Acute toxicity of second generation HIV protease-inhibitors in combination with radiotherapy: a retrospective case series

  • Alfred P See1,

    Affiliated with

    • Jing Zeng2,

      Affiliated with

      • Phuoc T Tran2, 3Email author and

        Affiliated with

        • Michael Lim1, 3

          Affiliated with

          Radiation Oncology20116:25

          DOI: 10.1186/1748-717X-6-25

          Received: 16 December 2010

          Accepted: 17 March 2011

          Published: 17 March 2011

          Abstract

          Background

          There is little data on the safety of combining radiation therapy and human immunodeficiency virus (HIV) protease inhibitors to treat cancers in HIV-positive patients. We describe acute toxicities observed in a series of HIV-positive patients receiving modern radiation treatments, and compare patients receiving HIV protease inhibitors (PI) with patients not receiving HIV PIs.

          Methods

          By reviewing the clinical records beginning January 1, 2009 from the radiation oncology department, we identified 29 HIV-positive patients who received radiation therapy to 34 body sites. Baseline information, treatment regimen, and toxicities were documented by review of medical records: patient age, histology and source of the primary tumor, HIV medication regimen, pre-radiation CD4 count, systemic chemotherapy, radiation therapy dose and fractionation, irradiated body region, toxicities, and duration of follow-up. Patients were grouped according to whether they received concurrent HIV PIs and compared using Pearson's chi-square test.

          Results

          At baseline, the patients in the two groups were similar with the exception of HIV medication regimens, CD4 count and presence of AIDS-defining malignancy. Patients taking concurrent PIs were more likely to be taking other HIV medications (p = 0.001) and have CD4 count >500 (p = 0.006). Patients taking PIs were borderline less likely to have an AIDS-defining malignancy (p = 0.06). After radiation treatment, 100 acute toxicities were observed and were equally common in both groups (64 [median 3 per patient, IQR 1-7] with PIs; 36 [median 3 per patient, IQR 2-3] without PIs). The observed toxicities were also equally severe in the two groups (Grades I, II, III respectively: 30, 30, 4 with PIs; 23, 13, 0 without PIs: p = 0.38). There were two cases that were stopped early, one in each group; these were not attributable to toxicity.

          Conclusions

          In this study of recent radiotherapy in HIV-positive patients taking second generation PIs, no difference in toxicities was observed in patients taking PIs compared to patients not taking PIs during radiation therapy. This suggests that it is safe to use unmodified doses of PIs and radiation therapy in HIV cancer patients, and that it is feasible to use PIs as a radiosensitizer in cancer therapy, as has been suggested by pre-clinical results.

          Background

          HIV and malignancies

          Historically, HIV infection is associated with a much higher risk of specific cancers [14]. In particular, diagnosis of Kaposi sarcoma, non-Hodgkin lymphoma (NHL), or cervical cancer are considered acquired immunodeficiency syndrome (AIDS)-defining malignancies [5]. However, increasing effectiveness of anti-retroviral therapy (ART) has led to decreased mortality in Europe and North America from opportunistic infections and AIDS-defining malignancies [58], while mortality from non-AIDS-defining and non-HIV-associated cancers has been increasing [8, 9].

          Response to cancer therapy is also different in the HIV patient population. Initial reports found increased radiotoxicity in HIV patients receiving treatment for Kaposi sarcoma, cervical carcinoma, while there was no difference in adverse effects of radiation therapy for other malignancies [10, 11]. Systemic glutathione deficiency [12], DNA repair deficiency, or cell cycle dysregulation may increase radiosensitivity [1315]. However, radiation therapy remains a cornerstone of therapy in a number of cancers such as anal cancer [16], prostate [17], breast [1820], and cervical cancer [16, 21].

          Protease inhibitors in the treatment of HIV

          PIs are anti-viral drugs that inhibit proteases, viral enzymes which cleave polyprotein precursors into mature viral proteins [22]. PIs are one class of anti-virals that is used as the 'base' in combination with two 'backbone' drugs for treatment of HIV, antiretroviral therapy (ART). There are currently ten PIs available; in chronological order of FDA approval, saquinavir, ritonavir, indinavir, nelfinavir, lopinavir, atazanavir, fosamprenavir (pro-drug of amprenavir, which is no longer available), tipranavir, and darunavir.

          Although PIs act by inhibiting HIV aspartyl protease, they also have off-target effects. The entire class is associated with dysregulation of glucose and lipid metabolism due to homology between HIV-1 protease and various human proteins [2326]. In addition, some PIs inhibit the phosphatidyl-inositol 3-kinase (PI3K)-Akt pathway, which is shared by numerous cell homeostasis pathways [27, 28].

