Breast cancer remains the most prevalent malignancy among women worldwide, accounting for approximately 2.3 million new cases and 685,000 deaths in 2022(1). In low- and middle-income countries (LMICs) like India, the disease poses a disproportionate burden due to late-stage presentations, limited access to screening, and suboptimal treatment infrastructure.(2) According to recent estimates from the National Cancer Registry Programme (NCRP), breast cancer constitutes 28.2% of all cancers in Indian women, with an age-adjusted incidence rate (AAR) of 25.8 per 100,000 population and a mortality rate of 12.7 per 100,000(3). Projections indicate a steady rise, with over 221,000 cases reported in 2023, underscoring the urgent need for effective, scalable therapeutic strategies(4). In Andhra Pradesh, where this study was conducted, regional registries report even higher localized burdens, exacerbated by socioeconomic disparities and comorbidities such as diabetes and hypertension prevalent in rural populations(5).The cornerstone of curative-intent therapy for early-stage and locally advanced breast cancer includes multimodal approaches: surgery, radiotherapy, and systemic chemotherapy(6). Adjuvant or neoadjuvant chemotherapy, particularly anthracycline- and taxane-based regimens, has significantly improved disease-free survival (DFS) and overall survival (OS) by targeting micro metastatic disease(7). Traditional schedules administer these agents every 3 weeks, but dose-dense chemotherapy-delivering the same cumulative dose over shorter intervals (e.g., every 2 weeks) with granulocyte colony-stimulating factor (G-CSF) support-has emerged as a paradigm shift(8). This strategy leverages the Gompertzian model of tumor growth, postulating that accelerated repopulation of surviving cancer cells post-chemotherapy can be curtailed by rapid cycle repetition, thereby enhancing efficacy without escalating dose intensity(9).Landmark trials, including the Cancer and Leukaemia Group B (CALGB) 9741 study, demonstrated that dose-dense scheduling reduces the risk of recurrence by 26% compared to conventional every-3-week regimens, with a hazard ratio (HR) of 0.74 for DFS (95% CI 0.60-0.91; P=0.01)(10). A subsequent patient-level meta-analysis of 37,298 women from 26 randomized trials confirmed these benefits, reporting a 15% reduction in breast cancer recurrence (rate ratio 0.85; 95% CI 0.78-0.93) and 17% in mortality (rate ratio 0.83; 95% CI 0.75-0.92) at 10 years, particularly in node-positive disease(11). In the neoadjuvant setting, dose-dense anthracycline-cyclophosphamide (AC) followed by paclitaxel has yielded pathologic complete response (pCR) rates of 15-20%, correlating with superior long-term outcomes(12). Recent real-world data from high-risk cohorts further affirm a 4.6% absolute improvement in 5-year event-free survival (EFS) with dose-dense approaches(13). Despite these advantages, adoption of dose-dense regimens in LMICs remains cautious due to apprehensions over heightened toxicity, patient compliance, and resource demands (14). Hematologic toxicities, such as grade 3/4 neutropenia, occur in up to 50% of cycles without prophylaxis, though G-CSF mitigates this to <5%, averting febrile neutropenia(15). Non-hematologic adverse events—nausea, fatigue, alopecia, and neuropathy—are often grade 1-2 but can impair quality of life and adherence(16). A phase II trial in European populations reported compliance rates of 85-90%, with dose delays in 10-15% due to extra-hematologic effects like mucositis and diarrhoea(17). In Indian contexts, where supportive care is variable and patients frequently endure financial and logistical barriers, tolerance data are sparse. Observational studies suggest higher discontinuation rates (up to 20%) in resource-constrained settings, potentially undermining efficacy(18).This study addresses these gaps by prospectively evaluating toxicity profiles, tumor response, compliance, and tolerance to dose-dense AC chemotherapy (doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m² every 2 weeks for 4 cycles, with G-CSF) in breast cancer patients at Kurnool Medical College, a tertiary referral centre serving predominantly rural Andhra Pradesh.

