Raab HR, Weitz J, Lordick F, et al. Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study). Ann Oncol 2014;25:1018-25.  Back to cited text no. 40
    
41.
Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: A multicenter study of the Gruppo Oncologico Dell'italia Meridionale. J Clin Oncol 2005;23:4866-75.  Back to cited text no. 41
    
42.
Aparicio J, Fernandez-Martos C, Vincent JM, Maestu I, Llorca C, Busquier I, et al. FOLFOX alternated with FOLFIRI as first-line chemotherapy for metastatic colorectal cancer. Clin Colorectal Cancer 2005;5:263-7.  Back to cited text no. 42
    
43.
Ostwal V, Engineer R, Ramaswamy A, Sahu A, Zanwar S, Arya S, et al. Surgical outcomes of post chemoradiotherapy unresectable locally advanced rectal cancers improve with interim chemotherapy, is FOLFIRINOX better than CAPOX? J Gastrointest Oncol 2016;7:958-67.  Back to cited text no. 43
    
44.
Gupta S, Bhattacharya D, Acharya AN, Majumdar S, Ranjan P, Das S, et al. Colorectal carcinoma in young adults: A retrospective study on Indian patients: 2000-2008. Colorectal Dis 2010;12:e182-9.  Back to cited text no. 44
    
45.
Tajiri K, Sudou T, Fujita F, Hisaka T, Kinugasa T, Akagi Y, et al. Clinicopathological and corresponding genetic features of colorectal signet ring cell carcinoma. Anticancer Res 2017;37:3817-23.  Back to cited text no. 45
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusions
References
Article Tables

 Article Access Statistics
    Viewed160    
    Printed9    
    Emailed0    
    PDF Downloaded34    
    Comments [Add]    

Recommend this journal