A randomized comparative study on maintenance gemcitabine versus supportive care in pleural mesothelioma

ABSTRACT

Background

Pleural mesothelioma (PM) is a rare aggressive cancer linked to asbestos exposure, with limited treatment options, especially in low-resource settings. While immune checkpoint inhibitors show promise, access remains limited in many countries.

Methods

This prospective study was conducted at Ain Shams University Hospital from November 2022 to December 2024. 42 patients with unresectable PM and no progression after 4–6 cycles of platinum-pemetrexed chemotherapy were randomized 1:1 to receive switch-maintenance gemcitabine (1000 mg/m² on days 1 and 8 every 21 days) or best supportive care (BSC). Progression-free survival (PFS), overall survival (OS), and toxicity (Common Terminology Criteria for Adverse Events CTCAE v5.0) were assessed.

Results

Maintenance gemcitabine significantly improved PFS in unresectable PM (8.9 vs. 5.2 months, p = 0.022), confirmed in univariate analysis (HR = 0.505, p = 0.040) but not multivariate (p = 0.069). OS also favored gemcitabine (16.2 vs. 13.4 months, p = 0.138). Multivariate analysis linked gemcitabine (p = 0.043), females, cisplatin use, and partial response to initial therapy with better OS, while ECOG II and occupational exposure predicted worse OS. Adverse events were manageable.

Conclusion

Maintenance gemcitabine significantly improved PFS and was well tolerated, offering a practical and affordable treatment option for PM.

Clinical trial registration

www.clinicaltrials.gov identifier is NCT05660616.

CAN CONTINUING CHEMOTHERAPY HELP CONTROL PLEURAL MESOTHELIOMA LONGER? PLAIN LANGUAGE SUMMARY

Pleural mesothelioma is a rare and serious cancer affecting the lining of the lungs, often caused by breathing in asbestos. Treatment usually begins with chemotherapy to control the disease. Afterward, many patients are monitored without further treatment unless the cancer worsens.

This study looked at whether continuing a chemotherapy drug called gemcitabine after initial treatment could help patients stay well for longer. We studied two groups of patients: one received gemcitabine regularly, while the other received no additional cancer treatment unless their disease progressed.

Patients who continued with gemcitabine had a longer time before their cancer worsened. They also lived slightly longer than those who had no further treatment. Most side effects were mild and manageable, such as tiredness, nausea, and low blood counts. Breathing problems like cough and shortness of breath were more common in the group without gemcitabine, likely because their disease progressed more quickly.

In summary, continuing with gemcitabine after first treatment may help keep pleural mesothelioma under control longer and delay worsening symptoms. This option may improve the quality of life for patients, with side effects that are generally manageable.

1. Introduction

Pleural mesothelioma (PM) is a rare but aggressive malignancy primarily arising from the pleura, with a global incidence of approximately 30,618 new cases annually and 25,372 deaths, representing 0.2% of all cancer diagnoses and 0.3% of cancer-related mortalities [1]. This malignancy is strongly associated with asbestos exposure, with a latency long period of 20 to 40 years [2]. Despite asbestos bans in many developed nations, continued use in regions such as parts of Asia and Africa ensures that PM remains a significant global health concern [3].

In Egypt, PM poses an increasing public health challenge. According to Globocan 2022, Egypt reported 583 new cases and 504 deaths from PM, highlighting its substantial mortality rate [4]. Although asbestos was officially banned in Egypt in 2005, the lingering effects of past exposure and improper handling of asbestos-containing materials continue to contribute to the disease burden. A higher burden is observed among residents of areas near asbestos factories and urban settings. Women and young adults are notably affected, and environmental exposure to asbestos contributes significantly to the disease’s epidemiology [5].

Pleural mesothelioma includes three main pathological subtypes: epithelioid (50–60%, best prognosis, median survival >12 months), sarcomatoid (10–20%, worst prognosis, median survival <6 months), and biphasic (intermediate prognosis depending on dominant component) [6]Clinically, PM presents with nonspecific symptoms like dyspnea, chest pain, and pleural effusion, often causing diagnostic delays. Imaging (CT, PET) is crucial for staging, but histopathological confirmation remains essential. Immunohistochemical markers help distinguish PM from metastatic tumors, and molecular tools like gene expression profiling enhance diagnostic accuracy and prognostication [7].

Definitive diagnosis requires biopsy, as imaging alone is insufficient. Techniques include CT-guided core needle biopsies, pleural fluid cytology, and thoracoscopic (Video-assisted thoracic surgery, VATS) biopsies. VATS is the gold standard due to larger tissue yield for precise analysis [8]. Core biopsies are less invasive but may yield limited tissue, while cytology is supportive but unreliable alone [9].

The standard treatment for PM includes platinum-based chemotherapy with pemetrexed, which has been the cornerstone for over two decades, providing modest survival benefits [10]. Surgical interventions, such as extrapleural pneumonectomy and pleurectomy/decortication, are considered for select patients with resectable disease and good performance status. Radiotherapy is primarily utilized for palliative care to alleviate symptoms such as pain and local disease control [9]. Recent advancements include immune checkpoint inhibitors like nivolumab and ipilimumab, which have shown promise in extending survival, particularly in non-epithelioid subtypes [11].