          Non-target effects of protease inhibitors

          A number of PIs have been associated with anti-cancer activity [29]. Through PI3K-Akt and closely related pathways, PIs induce apoptosis of tumor cells [3036]. Although PIs have been shown to directly effect tumor cell death, use of PIs has not reduced cancer risk in HIV patients, suggesting that PIs would not be clinically effective anti-cancer monotherapies [37]. Although ineffective alone, PIs synergize with other cancer therapies such as radiotherapy [38].

          Initial studies suggested that nelfinavir upregulates vascular endothelial growth factor (VEGF) and downregulates hypoxia-inducible factor 1 alpha (HIF-1α). Although VEGF can increase tumor oxygenation, the HIF1-α hypoxia factor can mediate radiation resistance [39, 40]. However, HIF-1α knockdown studies suggest that radiosensitivity induced by PIs is independent of HIF-1α [28, 4042]. In a number of cancers, resistance to radiotherapy is mediated by the PI3K-Akt pathway, suggesting an alternative mechanism of PI-induced radiosensitization [4345]. Preclinical studies with nelfinavir in head-and-neck cancer [46] and non-small cell lung cancer [28] cell lines found downregulation of Akt to be associated with increased sensitivity to radiation.

          Although PI-induced radiosensitization of cancers was shown to be independent of HIF-1α, PIs have been shown to induce systemic vascular stress [47]. Preclinical in vivo studies suggest that in addition to direct effect on the tumor cells, PIs may inhibit PI3K-Akt activation in tumor vasculature, suppressing hypoxia pathways and leading to reduced radiation resistance [48, 49]. Other clinical reports also suggest that PIs and radiotherapy interact on tumor vasculature similar to the effects of radiation and bevacizumab, an anti-angiogenic antibody [50].

          Protease inhibitors and radiotherapy

          A retrospective review (14 patients receiving PIs and 28 controls) did not find severe toxicities attributable to combination of PIs and radiotherapy for cancer in HIV+ patients [11, 5154]. There are ten prospective trials, nine of which are on-going (a phase II trial was terminated due to poor enrollment): five phase I studies, and four studies that have a phase II component. One published phase I trial in pancreatic cancer showed the following toxicites one of which was life-threatening: severe nausea and vomiting and increase in liver enzymes and bilirubin due to stent occlusion [55]. Given the inconclusive safety data on combining PIs and radiation therapy to treat cancer in HIV patients, we reviewed a series of HIV patients receiving radiation therapy for malignancies.

          Methods

          Patient identification

          In accordance with a research protocol approved by the Institutional Review Board, patients were identified by review of clinical records from January 1, 2009-October 31, 2010 in the Department of Radiation Oncology at The Johns Hopkins Hospital. Patients were included if they had documented HIV infection and received radiation therapy at Johns Hopkins.

          Retrospective review

          Medical records for included patients were reviewed for HIV medications, cancer diagnosis and stage, radiation therapy (site, dose, fractionation, completion or early stopping), age at time of radiation therapy, cancer chemotherapy, acute (< 6 weeks after end of radiation therapy) toxicities categorized by Common Toxicity Criteria for Adverse Events version 3.0 (CTCAE) grade. All patients receiving radiation therapy were evaluated at least once per week for treatment toxicity, and side effects were recorded prospectively in an electronic record system.

          Statistical analysis

          Patients were categorized by type of malignancy (AIDS-defining, HIV-associated, non-HIV associated), taking non-PI HIV medications (yes/no), and by baseline CD4 count (< 50, <200, <500, 500). Toxicities were categorized by CTCAE grade. Differences between the groups were analyzed using Pearson's chi-square test with JMP 8.0 (SAS Institute Inc.). Statistical significance was defined as a Pearson's chi-square p-value < 0.05.

          Results

          We retrospectively reviewed acute toxicities in a series of patients with a history of HIV infection and receiving radiation therapy; in this series, we compared patients who received concurrent PIs with patients who did not receive concurrent PIs. Eighteen patients received concurrent PIs and radiation therapy; one patient received radiation therapy for two different malignancies, and one patient received radiation for three recurrences of NHL. There were eleven patients with a history of HIV infection but not treated with PIs who received radiation therapy; one patient received three regimens of radiation therapy, twice for brain metastasis and once for testicular metastasis.