This prospective cross-sectional study was conducted over 18 months (2022–2024) at the Department of Radiotherapy, Kurnool Medical College and Government General Hospital, Kurnool, Andhra Pradesh, India. The sample size of 42 was calculated using the prevalence formula for breast cancer as per GLOBOCAN 2020 [1], with precision, yielding ~41, rounded to 42 for convenience sampling of consecutive eligible patients(19). Inclusion Criteria: Female breast cancer patients (stages II–III) receiving neoadjuvant/adjuvant dose-dense chemotherapy, ECOG 0–2, no prior chemo/radiotherapy, informed consent were considered. Exclusion Criteria: Metastatic disease, cardiac comorbidities, ECOG >2, no informed consent. Institutional Ethics Committee approval[IEC-KMC-GGH;No.39/2022; Dated:27.07.2022] was obtained; all adhered to Helsinki Declaration(20). Baseline assessment included clinical exam (tumor size, nodes), FNAC/core biopsy, mammography/ultrasonography (±MRI), labs (CBC, LFT/RFT), and cardiac evaluation (2D-ECHO/ECG)(21). Regimen: Dose-dense AC (doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m² IV q2w ×4 cycles; ± paclitaxel 175 mg/m² q2w ×4), with pegfilgrastim 6 mg SC day 2, antiemetics, and hydration. Pre-cycle labs ensured ANC >1500/mm³; delays/reductions per guidelines(22).Toxicity was graded per CTCAE v5.0 across 8 cycles: hematologic (e.g., neutropenia: ANC <1000/mm³ grade 3) and non-hematologic (e.g., nausea: grade 1 mild, grade 3 hospitalization)(23). Neoadjuvant response: RECIST 1.1 via clinical/radiologic measures (CR: lesion disappearance; PR: ≥30% reduction)(24). Compliance: Full cycles without >7-day delays/reductions; tolerance: No grade 3/4 discontinuations

The present cross-sectional study, we included 42 female patients with stage II-III breast cancer receiving dose-dense anthracycline-cyclophosphamide (AC)chemotherapy (doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m² IV every 2 weeks for 4 cycles, with G-CSF prophylaxis), followed by taxane consolidation in eligible cases, at Kurnool Medical College & Hospital. The mean age was 51 ± 10.5 years (range 25-70), with 62% aged 40-59 years, reflecting typical Indian perimenopausal presentations. Postmenopausal status predominated (69%), comorbidities affected 43% (hypertension 24%, diabetes 19%), and addictions were minimal (10%, mainly tobacco). Therapy was adjuvant in 74% and neoadjuvant in 26%, with 52% right-sided tumours and balanced staging (52% stage II, 48% stage III) observed in the present study[Table 1]. All patients (100%) completed the regimen without delays >7 days or reductions, indicating perfect compliance and tolerance, supported by proactive G-CSF and symptom management. No discontinuations occurred, and in neoadjuvant cases, 90% achieved operability post-AC (breast-conserving surgery 40%, mastectomy 60%).Toxicity, assessed per CTCAE v5.0 across 8 cycles, was predominantly mild (grade 1-2), with haematological events minimized (grade 3/4 neutropenia 2-5% per cycle; no febrile neutropenia)[Table 3]. Non-haematological toxicities peaked early (nausea 50-58%, vomiting 43-55% in cycles 1-2) but declined with antiemetics; fatigue affected 80% (patient-reported, grade 1-2), alopecia 40% by cycle 2 (100% by taxane phase), and other events like mucositis (9-13%) and diarrhoea (10-12%) were low-grade and outpatient-managed noted[Table 2]. Taxane cycles added grade 2 neuropathy (15%) and hand-foot syndrome (8%), but no grade 3/4 events caused modifications. No cardiotoxicity was noted (normal baseline ECHO).In the neoadjuvant subgroup (n=20), RECIST 1.1 evaluation post-AC via clinical exam, mammography, and ultrasound showed an overall response rate of 70% (complete response 10%, partial