To the Editors:

Kaposi sarcoma (KS), caused by human herpes virus 8,1 is the most common cancer in HIV-infected individuals. Immunosuppression is an important risk factor of KS development and before antiretroviral therapy (ART) treatment became widely available in a large proportion of people living with HIV developed KS.2 In 2020, KS was ranked as the fifth most common cancer in Malawi with an age-standardized incidence of 10.9 per 100,000.3 Effective management of KS requires combination treatment with ART and chemotherapy.4,5 The Malawi Clinical HIV guidelines (2022) recommend paclitaxel as first-line chemotherapy for advanced KS (T1 or disabling and T0—cosmetically or otherwise). The guidelines are following findings from a multinational, open-label clinical trial conducted between 2013 and 2018, which showed higher progression-free survival rates at week 48 with paclitaxel + ART administration than in etoposide + ART or vincristine + bleomycin + ART arms.6

An implementation evaluation to determine feasibility and safety of paclitaxel-based chemotherapy administered in an ART clinic setting was conducted at Lighthouse Clinic adjacent to Kamuzu Central Hospital, Lilongwe, Malawi. Lighthouse is a World Health Organisation recognized center of excellence for HIV care that has been providing ART since 20027 and supports the Ministry of Health efforts to reduce AIDS-related death from advanced HIV diseases. The clinic provides ART to more than 13,000 people living with HIV and acts as a referral site for complex cases.

During implementation, 6 nurses and 4 clinical officers experienced in ART delivery underwent a 1-day training on theoretical background of chemotherapy and paclitaxel treatment encompassing patient assessment, staging of the tumor, eligibility assessment, treatment administration, and patient counseling. The training also included basic management of hypersensitivity and infusion reactions. For practical experience, nurses were then paired with tertiary hospital oncology nurses for 3 days to practice safe reconstitution and administration of paclitaxel. Standard operating procedures and job aids were developed, and a dedicated treatment room for 6 patients equipped with electronic blood pressure monitor and pulse oximeter was prepared.

Management of KS with paclitaxel (dose 100 mg/m2 body surface area) was started in January 2021; patients were premedicated with dexamethasone 12 mg, metoclopramide 10 mg, and chlorphenamine 10 mg 30 minutes before chemotherapy. Paracetamol (1000 mg) was given to patients as take-home medication for pain, to be taken as needed. Granulocyte-stimulating factor was not available. Data were collected retrospectively from patient charts of those initiating paclitaxel chemotherapy between January and December 2021. Chemotherapy completion was defined as completion of 6 cycles given 2–3 weeks apart or achieving tumor resolution or signs of no active disease. Adverse events were graded by the National Cancer Institute8 Common Terminology Criteria for Adverse Events. Owing to gaps in routine data, all proportions were calculated using adjusted denominator based on available data. Short-term safety concerns included any documentation of infusion reaction, urticaria, shortness of breath, angioedema, or anaphylaxis within 10–15 minutes of paclitaxel administration. Patients with available phone numbers on file were contacted in beginning of 2022 to determine their subjective experience with the medication using a standardized questionnaire; involved health care workers were informally interviewed to understand their experience.

In 2021, 128 patients initiated paclitaxel therapy and 121 (95%) received more than 1 dose. One hundred ten (86%) were male patients, 124 (97%) were HIV-positive, the median age was 37 years [interquartile range (IQR) 30–42], and the median body mass index was 20.7 kg/m2 (IQR 19.0–22.3). 91/112 patients (81%) had T1 disease; those with T0 disease started therapy for widespread disease that had not improved with ART alone for at least 12 weeks. Information about ART duration was available for 100 patients; 38 patients (38%) newly started ART at the time of chemotherapy, and 62 (62%) were on ART before chemotherapy initiation. Among those previously on ART, the median time on ART was 12 months (IQR 3–60).

Five hundred eighty-one paclitaxel doses were administered successfully in the observation period; direct infusion reactions, allergies, and extravasation were not observed. Sixty-three patients (49%) received the initially planned 6 doses, 18 (14%) received 5 doses, and 47 patients (37%) received 4 or fewer. Sixty-seven patients (52%) were actively discharged (for 6 cycles completed or for tumor improvement). Seven deaths (5.5%) were recorded (3 died during treatment), and 54 (42%) defaulted treatment.

Baseline absolute neutrophil count, hemoglobin, platelets, and creatinine were available in 79/121 patients (66%) who received more than 1 dose of paclitaxel. At baseline, 6 patients (8%) had anemia <8 g/dL and 2 (3%) had platelets <50.000/uL; all received multiple treatment cycles, and the values normalized in the course of the paclitaxel treatment.

Four hundred fifty-one subsequent paclitaxel doses were administered; the median interval between cycles was 15 days (IQR 14–21). Laboratory results were available in 374 cycles (83%) (Table 1). Grade 3 or 4 neutropenia was seen in 9/374 samples (2%) from 8 patients. Most patients finished their treatment without further neutropenia; only 1 patient was lost to follow-up immediately after low absolute neutrophil count result, and a negative outcome cannot be excluded. Grade 3 anemia was documented in 17/374 samples (5%) from 12 patients; most patients were able to continue their treatment uneventfully after transfusion; 1 patient with anemia died after his second treatment cycle. Grade 3 or 4 thrombocytopenia was not detected. Elevated creatinine occurred in 1 patient with known chronic kidney disease; he tolerated the treatment well and completed therapy successfully. Bilirubin and other hepatic enzymes were only measured rarely, but no abnormalities were detected.

