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Evaluation of treatments for HIV-associated Kaposi sarcoma in Africa
Infectious Agents and Cancer ( IF 3.1 ) Pub Date : 2021-04-17 , DOI: 10.1186/s13027-021-00364-5
Susan E. Krown , Margaret Z. Borok

To the editors:

We write to comment on the recent article by Coldiron and colleagues [1] that describes Médecins Sans Frontières’ programmatic use of pegylated liposomal doxorubicin (PLD) for treatment of HIV-associated Kaposi sarcoma (KS) in Mozambique. Their discussion raises the important and very pertinent issue of health systems barriers to effective and sustainable cancer treatment in low- and middle-income countries, which is a problem for all cancers, not just for KS. That said, we wish to register our concerns about some of the particulars of their study and their interpretation of the data.

1.
Response to treatment: The authors cite an overall tumor response rate of 80% and a complete response (CR) rate of 13%. These response rates, and the CR rate in particular, are higher than would be expected even in highly resourced settings where the adverse socioeconomic factors the authors cite as reasons for their high mortality rate are not present. This raises concerns about the rigor with which KS response and progression-free survival were documented. Response of KS was measured infrequently (every 3 months in the first year, and then every 6 months), and response assessment was described as consisting of measurement of “sentinel KS lesions”, which is only one of several measures required for a full KS response assessment. In addition, the duration of response was not specified.

Of study participants who achieved a response to PLD and whose chemotherapy was then discontinued, 28% required re-treatment after subsequent KS progression. In our experience, recurrence or progression of KS after apparently successful chemotherapy is not uncommon, nor is response to a subsequent course of treatment. We are, however, puzzled by the authors’ statement that “this phenomenon does not seem to be related directly to PLD”, as most agree that chemotherapy is not expected to cure KS, and that the cause of progressive KS is likely multifactorial. Nonetheless, it is disappointing that the investigators did not track ART adherence and virological failure, which are likely contributing factors to KS progression.

2.
Safety: Except for blood counts performed prior to each chemotherapy cycle, formal assessments of safety and adverse events were done infrequently during the course of treatment. Other than blood counts, it is not stated whether any other tests to monitor safety (e.g., renal or hepatic function, cardiac function) were conducted routinely, and participants were apparently questioned about adverse events only at the times of their 3- to 6-monthly KS evaluations. Thus, it is not surprising that the reported rates of moderate to severe toxicities were lower than those reported from studies of PLD conducted in highly-resourced settings [2, 3]. Moreover, only significant adverse events (i.e., death or hospitalization) were described in detail, but details about other adverse events were not provided.

In this context, we highlight the authors’ comment regarding a prospectively randomized trial of chemotherapy with antiretroviral therapy (ART) in advanced KS [4], which we co-chaired. Our trial was conducted primarily in sub-Saharan Africa, and included frequent and intensive monitoring of KS response, safety, ART adherence and virologic control. Their comment that in our trial, “paclitaxel toxicities were largely the same compared to the vincristine/bleomycin group” seems to suggest that this was a failing of paclitaxel and that paclitaxel therefore suffers by comparison to PLD, whereas in fact the serious adverse event rate was low in both the paclitaxel and bleomycin/vincristine treatment arms of our trial.

We have additional concerns about participant screening. Formal assessment of cardiac function was done rarely (5 of 116 participants), and echocardiography was only performed if symptoms of CHF were detected. While we appreciate that the risk of cardiotoxicity is lower with PLD than with conventional doxorubicin, symptoms may be an unreliable indicator of cardiac dysfunction in this vulnerable patient population. For example, as noted in a recent review [5], although the incidence of HIV-associated cardiomyopathy has decreased from the pre-ART era, “the phenotype of cardiomyopathy has also changed markedly, from symptomatic systolic dysfunction … to asymptomatic systolic or diastolic dysfunction detected by echocardiography” in the post-ART era. Additionally, we are concerned about the infrequency with which the diagnosis of KS was pathologically confirmed (43%). As noted by Amerson et al [6], a clinical suspicion of KS is often not confirmed by pathology, and may be particularly challenging in people with darkly pigmented skin, so lack of a confirmed diagnosis risks unnecessarily exposing patients without KS to cytotoxic drugs.

3.
Mortality: Overall mortality and, especially, loss to follow-up were high in this study. The loss to follow-up rate of 13% compares unfavorably with the < 1% we observed in our randomized trial [4], and at least some of those “lost” are likely to have died [7].