A significant challenge in the management of PM is the variation in drug availability between high-income and low- to middle-income countries. While advanced therapies such as immune checkpoint inhibitors and novel targeted agents have shown promising outcomes in clinical trials, their widespread use is often hindered by high costs and limited access in resource-constrained settings [12].

Based on these challenges, maintenance gemcitabine has emerged as a viable option, particularly in settings like Egypt where cost-effectiveness and accessibility are paramount. Switch-maintenance gemcitabine, as demonstrated in the NVALT19 trial, has shown significant efficacy in prolonging progression-free survival for patients with PM [13].

This study investigates the effectiveness and safety of switch-maintenance gemcitabine after first-line chemotherapy in PM patients at Ain Shams University Hospitals, aiming to create a practical, cost-effective treatment approach suited to the Egyptian healthcare resources.

2. Patients and methods

2.1. Study setting

This single-center study was conducted at Ain Shams University Hospital between 1 November 2022, and 31 December 2024. Ain Shams University Hospital is a leading tertiary care center in Egypt, providing specialized oncology services, including the diagnosis, treatment, and management of pleural mesothelioma (PM).

2.2. Study population

The study enrolled patients with histologically or cytologically confirmed unresectable pleural mesothelioma (PM), deemed inoperable due to extensive local invasion precluding complete macroscopic resection, lymph node involvement, distant metastases, compromised pulmonary function, or preexisting cardiac conditions that rendered surgery unsafe [14]. Eligible participants were adults aged ≥18 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 [14] and measurable disease according to the revised modified response evaluation criteria in solid tumors for assessment of response in malignant pleural mesothelioma (version 1.1) [15]. All patients had completed 4–6 cycles of first-line platinum-based chemotherapy (cisplatin or carboplatin) in combination with pemetrexed, without radiological evidence of disease progression at the time of study entry.

Additional inclusion criteria required adequate hematological, renal, and hepatic function, defined as hemoglobin ≥9 g/dL, absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet count ≥ 100 × 10⁹/L, creatinine clearance ≥50 mL/min, total bilirubin ≤ 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × ULN (or ≤ 5 × ULN in cases of liver metastases). All participants provided written informed consent prior to study enrollment.

Patients were excluded if they had sarcomatoid histology, evidence of disease progression, ECOG performance status ≥ 3, pregnancy, or were candidates for curative surgical intervention – including those who had previously undergone curative-intent surgery followed by disease recurrence. Additionally, individuals with active second malignancies, including hematologic cancers, or a history of other malignancies within the past five years were excluded, except for those cured of nonmelanoma skin cancer or cervical intraepithelial neoplasia.

2.3. Sample size

The sample size was calculated based on detecting a difference in progression-free survival (PFS) between the gemcitabine maintenance arm and the supportive care arm. Assuming a hazard ratio of 0.50 (based on prior studies such as NVALT19), a two-sided alpha of 0.05, and 80% power, a total of 42 patients (21 per arm) were required. This calculation accounts for a 10% drop-out or ineligibility rate.

2.4. Ethical consideration

This study was conducted in accordance with the ethical principles of the Declaration of Helsinki governing research involving human subjects. The research protocol received approval from the Institutional Review Board of the Faculty of Medicine, Ain Shams University (FMASU MD 289/2022). Prior to enrollment, written informed consent was obtained from all participants after they were fully informed about the study’s objectives, potential risks and benefits, and their right to withdraw from the study at any time without any impact on their medical care. The trial is registered on ClinicalTrials.gov with the identifier NCT05660616.

2.5. Treatment plan

Patients were randomized in a 1:1 ratio into two study arms using a computer-generated randomization sequence to ensure allocation concealment and minimize selection bias. In the intervention arm, patients received maintenance gemcitabine at a dose of 1000 mg/m² administered intravenously on days 1 and 8 of each 21-day cycle. In the control arm, patients received best supportive care (BSC) alone or palliative interventions as clinically indicated. Supportive care in both arms included comprehensive symptom management, analgesia, nutritional support, psychosocial care, and management of pleural effusions. Palliative radiotherapy was permitted based on clinical need.

Treatment in the intervention arm was continued until radiologically confirmed disease progression, the occurrence of unacceptable toxicity, patient withdrawal of consent, or the initiation of alternative anticancer therapy outside the study protocol.

2.6. Dose modification

Gemcitabine dose modifications were applied based on toxicity levels, following established chemotherapy safety guidelines. If hematologic toxicities such as neutropenia (absolute neutrophil count < 1.0 × 10⁹/L) or thrombocytopenia (platelet count < 50 × 10⁹/L) occurred, treatment was delayed until recovery. In cases of Grade 3–4 hematologic toxicities, the dose was reduced by 25% for subsequent cycles. For non-hematologic toxicities (excluding alopecia), treatment was delayed until recovery to Grade 1 or baseline, and if toxicity recurred, a 25% dose reduction was applied. Persistent severe toxicities despite two dose reductions led to permanent discontinuation of treatment.

2.7. Efficacy assessment

Efficacy was assessed through both radiological and clinical parameters. Tumor response was measured every three cycles using contrast-enhanced computed tomography (CT) scans to evaluate changes in tumor burden. Clinical evaluations, including performance status and symptom assessment, were conducted at each treatment cycle. Indicators of disease progression, such as increased tumor thickness or worsening pleural effusion, were also documented.

