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Supportive Care in Cancer

, Volume 18, Issue 8, pp 993–1006 | Cite as

A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea

  • Sharon EladEmail author
  • Yehuda Zadik
  • Ian Hewson
  • Allan Hovan
  • M. Elvira P. Correa
  • Richard Logan
  • Linda S. Elting
  • Fred K. L. Spijkervet
  • Michael T. Brennan
  • Viral Infections Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO)
Review Article

Abstract

Purpose

Our aim was to evaluate the literature for the prevalence of and interventions for oral viral infections and, based on scientific evidence, point to effective treatment protocols. Quality of life (QOL) and economic impact were assessed if available in the articles reviewed.

Methods

Our search of the English literature focused on oral viral infections in cancer patients within the timeframe of 1989–2007. Review methods were standardized. Cohort studies were used to determine the weighted prevalence of oral viral infection in cancer patients. The quality of selected articles were assessed and scored with respect to sources of bias, representativeness, scale validity, and sample size. Interventional studies were utilized to determine management guidelines. Literature search included measures of QOL and economic variables.

Results

Prevalence of oral herpes simplex virus (HSV) infection in neutropenic patients was higher than in patients treated with radiotherapy for head and neck cancer (49.8% vs. 0%, respectively). In patients treated with radiochemotherapy for head and neck cancer, the prevalence of oral HSV infection increases up to 43.2% (CI, 0–100%). Prevalence of HSV infection was higher when oral ulcers existed. Information about other oral viral infections is sparse. There was a significant benefit of using acyclovir to prevent HSV oral infection (at 800 mg/day). Various dosing protocols of valacyclovir achieved prevention of HSV reactivation (500 or 1,000 mg/day). The prevalence of HSV reactivation was similar for acyclovir and valacyclovir. No information about impact on QOL and economic burden was available.

Conclusions

Acyclovir and valacyclovir are equally effective in preventing oral HSV infection. Neutropenic patients, who were primarily treated for hematological malignancies in the studies reviewed, are at a greater risk for viral infection.

Keywords

Viral Infection Herpes Oral Complication Cancer HSV Acyclovir Valacyclovir 

Introduction

Viral infections in the oral cavity or the perioral region are frequent complications of cancer treatment. Pain and discomfort are common and can lower intake of fluid and nutrients, which in severe cases can lead to dehydration and malnutrition, requiring hospitalization. Diagnosis of oral viral infection is important, since treatment can alleviate symptoms and reduce the likelihood of the spread of infection [1, 2, 3].

Since the 1989 consensus meeting organized by the National Cancer Institute (NCI) [4], numerous studies about viral infections in cancer patients have been published. These studies are diverse in their designs and, therefore, a systematic review allows for integration of different types and quality of studies.

The current systematic review of viral infections in cancer patients focused on patients whose infections demonstrated oral or perioral involvement. Most commonly, these infections were associated with herpesviruses: herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein–Bar virus (EBV), and cytomegalovirus (CMV).

The literature prior to 1989 demonstrated a wide range of prevalence for oral viral infection. Dreizen et al. [5] reported a large-scale study which looked at infections in 1,000 patients undergoing cancer treatment (carcinomas, sarcomas, and lymphomas). Overall, 9.7% patients developed oral infections during their treatment and, of these, 10.7% were viral [5]. Several studies suggested that the prevalence of oral infections was actually underreported in the literature based on a finding that 40–50% of patients following chemotherapy and/or bone marrow transplantation were found to have herpetic infections [6, 7]. In the monograph summarizing the 1989 NCI consensus meeting, even a higher incidence of HSV reactivation was reviewed, reaching up to 80% of hematopoietic stem cell transplantation (HSCT) patients [4]. Generally, infections were more prevalent in patients with hematological malignancies compared with those who had solid tumors.

Intervention studies published before 1989 marked the beginning of the era of acyclovir-based protocols. Before acyclovir was available, 5–10% of HSV-infected patients undergoing HSCT died [4]. Acyclovir offered effective control of HSV infection, whether administered prophylactically [8, 9, 10, 11] or therapeutically [12, 13, 14, 15]. Limited attention was given to brivudin (BVDU), a nucleoside analogue inhibitor of HSV replication. One study suggested BVDU may be an effective and safe drug for the oral treatment of HSV and VZV infections in severely immunosuppressed patients [16]. These interventional studies assessed all manifestations of viral infection and not only the oral tissues.

The aim of the current systematic review on the oncology literature was to evaluate the prevalence of oral viral infections. Additionally, we reviewed interventional studies to determine appropriate management protocols for oral viral infections. Lastly, we searched for information about the impact of oral viral infections on quality of life and economic burden.

Methods

A research librarian performed literature searches using the following online databases: Medline/PubMed, EMBASE, Cochrane Library, and Best Evidence.