In summary, while we applaud these investigators for attempting to provide improved treatment for patients with advanced HIV-associated KS, we urge caution in interpreting the results presented. We suggest a cautious approach to patient screening prior to initiating chemotherapy, and careful attention to response assessment, safety monitoring and control of HIV and concomitant illnesses during therapy. Finally, we agree that a rigorously controlled, prospective, head-to-head comparison of PLD and paclitaxel in Africa is warranted. Such a trial is being planned, which will include not only clinical and safety endpoints, but also formal evaluations of quality of life as well as cost- and cost-effectiveness comparisons.

Susan E. Krown

London, United Kingdom

Margaret Z. Borok

Faculty of Medicine and Health Sciences, University of Zimbabwe, Harare, Zimbabwe

Not applicable. No original data or materials presented.

ART:: Antiretroviral therapy
CR:: Complete response
HIV:: Human immunodeficiency virus
KS:: Kaposi sarcoma
PLD:: Pegylated liposomal doxorubicin

1.
Coldiron ME, Gutierrez Zamudio AG, Manuel R, Luciano G, Rusch B, Ciglenecki I, et al. Outcomes of AIDS-associated Kaposi sarcoma in Mozambique after treatment with pegylated liposomal doxorubicin. Infect Agent Cancer. 2021;16(1):2. https://doi.org/10.1186/s13027-020-00341-4 PMID: 33413521; PMCID: PMC7791748.
CAS Article PubMed PubMed Central Google Scholar
2.
Krown SE, Northfelt DW, Osoba D, Stewart JS. Use of liposomal anthracyclines in Kaposi's sarcoma. Semin Oncol. 2004;31(6 Suppl 13):36–52. https://doi.org/10.1053/j.seminoncol.2004.08.003 PMID: 15717737.
CAS Article PubMed Google Scholar
3.
Cianfrocca M, Lee S, Von Roenn J, Tulpule A, Dezube BJ, Aboulafia DM, et al. Randomized trial of paclitaxel versus pegylated liposomal doxorubicin for advanced human immunodeficiency virus-associated Kaposi sarcoma: evidence of symptom palliation from chemotherapy. Cancer. 2010;116(16):3969–77. https://doi.org/10.1002/cncr.25362 PMID: 20564162; PMCID: PMC3157242.
Article PubMed PubMed Central Google Scholar
4.
Krown SE, Moser CB, MacPhail P, Matining RM, Godfrey C, Caruso SR, 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(10231):1195–207. https://doi.org/10.1016/S0140-6736(19)33222-2 Epub 2020 Mar 5. PMID: 32145827; PMCID: PMC7236082.
CAS Article PubMed PubMed Central Google Scholar
5.
Hsue P, Waters D. HIV infection and coronary heart disease: mechanisms and management. Nat Rev Cardiol. 2019;16(12):745–59. https://doi.org/10.1038/s41569-019-0219-9 Retrieved from https://escholarship.org/uc/item/04n828dz.
Article PubMed PubMed Central Google Scholar
6.
Amerson E, Woodruff CM, Forrestel A, Wenger M, McCalmont T, LeBoit P, et al. Accuracy of Clinical Suspicion and Pathologic Diagnosis of Kaposi Sarcoma in East Africa. J Acquir Immune Defic Syndr. 2016;71(3):295–301. https://doi.org/10.1097/QAI.0000000000000862 PMID: 26452066; PMCID: PMC4770348.
Article PubMed PubMed Central Google Scholar
7.
Anderegg N, Hector J, Jefferys LF, Burgos-Soto J, Hobbins MA, Ehmer J, et al. Loss to follow-up correction increased mortality estimates in HIV-positive people on antiretroviral therapy in Mozambique. J Clin Epidemiol. 2020;128:83–92. https://doi.org/10.1016/j.jclinepi.2020.08.012 Epub 2020 Aug 20. PMID: 32828836.
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Affiliations

Member Emerita, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Susan E. Krown
Department of Medicine, Parirenyatwa Hospital, College of Health Sciences, University of Zimbabwe, Mazowe Street, Harare, Zimbabwe
Margaret Z. Borok

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Contributions

SEK and MZB jointly conceived of the letter, wrote the letter and approved of the contents of the letter.

Corresponding author

Correspondence to Susan E. Krown.

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Not applicable. This is not a clinical trial.

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The authors (SEK and MZB) grant BioMed Central a license to publish the article and identify itself as the original publisher.

Competing interests

SEK and MZB have no relevant competing interests. The authors declare the following interests that are not relevant to the content of this letter:

SEK and MZB have received grant funding from NIH/NCI.

MZB has received grant funding from NIH/NIAID.

SEK has received non-financial support from Celgene (drug donation for a clinical trial).

SEK has received personal fees for endpoint adjudications in clinical trials from Pfizer and Applied Clinical Intelligence LLC.

SEK has received royalties from Wolters-Kluwer/UpToDate.