2.8. Safety assessment

Adverse events were monitored and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [16]. Clinical evaluations were conducted at each treatment cycle, and toxicities were managed by treatment interruption, dose reduction, or supportive care measures. Additional interventions, such as hospitalization for severe toxicities or symptomatic management, were implemented as required.

2.9. Statistical analysis

Data were collected, reviewed, coded, and analyzed using International Business Machines Corporation Statistical Package for the Social Sciences (IBM SPSS) for Windows, Version 27.0 (IBM Corp., Armonk, New York, United States). Quantitative variables were expressed as means, standard deviations, and ranges for parametric data, while qualitative variables were summarized as frequencies and percentages. Comparisons between qualitative variables were performed using the Chi-square test or Fisher’s exact test, as appropriate. For quantitative data with a parametric distribution, comparisons between two independent groups were conducted using the independent samples t-test.

Univariate and multivariate analyses of progression-free survival (PFS) and overall survival (OS) were conducted using Cox proportional hazards regression models. The Enter method was applied in univariate analysis to assess the effect of individual covariates, while multivariate analysis employed the Backward Likelihood Ratio (LR) method to identify independent predictors. Survival outcomes were also evaluated using the Kaplan – Meier method, with differences between survival curves assessed using the log-rank test. PFS was defined as the time from randomization to documented disease progression or death from any cause, whichever occurred first. OS was defined as the time from randomization to death from any cause.

Reference groups for categorical variables were selected based on clinical relevance and standard epidemiological practice. Typically, groups with more favorable prognosis (e.g., younger age, epithelioid subtype, absence of pleural effusion) or standard-of-care status (e.g., supportive treatment arm, carboplatin use which is commonly used in daily practice due to lower toxicity) were chosen as the baseline to allow clearer interpretation of risk or benefit associated with comparison groups.

A 95% confidence interval was applied, and a margin of error of 5% was accepted. Statistical significance was defined as follows: p > 0.05 = not significant (NS), p < 0.05 = significant (S), and p < 0.01 = highly significant (HS).

3. Results

A total of 54 patients were assessed for eligibility, of whom 42 were randomized into two groups. The investigational group (n = 21) received maintenance gemcitabine, while the control group (n = 21) received the best supportive care. A total of 12 patients were excluded, with 8 patients not meeting the inclusion criteria and 4 patients declining participation. The detailed patient flow through each stage of the study is illustrated in the CONSORT diagram (Figure 1).

Figure 1.

CONSORT diagram of patient selection and randomization.

3.1. Baseline characteristics

The baseline clinical and demographic characteristics of patients in the maintenance gemcitabine and supportive care groups were well-balanced as presented in Table 1, with no statistically significant differences between the two groups. The median age was 58 years (range: 39–76) in the maintenance gemcitabine group and 60 years (range: 43–77) in the supportive care group (p = 0.499). The gender distribution was identical, with 52.4% males and 47.6% females in both groups (p = 1.000). Comorbidities were present in 42.9% of patients receiving maintenance gemcitabine and 52.4% in the supportive care group (p = 0.537), with diabetes mellitus (19.0% vs. 28.6%, p = 0.469) and hypertension (28.6% vs. 42.9%, p = 0.334) being the most common. Other comorbidities, including cardiac disease (4.8% vs. 9.5%, p = 0.549) and viral hepatitis (9.5% vs. 0%, p = 0.147), showed no significant differences between the groups.

Table 1.

Baseline clinical and demographic characteristics of patients and control Groups

Characteristic	Maintenance Group (N = 21)	Supportive Group (N = 21)	P-value
Gender			1.000
Male	11 (52.4%)	11 (52.4%)
Female	10 (47.6%)	10 (47.6%)
Age (years)			0.499
Median (Range)	58 (39–76)	60 (43–77)
Comorbidities			0.537
None	12 (57.1%)	10 (47.6%)
Any	9 (42.9%)	11 (52.4%)
Diabetes Mellitus	4 (19.0%)	6 (28.6%)	0.469
Hypertension	6 (28.6%)	9 (42.9%)	0.334
Cardiac Disease	1 (4.8%)	2 (9.5%)	0.549
Viral Hepatitis	2 (9.5%)	0 (0.0%)	0.147
ECOG Performance Status			0.116
I	15 (71.4%)	19 (90.5%)
II	6 (28.6%)	2 (9.5%)
Smoking Status			0.873
Smoker	5 (23.8%)	6 (28.6%)
Non-Smoker	14 (66.7%)	15 (71.4%)
Former Smoker	2 (9.5%)	0 (0.0%)
Occupational Hazard			0.739
Positive	6 (28.6%)	7 (33.3%)
Negative	15 (71.4%)	14 (66.7%)
Residency			0.766
Shobra El-Kheima	7 (33.3%)	5 (23.8%)
Helwan	5 (23.8%)	5 (23.8%)
Others	9 (42.9%)	11 (52.4%)
Pathological Type			0.679
Epithelioid	18 (85.7%)	17 (81.0%)
Biphasic	3 (14.3%)	4 (19.0%)
Tumor Stage			0.753
Stage I & II	9 (42.9%)	8 (38.1%)
Stage III & IV	12 (57.1%)	13 (61.9%)
Pleural Effusion			0.161
None	5 (23.8%)	3 (14.3%)
Mild	10 (47.6%)	11 (52.4%)
Moderate	3 (14.3%)	7 (33.3%)
Marked	3 (14.3%)	0 (0.0%)
Platinum Type (Induction)			0.733
Cisplatin	5 (23.8%)	7 (33.3%)
Carboplatin	16 (76.2%)	14 (66.7%)
Response to Induction Treatment			0.346
Stable Disease	11 (52.4%)	14 (66.7%)
Partial Response	10 (47.6%)	7 (33.3%)

ECOG = Eastern cooperative oncology group; N = number of patients.

