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Does Chemotherapy Reactivate SARS-CoV-2 in Cancer Patients Recovered from Prior COVID-19 Infection?
PDPI Malang, 12 Sep 2020 15:06:09

Recovered COVID-19 cancer patients remain negative for SARS-CoV-2 after delivery of chemotherapy

To the Editor:

Cancer patients are particularly vulnerable to coronavirus disease 2019 (COVID-19) [13]. These individuals are not only more susceptible to this infection, but also more frequently develop severe pneumonia during the disease course [13]. One factor associated with an increasing risk for developing severe events in this population is oncologic therapy, especially cytotoxic chemotherapy. Therefore, some oncologists and societies recommend that chemotherapy should generally not be started until COVID-19 symptoms have completely resolved and viral testing becomes negative [3, 4]. Additionally, some cancer patients who have recovered from infection are recommended to withhold, postpone, or switch to alternative routes of chemotherapy (e.g. oral instead of intravenous [IV] infusion) until the end of the COVID-19 pandemic [3, 4].

However, implications of the aforementioned recommendations remain uncertain in routine clinical practice. First, given the highly fluid state of our understanding of SARS-CoV-2 viral biology, the precise time interval between resolution of infection and initiating/restarting chemotherapy requires further evaluation. This is especially important in nations with continually rising coronavirus cases, where prolonged interruption of anti-tumor treatment may cause both patient anxiety as well as disease progression. Second, the delivery of immunosuppressive chemotherapy in recovered COVID-19 patients risks reactivation of disease. This concept is especially important because reports have highlighted that SARS-CoV-2 can reemerge in recovered (with negative viral RNA) patients [5]. This may potentiate the burgeoning notion of a “second wave” of the pandemic. As of May 31, 2020, a total of 271 cancer patients recovered from prior COVID-19 infection were screened in Hubei Cancer Hospital. The majority of patients (192 [71%]) had stage III or IV disease and therefore required urgent chemotherapy-based treatment. Thus, it became important to investigate whether chemotherapy can cause reactivation of SARS-CoV-2 in cancer patients with prior COVID-19 infection.

In this study, we collected and analysed data from 39 cancer patients with SARS-CoV-2 infection history (negative for viral RNA and positive for serum antibodies) who received subsequent chemotherapy from seven hospitals within Hubei Province, China, including Hubei Cancer Hospital, Union Hospital, Suizhou Hospital, Renmin Hospital of Wuhan University, The Fifth Hospital of Wuhan, People's Hospital of Dongxihu District, and Tongji Hospital. All serum samples were tested for specific antibodies against SARS-CoV-2 by the colloidal gold immunoassay (Innovita, Tangshan, Hebei, China) prior to intravenous infusional chemotherapy. The patients harboring positive SARS-CoV-2 specific antibodies were screened for SARS-CoV-2 RNA in throat swabs by real-time reverse transcriptase PCR (rRT-PCR). This investigation was approved by the institutional ethics board of Hubei Cancer Hospital of Huazhong University of Science and Technology in Wuhan, China (NO. LLHBCH2020LW-006).

The median age was 57 years (IQR: 46–63) and the median follow-up from initial administration of chemotherapy was 116 days (IQR: 100–125). Prior to chemotherapy administration, all patients were negative for SARS-CoV-2, and all had at least one positive result for anti-SARS-CoV-2 antibodies. In total, 5 (13%) patients were negative for immunoglobulin G (IgG) and positive for immunoglobulin M (IgM+), 30 (77%) were IgG+ IgM, and 4 (10%) were IgG+ IgM+. Among this cohort, lung cancer was the most frequent neoplasm (9 [23%] patients), followed by breast cancer (8 [21%]) and colorectal cancer (7 [18%]). Fifteen (38%) patients had stage IV disease with distant organ metastasis. Twenty-seven (69%) patients had received chemotherapy prior to initially developing COVID-19, and 12 (31%) patients were chemotherapy-naïve. Thirty-three (85%) patients received multi-agent chemotherapy or a combination of chemotherapy and targeted therapies (including 5 patients with intravenous chemotherapy plus a PD-1 inhibitor); 6 (15%) received either orally administered drugs or a combination of targeted drug therapies (table 1).