The period searched was from 1989 to 2007. This is further described in this monograph [17]. The primary outcome was to trace all literature containing original data on incidence/prevalence of viral infection in cancer patients, as well as the impact on oral health-related quality of life, economic burden, and preventive/management strategies of viral infection in cancer patients undergoing head and neck surgery, radiotherapy, or combined treatment modalities. A more specific literature search was completed with the keywords herpes, infection, viral infection, oral, intra-oral, cancer, leukemia, lymphoma, HSV, CMV, EBV, VZV, human herpes virus-6 (HHV-6), rubeola, rubella, mumps, and coxsackie. This additional search was conducted to confirm the primary literature search and to update it during the review process. The search focused on studies reporting oral manifestations related to the most common viral infections in cancer patients. Viruses with localized oral lesions human papilloma virus (HPV) were not included. Searches were limited to studies involving human subjects and that were published in the English language. Publication types included were meta-analyses, systematic reviews, randomized controlled trials (RCT), nonrandomized studies, cohort studies, case studies, and opinion documents. The meta-analysis and systematic reviews were used to identify studies that should be added to the review. Papers that did not report oral or perioral manifestations of viral infections were excluded.

The literature review and development of recommendations were based on the manual provided by leaders of the Oral Care Study Group (OCSG) of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and an experienced epidemiologist. This manual was composed as part of a wider project called Oral Care Systematic Review [17]. The Viral Infections Section was one of ten sections reviewing prevalence, quality of life, economic burden, and management/prevention strategies for various oral complications associated with cancer therapies. As part of the preparations for the systematic review, the methodology proposed by the leaders of the OCSG was tested by the Section Heads. An identical form was filled in by all members of the systematic review [17]. This form was used for calibration of all Section Heads following by calibration of the members of the Viral Infection Section. Conclusions from this calibration process were implemented into the next phase of the review.

Each of the studies was independently evaluated by two of the authors. Each two reviewers then discussed their review results and concluded their final decision in areas of conflict.

Cohort studies were used mainly to analyze the prevalence of oral HSV infections in respect to various patient populations. The prevalence was calculated separately for the two main cancer populations that the literature search revealed: (1) neutropenic patients (including patients with hematologic malignancies, patients undergoing bone marrow transplant, and other neutropenic cancer patients) and (2) head and neck cancer patients treated with radiotherapy.

Since the variables used in the literature to diagnose HSV infection varied greatly between studies, studies were grouped according to the sample characteristics. Prevalence was calculated for each of these four groups separately:
  1. 1.

    Oncologic patient population; culture was taken when an oral ulcer was observed; the endpoint was the percentage of patients with positive cultures out of the patient population.

     
  2. 2.

    Oncologic patient population; culture was taken whether or not an oral ulcer was observed; the endpoint was the percentage of patients with positive cultures out of patient population.

     
  3. 3.

    Oncologic patient population with an oral ulcer; culture was taken from the oral ulcer; the endpoint was percentage of patients with positive cultures out of patient population.

     
  4. 4.

    Oncologic patient population with an oral ulcer; culture was taken from the oral ulcer; the endpoint was percentage of lesions with positive cultures out of patient population.

     
  5. 5.

    Oncology patient population; culture was taken whether or not an oral ulcer was observed; the endpoint was the percentage of positive swabs out of the total number of swabs taken.

     

The development of recommendations was based on the findings of the interventional studies using a well-recognized system for grading the recommendation [18, 19]. Data collected for each interventional article such as type of study, blinding, presence of control group, scale validity, and samples size were use to determine the quality grading. Further details of this methodology can be reviewed in Brennan et al. [17].

Measures of quality of life and economic variables were documented if available.

Results

Forty-eight articles were retrieved during the literature search and reviewed (Fig. 1). The full-text version revealed several studies that were of lower level of evidence according to Hadron at al. [19], or irrelevant to the aim of this systematic review. These articles were removed from the summary process. We deleted publications due to the following reasons (Table 1): review, focus on non-viral oral infections, study population other than cancer patients, absence of data about oral viral infections, focus on the causal relationship between the virus and the cancer, published e-pub ahead of print, and case reports. A total of 21 publications related to HSV infections, one publication related to CMV infection, and one publication related to HHV6 infection were identified for review. No publications about viral infections with oral involvement in cancer patients that fulfilled the inclusion criteria related to rubeola, rubella, mumps, and coxsackie were identified.
Fig. 1

Process of filtering the publications after the primary literature search

Table 1

Articles reviewed

 

Reviewed and excluded from the summary (intermediate pool of publications), classification by reason for exclusion (n = 38)

Included in the summary (final pool of publications), classification by study design (n = 25)