Most patients had an ECOG performance status of I (71.4% in the maintenance gemcitabine group vs. 90.5% in the supportive care group, p = 0.116). Smoking status was similar between groups, with 23.8% of patients in the maintenance gemcitabine group and 28.6% in the supportive care group identified as current smokers (p = 0.873). Occupational hazard exposure was also comparable (p = 0.739). The distribution of residency was balanced across the groups, with no significant differences (p = 0.766).

In terms of pathological type, epithelioid mesothelioma was the predominant subtype in both groups (85.7% vs. 81.0%, p = 0.679). Tumor stage at diagnosis was similar, with 42.9% of patients in the maintenance gemcitabine group and 38.1% in the supportive care group classified as stage I or II, while 57.1% and 61.9% had stage III or IV disease, respectively (p = 0.753). The presence and severity of pleural effusion did not differ significantly between groups (p = 0.161). Among 17 patients with stage I – II, surgery was not performed due to patient refusal (n = 8), poor pulmonary function (n = 5), and significant comorbidities including cardiac disease (n = 4).

Regarding induction treatment, 23.8% of patients in the maintenance gemcitabine group and 33.3% in the supportive care group received cisplatin, while the remaining patients were treated with carboplatin (p = 0.733). Response to induction therapy was also comparable, with stable disease reported in 52.4% of patients in the maintenance gemcitabine group and 66.7% in the supportive care group, while 47.6% and 33.3% achieved a partial response, respectively (p = 0.346).

3.2. Progression-free survival (PFS) analysis

The median progression-free survival (PFS) was 8.9 months (95% CI: 6.83–10.97) in the maintenance gemcitabine group and 5.2 months (95% CI: 3.57–6.83) in the supportive care group. The mean PFS was 9.25 months (95% CI: 7.03–11.46) in the maintenance gemcitabine group and 5.64 months (95% CI: 4.48–6.80) in the supportive care group. Kaplan-Meier survival curves (Figure 2) illustrate a significant improvement in PFS for the maintenance gemcitabine group compared to the supportive care group (p = 0.022).

Figure 2.

Progression-free survival (PFS) in maintenance vs. Supportive group.

As shown in Table 2, univariate Cox regression analysis revealed that maintenance therapy significantly improved progression-free survival (PFS) compared to supportive care (HR: 0.505, 95% CI: 0.263–0.969, p = 0.040). Other variables such as age, gender, comorbidities, ECOG status, smoking, and disease stage were not significantly associated with PFS. In the multivariate analysis, maintenance therapy remained associated with a favorable trend toward longer PFS (HR: 0.541, 95% CI: 0.271–1.077, p = 0.069), though it did not reach statistical significance. Additionally, neither pathology subtype, platinum agent type, nor response to induction therapy showed significant independent associations.

Table 2.

Cox regression analysis for progression-free survival (PFS).

Variable	Comparison Group	Reference Group	Univariate HR (95% CI)	Univ. p-value	Multivariate HR (95% CI)	Multiv. p-value
Age Group	≥60	<60	1.036 (0.551–1.945)	0.913	–	–
Gender	Female	Male	0.693 (0.354–1.354)	0.283	–	–
Medical Comorbidities	Yes	No	0.958 (0.510–1.797)	0.893	–	–
ECOG Performance Status	II	I	0.911 (0.397–2.088)	0.825	–	–
Smoking Status	Smoker	Non-Smoker	0.802 (0.392–1.639)	0.544	–	–
Occupational Hazard	Positive	No	0.796 (0.397–1.595)	0.521	–	–
Pathology Subtype	Biphasic	Epithelioid	0.799 (0.331–1.928)	0.618	0.594 (0.231–1.524)	0.278
Disease Stage	Stage III & IV	I – II	1.639 (0.831–3.232)	0.154	–	–
Pleural Effusion – Mild	Mild	None	2.585 (0.940–7.112)	0.066	–	–
Pleural Effusion – Moderate	Moderate	None	2.782 (0.880–8.797)	0.082	–	–
Pleural Effusion – Marked	Marked	None	3.647 (0.813–16.370)	0.091	–	–
Type of Platinum in Induction	Cisplatin	Carboplatin	0.630 (0.308–1.290)	0.206	–	–
Response to Induction	Partial Response	Stable Disease	0.627 (0.321–1.224)	0.172	–	–
Treatment Group	Maintenance	Supportive Care	0.505 (0.263–0.969)	0.040*	0.541 (0.271–1.077)	0.069

PFS = progression-free survival; HR = hazard ratio; CI = confidence Interval; ECOG = Eastern cooperative Oncology group.*Statistically significant at p < 0.05. HR < 1 indicates improved survival for the comparison group relative to the reference group.

