The safety and effectiveness of Bevacizumab in Metastatic Colorectal Cancer with Unresectable Metastases: A Real-Life Study from the south of Morocco

doi:10.21203/rs.3.rs-3910738/v1

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Research Article

The safety and effectiveness of Bevacizumab in Metastatic Colorectal Cancer with Unresectable Metastases: A Real-Life Study from the south of Morocco

https://doi.org/10.21203/rs.3.rs-3910738/v1

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published 21 Mar, 2024

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Colorectal cancer constitutes a significant public health challenge, yet remarkable strides have been made in the last two decades, particularly in the medical management of metastatic stages. Notable progress has been achieved through targeted therapies such as Anti-EGFR or Anti-Angiogenic Antibodies, as well as advancements in surgical approaches for hepatic metastases. This study seeks to assess the efficacy and safety of Bevacizumab Plus Chemotherapy in individuals dealing with metastatic colorectal cancer."

This is a observational cross-sectional retrospective study of all the patients who were followed up for metastatic colorectal cancer with unresectable metastases and were treated by Bevacizumab in combination with a standard chemotherapy from January 2010 until December 2019 in the medical oncology department of the CHU Souss Massa of Agadir.

Of the total 162 cases,72% patients were with metastatic disease, 28% progressed to metastatic disease after initial treatment. The median age of patients were 55 (23–79 years) with a sex ratio of 1.1 (M / F) .The tumor was located in the left colon in 83.4% of the patients. The results represented: adenocarcinoma in 84,6% of the cases and mucinous subtype in 14.19% .The three most common sites of metastasis were: liver 61.6%,peritoneum 41.5% and lung 20.37%. In the first line, 100% of the patients received bi-chemotherapy plus bevacizumab: XELOX 54.3% ,FOLFOX 20.9%, XELERI 14.1% and FOLFIRI 10.4%. Response after first-line treatment were: 45,7% progression, 25.9% stability, 21.6% partial response, 6,8% complete response. 6% of patients were able to benefit from surgical resection of metastatic lesions. 25,8% of patients received 5FU in 2nd line chemotherapy with irinotecan in 20.7% of the cases or with oxaliplatin in 5.1% of the cases. Two patients developed undesirable side-effects under bevacizumab (hypertension). The median progression-free survival and median overall survival of study cohort were 9 months and 14 months respectively. Nevertheless, patients who underwent primary tumor resection (p 0.048), those with rightsided tumors (p 0.022), those who received a higher number of treatment cycles (p 0.020) and those who received maintenance treatment (p 0.001) had a longer median OS .

Chemotherapy combination with bevacizumab is considered as the cornerstone of mCRC treatment in our region. With the new healthcare and social security systems, easier access to expensive treatments and molecular pathology tests is currently available. It is important to highlight that real world data can offer valuable insights for daily clinical practice of medical oncology.

Cancer Biology

metastatic colorectal cancer

Bevacizumab

safety

Colorectal cancer is generally recognized as a common cancer and ranks second in terms of cancer related deaths (1). In Morocco, it holds the third position, among cancer types based on data from regional registries with its incidence showing an upward trend (2). Over many years, there have been significant advancements and changes in the treatment landscape for metastatic colorectal cancer (mCRC). These improvements can be attributed to several factors, including advancements in liver surgery and interventional radiology that now allow for liver metastasectomy which was previously considered impossible. Moreover, valuable knowledge on how to combine and use cytotoxic agents has been gained from numerous multicenter studies (3). Additionally, targeted treatments have played a role in these advancements by identifying molecular structures. Some notable examples include bevacizumab, a humanized monoclonal antibody targeting VEGF and panitumumab or cetuximab monoclonal antibodies targeting EGFR (4). These new therapies can now be used as an option for treating mCRC. In the part of Morocco, The Ministry of Health and the Lalla Salma Foundation collaborated to secure access to various expensive targeted drugs, including bevacizumab, for patients covered by public health insurance. However, this initiative has not been extended to cetuximab and panitumumab. Additionally, research on the RAS/RAF mutation has proven to be financially challenging for patients in this region, making access to these therapies more difficult. That is why we have undertaken this study on patients being treated for metastatic colon cancer, the first of its kind in southern Morocco.

The main aims of our study are to delineate patient characteristics, to assess the utilization of bevacizumab and its effectiveness on extending progression-free survival (PFS) and overall survival (OS), to identify predictive factors influencing outcomes, and finally to examine safety in patients with metastatic colorectal cancer (mCRC) undergoing treatment in routine medical practice.