Total number

Not oral cavity-oriented

Causal relationship to cancer

e-pub ahead of print

Case reports

Total number

RCT

Non-RCT

Cohort

Before and after

Case-control

HSV

28

3 [49, 50, 51]a

1 [52]

1 [53]

 

23c

5 [20, 24, 25, 26, 27]d

1 [28]

14 [23, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 42]e

1 [43]

 

CMV

5

2 [54, 55]

  

2 [56, 57]

1

  

1 [41]

  

VZV

3a

3 [51, 58, 59]a

   

0

     

EBV

2

1 [60]

1 [61]b

  

0

     

HHV6

1

    

1

    

1 [44]f

HHV8

1b

 

1 [61]b

  

0

     

aOne publication reported about VZV and HSV

bOne publication reported about HHV8 and EBV

cCount includes two references that were not reviewed in standard-forms (see comment d, e)

dAn additional RCT referred to different aspects of a study by Bergmann et al. (1995) is referred to in the Results [21] however was not included in the count because of overlapping study population

eAn additional cohort study including to the same study population as in a study by Sepulveda et al. (2005) is referred to in the Results [22] however was not included in the count

fThis reference assesses a specific point and not representing all cancer patients (relation of the virus to GVHD) [44]

Two randomized, controlled clinical trials (RCTs) referred to different aspects of a similar study population, and therefore, their conclusions were combined [20, 21]. Two cohort papers referred to the same study population, and therefore, only the larger study group was described in detail [22, 23].

The publications were classified according to their study design (Table 1). Studies that were defined as RCT [20, 24, 25, 26, 27], non-RCT [28], cohort studies [23, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42], before-and-after study [43], and case control studies [44] included in the analysis.

Prevalence of oral viral infections (cohort studies)

Fourteen cohort studies were identified for oral HSV infections and one for oral CMV infection (Table 2). There was a wide range of difference in study methodology of these cohort studies in respect to the primary endpoints, criteria for diagnosis, laboratory techniques used, and patient population.
Table 2

Cohort studies

Row

Author

Year

Patients

Anti-cancer treatment

No. of patients

Diagnosis by (clinical = oral lesions observed)

Lab. test

Prevalence of oral HSV infection (% of patients with oral lesions)

Prevalence of oral HSV infection (additional information)

Main finding

Comment

HSV

 

No intervention

1

Schubert [39]

90

Lymphoma, leukemia, aplastic anemia

BMT

627

Clinical and Lab. test

Tissue culture

37%

230/232 positive cultures are in seropositive pts.

HSV is common in allo-BMT in patients with no prophylaxis during the 100 days post-BMT

28.7% of population 11–20 years, 14.6% of population <10 years

2

Epstein [37]

90

Leukemia, severe aplastic anemia

CT, BMT

29

Clinical and Lab. test

Tissue culture and IF and cytology (Papanicolaou stain)

68.9%

 

Oral HSV infection is dependent upon intact cell-mediated immunity

 

3

Bergmann [34]

90

Lymphoma, leukemia

CT

46

Clinical and Lab. test

Tissue culture The authors referred to their previous study (Bergmann 1989)

61%

23.9% (11/46) of all pts. (with or without ulcerations)

Intra oral ulcers in these patients are associated with HSV-1 infection and in some cases are probably caused by the virus, especially in the alveolar process

 

4

Carrega [35]

94

Lymphoma, leukemia, Wilm's tumor, neuroblastoma

BMT

20

Clinical and Lab. test

Tissue culture

50%

 

HSV is a contributing factor in chemotherapy- or BMT-related mucositis

Pediatric

5

Stanberry [38]

94

Leukemia, osteosarcoma

CT, BMT

4

Clinical and Lab. test

Blood culture and tissue culture

50%

25% (1/4) of all cancer pts. (with or without ulcerations)

Detection of HSV in blood may promote early initiation of antiviral therapy and thereby improve prognosis

Acyclovir IV 30 mg/kg/day pediatric

6

Ramiraz-Amador [33]

96

Lymphoma, leukemia

CT

50

Clinical and Lab. test

Smear (inclusion bodies in the epithelial cells), stained with the Papanicolaou method

22.5%

9.9 lesions/100 patient-weeks

Herpetic infections are among the commonest chemotherapy-related oral manifestations

 

7

Gomez [36]

01

Lymphoma, leukemia, aplastic anemia

BMT

52

Clinical and Lab. test

Cytological, PCR, autopsy when available

26.9%

 

Oral recurrent HSV infection is independent negative prognostic variables in BMT patients' 24-month survival rates

Heterogeneous patient population (a mix of early and late viral reactivation: not necessarily due to CT/BMT)

No data about incidence of oral ulcers

8

Sepulveda [23]