3.3. Overall survival (OS) analysis

The median overall survival (OS) was 16.2 months (95% CI: 9.97–22.43) in the maintenance gemcitabine group compared to 13.4 months (95% CI: 10.78–16.02) in the supportive care group. The mean OS was 17.3 months (95% CI: 14.56–19.97) for the maintenance gemcitabine group and 13.2 months (95% CI: 11.20–15.19) for the supportive care group. Kaplan-Meier curves (Figure 3) show a trend toward improved OS in the maintenance gemcitabine group compared to the supportive care group. However, the difference was not statistically significant (p = 0.138).

Figure 3.

Overall survival (OS) in maintenance vs. Supportive groups.

Univariate analysis (Table 3) identified ECOG II status (HR 3.152, p = 0.031) and marked pleural effusion (HR 19.700, p = 0.007) as significant predictors of poorer survival. Multivariate analysis confirmed ECOG II as independently prognostic (HR 3.567, p = 0.049) while revealing additional significant factors: maintenance therapy (HR 0.262, p = 0.043), female sex (HR 0.181, p = 0.030), cisplatin use (HR 0.194, p = 0.026), and treatment response (HR 0.141, p = 0.019) were protective, whereas occupational exposure predicted worse outcomes (HR 19.522, p = 0.004).

Table 3.

Cox regression analysis for overall survival (OS).

Variable	Comparison Group	Reference Group	Univariate HR (95% CI)	Univ. p-value	Multivariate HR (95% CI)	Multiv. p-value
Age	≥60	<60	1.201 (0.484–2.983)	0.693	–	–
Gender	Female	Male	1.090 (0.438–2.708)	0.854	0.181 (0.039–0.849)	0.030*
Medical Comorbidities	Yes	No	1.269 (0.512–3.144)	0.607	–	–
ECOG	II	I	3.152 (1.112–8.938)	0.031*	3.567 (1.004–12.677)	0.049*
Smoking	Smoker	Non-Smoker	1.435 (0.405–5.077)	0.576	–	–
Occupational Hazard	Yes	No	1.214 (0.395–3.729)	0.734	19.522 (2.533–150.432)	0.004*
Pathology	Biphasic	Epithelioid	2.048 (0.649–6.462)	0.221	–	–
Stage	III – IV	I – II	1.988 (0.693–5.700)	0.201	–	–
Pleural Effusion – Mild	Mild	None	2.613 (0.511–13.368)	0.249	–	–
Pleural Effusion – Moderate	Moderate	None	2.752 (0.535–14.148)	0.226	–	–
Pleural Effusion – Marked	Marked	None	19.700 (2.223–174.546)	0.007*	–	–
Platinum Type	Cisplatin	Carpoblatin	0.964 (0.341–2.727)	0.945	0.194 (0.046–0.820)	0.026*
Induction Response	Partial Response	Stable Disease	0.473 (0.154–1.451)	0.191	0.141 (0.027–0.726)	0.019*
Treatment	Maintenance	Supportive Care	0.665 (0.256–1.724)	0.401	0.262 (0.071–0.961)	0.043*

OS = overall survival; HR = hazard ratio; CI = confidence Interval; ECOG = Eastern cooperative oncology group. *statistically significant at p < 0.05. HR < 1 indicates improved survival for the comparison group relative to the reference group.

3.4. Post-progression therapy

Following disease progression, patients were treated according to institutional guidelines and physician discretion. In the maintenance group, 18 of 21 patients experienced progression; 15 (83.3%) received second-line therapy: 8 received vinorelbine, 3 were rechallenged with pemetrexed, and 4 received gemcitabine plus carboplatin. In the supportive care group, all 21 patients progressed; 16 (76.2%) received further treatment: 9 received gemcitabine, 5 vinorelbine, and 2 pemetrexed rechallenge. A comparison of post-progression therapy rates between both groups using Fisher’s Exact Test yielded a p-value of 0.70, indicating no statistically significant difference.

3.5. Toxicity profile of single-agent maintenance gemcitabine

The treatment-related adverse events are summarized in Table 4. Fatigue, vomiting, anorexia, and alopecia were the most frequently reported toxicities in the gemcitabine group, with fatigue observed in 67%, vomiting and anorexia in 57% each, and alopecia in 43% of patients. Grade 3–4 fatigue occurred in 19% of patients receiving gemcitabine. Hematologic toxicities were generally infrequent, with grade 3–4 neutropenia and febrile neutropenia each occurring in 10% of gemcitabine-treated patients. In contrast, dyspnea, cough, and edema were more commonly reported in the supportive care group, with dyspnea occurring in 71% vs. 57%, cough in 62% vs. 52%, and edema in 67% vs. 57% in the supportive vs. gemcitabine arms, respectively. Grade 3–4 dyspnea and cough were also more frequent in the supportive group (24% and 10%, respectively), compared to the gemcitabine group (14% and 0%).

Table 4.

Toxicity profile according to CTCAE grading in gemcitabine and supportive care arms.