TABLE 1

Clinical Characteristics of Cancer Patients Receiving Systemic Therapy with Prior SARS-CoV-2 Infection

Patient No. Sex Age PS Cancer diagnosis Staging Chronic diseases Systemic therapy Time of systemic therapy The grade of neutropenia Time of nucleic acid testing
1 Female 56 1 NSCLC T3N2M1 Diabetes 2 cycles of paclitaxel+nedaplatin April 21; May 14 2 April 20; May 13; June 9
2 Male 70 1 NSCLC T4N2M0 COPD 4 cycles of vinorelbine+anlotinib April 3; April 30; May 22; June 16 0 February 21; April 2; April 28; May 15; June 15
3 Female 33 1 NSCLC T4N3M1 None 2 cycles of PP, 3 cycles of PP+bevacizumab March 20; May 13; June 4; June 25; July 16 0 March 18; April 2; May 12; June 1; June 22; July 14
4 Female 67 1 NSCLC T4N0M0 Hypertension; Diabetes 2 cycles of GP April 7; May 13 2 April 6; April 20; May 11; July 10
5 Male 59 1 NSCLC T3N1M0 None 4 cycles of DP April 4; May 11; June 3; June 26 1 April 3; May 8; May 27; June 24
6 Male 73 1 NSCLC T3N2M0 None 4 cycles of abraxane+nedaplatin April 11; May 5; June 3; June 25 2 April 9; May 4; June 1; June 23
7 Female 59 1 NSCLC T3N3M1 None 2 cycles of docetaxel+nedaplatin and 1 cycle of GP March 13; April 18; June 18 2 March 10;April 15;May 26; June 10; June 15; July 8; July 13
8 Male 72 1 NSCLC T3N1M0 Hypertension; Cardiovascular disease; COPD 2 cycles of abraxane and 2 cycles of abraxane+nedaplatin+PD-1 inhibitor March 25; May 6; June 6; July 1; 3 March 23; April 1; April 3; May 5; June 3; June 29
9 Male 64 1 Lung neuroendocrine carcinoma T4N3M0 Hypertension 3 cycles of abraxane+lobaplatin April 21; May 19; June 18 4 April 19; May 18; June 15
10 Female 64 1 Breast cancer T3N1M0 Diabetes 3 cycles of capecitabine and 2 cycles of docetaxel April 10; May 1; May 23; June 12; July 4; July 24 1 April 9; April 14; April 23; May 16; June 8; July 2; July 21
11 Female 49 2 Breast cancer T2N0M1 None 5 cycles of capecitabine+letrozole March 18; April 15; May 30; June 22; July 23 0 March 17; March 20; April 14; May 28; July 22
12 Female 45 1 Breast cancer T2N2M1 None 6 cycles of capecitabine+trastuzumab+partuzumab April 15; May 5; May 28; June 17; July 7; July 28 0 April 14; April 29;May 11; May 26; June 12; July 6; July 27
13 Female 37 1 Breast cancer T3N2M0 None 3 cycles of capecitabine and 2 cycles of AC March 26; April 16; May 25; June 17; July 18 2 March 25; April 15; May 22; June 15; July 16
14 Female 30 1 Breast cancer T2N0M0 None 4 cycles of AC and 1 cycle of docetaxel March 28; May 22; June 9; June 30; July 22 3 March 27; April 7; May 21; June 6; June 26; July 20
15 Female 63 1 Breast cancer T1N1M0 Hypertension 4 cycles of docetaxel March 15; April 19; May 13; June 19 1 March 13; April 18; May 10; May 23; June 17
16 Female 53 1 Breast cancer T4N3M1 Hypertension 5 cycles of capecitabine March 18; April 14; May 13; June 4; July 1 1 March 17; April 13; May 12;May 26; June 30
17 Female 40 1 Breast cancer T2N2M0 None 1 cycle of capecitabine+ 4 cycles of AC March 13; April 20; May 12; June 3; June 26 2 March 12; March 23; April 17; May 11; May 27; June 25; July 15
