|Year : 2013 | Volume
| Issue : 3 | Page : 254-260
Presentation, complications, and impact of concurrent malaria infection on anticancer therapy
V Noronha, G Goyal, A Joshi, S Gupta, J Ghosh, J Bajpai, K Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India
|Date of Web Publication||23-Sep-2013|
Department of Medical Oncology, Tata Memorial Hospital, Mumbai
Source of Support: None, Conflict of Interest: None
Background: There is very limited data on the effects of malaria on on-going anticancer therapy. Materials and Methods: We performed a retrospective analysis of adult solid tumor patients who contracted malaria while on active anticancer therapy. We noted their demographic profile, clinical course and the effects of malaria infection on their on-going anticancer therapy. Analysis was done with simple percentages. Results: We analyzed 33 malarial episodes in 30 patients over 3 months. Plasmodium vivax was the most common type of infection (75%). Presenting symptoms included the typical triad of fever with chills and rigors. Malaria caused multiple complications, necessitating hospitalization in half of the patients and intensive care unit care in 1 of 8 patients. Common complications included thrombocytopenia (73%), anemia (67%), hyponatremia (66%), hepatic dysfunction (27%), and hypotension (12%). There were no deaths as a result of malaria. Malaria caused treatment delays with an average of 2.42 days per event. Plasmodium vivax caused more complications and therapy delays, average: 3.7 days per event, while non-vivax malaria caused an average of 0.5 days delay per event. There was a high level of resistance to chloroquine. Conclusion: Malaria is a significant problem in adult solid tumor patients, leading to multiple complications and therapy delays.
Keywords: Drug therapy, infection, malaria, neoplasms, Plasmodium
|How to cite this article:|
Noronha V, Goyal G, Joshi A, Gupta S, Ghosh J, Bajpai J, Prabhash K. Presentation, complications, and impact of concurrent malaria infection on anticancer therapy. Indian J Cancer 2013;50:254-60
|How to cite this URL:|
Noronha V, Goyal G, Joshi A, Gupta S, Ghosh J, Bajpai J, Prabhash K. Presentation, complications, and impact of concurrent malaria infection on anticancer therapy. Indian J Cancer [serial online] 2013 [cited 2020 Jan 24];50:254-60. Available from: http://www.indianjcancer.com/text.asp?2013/50/3/254/118734
| » Introduction|| |
Malaria is a parasitic infection caused by the protozoan, Plasmodium, which infects human erythrocytes. Malaria may be caused by five species of Plasmodium, including Plasmodium vivax, Plasmodium falciparum, Plasmodium ovale, Plasmodium malariae and rarely, Plasmodium knowlesii.  According to the World Malaria report 2010, there are over 225 million cases of malaria each year, with 781,000 deaths, accounting for 2.23% of deaths worldwide.  70% of the 2.5 million cases of malaria that occur in South-East Asia, are from India.  Thus, malaria is a major public health problem in India. Drug-resistance to antimalarial is emerging and drug-resistant P. falciparum species are reported worldwide. 
People who are at risk for contracting severe malaria include people who lack immunity, especially children,  pregnant women,  human immunodeficiency virus (HIV)-infected persons, and persons living in non-endemic areas.  People with a diagnosis of carcinoma are immunosuppressed by virtue of their underlying cancer as well as their ongoing immunosuppressive chemotherapy. There are very little data in the literature on malaria infection in patients with carcinoma. We, therefore, analyzed the details of our patients who contracted malaria while receiving active therapy for solid tumors.
| » Materials and Methods|| |
This is a retrospective analysis conducted at a tertiary care cancer hospital in India. We reviewed the hematopathology records from August 2010 to October 2010 and noted the file numbers of all patients with a peripheral smear diagnosis of malaria. We selected only adult patients with a solid tumor diagnosis. We included those patients for whom clinical records were available and full information could be obtained. The diagnosis of malarial infection was by examination of the peripheral smear [Figure 1]; in some instances, serology (malaria antigen) and parasitic index (PI) (the parasite number per 1000 red blood cells in a thin smear, divided by 10 to get it in percentage) was also checked. Information collected included demographics, details of underlying malignancy and ongoing therapy, presenting features, investigations, therapy, complications and outcome of malaria. We also reviewed the charts to determine if the next cycle of chemotherapy or the patients' next planned anticancer therapy was affected by the malaria episode. Data was entered into an excel worksheet and the analysis was done with simple percentages.
