Keywords
Gastric - gastrointestinal malignancy - pancreatic
Colorectal
The optimal approach to maintenance treatment is less clear for patients with metastatic
colorectal cancer (mCRC) who achieve stability or deeper response with induction chemotherapy
with anti-endothelial growth factor receptor agents such as cetuximab or panitumumab.
In this Phase II VALENTINO trial,[1] 229 patients with previously untreated, RAS wild-type advanced mCRC were enrolled
to evaluate whether maintenance with panitumumab monotherapy was noninferior to maintenance
with 5-fluorouracil/leucovorin (5-FU/LV) plus panitumumab. After a median follow-up
of 13.8 months, the combination maintenance regimen showed a 10-month progression-free
survival (PFS) rate at 62.8% compared to 52.8% with monotherapy. The median PFS was
significant with the combination strategy at 13 months versus 10.2 months (Hazard
ratio [HR] 1.55, 95% confidence interval [CI] 1.09–2.02, P = 0.011). However, the trial failed to meet the criteria for noninferiority of panitumumab
monotherapy, which was set at a threshold of HR <1.515. Therefore, fluoropyrimidine
plus panitumumab should be the preferred maintenance option for patients who have
stopped oxaliplatin.
The current guidelines suggest preoperative fluoropyrimidine-based chemoradiation
for Stage 2 and 3 rectal cancer. Despite low local-regional relapse of 5%–6% with
preoperative chemoradiation (CRT), 30% of patients still develop distant metastasis.
The long-term survival is only 65% and needs improvement. Three randomized trials
evaluating the role of oxaliplatin to preoperative CRT and adjuvant therapy were presented
at a major conference recently.[2],[3],[4] Irrespective of Stage 2 or 3, the 5-year overall survival (OS) was similar with
or without oxaliplatin as radiation sensitizer. There was no improvement in the outcome
in terms of locoregional relapse and distant relapse. For locally-advanced rectal
cancer patients, neoadjuvant mFOLFOX6 ± radiation did not improve disease-free survival
compared to 5-FU CRT. However, mFOLFOX + RT improved the rate of pathologic complete
response (pCR), potentially enabling patients for a “watch and wait” options to avoid
or delay surgery.
For mCRCs with a molecular print of microsatellite-high, nivolumab has been approved
for the patients progressed on oxaliplatin and irinotecan-based regimen. Checkmate-142
is a multicenter, nonrandomized Phase 2 trial evaluated single-agent nivolumab or
in combination with other immune therapies in patients with microsatellite instability-high
(MSI-H) or deficient mismatch repair (dMMR) progressed on fluoropyrimidine, irinotecan,
and oxaliplatin.[5] The combination cohort received four doses of nivolumab at 3 mg/kg and ipilimumab
at 1 mg/kg every 3 weeks, followed by nivolumab at 3 mg/kg every 2 weeks. At a median
follow-up of 13.3 months, the overall response rate (ORR) was 55% in combination cohort
as compared to 31% in nivolumab monotherapy cohort. This needs to be interpreted cautiously,
as this is not a randomized trial and this is a cross-cohort comparison. Twelve-month
PFS was 71%, and 12-month OS was 85% in the combination cohort. Grade — adverse events
(AEs) were relatively common in combination cohort (32% vs. 20%). This combination
has now been incorporated in the National Comprehensive Cancer Network guidelines.
Regorafenib is an oral multikinase inhibitor that showed improved OS in previously
treated mCRCs in the CORRECT study.[6] The recommended dose was 160 mg oral daily once for 3 weeks in a 28-day cycle. However,
it is associated with significant toxicities such as hand-foot skin rash and fatigue
and almost every patient requires dose reductions or dose delays. The randomized Regorafenib
dose optimization study in 123 patients, compared fixed dose of regorafenib (160 mg)
to a dose-escalated regimen (80 mg/day with weekly dose escalation up to 160 mg) as
tolerated for 21 days during a 28-day cycle.[7] The primary endpoint was the patient proportion who completed two treatment cycles,
and this was met with 43% in escalated dose arm versus 24% in standard arm (P = 0.028). The incidence of Grade 3 or 4 toxicity was lower in escalation arm, thus,
considered as a reasonable strategy for treatment with regorafenib.