This study was an observational cross-sectional retrospective study. We analyzed patient’s records, who were diagnosed with metastatic colorectal cancer. This study was conducted at the Department of Medical Oncology in Souss Massa University Hospital Center of Agadir in Morocco, from January 2010 to December 2019. The research was carried out with the approval of the local hospital committee, and data was collected by reviewing the hospital's electronic database and patients' medical records. Our study strictly adhered to the ethical guidelines for medical research involving human subjects, as outlined in the Declaration of Helsinki issued by the World Medical Association. The study included patients who met specific eligibility criteria, which included a histopathological diagnosis of colorectal cancer with metastatic disease and unresectable metastases. These eligible patients underwent treatment with bevacizumab in combination with standard chemotherapy. Patients who had undergone a minimum of one chemotherapy cycle were enrolled in this study. Conversely, the study excluded individuals who received supportive care, chemotherapy alone or radiation therapy. For categorization purposes, tumors located in the rectosigmoid, descending colon, and splenic flexure were classified as left-sided colon cancers. Meanwhile, tumors located in the ascending colon were categorized as right-sided colon cancers. In the initial treatment phase, patients received first-line chemotherapy with bevacizumab, administered either at a dose of 5 mg/kg every two weeks or of 7.5 mg/kg every three weeks. This was associated with chemotherapy based on either 5FU or capecitabine in combination with oxaliplatin (FOLFOX, XELOX) or with irinotecan (FOLFIRI, XELERI). Afterwards, maintenance treatment involved the continuation of bevacizumab in combination with chemotherapy.

Treatment efficacy was assessed through clinical examinations, carcinoembryonic antigen levels, and contrast-enhanced computed tomography (CECT) scans interpreted following the RECIST guidelines (version 1.1). These evaluations were conducted after a minimum of 3–4 cycles (approximately 3 months) of treatment.

Gathered data included patient demographics, disease specificities, treatment details, disease evolution, and mortality. Safety assessment focused on recognizing adverse events related to bevacizumab encompassing proteinuria, hypertension, bleeding, bowel perforation, impaired wound healing, and arterial thromboembolisms. Several factors were analyzed to determine the treatment outcomes, including age, gender, primary tumor location (right or left colon), surgical resection of metastatic lesions, and treatment response.

Overall survival (OS) stands for the duration from the time of diagnosis of mCRC with CECT to either the time of death. Progression-free survival (PFS) delineates the time from the diagnosis establishment to the progression occurrence, the date of death, or the last day of follow-up. The scheduled follow-up date is 30/01/2022.

The Kaplan-Meier method was utilized to estimate PFS and OS, and comparisons were made using the log-rank test. P-value of < 0.05 was considered as statistically significant. To determine the associated factors for OS and PFS, we employed Cox proportional hazards models in both univariate and multivariate analyses. The factors with a significant p-value were introduced into the multivariate model. Then, we forced the model by introducing the variable (side) into the multivariate analysis of OS because it was described in other series (14)(18).

Socio-Demographic data

Between January 2010 and December 2019, a total of 162 patients were enrolled. The median age of our patient’s cohort was 55 years (23-79 years). 22.6% were categorized as young patients, aged 45 years or younger. The study had a sex ratio of 1.1 (M/F), with 54% of male and 46% of female patients.

In terms of comorbid conditions, only 8,1% of patients had additional health issues, which included diabetes (4.9%), hypertension (1.8%), and heart disease (1.2%). Additionally, two patients had a familial background of cancer (table 1).

Table 1. Patients’demographics

Patients’ characteristics (n=162)

N (%)

Gender

Female

Male

75 (46)

87 (54)

Age (mean ± SD)

Age groups

≤ 45

46–69

≥ 70

55 ± 12.1 years (Range : 23-79 years)

37 (22.6)

110 (68.2)

15 (9.2)

Comorbid conditions

Yes

13 (8.1)

149(91.9)

Type of comorbidities

Hypertension

Heart disease

Diabetes

3 (1.8)

2 (1.2)

8 (4.9)

Clinical Characteristics

Regarding tumor location, 49.3% of patients had tumors in the left colon, 16.6% in the right colon, and 33.9% in the rectum. RAS mutational profiling was conducted in three patients in our study. Among the cases of colorectal cancer, 84,6% were classified as adenocarcinoma and 14.19% as mucinous subtype. Additionally, there were two cases with a kitten-ring cell component.

On all of our patients, 117 (72%) had de-novo metastatic disease, while the 45 (28%) remaining patients experienced disease progression leading to metastasis after their initial treatment.

The most prevalent metastasis sites were liver, accounting for 61.1% of cases, followed by peritoneum (41.3%), lungs (20.3%), non-regional lymph nodes (12.9%), and less commonly ovaries (3.7%) and bone (1.8%) (table 2).