|Figure 1: Peripheral smear shows crescent shaped gametocytes of Plasmodium falciparum on Wright stain|
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| » Results|| |
During the 3-month period, there were 30 adult patients with solid tumors on active therapy with a total of 33 malaria episodes (one patient was infected by malaria on three different occasions). Demographic details of the patients along with details of underlying carcinoma and ongoing therapy are provided in [Table 1].
The presenting symptoms are detailed in [Table 2]. The median number of days from onset of symptoms to time of seeking medical attention was 2 (range 1-10 days). At the time of initial evaluation, four patients had hypotension.
|Table 2: Presenting symptoms of patients with solid tumor on active therapy who developed malaria|
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The most common type of malaria was P. vivax in 25 patients (75%). 15% (5/33) patients had concomitant P. falciparum. Malarial antigen was checked in three patients (1: P. falciparum and 2: P. vivax); in all three cases, the serology corroborated the peripheral smear diagnosis. Both peripheral smear and serology were negative at presentation in two patients. Subsequent repeat testing of the peripheral smear revealed the malaria parasite (1: P. vivax and 1: P. falciparum). PI was checked in nine patients: The median PI was 1.5% (range 0.01-10%).
Laboratory parameters at presentation
The laboratory parameters at presentation are shown in [Table 3]. At initial presentation, 94% of patients were anemic, 64% were leukopenic, 15% had severe neutropenia (absolute neutrophil count <0.5 × 10 9 /l) and 73% were thrombocytopenic. 45% of patients had malaria along with febrile neutropenia. Of the patients who were not on chemotherapy, i.e. post-operative, scheduled for surgery, or receiving radiation therapy (n = 12), overall the hematologic parameters revealed a similar incidence of anemia and thrombocytopenia but a lower incidence of leukoneutropenia. 11 of the 12 patients were anemic with median hemoglobin of 10.2 g/dl (range 6.5-13.4 g/dl), 42% of the patients were leukopenic, only 1 patient was neutropenic (none with severe neutropenia) and 67% patients were thrombocytopenic.
Forty eight percent of the patients needed hospitalization due to malaria-related complications. Four patients required admission to the intensive care unit (ICU). Overall, thrombocytopenia was the most common complication, seen in 73% patients, followed by anemia in 64% of the patients. No deaths occurred as a result of malaria. The complications noted in our patients with malaria are detailed in [Table 4].
|Table 4: Complications of malaria in patients with solid tumors on active therapy|
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Details of antimalarial therapy, in terms of initial empiric therapy prescribed, resistance to first line antimalarial, and the second line antimalarial therapy administered, are given in [Table 5]. 21% patients received concurrent antibiotics.
Impact on anticancer management
The total number of days of delay in therapy was 80 days/33 events or 2.42 days per episode (range 1-15 days). The maximum deleterious effect on anticancer therapy was seen in patients of P. vivax malaria. 55% of the patients (11/20) with P. vivax had treatment disruption in the form of delay in chemotherapy (8 patients), radiotherapy (1 patient), chemoradiotherapy (1 patient), or surgery (1 patient). This amounted to a treatment delay of 3.4 days per malaria episode as a result of P. vivax infection. Only 15% of patients who contracted non-vivax malaria (both P. falciparum and combined P. vivax and P. falciparum) had a delay in therapy, amounting to 0.5 days delay per episode.