TABLE 1. - Frequency of Laboratory Adverse Events by Common Terminology Criteria for Adverse Events Version 5.0 During Paclitaxel Treatment Laboratory Test Grade 3* Grade 4* Neutropenia 9/374 (2%) 1/374 (0.3) Anemia 17/374 (5%) 0/376 (0%) Low platelets 0/374 (0%) 0/374 (0%) Creatinine increased 4/357 (1%) 0/357 (0%) Bilirubin increased 0/29 (0%) 0/29 (0%)

Denominator is the number of available laboratory tests to account for occasional missing values.

*ANC: grade 3: <1000/mL, grade 4: <500/mL; Hb: grade 3: <8 g/dL, grade 4: life-threatening; platelets: grade 3: <50.000/mL, grade 4: <25.000/mL; creatinine: grade 3: >3–6 mg/dL, grade 4: >6 mg/dL; total bilirubin: grade 3: >3 mg/dL, grade 4: >10 mg/dL.

At the end of the observation period, follow-up phone calls were made, and 41 phones were reached. 37 patients (83%) were alive, and 4 patients (18%) were reported dead by relatives. Of the 4 deaths, 2 were discharged from treatment alive after the 6 cycles, and 2 had interrupted treatment after 2 cycles without further information to the clinic. The actual cause of death of these patients could not be determined. Subjective side effects were reported in 23/41 calls (51%); most of them were minor including hair loss (n = 16), nausea/vomiting (n = 2), and intercurrent burning/tingling sensations (n = 2). Most of the clients (29 of 30) providing feedback on service satisfaction reported having been satisfied and had no complaints; 1 complaint mentioned was delay in prechemotherapy laboratory results.

In an informal survey among our health care workers involved in paclitaxel administration at our clinic, prescription, reconstitution, and administration of the treatment was perceived easy and safe. Those who had experience with previous KS chemotherapy (mainly vincristine/bleomycin) believed paclitaxel was better tolerated with fewer side effects and higher chances of improvement.

In light of our experiences, we consider paclitaxel administration safe and effective in our ART outpatient clinic at the dose given for KS treatment and at treatment intervals of 2–3 weeks. Owing to its low toxicity and to trained personnel handling drug administration, the treatment was well-tolerated, and only mild side effects were detected. Hematological monitoring is desirable although the proportion of patients with myelosuppression was low at the prescribed dose and likely hemoglobin is the key parameter to monitor. However, gaps were detected in treatment continuation because 42% of patients defaulted chemotherapy and could not be traced. We partially attribute this to the study setting, a referral clinic in an urban area where a lot of people migrate within and outside the city for work, leading to attrition. Patients may feel subjectively better and thus consider interrupting further chemotherapy treatment and may return to their primary ART clinics. Obviously, an alternative explanation of clinical deterioration as cause of the attrition cannot be ruled out.

Our findings highlight the feasibility and safety of paclitaxel treatment of KS in ART clinics with limited monitoring outside hospital oncology units; at the same time, they stress the need for interventions to improve KS patient retention. Leveraging “back-to-care services” and other adherence retention strategies available in ART clinics can be used to manage lost to follow-up during chemotherapy allowing also better determination of overall treatment outcomes.

1. Mesri EA, Cesarman E, Boshoff C. Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer. 2010;10:707–719. 2. Whitby D, Howard MR, Tenant-Flowers M, et al. Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma. Lancet. 1995;346:799–802. 3. Global cancer observatory. Available at: https://gco.iarc.fr/. Accessed November 22, 2023. 4. Schwartz RA. Kaposi sarcoma treatment protocols: treatment protocols. Available at: https://emedicine.medscape.com/article/2006845-overview. Accessed November 22, 2023. 5. Herce ME, Kalanga N, Wroe EB, et al. Excellent clinical outcomes and retention in care for adults with HIV-associated Kaposi sarcoma treated with systemic chemotherapy and integrated antiretroviral therapy in rural Malawi. J Int AIDS Soc. 2015;18:19929. 6. Krown SE, Moser CB, MacPhail P, et al. Treatment of advanced AIDS-associated Kaposi sarcoma in resource-limited settings: a three-arm, open-label, randomised, non-inferiority trial. Lancet. 2020;395:1195–1207. 7. Phiri S, Neuhann F, Glaser N, et al. The path from a volunteer initiative to an established institution: evaluating 15 years of the development and contribution of the Lighthouse trust to the Malawian HIV response. BMC Health Serv Res. 2017;17:548. 8. National Cancer Institute C. Common terminology criteria for adverse events (CTCAE). 2017. Available at: https://ctep.cancer.gov/search/search.asp?zoom_query=Common+Terminology+Criteria++for+Adverse+Events+%28CTCAE%29&Action.x=0&Action.y=0. Accessed November 24, 2023.