Table 2. Clinical characteristics of study participants

Patients’ characteristics

N (%)

Primary tumor site

Left colon

Right colon

Rectum

80 (49.3)

27 (16.6)

55 (33.9)

RAS status availability

Yes

3 (1.8)

159 (98.2)

Morphology

Well differentiated adenocarcinoma

moderately differentiated Adenocarcinoma

Indifferentiated Adenocarcinoma

Signet ring

Mucinous

87(53.7)

42(25.9)

8(4.9)

2(1.2)

23(14.19)

patients

de novo metastatic disease

progressed to metastatic disease after initial treatment

117 (72)

45(28)

Metastasis

Liver

Peritoneum

Lung

Non regional lymph nodes

Ovary

Bone

99(61.1)

67(41.3)

33(20.3)

21(12.9)

6(3.7)

3(1.8)

Number of organ involved

≥ 3

103(63.5)

47(29.0)

11(6.7)

Treatment and safety :

In the first-line setting, all patients received chemotherapy (CMT) combination regimen associated with bevacizumab. 75% of patients received Oxaliplatin-based chemotherapy (FOLFOX 20.9% and XELOX 54.3%) and 25% of patients received Irinotecan-based chemotherapy (FOLFIRI 10.4% and XELERI 14.1%) (table 3). Median number of received cycles was 6. After first line CMT, the observed response was progression in 35 % of cases, stability in 27.16 % of cases and either partial or complete response in 20.98% and 8.64% of cases, respectively (table 4). 6% of patients had metastatic resection after first line CMT. 47% of patients received a second line CMT, based on 5-FU with irinotecan in 49.3% of cases or with oxaliplatin in 40.7% of cases (table 3). Regarding side effects, two patients developed bevacizumab related adverse events (hypertension).

Table 3: Chemotherapy regimen given in first- and in second-line setting.

Chemotherapy lines

Regimen

N (%)

First-line

N= 162

FOLFOX

XELOX

FOLFIRI

XELERI

34(20.9)

88(54.3)

17(10.4)

23(14.1)

Second-line

N=77

FOLFOX

XELOX

FOLFIRI

XELERI

GEMOX

4(5.1)

26(33.7)

16(20.7)

24(31.1)

7(9.0)

Table 4: Response rate to first- and second-line chemotherapy.

Response

First line (%, N 162)

Second line (%, N 77)

Progression

Stability

Partial response

Complete response

45.7%

25.9%

21.6%

6.8%

58.9%

21.4%

14.3%

5.4 %

Survival analysis

The median progression-free survival (PFS) for patients receiving bevacizumab as first-line treatment was 9 months (95% CI: 7.58 –10.15) (Figure 1 (A)). In term of PFS, factors that showed significance during univariate analysis included primary tumor resection and number of CMT Cycles. However, no differences were found according to age, gender, side or CMT regimen. Multivariate analysis revealed that two factors remained significantly associated to a lower PFS: patients without primary tumor resection and patients who received a lower number of treatment cycles (Table 5).

The median overall survival (OS) for the study cohort was 14 months (95% CI: 11.99 –16.00) (Figure 1 (B)). No significant disparity was observed in the median OS based on gender, age (either less or more than 45 years old), CMT regimen and liver or peritoneum metastasis. Nevertheless, patients who underwent primary tumor resection (p 0.048), those with right‑sided tumors (p 0.022), those who received a higher number of treatment cycles (p 0.020) and those who received maintenance treatment (p 0.001) had a longer median OS (Table 6).

Table 5: Univariate and multivariate analysis of different prognostic factors for progression free survival.

Variable		Univariate Analysis		Multivariate Analysis
Variable		Hazard Ratio (CI)	p‑Value	Hazard Ratio	p‑Value
Age	(<45 years vs. ≥ 45 years)	1.424 (0.966–2.098)	0.074
Gender	(female vs male)	0.978 (0.708–1.351)	0.891
Tumor location	(left-sided vs right-sided)	0.828 (0.539–1.271)	0.389
Chemotherapy regimen	(Irinotecan vs oxali‑based)	1.233 (0.848–1.794)	0.273
Number of cycles		0.757 (0.668–0.858)	0.002	0.758 (0.669–0.860)	0.001
Peritoneum metastasis	(Yes vs No)	1.328 (0.958–1.840)	0.89
Liver metastasis	(Yes vs. No)	1.255 (0.899–1.752)	0.182
Resection of the primary tumor	(Yes vs. No)	0.313 (0.144–0.678)	0.003	0.197 (0.086–0.451)	0.0001

Table 6: Univariate and multivariate analysis of different prognostic factors for Overall survival.