Assessment of factors affecting complications
We attempted to analyze whether there was a difference in complications and treatment delays as a result of Plasmodium-related factors or patient-related factors. There appeared to be a difference in complications between vivax and non-vivax malaria patients [Table 6]. In the vivax group, three patients presented with hypotension, compared with a single patient in the non-vivax group. P. vivax caused more renal dysfunction, while patients with non-vivax malaria developed more hepatic dysfunction. The non-vivax set had more neutropenic patients: 66% in the non-vivax group compared to 33% in vivax group, perhaps suggesting a role of P. falciparum in neutropenia. The effect on planned treatment was mainly seen in the vivax group. 55% patients had delayed treatment with 75% of patients on chemotherapy requiring treatment delays as a result of vivax malaria. The delay caused by vivax malaria was 3.7 days per episode of malaria, compared to 0.5 days per episode for non-vivax malaria.
|Table 6: Comparison of complications caused by Plasmodium vivax versus Plasmodium falciparum|
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Approximately one-third of the malaria episodes occurred in patients who were not on any type of chemotherapy at the time of malaria. As expected, there were more complications noted in patients who were on chemotherapy at the time they contracted malaria [Table 7]. Pancytopenia was exclusively found in patients on chemotherapy. There were 11 febrile neutropenic episodes in the chemotherapy group compared to a single episode in the non-chemotherapy group. Patients on chemotherapy also had more anemia, thrombocytopenia, renal dysfunction, requirement for blood products, and treatment delays. Overall, there were 25% more events in patients on chemotherapy than in patients on other types of therapy.
|Table 7: Comparison of complications of malaria based on whether patients were on chemotherapy versus on other therapies|
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| » Discussion|| |
The incidence of malaria in patients with malignancy is not known. A previous report from our institution revealed malaria to be the etiologic factor in 4% of acute leukemic patients on chemotherapy who developed febrile neutropenia.  We could not find any data as to the incidence of malaria infection in patients with solid tumors, but this is likely to vary based on geographic location and season.
The presentation of malaria in our patients was similar to that described in the literature for patients without an underlying malignancy. 61% of our patients presented with the classic triad of fever with chills and rigors, of which 1 patient reported high grade fever with chills on alternate days. Additionally, 33% patients reported only fever as the presenting symptom; however, given the retrospective nature of this analysis, it is possible that these patients also had chills and/or rigors, which was not documented. Almost 20% of the patients had nausea/vomiting and 12% of the patients had generalized body-ache at presentation. Thus, although our patients undoubtedly had some degree of immunosuppression due to underlying malignancy and ongoing therapy, the presenting features of malaria were not blunted.
Mirroring the distribution of malaria species in India  and worldwide,  we found that the most common species of malaria in our patients was P. vivax. 60% of the patients had only P. vivax infection, 15% had double infection with P. vivax and P. falciparum. Therefore, 75% of the patients were infected with P. vivax. In our patients, there were no reported cases of P. ovale, P. malariae or P. knowlesii.
The WHO defines severe malaria as malaria with a PI of 10% or more, in a high transmission area.  Of the nine patients who had a PI checked, only one patient had PI of 10%. This patient had combined infection with both P. vivax and P. falciparum and had a complicated clinical course. He developed tumor rupture requiring emergency surgery and ICU management. There were 8 patients (4: P. vivax, 3: P. falciparum, and 1: Combined P. vivax and P. falciparum) who had clinical features of severe or complicated malaria as defined by White et al.  including, hypotension, altered consciousness, and hepatic failure. The PI was reported in 3 of these cases; 1 patient had a PI of 10%, the other two patients had PI of only 1% and 0.8%. Patients with an underlying malignancy on active therapy are probably pre-disposed to developing severe malaria even with a lower parasitic burden.
Malaria caused a large number of complications in our patients, both hematologic as well as non-hematologic. 48% of the patients had to be hospitalized and 12% needed ICU care. Hematologic complications were the most common, with a third of the patients experiencing severe hematologic complications. Approximately 15% patients required transfusion of blood products, both red cells and platelet. The most common non-hematologic complications included hypotension, and severe hyponatremia, while less-commonly seen complications included altered sensorium, hepatic dysfunction, and tumor rupture. None of the patients had severe renal dysfunction, acidosis, hypoxemia or respiratory failure. In spite of the large number of complications, there were no deaths attributable to malaria. Patients who were on chemotherapy when they contracted malaria developed more complications such as febrile neutropenia, pancytopenia, renal dysfunction, and treatment delays. P. vivax caused more complications, including hypotension and renal dysfunction and more treatment delays amounting to 3.7 days per episode. Traditionally, P. falciparum is considered to be associated with severe and complicated malaria. However, in our patients, P. vivax appeared to have larger detrimental effect than in both P. falciparum or combined P. vivax/P. falciparum infection. Earlier studies from Papua, New Guinea have suggested that both P. vivax and mixed Plasmodium infections may be associated with severe malaria and multiple complications. , Recent studies from India have suggested that the profile of severe malaria in North Indian children is changing and that P. vivax is increasingly causing episodes of severe malaria. ,, Certainly, our sample size is small and there is a possibility that this observation may be due to random chance.