18 Female 61 1 Rectal cancer T2N1M1 Hypertension 2 cycles of FOLFOX and 2 cycles of DC May 12; May 26; June 16; July 16 1 April 24; April 27; May 11; June 12; July 14
19 Male 52 1 Rectal cancer T4N1M0 Diabetes 4 cycles of capecitabine April 16; May 19; June 12; July 6 0 April 14; May 18; June 10; July 3
20 Female 51 1 Rectal cancer rT0N0M1 None 4 cycles of XELOX+PD-1 inhibitor April 18; May 7; June 1; July 3 4 April 16; May 5; May 29; July 1
21 Female 37 1 Colon cancer T3N1M1 None 7 cycles of FOLFIRI+bevacizumab March 21; April 8; May 8; May 28; June 15; July 1; July 20 2 March 19; April 7;May 5; May 27; June 12; June 29; July 16
22 Male 37 1 Colon cancer T4N2bM1 None 4 cycles of FOLFIRI+bevacizumab May 15; May 31; June 15; July 6 2 May 14; May 29; June 12; July 2; July 29
23 Male 47 1 Colon cancer T2N1M0 None 2 cycles of capecitabine and 2 cycles of XELOX April 12; May 10; June 3; June 25 1 April 8; April 11; May 9; May 23; June 1; June 24
24 Male 63 1 Colon cancer T3N1M1 Hypertension 5 cycles of XELOX+bevacizumab April 3; May 1; May 22; June 17; July 7 1 April 2; April 30; May 15; June 15; July 3
25 Male 58 1 NPC T3N2M0 None 2 cycles of DP; RT+ 1 cycle of cisplatin April 8; May 1; June 11 2 April 6; April 30; May 23; June 8; June 26
26 Male 41 1 NPC T3N2M0 None 2 cycles of GP+PD-1 inhibitor; RT+2 cycles of cisplatin+PD-1 inhibitor March 26; April 19; May 15; June 7 2 March 25; April 17; May 29;
27 Male 62 1 NPC T4N2M0 None 3 cycles of abraxane+nedaplatin March 9; April 1; June 18 2 March 8; March 31; May 28; June 15
28 Female 59 1 NPC rT0N1M0 None 2 cycles of GP and 2 cycles of GP+PD-1 May 19; June 9; July 1; July 24 2 April 21; May 15; June 3; June 6; June 30; July 20
29 Male 40 1 NPC T3N2M0 None 2 cycles of DP; RT+2 cycles of cisplatin April 17; May 8; June 1; June 23 2 April 15; May 6; May 26
30 Male 59 1 Esophagus cancer T4N2M0 None 3 cycles of docetaxel+S1 May 1; May 29; June 25 2 April 30; May 6; May 28; June 22
31 Male 67 2 Esophagus cancer T3N1M1 None 2 cycles of TP March 18; May 12 1 March 17; May 11; May 26
32 Male 57 1 Esophagus cancer T4aN2M0 Hypertension; Diabetes 3 cycles of capecitabine+nedaplatin+PD-1 inhibitor March 23; June 8; July 3 1 March 20; June 1; July 2
33 Male 64 1 Gastric cancer T3N2M1 None 3 cycles of EP May 22; June 11; July 7 1 April 15; May 20; June 8; July 4
34 Male 55 1 Gastric cancer T3N3M1 None 3 cycles of oxaliplatin+S1 March 25; April 18; May 10 0 March 24; April 16; May 9; May 22
35 Female 48 1 Cervical cancer IIB (FIGO) None 3 cycles of DP May 22; June 12; July 7; 1 April 22; May 20; June 10; July 3
36 Female 60 1 Ovarian cancer IIIc (FIGO) None 4 cycles of etoposide+apatinib March 23; April 21; May 6; May 29 2 March 23; April 20;May 5;May 28
37 Female 62 1 Ampullary carcinoma T4N0M1 None 1 cycle of capecitabine+temozolomide and 1 cycle of abraxane April 2; June 1 1 March 31; May 28; June 5
38 Male 71 1 Soft tissue sarcoma T3N0M0 G3 None 2 cycles of gemcitabine+anlotinib+PD-1 inhibitor June 5; July 3 0 May 20; June 3; June 4; June 29
39 Male 41 1 Glioblastoma   None 3 cycles of temozolomide April 24; May 22; June 19 0 April 23; May 19; June 17