Variable		Univariate Analysis		Multivariate Analysis
Variable		Hazard Ratio	p‑Value	Hazard Ratio	p‑Value
Gender	(female vs male)	0.946 (0.686–1.304)	0.735
Age	(<45 years vs. ≥ 45 years)	1.310 (0.896–1.914)	0.164
Tumor location	(left-sided vs right-sided)	0.642 (0.407–1.013)	0.057	0.578 (0.361–0.924)	0.022
Chemotherapy regimen	(Irinotecan vs oxali‑based)	0.784 (0.541–1.135)	0.197
Number of cycles		0.911 (0.847–0.980)	0.012	0.915 (0.849–0.986)	0.020
Liver metastasis	(Yes vs. No)	0.817 (0.588–1.136)	0.230
Peritoneum metastasis	(Yes vs No)	0.952 (0.691–1.313)	0.766
Resection of the primary tumor	(Yes vs No)	0.426 (0.207–0.877)	0.014	0.476 (0.228–0.994)	0.048
Maintenance treatment	(Yes vs No)	0.496 (0.353–0.698)	0.0001	0.536 (0.377–0.763)	0.001

This retrospective and observational study, which is the first of its kind in southern Morocco, was conducted to analyze the characteristics of our population and assess the efficacy and safety of treatment with bevacizumab in metastatic colorectal cancer (mCRC).

The bevacizumab introduction into treatment regimen has deeply modified the management of mCRC. Its use in conjunction with chemotherapeutic regimens has quickly become the standard of care in first- and second-line treatment (5–8). Bevacizumab is a humanized monoclonal IgG1 antibody that inhibits tumor neovascularization and endothelial cell response associated with tumor permeability, proliferation, and migration (9). The first trial that evaluated Bevacizumab in mCRC, the AVF2107 trial, demonstrated its efficacy in combination with 5FU and irinotecan with an improvement in overall survival of 4.7 months, leading to its approval by the FDA (10). Bevacizumab was expected to have an activity as a single agent by reducing the blood vessel density within tumors. However, it provided a modest response rate (RR) contrary to its combination with chemotherapy, which demonstrated significant efficacy in terms of OS, PFS, and RR (11). Obviously, survival rates (OS) have been raised from 8 to 10 months with a solitary drug, extending to more than 18 to 24 months when using combinations of chemotherapeutic agents, and peaking up to 34 months when bevacizumab has been introduced (12).

Age is a principal risk factor for colorectal cancer. This type of cancer is uncommon before the age of 40. Its incidence rises notably from age 40 to 50, with age-specific incidence rates growing with each following decade. Data from the U.S. Surveillance, Epidemiology, and End Results (SEER) and other Western cancer registries indicate that CRC incidence is on the rise in the under-50 age group, and on the decline in older age groups (13). The median age within our population is 55 years old. A similar median age of 52 was found in a study carried out in the eastern region of Morocco, specifically in Oujda (14).

Colorectal cancer is heterogeneous in its tumor type, with pathogenesis determined by anatomical location, particularly the distinction between the right and left sides of the colon. Response to treatment varies considerably between these distinct tumor entities. Right-sided tumors often present with mutations in the DNA mismatch repair pathway and generally have a flat histology. Conversely, left-sided tumors often present with mutations in the chromosomal instability pathway, involving mutations in KRAS, APC, PIK3CA and p53, and have a polypoid-like morphology. (15) In our study, the left side accounts for 83.2%, while the right side represents only 16.6% of cases. These findings align with the results of other studies (12) (14).

The majority of malignant tumors in the colon and rectum are carcinomas, of which 90% are adenocarcinomas. Signet ring cell carcinomas constitute an aggressive subtype of adenocarcinomas associated with an unfavorable overall prognosis. Mucinous carcinomas represent approximately 11 to 17% of all colorectal cancers. This histological type has a predilection for the right side of the colon and may exhibit low sensitivity to initial chemotherapy (16). In our study, adenocarcinoma constitutes the most common histology (84.6%), followed by mucinous (14%) and signet ring cells (1.2%) histologies, which is similar to the literature data (16). The department had limited information regarding the RAS mutation profile and other molecular characteristics, due to the lack of other target therapies and the high cost of these analyses. Thus, we have to better investigate the molecular aspect in the future and request RAS and MSI status for an effective therapeutic strategy.

Common sites for distant metastasis involve the liver and peritoneum. Roughly 20% of patients display synchronous metastases, with the liver being the primary location. Peritoneal metastases were identified in 25% of patients, which implied an inferior prognosis in comparison to metastases occurring in other locations (17). We observed a liver metastases rate of nearly 61%, which closely aligns with the 73% reported by Hugens et al. The elevated prevalence of adenocarcinoma within our cohort likely contributes to the heightened occurrence of liver metastases (18).