Toxicity	Gemcitabine Grade 1–2 (n, %)	Supportive Grade 1–2 (n, %)	Gemcitabine Grade 3–4 (n, %)	Supportive Grade 3–4 (n, %)
Anemia	3 (14%)	2 (10%)	1 (5%)	0 (0%)
Neutrophil Count Decreased	2 (10%)	1 (5%)	1 (5%)	0 (0%)
Febrile Neutropenia	0 (0%)	0 (0%)	2 (10%)	0 (0%)
Thrombocytopenia	9 (43%)	3 (14%)	1 (5%)	0 (0%)
Fatigue	14 (67%)	12 (57%)	4 (19%)	2 (10%)
Nausea	5 (24%)	3 (14%)	0 (0%)	0 (0%)
Vomiting	12 (57%)	4 (19%)	2 (10%)	0 (0%)
Diarrhea	2 (10%)	1 (5%)	0 (0%)	0 (0%)
Stomatitis	7 (33%)	2 (10%)	1 (5%)	0 (0%)
Anorexia	12 (57%)	5 (24%)	2 (10%)	1 (5%)
Weight Loss	9 (43%)	4 (19%)	2 (10%)	1 (5%)
Elevated AST/ALT	1 (5%)	0 (0%)	1 (5%)	0 (0%)
Elevated Bilirubin	1 (5%)	0 (0%)	0 (0%)	0 (0%)
Renal Toxicity	3 (14%)	1 (5%)	1 (5%)	0 (0%)
Alopecia	9 (43%)	2 (10%)	0 (0%)	0 (0%)
Rash	8 (38%)	2 (10%)	1 (5%)	0 (0%)
Dyspnea	12 (57%)	15 (71%)	3 (14%)	5 (24%)
Cough	11 (52%)	13 (62%)	0 (0%)	2 (10%)
Edema	12 (57%)	14 (67%)	2 (10%)	3 (14%)
Peripheral Neuropathy	5 (24%)	2 (10%)	0 (0%)	0 (0%)
Arthralgia	10 (48%)	4 (19%)	1 (5%)	0 (0%)
Myalgia	8 (38%)	4 (19%)	1 (5%)	0 (0%)

CTCAE = common Terminology criteria for adverse events; AST = aspartate aminotransferase; ALT = alanine aminotransferase. Toxicities are reported by grade: grade 1–2 (mild to moderate) and Grade 3–4 (severe to life-threatening), with the number and percentage of affected patients in each treatment group.

4. Discussion

Pleural mesothelioma (PM) is an aggressive cancer with poor survival, mainly linked to asbestos exposure and therapy resistance [17]. Platinum-based chemotherapy with pemetrexed, established by the EMPHACIS trial, improved median overall survival to 12.1 months compared to 9.3 months with cisplatin alone [10]. Subsequent modifications, such as the substitution of carboplatin for cisplatin, aimed to improve tolerability while maintaining efficacy [18].

Despite these advances, most patients progress after first-line chemotherapy, highlighting the need for new strategies. While maintenance therapy is standard in NSCLC, trials in PM, including pemetrexed and nintedanib, showed no survival benefit [19–21]. However, The NVALT19 trial demonstrated improved progression-free survival with gemcitabine maintenance, though overall survival gains remained uncertain [13].

Our study evaluated switch-maintenance gemcitabine following first-line platinum-pemetrexed chemotherapy in patients with PM. We observed a significant improvement in PFS in the maintenance gemcitabine group (8.9 vs. 5.2 months, p = 0.022), while the OS benefit did not reach statistical significance (16.2 vs. 13.4 months, p = 0.138).

Gemcitabine maintenance therapy demonstrated a tolerable safety profile, with most adverse events being grade 1–2 and clinically manageable. Common toxicities included fatigue, anorexia, and vomiting, while hematologic events such as neutropenia and thrombocytopenia were infrequent and resolved with supportive care. Notably, dyspnea and cough were more frequent and severe in the supportive care group, likely reflecting disease progression in the absence of maintenance treatment. This suggests a potential role for gemcitabine in delaying respiratory symptom deterioration in malignant pleural mesothelioma.

These findings indicate that maintenance gemcitabine can effectively delay disease progression while maintaining an acceptable safety profile. Importantly, the improvement in PFS observed in our study is greater than that reported in previous maintenance trials, reinforcing the potential role of gemcitabine in extending disease control.

Compared to other trials, our cohort had a median age of 58.5 years, younger than MAPS (65.7), NVALT19 (64), and CheckMate 743 (69), reflecting earlier mesothelioma onset in Egypt due to environmental asbestos exposure. This may have improved treatment tolerance. The male proportion (74%) was similar to MAPS (75%) and CheckMate 743 (73%), consistent with occupational exposure patterns. ECOG 0–1 status (71.4%) was comparable to NVALT19 (72%) and slightly higher than CheckMate 743 (67%), suggesting better fitness. Pleural effusions (47%) were slightly lower than MAPS (50%) but similar to NVALT19, potentially contributing to better PFS outcomes [5,11,13,22].

Treatment-related outcomes also varied among studies. The MAPS trial [22], which evaluated bevacizumab in combination with chemotherapy, reported a median OS of 18.8 months in the triplet arm and 16.1 months in the chemotherapy-alone group. While our OS (16.2 months) is comparable to the chemotherapy-alone group in MAPS, our improved PFS (8.9 months vs. 7.6 months in MAPS) suggests that maintenance gemcitabine may offer a degree of disease control comparable to that provided by anti-angiogenic therapy.

When comparing our results with the NVALT19 trial [13], our study demonstrated a longer PFS (8.9 months vs. 6.2 months in NVALT19), while OS remained comparable (16.2 months vs. 15.4 months). These findings suggest that, despite regional and demographic differences, gemcitabine maintenance provided consistent survival benefits in patients with pleural mesothelioma (PM).

