Is regorafenib providing clinically meaningful benefits to pretreated patients with metastatic colorectal cancer?

Treatment with regorafenib has demonstrated statistically significant improvements in terms of overall survival, progression-free survival and disease control when compared with placebo in pretreated patients with metastatic colorectal cancer in two placebo-controlled, randomized, phase III trials (CORRECT and CONCUR). Similar results were observed in two open-label, single-arm studies (REBECCA and CONSIGN) performed in the real-world setting. But several authors have suggested that the benefit provided by regorafenib may not be clinically meaningful for these patients. Moreover, it has been suggested that not all subgroups of patients might benefit from regorafenib. The intention of this review is to provide an overview of the existing evidence for regorafenib in terms of efficacy, tolerability and quality of life in different subpopulations according to clinical and biological characteristics. Additionally, the magnitude of the clinical benefit provided by regorafenib to these patients has been explored and whether there are poorer outcomes in certain subpopulations.     

How do patients who participate in cancer support groups differ from those who do not?

Research has shown that cancer patients in general benefit from support group participation. However, few patients attend such groups. This study investigated differences between participants of a community cancer support group and a random selection of non-participants from the Cancer Registry. Data were collected through mail survey, and included variables identified through past research and variables derived from Leventhal's self-regulatory model of illness representations and the theory of planned behaviour. Sixty-three support group participants and 44 comparison sample respondents were recruited. Support group participants were more likely to be female, without a partner, younger, and to have more education and formal support than non-participants. They held more favourable views of support groups, believed that significant others were favourable towards participation, and perceived less difficulty in joining a group. They furthermore used more active, adaptive coping strategies and felt more control over their cancer, but were more distressed and anxious. Non-participants reported more support from a special person. A multivariate logistic regression analysis showed only psychosocial variables to be independent predictors of participation. As psychological variables are amenable to change, increase of appropriate support group participation should be possible, for instance by addressing patients' beliefs about support groups.     

How do cancer patients who try to take control of their disease differ from those who do not?

The objective of this study was to compare patients who do and do not describe their coping strategies as attempts to control their cancer. This was a cross‐sectional study of adult, oncology outpatients from an urban medical centre diagnosed 6–24 months previously. Using open‐ended questions, we asked participants if they tried to ‘control’ their cancer or situation. If ‘yes’, how? If ‘no’, how had they ‘dealt with’ it? The Hospital Anxiety and Depression Scale (HAD) measured anxiety and depression. The Mental Adjustment to Cancer Scale (MAC) assessed six coping styles. Of the 44 participants, 57% were female. The mean age was 57 years. Eighteen (41%) said they used control strategies (control‐yes), 11 (25%) said they did not (control‐no), and 15 (34%) gave unclear responses (control‐unclear). Participants cited 97 different coping strategies that were grouped into proactive (e.g. lifestyle changes) and reactive strategies (e.g. stoic behaviour). In comparing these groups, the control‐yes group was more likely to be younger (P = 0.0001), live with other(s) (P = 0.003), be confident of being cured (P = 0.006), have greater ‘fighting spirit’ on the MAC (P = 0.04) and use more proactive strategies (P = 0.0001). The conclusion of this study is that cancer patients use many coping strategies, but those who think of them as methods of control are younger and more confident of being cured, and use more proactive strategies.     

Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis

BackgroundMicrosatellite instability (MSI) status in predicting the efficacy of adjuvant chemotherapy in colorectal cancer remains controversial.Materials and methodsStudies were identified through PubMed, Embase and ASCO proceedings with a combination of keywords (colorectal cancer, chemotherapy and MSI).ResultsA MA was performed for treated and non-treated MSI population on seven studies. Statistical calculations were performed on 7 studies representing 3690 patients; mean age: 65.5 years; 810 stage II and 2444 stage III (75%). MSI-high (MSI-H) was found in 454 patients (14% of the global population), and microsatellite stable (MSS) in 2871. A total of 1444 patients received 5-fluorouracil (5FU)-based chemotherapy, whereas 1518 patients did not.For MSI-H patients, there was no statistically significant difference for RFS whether or not they received chemotherapy (5 studies); HR RFS: 0.96 (95% confidence interval (CI): 0.62–1.49); HR OS (6 studies): 0.70 (95% CI: 0.44–1.09; p = 0.12). Elsewhere, we found a significant interaction between MSI status (MSI-H or MSS) and therapeutic status suggesting a lesser benefit for MSI-H than for MSS patients (HR interaction RFS: 0.77 (95% CI: 0.67–0.87)).ConclusionWe found similar RFS for treated and untreated MSI-H patients, showing that MSI-H status, in addition to being a good prognostic factor is also a predictive factor of non response.     

Is the combination of immunotherapy with conventional chemotherapy the key to increase the efficacy of colorectal cancer treatment?

Colorectal cancer(CRC) is among the most prevalent and deadly neoplasms worldwide. According to GLOBOCAN predictions, its incidence will increase from 1.15 million CRC cases in 2020 to 1.92 million cases in 2040. Therefore, a better understanding of the mechanisms involved in CRC development is necessary to improve strategies focused on reducing the incidence, prevalence,and mortality of this oncological pathology. Surgery, chemotherapy, and radiotherapy are the main strategies for treating CRC....     

Do all patients with metastatic colorectal cancer need chemotherapy until disease progression?

The question of continuous versus intermittent chemotherapy for patients with metastatic colorectal cancer has been an ongoing issue of debate for determining the optimum duration of treatment. The results from 2 major trails addressing this issue were recently presented at the 2006 Annual Meeting of the American Society of Clinical Oncology. The OPTIMOX2 trial evaluated the efficacy and safety of oxaliplatin reintroduction after a complete chemotherapy-free interval or maintenance therapy in patients with previously untreated disease. The GISCAD (Italian Group for the Study of Digestive Tract Cancer) study investigated the utility of intermittent versus continuous irinotecan-based chemotherapy. Both studies demonstrated that chemotherapy can be administered intermittently without affecting the overall efficacy of treatment.     

Chemotherapy rechallenge after regorafenib treatment in metastatic colorectal cancer: still hope after the last hope?

Introduction: The introduction of biological agents in cancer therapy is changing the progression of metastatic colorectal cancer. Currently, resistance to biological agents is an emerging problem; the progression of the disease is caused by the development of resistant clones. According to some authors, these clones can be re-sensitized to traditional and previously utilized chemotherapy agents. The results of the CORRECT study demonstrated the efficacy of regorafenib monotherapy in both KRAS wild type and mutant pretreated patients (pts). Two recent reports showed the potential of reintroduction of chemotherapy, even after treatment with regorafenib.

Patients and methods: We performed a retrospective review of clinical data from patients treated with regorafenib at our institution between March 2012 and March 2013. We analysed patient characteristics, KRAS/NRAS status, response to treatment (evaluated by RECIST v1.1 criteria) and survival.

Results: Regorafenib was administered to 128 patients, and 11 (8.6%) received post-regorafenib therapy (to our knowledge). Seven (63.6%) patients were wild type for KRAS/NRAS. Post-regorafenib therapy represented for all the patients at least the fourth line: all the pts received both oxaliplatin- and irinotecan-based chemotherapy, all of them were treated with bevacizumab, and 7 patients also received cetuximab. Eight patients (72.7%) were treated with standard chemotherapy after regorafenib (irinotecan monotherapy, capecitabine plus oxaliplatin or irinotecan, dacarbazine or raltitrexed), while 3 patients received an experimental therapy (clinical trial). Nine of the 11 (81.8%) patients had PD and 2 patients had SD. The median progression-free survival was 1.6+ months (range 0.5–3.5), the median OS post-regorafenib was 2.1+ months (range 0.5–10.2) and the 6-month OS was 27.3%.