Approximately, one-fifth of the patients with mCRC will develop peritoneal carcinomatosis
(PC) and is associated with worse survival outcomes.[8] The phase III PRODIGE 7[9] was the first prospective French randomized trial to evaluate hyperthermic intraperitoneal
chemotherapy (HIPEC) in mCRC patients with PC. In this study, 265 patients were randomly
assigned in the operating room to the HIPEC or non-HIPEC group. Patients in the HIPEC
arm received intraperitoneal oxaliplatin 460 mg/m2 heated to 43°C over 30 min following
cytoreduction surgery. At the median follow-up of 64 months, no significant difference
was reported in terms of recurrence free (13.1 vs. 11.1 months; P = 0.486) and OS (41.7 vs. 41.2 months; P = 0.995) between HIPEC and nonHIPEC groups. The perioperative mortality was high
in the HIPEC arm. Therefore, the authors concluded that given the lack of survival
benefit and the increased risk of postoperative complications, the HIPEC has a limited
role for PC patients undergoing optimal debulking surgery.
Noncolorectal
Pancreas
It is estimated that by the year 2020, pancreatic cancer would be the second-most
leading cause of cancer-related deaths in the United States. Hence, there is a need
to improve treatment strategies in metastatic and nonmetastatic diseases.
PRODIGE 24/CCTGPA is a randomized adjuvant trial of modified FOLFIRINOX versus gemcitabine
for 6 months after surgery in 493 patients with resectable cancers.[10] Adjuvant therapy was initiated 3–12 weeks following surgery. Modified FOLFIRINOX
yielded an improved median OS of 54 months versus 35 months with gemcitabine. The
median disease-free survival was 22 months versus 13 months. However, as expected,
modified FOLFIRINOX was associated with severe treatment-related AEs. Modified FOLFIRINOX
is now been considered as one of the standards of care for adjuvant management in
good performance status patients.
PREOPANC–1 demonstrated neoadjuvant CRT followed by surgery is superior to upfront
surgery for localized and borderline resectable pancreatic cancers.[11] Two hundred and forty-six patients with resectable cancers were randomly assigned
to surgery upfront versus gemcitabine-based chemotherapy plus radiation for 10 weeks
before surgery. Median OS was 17.1 months with preoperative CRT compared to 13.7 months
with upfront surgery. Furthermore, the 2-year survival rate was 42% in the preoperative
CRT arm compared to surgery alone arm. The radial surgical resection in the neoadjuvant
therapy group was significantly improved to 63% (R0 resection) compared to 31% in
the group that did not receive neoadjuvant therapy. This trial emphasizes the importance
of neoadjuvant therapy even in resectable cancers, and several high volume institutions
do reflect this change of pursuing neoadjuvant therapy before surgery for resectable
cancers.
The maintenance strategy for metastatic pancreatic cancer patients who achieved a
maximal response or long-term stability on FOLFIRINOX is unknown. PRODIGE 35-PANOPTIMOX
is a randomized Phase II trial, evaluated oxaliplatin “stop-and-go” strategy and an
alternative sequential strategy in metastatic pancreatic cancers.[12] Two hundred and seventy-three patients were randomized to receive 6 months of FOLFIRINOX
(Arm A) or 4 months of FOLFIRINOX followed by LV5FU2 (fluoropyrimidine/LV) maintenance
(Arm B) or alternating gemcitabine and FOLFIRI (Arm C). The median PFS was 6.3, 5.7,
and 4.5 months, with a median OS of 10.1, 11.2, and 7.3 months, respectively. The
trial failed to show the benefit of stop-and-go as PFS/OS was similar and neuropathy
was worse in arm B. Therefore, an induction-maintenance strategy with discontinuing
oxaliplatin and irinotecan after 4 months of FOLFIRINOX is a reasonable strategy in
metastatic pancreatic cancer.
Pancreatic neuroendocrine tumors (pNETs) are treated with everolimus or sunitinib
that have a minimal response. In the randomized cooperative group study of temozolomide
or temozolomide and capecitabine in patients with advanced pNETs, a total of 144 patients
with progressive, Grade 1/2, metastatic pancreatic NETs were randomized into either
temozolomide alone or capecitabine/temzolomide (CAPTEM).[13] Median OS was 38 months with temozolomide alone, and it had not yet been reached
at the time of presentation of this data with CAPTEM (HR 0.41, P = 0.012). ORR was 27.8% with monotherapy and 33.3% with CAPTEM (P = 0.47). Duration of response was longer with the CAPTEM, at 12.1 months versus 9.7
months. Temozolomide + capecitabine demonstrated improved PFS and OS versus temozolomide
alone in patients with advanced pNETs. The ORR was high compared with most approved
therapies, but there was no significant difference between the treatment arms.