A key difference between the two studies is the gemcitabine dosing regimen. In our study, a lower dose of gemcitabine (1000 mg/m² on days 1 and 8 every 21 days) was used compared to the NVALT19 trial (1250 mg/m² on the same schedule). Despite this dose reduction, our study achieved superior PFS and comparable OS, suggesting that a lower-dose approach may be sufficient to maintain disease control while potentially reducing toxicity.

In terms of safety, significant differences in toxicity profiles were observed between the two studies. While neutropenia rates were much lower in our study (5% Grade III-IV vs. 33% in NVALT19), febrile neutropenia was notably higher (10% vs. 2%), possibly reflecting differences in patient characteristics, bone marrow reserve, or supportive care measures. Fatigue was also significantly more common in our study (19% Grade III-IV vs. 3% in NVALT19), which may suggest a greater impact on patient-reported quality of life.

Notably, thrombocytopenia rates were low in both studies (5% vs. 2%), indicating that gemcitabine at either dose level does not result in significant platelet suppression. Gastrointestinal toxicities, including nausea and vomiting, were frequent but predominantly low-grade, with no Grade III-IV nausea in our study compared to 8% in NVALT19. Dyspnea of Grade III-IV severity was slightly higher in our study (15% vs. 3%), which may be attributed to disease-related respiratory impairment rather than direct drug toxicity.

The implications of these findings are significant. The comparable efficacy observed with a lower gemcitabine dose suggests that reducing the drug burden may not compromise survival outcomes while potentially improving tolerability by lowering rates of severe hematologic toxicity. This could be particularly beneficial for patients with preexisting comorbidities or impaired bone marrow function. However, the higher rates of febrile neutropenia and fatigue in our study highlight the need for careful monitoring and proactive supportive care.

Our study and the phase II randomized the Egyptian NCI GEMO trial [23,24] were different in study design, induction regimens, and clinical outcomes, despite both evaluating gemcitabine maintenance therapy in malignant pleural mesothelioma. In our study, patients received six cycles of platinum-pemetrexed chemotherapy, and those achieving a partial response or stable disease were randomized to gemcitabine maintenance or supportive care. In contrast, the GEMO trial included patients after 4–6 cycles of first-line platinum-based chemotherapy, incorporating both platinum-pemetrexed and platinum-gemcitabine regimens before randomization. A key difference is that 50% of patients in GEMO had prior gemcitabine exposure, which may have led to lower efficacy of maintenance therapy due to potential resistance mechanisms. In contrast, our study introduced gemcitabine as a novel maintenance agent, potentially contributing to the longer PFS (8.9 months vs. no reported PFS in GEMO).

Regarding efficacy, our study reported a median PFS of 8.9 months and OS of 16.2 months, whereas the GEMO trial highlighted a significant improvement in objective response rate (ORR: 84.4% vs. 25.8%, p < 0.001) with maintenance therapy but did not provide explicit PFS or OS values. The toxicity profiles also varied; no Grade 3–4 toxicities were reported in the GEMO trial, whereas our study observed low but notable rates of severe adverse events, including febrile neutropenia (10%) and Grade III – IV fatigue (19%). These differences suggest that patient selection, prior gemcitabine exposure, supportive care strategies, and study design variations may have influenced the efficacy and toxicity outcomes between the two trials.

Compared to the CheckMate 743 [11] and BEAT-meso trials, which evaluated immunotherapy in PM, our study focused on gemcitabine maintenance post-platinum-pemetrexed chemotherapy, offering a more accessible alternative in resource-limited settings. CheckMate 743 (nivolumab + ipilimumab) improved OS (18.1 vs. 14.1 months, HR 0.74, p = 0.0020), while BEAT-meso (atezolizumab + bevacizumab-chemotherapy) reported 20.5 vs. 18.1 months (HR 0.84, p = 0.14) but failed to show significant OS benefit. Our study demonstrated a median OS of 16.2 months, suggesting chemotherapy-based maintenance remains a viable option.

For PFS, CheckMate 743 showed no significant benefit, BEAT-meso reported 9.2 vs. 7.6 months (HR 0.72, p = 0.0021), and our study showed 8.9 months, reinforcing gemcitabine’s role in delaying disease progression. Toxicity rates were higher in BEAT-meso (55% Grade ≥ 3) and CheckMate 743 (30%) compared to our study (e.g., febrile neutropenia 10%, Grade III – IV fatigue 19%), highlighting the better tolerability of chemotherapy maintenance. While immune checkpoint inhibitors improve OS, their accessibility is limited, making gemcitabine maintenance a practical, effective alternative in resource-constrained settings.

While the distribution of response to induction therapy (partial response vs. stable disease) between the two treatment groups was not statistically significant (p = 0.346), the numerically higher rate of partial responses in the gemcitabine arm may have contributed to prolonged progression-free survival. This potential source of bias should be considered when interpreting the comparative efficacy outcomes

Cox regression analyses were conducted to evaluate factors associated with progression-free survival (PFS) and overall survival (OS). In the univariate analysis, maintenance gemcitabine was associated with improved PFS compared to supportive care. However, in the multivariate model, this association did not retain statistical significance after adjusting for other covariates. In contrast, maintenance therapy showed a significant association with improved OS in the multivariate model, despite not reaching significance in the univariate analysis. This discrepancy suggests that the survival benefit of maintenance gemcitabine may have been masked by confounding factors – such as ECOG performance status, gender, occupational exposure, platinum type, and response to induction – that were accounted for in the multivariate model. Additionally, female gender, ECOG I, use of cisplatin, and partial response to induction therapy were independently associated with better OS outcomes, while occupational hazard exposure and ECOG II were linked to poorer OS. These findings underscore the importance of adjusting for clinical and demographic covariates when assessing treatment effects in real-world settings and support the potential value of maintenance gemcitabine in selected patients

The lack of a statistically significant difference in OS may partly reflect the effect of post-progression therapy. A high proportion of patients in both groups received second-line treatment (83.3% in the maintenance group and 76.2% in the supportive care group), and many in the supportive care group received gemcitabine after progression. This crossover effect may have attenuated survival differences. Statistical comparison showed no significant difference in post-progression therapy rates between groups (p = 0.70), but the potential confounding impact of post-study treatments should be acknowledged when interpreting OS results.