Abbreviations: NPC: nasopharyngeal cancer; NSCLC: non-small cell lung cancer; COPD: chronic obstructive pulmonary disease; GP: gemcitabine+cisplatin; FOLFOX: oxaliplatin+5-fluorouracil+leucovorin; FOLFIRI: irinotecan+5-fluorouracil+leucovorin; EP: etoposide+cisplatin; XELOX: oxaliplatin+capecitabine; AC: adriamycin+cyclophosphamide; RT: radiotherapy; PP: pemetrexed+cisplatin; TP: paclitaxel+cisplatin; DC: docetaxel+carboplatin.

At the time of last follow-up, all patients remained negative for SARS-CoV-2, without suspicious changes on chest CT. Twenty-two (56%) patients experienced altered immunoglobulin test results; specifically, twelve (31%) patients who were initially IgG+ IgM became IgG IgM after the median 57 days (IQR: 36–66) from initial administration of chemotherapy. Among the four (10%) patients who were initially IgG+ IgM+, three patients became IgG IgM+, and one became IgG+ IgM respectively after 54, 65, 101, and 23 days of chemotherapy. Two (5%) patients who was initially IgG+ IgM became IgG+ IgM+ after 55, 72 days of chemotherapy. Three patients who was initially IgG IgM+ became IgG IgM after 59, 94 and 101 days of chemotherapy and only one patient initially IgG IgM+ became IgG+ IgM.

Treatments were tolerated well in this cohort. At least one therapy-associated adverse event was registered in 31 (79%) patients and all adverse events were of grades I or II, except for four cases of grade III-IV neutropenia which returned to normal after treatment with Granulocyte colony-stimulating factor (G-CSF).

Potential re-emergence of COVID-19 in recovered patients receiving immunosuppressive chemotherapy is a major oncologic and public health concern. Concerns of reactivation of a prior infection are not limited to COVID-19. Previous studies have shown that reactivation of hepatitis B virus (HBV) occurs in nearly 20% of cancer patients undergoing chemotherapy, and may result in varying degrees of liver damage [6, 7]. There has also been a report that chemotherapy may cause reactivation of tuberculosis [8]. Additionally, many studies have illustrated (in the recovered COVID-19 population) that chemotherapy is associated with a higher risk of developing severe events (e.g. pneumonitis), as compared to cancer patients without receipt of recent chemotherapy [1, 2]. However, not all studies have supported such conclusions; some have found no significant effect on mortality for patients having undergone chemotherapy within the prior 4 weeks [9, 10]. Those studies mainly addressed whether chemotherapy could predict for hospitalisation, severe disease, and mortality in cancer patients with COVID-19 infection. However, limited information is known about the outcome of chemotherapy for cancer patients with prior COVID-19 infection. To address this knowledge gap, this study's findings suggest that administering chemotherapy to this population is associated with a very low short-term risk of SARS-CoV-2 reactivation. Further work is required to prospectively follow these subjects in the longer term.

Many studies have indicated that patients with COVID-19 have varying degrees of multiple organ dysfunction [1113], especially those who are critically ill [13]. The rate of liver dysfunction, acute kidney injury, and cardiac injury were as high as 29%, 29% and 23%, respectively [13]. To date, it is unknown whether chemotherapy would make cancer patients with prior COVID-19 infection more vulnerable to organ damage. Although our data demonstrate that this population does not demonstrate an overtly increased susceptibility to organ dysfunction in the short term, corroboration with longer-term prospective data is required for firmer conclusions.

Our study has several limitations. First, according to the updated COVID-19 Diagnostic Criteria (7th Edition) [14], viral serum antibody-based tests are indeed valid for diagnosis; however, false positive and false negative test results can occur. The sensitivity and specificity of the colloidal gold immunoassay utilised herein for IgG, IgM, and IgG/IgM was 83%/74%/84% and 99%/97%/95%, respectively [15]. Second, the number of cases in this study is relatively small, and retrospective assessment can never exclude biases in patient selection. Third, the duration of follow-up in this study was relatively short and it may take a longer period of time to determine immune-related alterations caused by chemotherapy in cancer patients who have recovered from COVID-19 infection. Nevertheless, when conservatively interpreted, our study indicates no overt short-term increase in the risk for SARS-CoV-2 reactivation following immunosuppressive chemotherapy in this uniquely vulnerable population.

To our knowledge, this is the first study reporting that recovered COVID-19 cancer patients remain negative in the short-term for SARS-CoV-2 after delivery of chemotherapy. The knowledge/experience gained from this study may aid guidelines on delivering chemotherapy to cancer patients recovered from COVID-19 infection during this pandemic as well as to address potential “second waves” in the future.

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