03

Lymphoma, leukemia, severe aplastic anemia

CT, CT&RT

19

Clinical and Lab. test

  

10 samples positive for HSV/30 lesions

Location of HSV lesions is not limited to attached mucosa

Pediatric

No data about number of patients with ulcers

In 2/19: CT&RT

9

Redding [29]

90

H&N cancer

RT

18

Lab. test

Tissue culture

0%

0/21 lesions

HSV is not a significant contributing factor in RT-related mucositis. No need for prophylaxis

 

10

Epstein [30]

02

H&N cancer

RT

20

Lab. test

Tissue culture + direct IF for cytopathic effect

 

3.6% (4/110 swabs)

HSV reactivation is not common in RT. No need for anti-HSV prophylaxis before RT

No data about incidence of oral ulcers

11

Nicolatou-Galitis [31]

06

H&N cancer (including lymphoma)

RT, RT&CT

60

Clinical and Lab. test

Smear and immunohistochemistry

 

48.3% (14/29 swabs in 48 pts. with oral mucositis)

HSV infection was a component of ulcerative radiation mucositis in patients with positive HSV culture

29/60: relevant to HSV study (only they were tested for HSV)

48/60: mucositis

In 16/60: RT&CT

In 8/29: RT&CT

11/14 responded to antivirals

12

Beattie [32]

89

Extra-oral solid tumors (22), lymphoma (6)

CT

28

Clinical and Lab. test

 

46%

 

HSV may be an etiology for oral ulcers. Prophylaxis is needed

 

13

Chandrasekar [40]

01

Breast cancer

HSCT

105

Clinical and Lab. test

N/A

9.5%

12.3% [9.5% (10 by lab.) + 2.7% (3 by clinical only)]

Oral cavity is a main site of HSV infection in CT breast ca. pts.

No data about incidence of oral ulcers

Interventional

 

14

Nicolatou-galitisa [42]

01

H&N cancer (including lymphoma)

RT, RT&CT

61

Clinical and Lab. test

Tissue culture, PCR

 

36% (5/14 swabs in 46 pts. with oral mucositis)

The role of HSV in oral mucositis during H&N RT needs additional study (main findings relates to candidiasis)

14/61: relevant to HSV study (only they were tested for HSV)

In 4/14: RT&CT

3/5 HSV infections were post-RT&CT

Treated with GM-CSF from onset of ulcers until end of RT

4/5 treated with antivirals (unspecified)

CMV

 

15

Loid [41]

94

Lymphoma, leukemia

BMT

7

Clinical (tongue lesion) and Lab.

Tissue biopsy for histopathology, immunohistochemistry, in situ hybridization, culture

 

5 CMV + (all 7 pts. had ulcers and no positive culture for “viral culture”)

Tongue lesions in BMT patients indicate that CMV should be considered in the DD for similar ulcerations in other immunocompromised patients

Sample method is not clear (which virus was excluded at entry to study)

CT chemotherapy, RT radiotherapy, BMT bone marrow transplantation, H&N head and neck, No. number, Lab. laboratory, HSV herpes simplex virus, IV intravenous, IF immunofluorescence, PCR polymerase chain reaction, CMV cytomegalovirus, GM-CSF granulocyte macrophage colony stimulating factor, ca. carcinoma, pts. patients, HSCT hematopoietic stem cell transplantation

a25 of pts in this study (row 14) were included in the study in row 11

Most of the studies reported patients with hematological malignancies (Table 2, rows 1–8). The prevalence of oral HSV infection was 49.8% in patients with oral ulcerations (Table 3). The prevalence was found to be lower when percentage was calculated relative to the patient population independently of the presence of oral ulcerations—33.8%, reflecting that a portion of the patient population showed no signs or symptoms compatible with oral HSV infection (Table 3). The prevalence was much lower when the oral cavity was cultured routinely, independently of the presence of oral ulceration—0% (Table 3). However, this later value was based on a single study with only 23 patients [34].
Table 3

Weighted prevalence of oral herpes simplex virus infection by patient population

Patient population

Sample characteristics (patient population, criterion for culturing, and endpoint)

Number of studies

No. of patients in each study

Prevalence (%)

Std. error

95% confidence interval

Neutropenic patientsa

1. Oncologic pts.; from lesion; % of pts. with positive cultures out of patient population [33, 36, 37, 38, 40]

5

105, 4, 52, 38, 29

33.8

0.14

0–77.4%

2. Oncologic pts.; routine sampling (i.e., with or without lesion); % of pts. with positive cultures out of patient population [34]

1

23

0

NA

NA

3. Oncologic pts. with oral ulcers; from lesion; % of pts. with positive cultures out of patient population [32, 34, 35]

3

28, 18, 20

49.8

0.06

31.3–68.2%

4. Oncologic pts. with oral ulcers; from lesion; % of lesions with positive cultures out of patient population [23]

1

30

33.3

NA

NA

5. Oncologic pts.; routine sampling (i.e., with or without lesion); % of positive swabs with positive culture out of the total number of swabs [39]