Conclusion: Our retrospective analysis showed that after regorafenib therapy, re-introduction of chemotherapy is possible. Unfortunately, we reported a high percentage of disease progression beyond regorafenib, which is likely due to the high percentage of heavily pretreated patients (some received four or five types of therapy before regorafenib). We think that regorafenib could represent a chemotherapy resensitizing agent; however, additional studies are needed in patients who have received less pretreatment.     

Does chemotherapy prior to liver resection increase the potential for cure in patients with metastatic colorectal cancer? A report from the European Colorectal Metastases Treatment Group

Liver resection offers the only chance of cure for patients with advanced colorectal cancer (CRC). Typically, the 5-year survival rates following liver resection range from 25% to 40%. Unfortunately, approximately 85% of patients with stage IV CRC have liver disease which is considered unresectable at presentation. However, the rapid expansion in the use of improved combination therapy regimens has increased the percentage of patients eligible for potentially curative surgery. Despite this, the selection criteria for patients potentially suitable for resection are not well documented and patient management by multidisciplinary teams, although essential, is still evolving. The goal of the European Colorectal Metastases Treatment Group is to establish pan-European guidelines for the treatment of patients with CRC liver metastases that can be adopted more widely by established treatment centres and to develop more accurate staging systems and evaluation criteria.     

Clinical observation of Endostar? combined with chemotherapy in advanced colorectal cancer patients

Objective: Endostar® (Rh-endostatin injection) is a new recombinant human endostatin developed by Shandong Simcere-Medgenn Bio-Pharmaceutical Co., Ltd in China. This study was performed to evaluate the efficacy and safety of Endostar plus leucovorin calcium/ 5-fluorouracil/oxaliplatin (FOLFOX4) in treating patients with advanced colorectal cancer. Methods: Thirty-six patients with advanced colorectal cancer were retrospectively assigned to one of two treatment groups: FOLFOX4 (control) or FOLFOX4 plus Endostar (Endostar) according to patient accreditation. The observational end points were overall response rate, overall survival, progression-free survival and toxicity. Results: The response rate and progression-free survival of Endostar were significantly better than those of control group (P <0.05), but significance was not observed for median survival. In addition, gastrointestinal side effects and incidence of leucopenia were not lower than in the control group (P<0.05). Conclusions: The addition of Endostar to FOLFOX4 resulted in a higher objective response rate and longer time to disease progression. Hypertension and cardiac ischemia were the principal safety concerns, but were manageable. Endostar deserves to be further investigated by randomized controlled clinical trails.     

Impact of granulocyte colony–stimulating factors in metastatic colorectal cancer patients

Background

Delays in chemotherapy because of neutropenia may be associated with poorer outcomes. The purpose of the present study was to examine the effect that granulocyte colony–stimulating factors (g-csfs) have on survival.

Methods

We conducted a chart review of all outpatients diagnosed with metastatic colorectal cancer and treated with folfiri chemotherapy (irinotecan, 5-fluorouracil, leucovorin) with or without bevacizumab at Mount Sinai Hospital between 2007 and 2012. Multivariable Cox proportional hazards models were used to compare survival in neutropenic patients treated with g-csf, in neutropenic patients not so treated, and in patients without neutropenia.

Results

The review identified 93 patients, 31 of whom did not experience a neutropenic event. Of the 62 who experienced neutropenia, 18 were managed with g-csf support, and 44, with reductions or delays in dose. Compared with patients experiencing a neutropenic episode not treated with g-csf, those treated with g-csf experienced a nonsignificant increase in time to event [progression or death: hazard ratio (hr): 1.37; 95% confidence limits (cl): 0.72, 2.61], but compared with patients not having a neutropenic episode, the same patients experienced a significant increase in time to event (hr: 2.07; 95% cl: 1.03, 4.15).

Conclusions

In patients who experienced neutropenia, g-csf did not have a statistically significant impact on survival. Time to event was prolonged in g-csf–treated patients compared with patients who did not experience neutropenia.     