Hepatocellular Cancer
Over the past years, major clinical trials on hepatocellular cancers have witnessed
some promising results. However, numerous questions remain unanswered regarding the
optimal incorporation of these advances into routine practice, and to complicate matters
further, new findings are constantly being unveiled. Disease stage and treatment response
were considered to be the most important prognostic indicators. With multiple viable
therapeutic options, the treatment sequencing plays a critical role in management,
especially for transitioning from locoregional to systemic therapy.
CELESTIAL is the Phase 3 study of cabozantinib (C) versus placebo (P) in patients
(pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib.[14] In this study, 707 patients with Child-Pugh A cirrhosis progressed on at least 1
prior systemic therapy were randomized in a 2:1 ratio to treatment with cabozantinib
at 60 mg daily or placebo. The disease control rate was 64% with cabozantinib versus
33% with placebo and the median OS with cabozantinib was 10.2 months versus 8.0 months
with placebo, resulting in a 24% reduction in the risk of death (HR, 0.76). The median
PFS favored cabozantinib with 5.2 months versus 1.9 months with placebo (HR, 0.44,
P < 0.0001). Common AEs with cabozantinib include hand-foot syndrome (17%), hypertension
(16%), fatigue (10%), and diarrhea (10%). It is now considered the standard of care
in the second-line setting for the management of advanced HCC.[15]
The phase III REACH-2 trial reported that ramucirumab improved overall and PFS versus
placebo in patients with advanced HCC and increased α-fetoprotein levels in those
who had previously received sorafenib.[16] Previous biomarker-driven trials such as upregulation of expression of MET had failed
in HCC. REACH-2 is the very first Phase 3 trial in biomarker-selected HCCs with positive
outcomes. Subgroup analysis in earlier REACH phase 3 study in AFP high patients showed
an OS improvement with ramucirumab. This led to the phase III REACH-2, a multicenter,
randomized, double-blind study in advanced HCC who were either progressed or intolerant
to sorafenib and had elevated AFP ≥ 400 ng/mL. Patients were randomized to ramucirumab
8 mg/kg at every 2 weeks versus placebo. Ramucirumab significantly improved overall
and PFS versus placebo with a median OS of 8.5 months versus 7.3 months (HR, 0.674;
95% CI, 0.51–0.90; P = 0.0059). The most common AEs in the ramucirumab group were fatigue (27%), peripheral
edema (25%), hypertension (25%) with grade ≥3 AEs of hypertension (13%) in the ramucirumab
arm.
In the phase II TACTICS trial,[17] 56 patients with unresectable HCC were randomized to receive transarterial chemoembolization
(TACE) alone (n = 76) or sorafenib plus TACE (n = 80). The investigators introduced a new endpoint in this clinical trial, time to
untreatable progression (TTUP) and/or progression to TACE refractoriness. Treatment
with sorafenib following TACE was continued until TTUP, decline in liver function
to the Child–Pugh class C, or the development of vascular invasion and/or extrahepatic
spread. Development of new lesions while on sorafenib was not considered as a progressive
disease in this study because this is attributable to the natural tumor biology of
HCC and does not indicate treatment failure. It was reported that PFS was longer with
sorafenib + TACE compared to TACE alone (26.7 vs. 20.6 months; P = 0.02). The TTUP endpoint needs validation and it is critical to await more mature
survival outcomes of this study.
TACE is often used to treat unresectable HCC; however, no consensus on the definition
of TACE failure, hence, used in broader unselected populations.[18] Retrospective studies suggest that continuing TACE after refractoriness or failure
may not be beneficial and may delay from receiving subsequent treatments because of
the deterioration of liver function. With recent approvals of systemic therapy options,
it is vital to reassess the risks of continuing TACE after failure. The OPTIMIS was
an international, prospective, noninterventional study designed to assess the outcomes
of patients with HCC treated with TACE, followed or not followed by sorafenib, in
real-world clinical practice.[19] Evaluating patients with HCC for whom a decision to treat with TACE was made at
study entry. This study enrolled patients with the Barcelona Clinic Liver Cancer stage
B or higher. After propensity score matching to balance the cohorts, it was found
that patients who were started on sorafenib immediately following TACE ineligibility
had significantly increased median survival of 16.2 months compared to 12.1 months
in those who did not receive systemic treatment following TACE ineligibility. These
data highlight the importance of the earlier start of systemic therapy.