1

627

37

NA

NA

H&N radiotherapy

1. Oncologic pts.; from lesion; % of pts. with positive cultures out of patient population [29]

1

18

0

NA

NA

3. Oncologic pts. with oral ulcers; from lesion; % of pts. with positive cultures out of patient population [31, 42]b

2

14, 29

43.2

0.06

0–100%

5. Oncologic pts.; routine sampling (i.e., with or without lesion); % of positive swabs with positive culture out of the total number of swabs [30]

1

20

3.6

NA

NA

No. number, Std standard, pts. patients, % percentage, H&N head and neck, NA not applicable

aInclude patients with hematologic malignancies, patients undergoing bone marrow transplant, and other neutropenic cancer patients

bIn these two studies, head and neck cancer patients were treated with radiotherapy and adjunctive chemotherapy

Prevalence according to the percentage of positive lesions or swabs (Table 3, sample characteristics 4 and 5, respectively) present additional aspects of oral HSV infection, however, arguably of lesser clinical relevance to the individual patient.

A few studies reported the prevalence of oral HSV infection in patients receiving radiotherapy (Table 2, rows 9–11 and 14). The prevalence of oral HSV infection was 0% when cultures were taken when oral ulceration was present (Table 3) [29]. The prevalence was much higher when calculated relative to the number of patients with oral ulcerations only—43.2% [31, 42]. However, in these two studies, patients received adjunctive chemotherapy. Thus, it is difficult to separate the effect of each treatment modality on oral HSV prevalence. There were different methodologic approaches: two studies in which sampling of patients with intact mucosa receiving radiotherapy used culture and direct immunofluorescence, whereas the two studies sampling oral ulcerations in irradiated patients used polymerase chain reaction (PCR) and immunohistochemistry.

There was insufficient information about oral CMV infection to allow an insight about its prevalence (Table 2, row 15) [41].

Articles with a study design other than the studies detailed above presented insufficient information about the drug of choice for the management of oral viral infections or the prevalence of viral reactivation [43, 44].

Intervention studies (RCTs and non-RCTs)

The RCT and non-RCT studies provided the core information about interventional approaches for oral viral infections and are presented in detail (Table 4). A total of 558 patients were included in these studies, and their characteristics were adults, mainly diagnosed with hematological malignancies, administered chemotherapy, or undergoing bone marrow transplantation.
Table 4

Randomized controlled trials (RCTs) and non-RCTs

  

Cancer type

Anti-cancer treatment

Serology before trial

Aim of treatment

Groups (comparison)

Groups' size (n)

Dosing

Clinical criterion

Lab. criterion

Lab. test

Results

Cost

Conclusion

Major flaws

RCT

 

Bergmann [20]

95

Leukemia

CT

All pts pos.

Prevention

Acyclovir vs. Placebo

Acyclovir, 37; placebo, 37

Acyclovir, 400 mg × 2/day PO

Reported oral complications/ulcerations

Yes

Culture (ELISA)

Prevalence of HSV infection: herpes labialis 3% and 22%, respectively (p = 0.03) RR 0.13 (95 CI, 0.02–0.95)

N/A

Prophylaxis with acyclovir should be considered for patients with AML during remission induction therapy

No report about mucositis prevalence

HSV isolation rate, 3% and 41%, respectively (p = 0.0001). RR 0.07 (95 CI, 0.01–0.48)

Bergmann [21]a

97

Leukemia

CT

All pts pos.

Prevention

Acyclovir vs. placebo

Acyclovir, 45; placebo, 45

Acyclovir, 400 mg × 2/day PO

Reported oral complications/ulcerations

Yes

Culture (cytopathic effect), ELISA (type)

Prevalence of HSV infection, 22.2% and 48.9%, respectively (p = 0.01)

N/A

Acyclovir changes the presentation of acute oral infections (the primary endpoint was days of fever): acyclovir prophylaxis has an impact on fever development, but not on the duration of fever or the need for antibiotics

None

RR 0.45 (95%CI, 0.24–0.85)

Orlowski [26]

00

Leukemia

CT

Intent-to-treat: some neg. on-treatment: all pts pos.

Prevention

Valacyclovir vs. valacyclovir

Valacyclovir, 40; valacyclovir, 41

Valacyclovir, 500 mg × 3/day PO; valacyclovir, 1,000 mg × 3/day PO

Reported oral complications/ulcerations

Yes: routine and when suspected

Culture

Prevalence of HSV infection, 0% and 0%, respectively

N/A

Valacyclovir provides effective prophylaxis against reactivation of HSV

CT protocols were not described. CT is a possible bias. Very high dose preventive protocols

Warkentin [24]

02

Leukemia, lymphoma, MDS, MM, other

CT and BMT

All pts pos.