Severe hepatic sinusoidal obstruction and oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer: a real entity?

We have read with interest the study of Rubbia-Brandt et al.[1] entitled ‘Severe hepatic sinusoidal obstruction associatedwith oxaliplatin-based chemotherapy in patients with metastaticcolorectal cancer’. In this study, the investigators identifiedin the specimens from liver resection for colorectal metastases,some histological lesions of the non-tumoral liver parenchymaattributed to oxaliplatin-based chemotherapy. The results ofthis study     

Does chemotherapy regimen matter in the neoadjuvant treatment of esophageal cancer?

BackgroundNeoadjuvant chemoradiotherapy has become the mainstay of treatment for locally advanced esophageal cancer. CALGB 9781 trial established cisplatin and 5-flourouracil (5-Fu) with radiotherapy as superior to surgery alone while the CROSS trial established paclitaxel, carboplatin, and radiotherapy as superior to surgery alone. Previous data has been unclear as to which regimen provides a superior pathologic response. This study aims to look at this. This study aims to look at this.MethodsA retrospective chart review at a single institution of patients who underwent esophagectomies after neoadjuvant chemoradiotherapy with either cisplatin and 5-Fu or carboplatin and paclitaxel between 2012–2020 was performed. Demographics as well as staging, response rates, and modified Ryan scores were collected. Univariate analysis between the two groups was performed.ResultsA total of 82 patients were identified between 2012–2020 who underwent esophagectomy after neoadjuvant chemoradiotherapy. In total, 74 (90.2%) received carboplatin and paclitaxel while 8 (9.8%) received 5-Fu and carboplatin. Both groups included patients with squamous cell carcinoma (SCC) and adenocarcinoma. No significant factors were found in terms of patient comorbidities or pathologic staging. There was no significant difference in modified Ryan score between the two groups (P=0.745).ConclusionsThis study evaluates the degree and presence of pathologic response between the two neoadjuvant chemoradiotherapy modalities used for esophageal cancer. Our results, in contrast to other studies, suggest no significant difference with regards to pathologic response rate. Furthermore, our findings suggest that use of the least toxic regimen would make sense.     

Single-arm phase II trial to evaluate efficacy and tolerance of regorafenib monotherapy in patients over 70 with previously treated metastatic colorectal adenocarcinoma FFCD 1404 – REGOLD

BackgroundRegorafenib significantly increases overall survival (OS) in patients with metastatic colorectal cancer previously treated but gives toxicities.Objectivesto assess the efficacy and safety of regorafenib at it's approved dose in the older population.Patients and methodsThis multicenter single-arm phase II enrolled patients ≥70 years old after the failure of fluoropyrimidine-based chemotherapy, anti-VEGF, and anti-EGFR treatment. The primary endpoint was disease control rate (DCR) 2 months after initiation of regorafenib (160 mg/day, 3 weeks on/1 week off).ResultsForty-three patients were enrolled, with a median age of 77 years. The 2 months DCR was 31.4% in the 35 evaluable patients. For the 42 patients that received at least one dose of regorafenib, median progression-free survival and OS were 2.2 and 7.5 months. The median time to autonomy degradation and quality of life degradation was 3.1 and 3.2 months, respectively. A grade 3–4 treatment-related adverse events was observed in 35/42 patients, notably: fatigue (45.2%), hand-foot skin reaction (19.0%), hypertension (21.4%), and diarrhea (7.1%). There is a trend to achieve DCR in patients ≤80 years and a trend to discontinue the study due to toxicity in patients with ECOG ≥1, over 80 years and with impaired baseline autonomy.ConclusionTreatment with regorafenib in pretreated patients ≥70 years is feasible and demonstrate similar efficacy that was observed in previous studies in young patients. Fatigue is the most frequent severe adverse event. However, caution should be taken for older patients with ECOG ≥1, over 80 years, and with impaired baseline autonomy.