Regarding PFS, the lack of statistical significance in multivariate analysis may be due to the small sample size, limiting power to detect independent associations. Despite this, the observed improvement in PFS with a lower gemcitabine dose supports its potential role in maintenance therapy. Larger, multicenter studies are needed to validate these findings and refine patient selection criteria, particularly in those with smoking history or significant pleural effusion.

A key strength of our study is its relevance to resource-limited settings where immunotherapy and targeted therapies are unavailable. It demonstrates that gemcitabine maintenance is a feasible and effective option for prolonging disease control. Conducted in a real-world setting, the study highlights its practicality and manageable toxicity, making it a cost-effective alternative in malignant pleural mesothelioma.

Several limitations should be considered. The single-center design may restrict the generalizability of the findings, and the relatively small sample size (n = 42) limits statistical power for overall survival analysis. The lack of biomarker assessment, such as PD-L1 expression, prevents identification of subgroups that may benefit most from maintenance therapy. Additionally, the absence of an active comparator limits direct comparisons with alternative maintenance strategies

Future research should focus on larger, multi-center trials to validate these findings and explore biomarker-driven patient selection. Combining maintenance gemcitabine with immunotherapy or anti-angiogenic agents may enhance efficacy while maintaining tolerability. Cost-effectiveness analyses comparing maintenance chemotherapy with immunotherapy-based approaches would help guide treatment decisions in resource-limited settings. Further investigation into the optimal duration of maintenance therapy and its impact on quality of life is warranted.

5. Conclusion

Our study highlights the efficacy of maintenance gemcitabine in prolonging PFS in PM, particularly in patients who have completed first-line chemotherapy and lack access to targeted agents or immunotherapy. However, the lack of a statistically significant OS benefit and the relatively small sample size limit the strength of these findings. The results should therefore be interpreted with caution. Given its affordability, feasibility, and manageable toxicity, gemcitabine maintenance still represents a viable strategy in resource-limited settings. Larger, multi-center trials are needed to confirm these outcomes and optimize treatment sequencing.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Funding Statement

This paper was not funded.

Article highlights

• Pleural mesothelioma (PM) is a rare, aggressive cancer with limited treatment options after first-line therapy.

• Maintenance strategies to delay disease progression post-chemotherapy remain under-investigated, particularly in resource-limited settings.

• This was a randomized controlled trial comparing maintenance gemcitabine versus supportive care alone in patients with unresectable PM who achieved disease control after first-line platinum-based chemotherapy.

• The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and toxicity profile.

• Patients were followed until disease progression or death, and toxicities were recorded according to CTCAE v5.0.

• Maintenance gemcitabine significantly prolonged PFS (8.9 vs. 5.2 months, p = 0.022). A trend toward improved OS was observed in the gemcitabine arm (16.2 vs. 13.4 months), though not statistically significant (p = 0.138).

• Most adverse events were grade 1–2 and manageable, including fatigue, nausea, and thrombocytopenia.

• Febrile neutropenia occurred in 10% of gemcitabine patients; no unexpected toxicities were observed.

• Dyspnea and cough were more frequent and severe in the supportive care group, likely due to disease progression.

• Maintenance gemcitabine is a feasible, low-toxicity option that may extend disease control in patients with PM after initial chemotherapy.

• These findings support further evaluation of maintenance approaches in mesothelioma, particularly in low- and middle-income countries.

Authors’ contributions

MOA, SA, and MM collaboratively designed the research study, established the methodological framework, and defined the research objectives. ASK was responsible for data acquisition, including the collection, organization, and preliminary processing of research data. MM, MOA, and SA conducted comprehensive analysis and interpretation of the results. MOA took a leading role in drafting the manuscript, with ASK and MM contributing substantially to writing specific sections and synthesizing the findings. All authors participated actively in the critical review process, provided intellectual input during revisions, and gave final approval of the manuscript version to be published.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Ethics approval and consent to participate

This study was conducted in accordance with the ethical principles of the Declaration of Helsinki governing research involving human subjects. The research protocol received approval from the Institutional Review Board of the Faculty of Medicine, Ain Shams University (FMASU MD 289/2022). Prior to enrollment, written informed consent was obtained from all participants after they were fully informed about the study’s objectives, potential risks and benefits, and their right to withdraw from the study at any time without any impact on their medical care. The trial is registered on ClinicalTrials.gov with the identifier NCT05660616.

Data availability statement

The datasets generated and/or analyzed during the current study, as well as the full trial

protocol, are available from Dr, Abanoub Samir Karam (abanoub.samir@med.asu.edu.eg) upon reasonable request.