Keywords:
Gastrointestinal neoplasms - Stomach neoplasms - Esophageal neoplasms - Pancreatic
neoplasms - Colorectal neoplasms - Anal canal.
Descritores:
Neoplasias gastrointestinais - Neoplasias estomacais - Neoplasias esofágicas - Neoplasias
pancreáticas - Neoplasias colorretais - Canal anal.
INTRODUCTION
Gastrointestinal (GI) tumors include at least 8 different entities of cancer located
throughout the digestive tract and they represent a high proportion of all malignancies.
Data regarding incidence and mortality in the U.S.A. estimate that colorectal cancer
is the third malignancy in new cases and mortality in 2018.[1] All together, the incidence of GI tumors is superior to the incidence of either
breast or lung cancers.[2] Besides, just considering the location, GI tumors have a high morbidity potential,
and consequently, every new promising treatment is welcome. The aim of this article
is to present and review the most relevant studies presented or published during 2018
within a horizon of incorporation into clinical practice in a near future.
In September 2018, pembrolizumab was approved in Brazil for patients with metastatic
PDL1 positive gastroesophageal cancer based on the results of the phase II open-label
Keynote-059 trial. In this study, 259 patients (either PD-L1 positive or negative)
received pembrolizumab 200 mg IV every 3 weeks. Objective response rate in the overall
population was 11.6% (15.5% for those with PD-L1 positive tumors) with a median duration
of response of 8.4 months. Only 17.8% of the patients developed grade 3 or higher
adverse events.[3]
PANCREATIC CANCER
The study PRODIGE24/CCTG.PA.6, presented at ASCO 2018, compared adjuvant mFOLFIRINOX
versus gemcitabine in patients who had undergone complete macroscopic resection (R0
or R1) of a pancreatic adenocarcinoma. The study included 493 patients with ECOG PS
of 0-1, between the ages of 18 and 79 years and with a CA 19-9 < 180 U/mL within 12
weeks after surgery. The results demonstrated a significant improvement in disease-free
survival (DFS) and overall survival (OS), as well as in metastasis-free survival and
specific survival in all subgroup of patients. The median DFS improved from 12.8 months
in the gemcitabine group to 21.6 months in the mFOLFIRINOX group of patients (HR=0.58;
0.46-0.73; p<0.0001). The median OS improved from 35 months in the gemcitabine treated
patients to 54.4 months in the mFOLFIRINOX treated patients (HR=0.64; 0.48-0.86; p=0.003).
Patients treated with mFOLFIRINOX had significantly more diarrhea, neutropenic fever,
fatigue, vomiting, hand-foot syndrome, peripheral neuropathy and use of G-CSF while
gemcitabine treated patients had more flu-like symptoms. However, toxicity was manageable
and mFOLFIRINOX is the new standard in good performance status patients who have undergone
complete resection of a pancreatic adenocarcinoma.[4]
COLON CANCER
ReDOS is a phase II study that evaluates a lower starting dose of regorafenib followed
by a planned escalation compared to the standard dose in refractory metastatic colorectal
cancer. The dose escalation started at 80 mg/day in week one, with increasing dose
in weeks 2 and 3 (120 mg/day and 160 mg/day, respectively) if no significant drug-related
toxicities occurred. The standard dose arm started with the total dose of 160 mg/day.
Primary endpoint was the proportion of patients who completed 2 cycles of treatment
with intention to initiate the third cycle, and was significantly higher among the
experimental arm (43% versus 25%, p=0.028). This study brought a more acceptable schedule
option into clinical practice and potentially establishes a new standard for optimizing
regorafenib use.[5]
In 2017, the FDA approved anti-PD1 antibodies, such as pembrolizumab and nivolumab,
for cancers demonstrated to have high microsatellite instability (MSI-H) or with mismatch
repair deficiency (dMMR), regardless of tumor site or histology.[6] This year during the ESMO meeting results of one cohort of the CheckMate 142, a
nonrandomized phase II study, were presented. In this cohort, nivolumab plus low-dose
ipilimumab were evaluated as firstline therapy in 45 MSI-H/dMMR metastatic colorectal
cancer patients. Results demonstrated a response rate of 60% 44.3-74.3, disease control
rate of 84% 70.5-93.5 and a 12-months OS rate of 83% 67.6-91.7. Median OS has not
yet been reached. The combination was well tolerated, with only 16% of the patients
experiencing grade 3-4 toxicities. Although early, these results indicate a potential
new first line treatment option for patients with MSI-H/dMMR tumors.[7]
The phase III study PRODIGE 7 was presented at the ASCO meeting 2018 and demonstrated
no benefit in adding HIPEC (hyperthermic intraperitoneal chemotherapy) to surgery
in patients with colorectal peritoneal carcinomatosis. This multicenter trial randomized