Esophageal Cancer
The impact of the CRT to surgery interval on pathological complete response has been
evaluated retrospectively in the National cancer database.[20] As pCR is an indicator of better disease-free and OS, previous data on esophageal
cancer and other solid malignancies showed higher pCR rates if time intervals between
CRT and surgery were longer. It was shown in this study that pCR rates increased as
the interval between neoadjuvant CRT and surgery increased; however, the corresponding
90-day mortality rates also increased (P = 0.04). Overall, this translated into an 11% increase in the pCR rate and a 5% increase
in the 90-day mortality rate for each additional week between CRT and surgery. The
authors concluded that esophagectomy is preferred to be performed within 65 days after
CRT to avoid worsened 90-day mortality risk.
Gastric and Esophageal Cancer
Gastric and Esophageal Cancer
The standard chemotherapy for advanced gastric cancer includes fluoropyrimidines,
platinum, taxanes, or irinotecan with biologics, including ramucirumab or trastuzumab
(for Her2-Neu positive tumors). Immunotherapy has been recently considered as an option
for MSI-H or PDL-1 >1 tumors. However, after the failure of the first- and second-line
therapies, effective cytotoxic options are limited. The TAGS study is a pivotal phase
III study that investigated the efficacy and safety of TAS-102 (trifluridine/tipiraci
or Lonsurf) plus best supportive care (BSC) compared with placebo plus BSC in patients
with metastatic gastric cancer that was refractory to standard treatments.[21] TAS-102 provided a 31% reduction in the risk of death compared with placebo with
median OS of 5.7 months compared with 3.6 months for placebo (HR, 0.69; P = 0.0003). Based on this study, the Food and Drug Administration has granted a priority
review for TAS-102 for use in previously treated patients with advanced or metastatic
gastric adenocarcinoma, including cancer of the gastroesophageal junction.
Pembrolizumab has been approved for treatment of advanced gastric/gastroesophageal
junctional (GEJ) tumors with MSI-H or positive expression of PDL-1. KEYNOTE-061 was
a randomized clinical trial that assessed the efficacy and safety of pembrolizumab
versus paclitaxel in previously treated patients with advanced gastric/GEJ cancer.[22] That study failed to show a survival improvement with pembrolizumab versus paclitaxel
as the median OS was 9·1 months with pembrolizumab versus 8·3 months with paclitaxel
(HR 0.82, P = 0.0421). In fact, what was disappointing was that the PFS was worse with pembrolizumab
compared to paclitaxel (1.5 months vs. 4.1 months). It was concluded that the study
did not meet the endpoint on OS. In a subset analysis, improvements in OS with pembrolizumab
were noted in patients with ECOG PS 0, PD-L1 CPS ≥10 and MSI-high tumors.
Conclusion
Addition of oxaliplatin as a radiation sensitizer to fluoropyrimidine during radiation
therapy did not improve clinical outcome in Stage 2/3 rectal cancer. FOLFOX is reasonable
adjuvant treatment option for rectal cancer, particularly in pathologic Stage III
disease. mCRC patients with PC could be managed with effective cytoreductive surgery
alone. The combination of nivolumab and ipilimumab emerged as one of the therapeutic
options for patients with mCRC with MSI-H or dMMR. The modification of the regorafenib
dosing made relatively more leading to better clinical outcomes. Modified FOLFIRINOX
is the potentially new adjuvant standard of care for resected pancreatic cancers.
Neoadjuvant therapy is an emerging therapeutic strategy in patients presented with
resectable or borderline pancreatic cancer. Combination of capecitabine and temozolomide
showed the longest PFS reported for pNETs-directed therapy. Several therapeutic options
are available for advanced or BCLC-C that draws attention on considering systemic
therapy early in the treatment sequence than delaying it by multiple locoregional
therapies. TAS 102 represents an effective therapeutic option for patients with heavily
pretreated metastatic gastric cancer.