Prevention

Acyclovir vs. valacyclovir (at 2 doses)

Acyclovir, 51; valacyclovir, 48; valacyclovir, 52, respectively

Acyclovir, 400 mg × 3/day PO; valacyclovir, 500 mg × 2/day; valacyclovir, 250 mg × 2/day

Reported oral ulcerations

Yes

Culture

Prevalence of HSV infection, 4.1%, 4.8%, and 0%, respectively (p = 0.32)

N/A

Prophylactic treatment with valacyclovir is an effective and safe alternative to acyclovir

None

Liesveld [27]

02

Lymphoma, breast ca., leukemia, MM

BMT

All pts pos.

Prevention

Acyclovir vs. valacyclovir

Acyclovir, 16; valacyclovir, 14

Acyclovir, 250 mg × 2/day IV; valacyclovir, 1,000 mg × 2/day PO

Clinical suspected lesions

Yes: routine and when suspected

Culture

Prevalence of HSV infection, 0% and 0%, respectively

Valacyclovir PO is cheaper than acyclovir IV

Oral valacyclovir is a cost-effective alternative to IV acyclovir for HSV prophylaxis

The doses of acyclovir and valacyclovir were not proportional (too low for acyclovir and too high for valacyclovir relative to the therapeutic levels)

Rojas De Morales [25]

02

 

CT

No information

Prevention

Active arm: physiotherapy + 0.05% fluoride (NaF) mouthwash + miconazole gel vs. control arm: physiotherapy

Active, 5; control, 7

N/A

   

Prevalence of HSV infection, 0% and 1/7, respectively

N/A

Prior control of oral infection prevents complications during cancer therapy. No difference between protocols

Small samples, no information about HSV serology prior to study, about anti-viral prophylaxis and about duration of neutropenia

Non-RCT

 

Eisen [28]

03

Lymphoma, leukemia, breast ca., ovarian ca., MM

BMT

All pts pos.

Prevention

Acyclovir vs. valacyclovir

Acyclovir, 60; valacyclovir, 60

Acyclovir, 600 mg × 4/day PO or 125 mg × 4/day IV; valacyclovir (500 mg × 2/day IV or PO)

Reported suspected clinical herpetic infections

Yes: routine and when suspected

Culture

Prevalence of HSV infection (clinical presentation and culture)

N/A

Valacyclovir as effective as acyclovir in preventing HSV infections during autologous BMT and stem cell rescue with high-dose chemotherapy

Historic control (acyclovir group)

0% in both groups. Dose adjustments were needed due to creatinine↑: in acyclovir 21/60, in valacyclovir 6/60

CT chemotherapy, BMT bone marrow transplantation, pos. positive, Lab. laboratory, vs. versus, PO per os, ELISA enzyme linked immunostaining assay, N/A not available, HSV herpes simplex virus, IV intravenous, MDS myelodysplastic syndrome, MM multiple myeloma, ca. cancer

aProbably same patient population as in the study of Bergmann 1997 [21]

Anti-viral protocols were preventive and aimed at HSV infection. All interventions provided a clear description of the interventions including the dose and method of administration for the test and control groups, except for one study which was not a specific anti-viral protocol [25]. The interventions for the prevention of HSV infection were acyclovir and valacyclovir. The dosage of the test agents varied for similar products. Two studies used a placebo [20, 21], and one study used a historical control [28].

There was consistency of main outcome measures, with all controlled trials utilizing a culture to confirm a clinically suspected diagnosis of HSV infection. Most described the clinical parameter used in suspected HSV oral infection. There was little consistency on the other outcome measures reported such as oral hygiene measures, febrile episodes, laboratory changes, treatment interruption, duration of hospitalization, anti-viral induced toxicity, cost, patient quality of life, eating/drinking difficulty, and death.

The effects of interventions are presented relating to the following interventions:
  1. 1.

    Acyclovir versus placebo: Two studies referred to an overlapping patient population compared acyclovir with a placebo [20, 21]. There was a significant benefit for acyclovir preventing HSV oral infection in these trials as well as improvement in the secondary outcome of fever development.

     
  2. 2.

    Different doses of valacyclovir: One study compared two dosing protocols of valacyclovir (1,500 or 3,000 mg/day) [26]. No HSV reactivation was diagnosed in either groups, and it was concluded that valacyclovir provides effective prophylaxis against reactivation of HSV. Comparison of two valacyclovir doses was included in a three-arm comparative study (500 or 1,000 mg/day) [24]. There was no significant difference between these two valacyclovir doses in respect to the prevalence of reactivation, which was low to zero. Therefore, prophylactic treatment with valacyclovir was considered effective in both doses.