Approximately, one-third of the patients were initially treated with chloroquine and the remainder with artesunate-based combination therapy (ACT). Resistance to Chloroquine was high at 27% (all resistance noted in patients infected with P. vivax), while resistance to ACT was also noted, although at a lower rate of 9.5%. All patients who were resistant to chloroquine responded to ACT. The WHO recommends that ACT be used for empiric therapy of P. falciparum strains.  Given the high-level of resistance to chloroquine, it may be appropriate to empirically treat all patients with malaria, who have an underlying malignancy, with ACT. All patients who were resistant to ACT responded to mefloquine.
The therapy of malaria may also have an impact on the underlying malignancy. Some antimalarial agents, including, Quinacrine and Artesuntate , have been shown to have anticancer activity in cell lines. Chloroquine sensitizes cells to the cytotoxic activity of radiation and chemotherapy, thereby enhancing efficacy.  Whether the antimalarial therapy enhanced the effect of the ongoing anticancer therapy is unknown and beyond the scope of this retrospective analysis.
Patients with cancer in malaria endemic areas may contract malaria during the course of their cancer illness. Malaria being a life-threatening condition usually takes priority in terms of treatment over cancer, but as far as possible, delays in cancer therapy should be avoided. If malaria is suspected in a patient on active anticancer therapy, the patient needs to be aggressively, and initially empirically, treated for malaria and anticancer therapy should be restarted as soon as possible. This is especially true during seasonal periods of increased malaria infection in an endemic area, as was the case during the time period that we collected the data presented in this paper. Once therapy is restarted, there does not appear to be a need for dose reduction or discontinuation of chemotherapy as malaria is by and large, a single infectious episode, without long-lasting hematologic effects. Most of our patients successfully continued on therapy with no dose reduction or modification.
Antimalarial prophylaxis is routinely recommended for certain groups of people like non-immune travelers who are visiting an endemic area, pregnant women and immunodeficient individuals like HIV infected persons. Given the large number of complications ensuing from malaria in our immunocompromised patients, there may be a role for antimalarial prophylaxis for patients with malignancy undergoing treatment in malaria-endemic regions, especially for patients who may be at a higher risk for hematologic complications. This may be especially true during periods when the occurrence of malaria is higher, e.g. during the monsoon season.
There are very few prior reports in the literature on malaria in patients with underlying malignancy. Rapoport et al. described malaria parasitemia in three South African patients with hematologic malignancies and febrile neutropenia.  All the patients were treated with intravenous quinine, one patient developed progressive renal failure and hypotension and died as a result of malaria. Taylor et al. report on the outcome of malaria in 51 pediatric oncology patients in Senegal over a 10 year period.  Similar to our data, they found no increase in the fatality rate as a result of malaria infection. To the best of our knowledge, our report is the first description of malaria in adult patients with solid tumors.
| » Conclusions|| |
Malaria is a significant problem in adult solid tumor patients, especially in patients who are on chemotherapy. Concurrent malaria infection in these patients who are in the midst of antineoplastic therapy often leads to hospitalization, intensive care, multiple complications, and treatment delays. A high-index of suspicion in a patient who presents with the classic triad of symptoms in an endemic area, early performance and interpretation of the peripheral smear for malarial parasite and empiric antimalarial therapy in the appropriate patient are warranted. A comprehensive adoption of malaria control measures will help to curb this malaria menace and allow our patients to continue their main anticancer therapy without interruption.
| » Acknowledgments|| |
Dr. P. G. Subramanian, Mr. Shashikant Mhadik and Mrs. Shyla C. Shinde from the hematopathology laboratory at Tata Memorial Hospital for performing and interpreting the peripheral smears for the patients included in this paper.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]