265 patients with colorectal cancer and peritoneal metastasis for surgery only (non-HIPEC)
versus surgery plus HIPEC. Results showed a median OS of 41.2 versus 41.7 months (HR=1.00
0.73-1.37, p=0.995), respectively. Despite negative results, this was an expected
and important trial, which raises questions regarding the benefit of HIPEC in colorectal
cancer.[8]
The PROPHYLOCHIP trial aimed to define the role of a second-look surgery and HIPEC
in patients at a high risk of developing colorectal peritoneal metastases. The high-risk
group was defined as minimal peritoneal disease resected at the moment of the primary
tumor surgery, a history of ovarian metastases, or perforated tumors. Between 2012
and 2015, 150 patients were randomized to receive surveillance after adjuvant treatment
or a second-look surgery, with cytoreduction plus HIPEC with oxaliplatin if any carcinomatosis
were found. The selection criteria proved to be effective in detecting the high-risk
group patients, since at the moment of the second-look procedure, 52% of them presented
with peritoneal recurrence, with a median peritoneal cancer index of 4 and 25 patients
(33%) in the surveillance group experienced a peritoneal recurrence. Unfortunately,
the primary end-point of the study was not met, with a 3-year DFS of 44% in the second
look group and 51% in the surveillance group (p=0.75). The second end-point was also
not met, with a 3-year OS of 80% and 79% in the surveillance and second-look group,
respectively. The PROPHYLOCHIP study contributes to understanding the role of CRS
in the management of peritoneal recurrence of colorectal cancer and confirmed the
lack of benefit of the addition of HIPEC with oxaliplatin in this scenario.[9]
RECTAL CANCER
Long term results of the ADORE trial showed the benefit of adjuvant chemotherapy with
oxaliplatin for patients with yp stage III rectal cancer. DFS was significantly improved
for patients with yp stage III (HR=0.59 0.38-0.92, p=0.019), high grade histology
(HR= 0.28 0.08-0.97, p=0.045), tumors with minimal pathological regression (HR= 0.40
0.19-0.85 p=0.016), absence of lymphovascular (HR= 0.55 0.34-0.88, p=0.013) or perineural
invasion (HR=1.53 0.33-0.86, p=0.01). OS benefit was restricted to the group of patients
with ypN2 (HR=0.42 0.180.96, p=0.04) and tumors with minimal pathological regression
(HR=0.42 0.19-0.97, p=0.043).[10]
ANAL CANAL
A French multi-centric phase II trial enrolled 69 patients to evaluate clinical activity
and safety of docetaxel, cisplatin, and fluorouracil (DCF) chemotherapy in good performance
(ECOG 0-1) patients with metastatic or unresectable locally recurrent anal squamous
cell carcinoma (ASCC). Sixty-six patients received treatment, 36 received the standard
DCF (sDCF) regimen and 30 received the modified DCF (mDCF). Response rate (RR) was
86% with an impressive 44% CR rate. The median PFS for the overall population was
11.0 months (95% CI 9.3-16.4). OS at 12 months for the overall population was 83.1%
(95% CI 71.5-90.3). No significant difference was found comparing the efficacy of
mDCF to sDCF. As expected, toxicity was more frequent on the sDCF group with 30 of
36 83% patients presenting at least one grade 3-4 adverse events and 16 of 30 53%
in the mDCF regimen. In our opinion, despite the single arm design, this clinical
trial establishes mDCF as a first line option for ECOG 0-1 patients.[11]
Last, but not least, an international randomized phase II trial enrolled 91 patients
with inoperable locally recurrent or metastatic treatment-naïve, advanced ASCC to
receive cisplatin at 60 mg/m2 on D1 of a 21 day cycle plus 5-FU at 1000 mg/m2 /day over 24 hours on D1-D4, or carboplatin AUC 5 on D1 every 28 days plus paclitaxel
at 80 mg/m2 on D1, 8, and 15 every 28 days. The primary endpoint was RR, and secondary endpoints
included PFS, OS, toxicity and quality of life (QoL). The RRs to treatment were 57.1%
with cisplatin/5FU compared to 59.0% with carboplatin/paclitaxel. Median PFS was 5.7
months for cisplatin/5-FU versus 8.1 months for carboplatin/paclitaxel (p=0.375) while
median OS with the respective treatments were 12.3 and 20 months (HR=2.0; p=0.014).
Cis/Fu was significantly more toxic and severe adverse events were reported in 62%
of Cis/FU patients compared with 36% of patients receiving carboplatin/paclitaxel
(p=0.016). This trial in one of the few randomized trials on ACC and, despite the
small sample size, the benefit in terms of OS should be taken into account. Therefore,
we consider carboplatin/paclitaxel as a new standard of care for advanced/recurrent
anal cancer.[12]
Bibliographical Record
Anelisa K. Coutinho, Gabriel Prolla, Gustavo dos Santos Fernandes, Heber Salvador,
Renata D'Alpino Peixoto, Rui F. Weschenfelder. Year in Review 2018 by the Brazilian
Gastrointestinal Tumors Group - GTG: Gastrointestinal Tumors. Brazilian Journal of
Oncology 2019; 15: e-20190014.
DOI: 10.5935/2526-8732.20190014