     
  3. 3.

    Acyclovir versus valacyclovir: Two RCTs and one non-RCT compared acyclovir to valacyclovir in respect to its prophylactic effect on oral HSV infection [24, 27]. The RCTs demonstrated low prevalence of HSV reactivation in both study arms. Therefore, it was concluded that prophylactic treatment with valacyclovir is an effective and alternative to acyclovir. This conclusion was supported by a finding from the non-RCT that showed higher prevalence of renal toxicity due to acyclovir relative to valacyclovir [28]. Moreover, this conclusion was also substantiated from the economic aspect [27].

     
  4. 4.

    Different oral care protocols: The components of the oral care protocols were physiotherapy, 0.05% fluoride (NaF) mouthwash, and miconazole gel [25]. There was no difference in the prevalence of oral complications, including oral viral infection, between the two oral care protocols tested. Therefore, both oral care protocols had a similar role in the prevention of complications during cancer treatment. The groups' size in this study was small, and for this reason, its conclusion is doubtful.

     

Impact on quality of life

No studies were identified that assessed quality of life in patients with an oral viral infection.

Economic impact

There were no studies evaluating the economic impact of oral viral infection.

Discussion

We reviewed scientific reports published between 1989 and 2007 in order to propose evidence-based recommendations for prevention and treatment of oral viral infections in cancer patients. Although the literature search was directed to all oral viral infection, studies available referred mainly to HSV infection and, to a lesser extent, to other members of the Herpesviridea family.

Several points can be learned from the review of the cohort studies:
  1. 1.

    Most of cohort studies involved patients with hematological malignancies. The special attention given to this patient population reflects that they are at a higher risk for viral infection compared to patients with head and neck cancer or solid cancers. Our review also demonstrated a higher prevalence of viral infections in neutropenic patients, mostly patients with hematological malignancies, compared to the head and neck cancer patients. This finding is not surprising as these patients develop deeper immunosuppression during cancer treatment than other cancer patients. Of note, head and neck cancer patients treated with combined radio- and chemotherapy demonstrated a similar prevalence of oral HSV infection as in neutropenic patients.

     
  2. 2.

    The early studies in RT patients showed a low prevalence of HSV reactivation [29, 30]. Later studies showed a much higher prevalence [31, 42]. There are several possible explanations: (1) the study design in the newer studies sampled a specific portion of the patients which are more likely to have viral infection (i.e., in the newer studies, patients were included if there was an oral ulcer, while in past studies, patients with intact oral mucosa were also included); (2) laboratory techniques are more sensitive (i.e., old studies reported of the use of culture and immunofluorescence, whereas newer studies reported to the use of PCR); (3) in the last decade, treatment protocols for head and neck cancer combine radiotherapy with adjunct chemotherapy. This combination may expose the patients to a higher level of immunosuppression compared to older protocols.

     
  3. 3.

    The literature offers very little information about oral CMV infection. These infections should be assessed in a large cohort of patients in order to explore their prevalence and the clinical importance of oral involvement.

     
  4. 4.

    No studies were identified that assessed the quality of life impact or economic impact of oral viral infection.

     

The eligible trials for this review varied in their design and quality; it was especially unfortunate that many studies presented data in an unusable form. On the basis of the RCT and non-RCT, a guideline is possible. Both anti-viral agents, acyclovir and valacyclovir, are recommended for the prevention of HSV infection (Grade of recommendation A, level of evidence I) [17, 18, 19]. Prevention may be achieved with acyclovir dose of 800 mg/day or with valacyclovir dose of 500 mg/day [20, 24].

There may be superiority of valacyclovir compared to acyclovir in respect to toxicity and to cost (depends on the route of administration of acyclovir—PO or IV) [27]. However, the literature retrieved in this systematic review was not aimed at toxicity studies, and this aspect needs to be confirmed separately. Likewise, information about cost of these interventions may be available in studies whose focus is not limited to oral viral infections.

The scope of this review was defined as oral viral infections in cancer patients. However, the vast majority of studies considered HSV infection. The scarce literature about non-HSV infections may indicate the non-specific clinical oral presentation of these types of infections which elude their diagnosis, the relative infrequency of non-HSV viral infections, and the financial obstacles on the way to use diagnostic tests for non-HSV viral infections routinely. A surveillance study for CMV infection in hematology cancer patients may contribute to the question of prevalence of CMV infection.

The number and range of interventions included in this review indicates the sufficient effectiveness of the two common anti-viral drugs, acyclovir and valacyclovir. However, since some studies pointed at HSV reactivation during acyclovir and valacyclovir prophylaxis (up to 29%) [20, 24, 45], resistant strains may exist. Moreover, the renal toxicity associated with these two drugs should be an additional motive for the development of additional anti-viral drugs.