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Cite this article

Krown, S.E., Borok, M.Z. Evaluation of treatments for HIV-associated Kaposi sarcoma in Africa. Infect Agents Cancer 16, 25 (2021). https://doi.org/10.1186/s13027-021-00364-5

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Received: 19 February 2021
Accepted: 08 April 2021
Published: 17 April 2021
DOI: https://doi.org/10.1186/s13027-021-00364-5

Keywords

Kaposi sarcoma
Human immunodeficiency virus
Chemotherapy
Paclitaxel
Pegylated liposomal doxorubicin

中文翻译：

在非洲评估与艾滋病毒相关的卡波济肉瘤的治疗方法

致编辑：

我们对Coldiron及其同事最近发表的文章发表评论[1]，该文章描述了无国界医生通过聚乙二醇化脂质体阿霉素（PLD）在莫桑比克治疗与HIV相关的卡波西肉瘤（KS）的程序性使用。他们的讨论提出了一个重要且非常相关的问题，即低收入和中等收入国家中有效和可持续地治疗癌症的卫生系统壁垒，这是所有癌症的问题，而不仅仅是KS。也就是说，我们希望对他们的研究和数据解释的某些细节表示关注。

1。
对治疗的反应：作者认为总体肿瘤反应率为80％，完全反应（CR）率为13％。即使在资源充沛的环境中，作者给出的不良社会经济因素均不存在导致死亡率高的原因，这些响应率，尤其是CR率也比预期的要高。这引起了人们对记录KS反应和无进展生存期的严格性的担忧。很少测量KS的反应（第一年每3个月一次，然后每6个月一次），并且反应评估被描述为包括“前哨KS病变”的测量，这只是完整KS所需要的几种测量之一反应评估。此外，未指定响应时间。

在对PLD产生反应并随后中止化疗的研究参与者中，有28％的患者在随后的KS进展后需要重新治疗。根据我们的经验，明显成功的化疗后KS复发或进展并不罕见，对随后的治疗过程也没有反应。但是，我们对作者的陈述感到困惑，因为“这种现象似乎与PLD并不直接相关”，因为大多数人都认为化学疗法不能治愈KS，而进行性KS的病因可能是多因素的。尽管如此，令人失望的是，研究人员没有追踪ART的依从性和病毒学失败，这可能是导致KS进展的因素。

2。
安全性：除了在每个化疗周期之前进行血细胞计数外，在治疗过程中很少对安全性和不良事件进行正式评估。除血液计数外，没有说明是否常规进行任何其他监测安全性的测试（例如，肾或肝功能，心脏功能），并且显然仅在参与者3至6岁时才询问参与者有关不良事件的信息。每月KS评估。因此，所报道的中度至重度毒性的发生率低于在资源丰富的地区进行的PLD研究所报告的发生率[2，3]，这不足为奇。此外，仅详细描述了重大不良事件（即死亡或住院），但未提供有关其他不良事件的详细信息。

在这种情况下，我们强调了作者对晚期KS [4]联合抗逆转录病毒疗法（ART）进行的一项前瞻性随机试验的评论[4]，该研究由我们共同主持。我们的试验主要在撒哈拉以南非洲进行，包括对KS反应，安全性，ART依从性和病毒学控制的频繁和深入监测。他们的评论是，在我们的试验中，“紫杉醇的毒性与长春新碱/博来霉素组基本相同”，似乎表明这是紫杉醇的一种失败，因此紫杉醇与PLD相比受苦，而事实上不良事件发生率很高在我们的试验中，紫杉醇和博来霉素/长春新碱的治疗组均偏低。

我们还有其他与参与者筛选有关的问题。很少进行心脏功能的正式评估（116位参与者中的5位），只有在检测到CHF症状时才进行超声心动图检查。尽管我们认识到，PLD的心脏毒性风险要低于传统的阿霉素，但在这种脆弱的患者群体中，症状可能是心脏功能障碍的不可靠指标。例如，如最近的一篇综述[5]所述，尽管与艾滋病毒相关的心肌病的发病率已从抗逆转录病毒治疗前时代开始下降，但“心肌病的表型也发生了显着变化，从有症状的收缩功能障碍…变为无症状的收缩或舒张期。 “在后ART时代，通过超声心动图检测到的功能障碍”。此外，我们担心病理诊断证实KS的频率不高（43％）。正如Amerson等[6]指出的那样，通常无法通过病理学证实KS的临床怀疑，并且在皮肤色素沉着的人群中尤其可能具有挑战性，因此，缺乏确诊的风险会不必要地使没有KS的患者暴露于细胞毒性药物中。