Regarding chemotherapy combinations used with bevacizumab, several studies have compared the FOLFOX with FOLFIRI protocols in combination with bevacizumab. Notably, Giuseppe et al. demonstrated that there is no disparity in RR (31% vs 34%), overall survival (14 vs 15 months) or progression-free survival (7 months in both regimens) for individuals undergoing either regimen. Both combination therapies appeared to be effective as initial treatment for advanced colorectal cancers (19). The BEAT study has reported the benefits of adding bevacizumab to various chemotherapy protocols. This study showed that bevacizumab improved RR, OS, and PFS when combined with 5-fluorouracil/leucovorin (LV5FU), irinotecan and 5-FU/LV (Folfiri), 5-FU/LV + oxaliplatin (FOLFOX), or capecitabine plus oxaliplatin (XELOX). Tri-chemotherapy can also be utilized, as indicated by the TRIBE study for patients with RAS mutation, good performance status, and those who are fit for this regimen (20). Capecitabine mono-chemotherapy, when combined with bevacizumab, is an interesting option for elderly and vulnerable individuals, as suggested by the AVEX study. This combination of bevacizumab and capecitabine has been shown to be an efficient and well-tolerated treatment regimen for elderly patients dealing with metastatic CRC (21).

XELOX combined with bevacizumab was the most administered regimen in first-line chemotherapy (54.3%), aligning with findings from a real-world study conducted in the UK and Romania (22) (23).

The 9 months PFS [IQR, 7.58 − 10.15] noted in patients treated with first-line bevacizumab was nearly comparable to the findings of other observational studies (Romania: 8.4, India: 7.13, Oujda: 13) (12)(14)(23) and some clinical trials involving more interventions (9.3–17 months) (8)(24).

The median OS of 14 months [IQR, 11.99–16.00] was comparatively shorter than other observational studies such as BRiTE (22.9 months) (24), BEAT (22.7 months) (25), and those reported in similar retrospective studies (Romania: 17.7, India: 18.5, Oujda: 22) (12)(14)(23). Nevertheless, variations in study design and population demographics could also contribute to the disparities in overall survival rates.

In our study, resection status of the primary tumor in mCRC patients had a significant impact on PFS and OS of patients treated with bevacizumab. A meta-analysis of seven studies involving 2760 patients found that the resection group had a longer OS after bevacizumab treatment than the non-resection group (24.6 months versus 17.5 months, respectively). Furthermore, for patients who underwent primary tumor resection, OS was significantly improved when bevacizumab was added to chemotherapy compared to chemotherapy alone (27). Also, tumor location was a significant prognostic factor in overall survival, which aligns with the literature findings. A recent meta-analysis comprising 21 studies indicated that treatments based on bevacizumab are more effective in patients with left-sided mCRC in comparison to those with right-side tumors. Moreover, right-sided CRC is typically characterized by poorly differentiated, mucinous, signet ring histology with microsatellite instability and a mutation in RAS/RAF, in contrast to the left side (14).

The safety profile of bevacizumab met our expectations and showed good tolerance among our study population. Hypertension was the most common adverse event associated with bevacizumab, according to several studies. Its incidence varies from 19 to 34% for grades 1 and 2. Grade 4 was reported in less than 1% of cases and causes treatment interruption (28). It is often explained by a mechanism of vascular resistance induced by bevacizumab. It was reported in 1.2% of our patients.

Our study limitations include the unavailability of the molecular profile, particularly for RAS mutation and MSI status, as well as the absence of other anti-EGFR treatments. Additionally, the retrospective nature of this study and the unresectable CRC status of all study population may potentially have negatively impacted our data, especially regarding survival.

Chemotherapy combination with bevacizumab is considered as the cornerstone of mCRC treatment in our region. This approach is favored due to the unavailability of treatments targeting EGFR, immunotherapy, or the characterization of RAS and MSI tumors. With the new healthcare and social security systems, easier access to expensive treatments and molecular pathology tests is currently available. It is important to highlight that real world data can offer valuable insights for daily clinical practice of medical oncology. Thus, in the current study progression-free survival showed more favorable outcomes compared to other studies, while overall survival was relatively shorter. However, bevacizumab safety profile was largely concordant with our expectations and those from the literature.

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The authors declare no competing interests.

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The safety and effectiveness of Bevacizumab in Metastatic Colorectal Cancer with Unresectable Metastases: A Real-Life Study from the south of Morocco

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