response 60%), stable disease 25%, and progressive disease 5%, facilitating downstaging and surgery in 90% (from 60% baseline inoperable)were recorded in our study [Table 4]. Table 1: Demographic and Clinical Profile (n=42) Demographic and Clinical Profile (n=42) Frequency Percentage (%) Age (years): Mean 51 ± 10.5 (range 25-70) - - <30 2 4.8 30-39 4 9.5 40-49 12 28.6 50-59 14 33.3 ≥60 10 23.8 Menopausal Status: Postmenopausal 29 69.0 Premenopausal 8 19.0 Perimenopausal 5 12.0 Comorbidities: Yes (HTN 24%, DM 19%) 18 42.9 No 24 57.1 Addictions: Yes (Tobacco 7%, Alcohol 3%) 4 9.5 No 38 90.5 Therapy Type: Neoadjuvant 11 26.2 Adjuvant 31 73.8 Tumor Side: Right 22 52.4 Left 20 47.6 Stage: II 22 52.4 III 20 47.6 Table 2: Key Non-Hematological Toxicities Across Cycles (n=42) Key Non-Haematological Toxicities Across Cycles Cycle I Cycle II Cycle III-IV (AC) Cycles V-VIII (Taxane) Nausea 51.2 52.5 49.0 55.0 Vomiting 43.9 55.0 45.7 50.0 Diarrhoea 12.2 7.5 10.0 12.0 Alopecia (Grade 2) 0 0 40.0 100.0 Nail Discoloration (Grade 1) 12.2 12.5 18.5 24.0 Oral Mucositis (Grade 1) 14.6 15.0 11.0 13.0 Fatigue (Patient-Reported, Grade 1-2) 70.0 80.0 81.3 85.0 Table 3: Haematological Toxicities Across Cycles (n=42) Haematological Toxicities Across Cycles Cycle I-II Cycle III-IV (AC) Cycles V-VIII (Taxane) Neutropenia 2.5 4.9 2.0 Anaemia 0 2.5 0 Thrombocytopenia 0 0 0 Febrile Neutropenia 0 0 0 Table 4: Tumor Response in Neoadjuvant Subgroup (n=20) Tumor Response in Neoadjuvant Subgroup Frequency Percentage (%) Complete Response (CR) 2 10.0 Partial Response (PR) 12 60.0 Stable Disease (SD) 5 25.0 Progressive Disease (PD) 1 5.0 Total 20 100.0

This study demonstrates the safety, compliance, and efficacy of dose-dense AC chemotherapy in 42 Indian breast cancer patients (mean age 51 years, 69% postmenopausal, 43% with comorbidities), with 100% regimen completion, low grade 3/4 toxicities (neutropenia 2-5%; no febrile neutropenia), mild non-haematological events (nausea 50-58%, fatigue 80%), and 70% ORR in neoadjuvant cases (n=20). These outcomes support its use in rural LMICs, leveraging G-CSF and supportive care to mitigate risks, while addressing the Gompertzian model of tumor kinetics that underpins dose intensification for better DFS(9).Haematological toxicities were minimal, aligning with CALGB 9741 (G-CSF reduced neutropenia to <10%) and a 2022 South Indian study (3% febrile neutropenia in 101 patients)(8,10,26). Our rates (2-5%) were lower than unprotected global trials (up to 50%), confirming prophylaxis efficacy, as echoed in a 2024 real-world analysis showing no increased infection risks with routine pegfilgrastim(11,27). Non-hematological events (grade 1-2 predominant) matched HE 10/05 (<5% grade 3/4) but showed fewer severe GI issues than European trials (15-20%), likely due to enhanced antiemetics like aprepitant(28). Neuropathy (15% grade 2) and no cardiotoxicity echoed MA.21 (2-3% LVEF drops), reinforcing baseline cardiac screening(29,30).Compliance (100%) exceeded ARTemis (85-90%) and Indian data (80%), highlighting feasibility in resource-limited settings with minimal delays, potentially translating to the 15-17% DFS gains from meta-analyses(13,18,26,11). Neoadjuvant ORR (70%) compared to GeparQuattro (65-75%), aiding 90% operability despite aggressive stage III disease (48% of cohort)(12,31). Limitations Small, single-center sample; no pCR, molecular subtyping, or long-term survival data. Strengths: Prospective real-world insights in underserved populations. Dose-dense AC is recommended for Indian cohorts to optimize equity in care; multicenter, biomarker-driven trials are needed for validation and QOL integration.

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