The most important outcome is considered to be whether HSV-associated oral infection was present or not, based on clinical and laboratory findings. Other than clinical diagnosis of viral infection, outcome measures such as oral pain, oral intake, duration of hospital stay, and mortality are rarely considered clinically meaningful [39].

There are distinct deficiencies within the literature. The prevalence of other infections such as coxsackie virus and other types of herpes virus (VZV and HHV-6) has not been assessed. There need to be large-scale cohort studies designed to ask specific questions regarding prevalence of oral infections rather than relying on retrospective data where this information may be overlooked. Such information will enable the development of strategic treatment protocols. Likewise, there are no studies about the efficacy of topical application of acyclovir or new-generation systemic anti-viral agents (i.e., famciclovir). The findings of this review should be considered in context with the general medical management of patients with cancer. Our guideline supports the guidelines of The CDC, Infectious Diseases Society of America, and American Society for Blood and Marrow Transplantation for the prevention of oral infections in bone marrow recipients [46]. These three groups concluded that acyclovir prophylaxis is recommended for all HSV seropositive allograft recipients. Most centers administer acyclovir from the onset of conditioning until engraftment and resolution of mucositis (usually before day 30 post-transplant), as recommended. Per these guidelines, routine extension of HSV prophylaxis beyond day 30 is not recommended in the absence of randomized trials; however, patients with frequent recurrences might benefit from extended suppressive therapy. Although the original studies were performed with intravenous acyclovir, oral administration is often used in individuals who can take oral medication; however, attention should be given to adequate dosing. Routine acyclovir prophylaxis in HSV seronegative recipients is not indicated, even if the donor is seropositive. Valacyclovir has been ranked moderately as an effective prevention for HSV in HSCT instead of oral acyclovir, and foscarnet was mentioned as a drug to avoid for routine HSV prophylaxis due to substantial renal toxicity. These guidelines extend where our systematic review failed to provide sufficient evidence (CMV, VZV, and EBV infections); however, evidence is not specific for infections for oral involvement. The guidelines of these three American Societies are in line with the recommendations of the German Society of Hematology [47] and the European Group for Blood and Bone Marrow Transplantation [48]. The publications made by these societies are an additional indication of the higher risk of infectious complications in patients with hematology malignancies or undergoing HSCT.

Future directions

This systematic review stresses the relevance of several viral infections with oral manifestations to the general clinical practice of cancer patients. The knowledge that oral viral infection is a manifestation of a systemic disease rather than a local isolated episode of viral infection is crucial for providing optimal medical treatment. Future studies should focus on more sensitive and cost-effective diagnostic tests for a battery of viruses that affect oral tissues. This will enable clinicians a rapid and reliable diagnosis that will lead to the initiation of anti-viral treatment. The possible acyclovir and valacyclovir resistance, as well as their toxicity, indicates the need to explore new anti-viral therapies. The relation between viruses and oral cancer or graft versus host disease in immunosuppressed patients and HSCT patients is a topic for future studies.

Box 1: Conclusions from RCTs and non-RCTs

• Acyclovir is an effective prevention for oral HSV infection. Level of evidence: I, grade of recommendation A, recommend for the prevention of oral HSV infection

• Valacyclovir is as effective as acyclovir in preventing oral HSV infection. Level of evidence: I, grade of recommendation A, recommend for the prevention of oral HSV infection

• There are no studies about protocols for anti-viral treatment (only for prevention)

Notes

Conflict of interest

None to declare.

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Sharon Elad
    • 1
    Email author
  • Yehuda Zadik
    • 1
  • Ian Hewson
    • 2
  • Allan Hovan
    • 3
  • M. Elvira P. Correa
    • 4
  • Richard Logan
    • 5
  • Linda S. Elting
    • 6
  • Fred K. L. Spijkervet
    • 7
  • Michael T. Brennan
    • 8
  • Viral Infections Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO)
  1. 1.Department of Oral MedicineHebrew University, Hadassah School of Dental MedicineJerusalemIsrael
  2. 2.Dental UnitRoyal Melbourne HospitalParkvilleAustralia
  3. 3.Program in Oral OncologyBC Cancer AgencyVancouverCanada
  4. 4.Ambulatory of Oral Medicine, Hematology and Blood Transfusion CenterUniversity of CampinasCampinasBrazil
  5. 5.Oral Pathology, School of Dentistry, Faculty of Health SciencesThe University of AdelaideAdelaideAustralia
  6. 6.Department of BiostatisticsThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  7. 7.Department of Oral & Maxillofacial SurgeryUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
  8. 8.Department of Oral MedicineCarolinas Medical CenterCharlotteUSA

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