3。
死亡率：这项研究的总体死亡率很高，尤其是随访失败。与我们在随机试验中观察到的<1％相比，随访率降低了13％，这是不利的，并且至少有一些“丧失”者可能已经死亡[7]。

总而言之，尽管我们赞扬这些研究人员试图为晚期HIV相关KS患者提供更好的治疗，但我们在解释呈现的结果时仍要谨慎行事。我们建议在开始化疗之前对患者进行筛查时应采取谨慎的态度，并在治疗期间应特别注意对反应评估，安全性监测和控制HIV及其伴随疾病的注意。最后，我们同意在非洲对PLD和紫杉醇进行严格控制，前瞻性的正面对比。正在计划进行这样的试验，该试验不仅包括临床和安全性终点，还包括生活质量的正式评估以及成本和成本效益比较。

苏珊·克鲁恩（Susan E.Krown）

伦敦，英国

玛格丽特·布洛克（Margaret Z.

津巴布韦大学医学与健康科学学院，津巴布韦哈拉雷

不适用。没有原始数据或资料。

艺术：: 抗逆转录病毒疗法
CR：: 完整回应
艾滋病病毒：: 人类免疫缺陷病毒
KS：: 卡波济肉瘤
PLD：: 聚乙二醇脂质体阿霉素

1。
Coldiron ME，Gutierrez Zamudio AG，Manuel R，Luciano G，Rusch B，Ciglenecki I等。用聚乙二醇化脂质体阿霉素治疗后，莫桑比克与艾滋病相关的卡波西肉瘤的结果。感染剂癌症。2021; 16（1）：2。https://doi.org/10.1186/s13027-020-00341-4 PMID：33413521; PMCID：PMC7791748。
CAS Article PubMed PubMed Central Google学术搜索
2。
Krown SE，Northfelt DW，Osoba D，Stewart JS。脂质体蒽环类药物在卡波济肉瘤中的使用。Semin Oncol。2004; 31（6 Suppl 13）：36-52。https://doi.org/10.1053/j.seminoncol.2004.08.003 PMID：15717737。
CAS文章PubMed Google学术搜索
3。
Cianfrocca M，Lee S，Von Roenn J，Tulpule A，Dezube BJ，Aboulafia DM等。紫杉醇与聚乙二醇脂质体阿霉素治疗晚期人类免疫缺陷病毒相关的卡波西肉瘤的随机试验：化学疗法减轻症状的证据。癌症。2010; 116（16）：3969-77。https://doi.org/10.1002/cncr.25362 PMID：20564162; PMCID：PMC3157242。
文章PubMed PubMed Central Google学术搜索
4，
Krown SE，Moser CB，MacPhail P，Matining RM，Godfrey C，Caruso SR等。在资源有限的环境中治疗晚期艾滋病相关的卡波济肉瘤：一项三臂，开放标签，随机，非自卑性试验。柳叶刀。2020; 395（10231）：1195–207。https://doi.org/10.1016/S0140-6736(19)33222-2 Epub 2020 Mar 5.PMID：32145827; PMCID：PMC7236082。
CAS Article PubMed PubMed Central Google学术搜索
5，
Hue P，Waters D. HIV感染和冠心病：机制和管理。Nat Rev Cardiol。2019; 16（12）：745-59。https://doi.org/10.1038/s41569-019-0219-9取自https://escholarship.org/uc/item/04n828dz。
文章PubMed PubMed Central Google学术搜索
6，
Amerson E，Woodruff CM，Forrestel A，Wenger M，McCallmont T，LeBoit P等。东非卡波西肉瘤的临床怀疑和病理诊断的准确性。J Acquir免疫缺陷综合症。2016; 71（3）：295-301。https://doi.org/10.1097/QAI.0000000000000862 PMID：26452066; PMCID：PMC4770348。
文章PubMed PubMed Central Google学术搜索
7。
Anderegg N，Hector J，Jefferys LF，Burgos-Soto J，Hobbins MA，Ehmer J等。莫桑比克接受后续纠正的损失增加了接受抗逆转录病毒治疗的HIV阳性患者的死亡率估计。临床流行病学杂志。2020; 128：83-92。https://doi.org/10.1016/j.jclinepi.2020.08.012 Epub 2020年8月20日。PMID：32828836。
文章PubMed Google学术搜索

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隶属关系

美国纽约纪念斯隆-凯特琳纪念癌症中心Emerita成员
苏珊·克鲁恩（Susan E.Krown）
津巴布韦大学健康科学学院Parirenyatwa医院医学系，津巴布韦哈拉雷Mazowe Street
玛格丽特·布洛克（Margaret Z.

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MZB已从NIH / NIAID获得了资助资金。

SEK已从Celgene获得了非财务支持（用于临床试验的药物捐赠）。

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