          Patient characteristics

          Characteristics of patients receiving concurrent protease inhibitor are presented in Table 1 while characteristics of patients not receiving concurrent protease inhibitor are presented in Table 2. There were 34 total courses of radiation treatment delivered (21 with PIs, 13 without PIs) for a variety of histologies, including HIV-defining (0 with PIs; 3 [23%] without PIs), HIV-associated (11 [58%] with PIs; 5 [38%] without PIs), non-HIV-associated malignancies (8 [42%] with PIs, 5 [38%] without PIs), and non-malignancies (keloid scar and dural arteriovenous fistula with PIs, none without PIs). The median age was 50 (interquartile range [IQR] 47-56). The difference between the two groups in number of AIDS-defining malignancies almost reached statistical significance (p = 0.06), but the remainder of the malignancies (HIV-associated and non-HIV-associated) are not differently distributed in the two groups (p = 0.9). 29 cases had documented pre-treatment CD4 counts; 4 were <50 (4 [24%] with PIs), 13 were <200 (9 [53%] with PIs, 4 [33%] without PIs), and 21 were <500 (10 [59%] with PIs; 11[92%] without PIs). Patients taking PIs were more likely than patients not taking PIs to have a CD4 count≥500 (7 [41%] with PIs; 1 [8%] without PIs; p-0.006).
          Table 1

          Baseline data: patients receiving concurrent protease inhibitor

          #

          Cancer diagnosis

          Age

          Concurrent systemic therapy

          Baseline CD4

          Non-PI HIV regimen

          PI

          1a

          Ductal carcinoma, breast T2N1M0

          47

          None

          104

          lamivudine, raltegravir

          RTV, DRV

          1b

          SCC, anus T3N0M0

          49

          5-FU, mitomycin C

          68

          lamivudine, raltegravir

          RTV, DRV

          2

          SCC, vulva T1bN1b, stage IIIa

          26

          cisplatin

          1647

          emtricitabine, tenofovir

          RTV, ATZ

          3

          Ductal carcinoma, breast T1cN0M0, stage I

          47

          None

          474

          emtricitabine, tenofovir, raltegravir

          RTV, ATZ

          4

          SCC, anus T2N0M0, stage II

          47

          None

          NR

          emtricitabine, tenofovir, raltegravir

          RTV, DRV

          5

          Adenocarcinoma, prostate cT2bNXM0, GS 3+3, PSA 8.7, stage II

          58

          None

          WNL

          efavirenz, emtricitabine, tenofovir

          RTV, LPV

          6

          Adenocarcinoma, prostate cT1cNXM0, GS 3+4, PSA 4.9, stage II

          73

          androgen deprivation

          1105

          raltegravir

          RTV, DRV

          7

          Adenocarcinoma, prostate cT1cNXM0, GS 4+3, PSA 5.1stage II

          69

          androgen deprivation

          536

          abacavir, lamivudine

          RTV, ATZ

          8

          Renal cell carcinoma, lateral chest wall, metastatic, stage IV

          50

          sutent

          766

          emtricitabine, tenofovir, efavirenz

          RTV, ATZ

          9

          Arteriovenous fistula, dura mater

          57

          None

          944

          abacavir, lamivudine, raltegravir

          RTV, LPV

          10

          SCC, tonsil T2N2bM0

          53

          cisplatin

          956

          emtricitabine, tenofovir

          RTV, LPV

          11

          Primary CNS lymphoma, CNS

          44

          None

          4

          None

          RTV, DRV

             

          doxil, cytoxan,

             

          12

          NHL, neck and axilla, stage IV

          53

          vincristine, prednisone

          57

          abacavir, lamivudine

          RTV

          13a

          NHL, pelvis, stage IV

          53

          None

          120

          abacavir, lamivudine

          RTV, ATZ

          13b

          NHL, axilla, stage IV

          55

          None

          39

          abacavir, lamivudine

          RTV, LPV

          13c

          NHL, temple, stage IV

          56

          None

          87

          abacavir, lamivudine

          RTV, LPV

          14

          Primary CNS lymphoma, CNS

          21

          None

          0

          emtricitabine, tenofovir

          RTV, DRV

          15

          Ductal carcinoma, breast T2N0M0, stage IIa

          58

          None

          NR

          emtricitabine, tenofovir

          RTV, LPV

          16

          SCC, anus T1N0M0, stage I

          43

          5-FU, mitomycin C

          547

          abacavir, lamivudine

          RTV, LPV

          17

          Primary CNS lymphoma, CNS

          23

          None

          10

          emtricitabine, tenofovir

          RTV, DRV

          18

          Keloid scar, posterior scalp

          47

          None

          WNL

          zidovudine 300 mg, lamivudine 150 mg

          NFV

          Patients are uniquely identified by numbers, repeated treatments on a patient are distinguished by a letter after the number.

          NHL = non-Hodgkin lymphoma

          cT = clinical tumor, pT = pathological tumor, GS = Gleason score, PSA = prostate specific antigen

          RTV = ritonavir, DRV = darunavir, ATZ = atazanavir, LPV = lopinavir, NFV = nelfinavir

          WNL = Reported as within normal limits, NR = not reported

          Table 2

          Baseline data: patients not receiving concurrent protease inhibitor

          #

          Cancer diagnosis

          Age

          Concurrent

          systemic therapy

          Baseline

          CD4

          Non-PI HIV regimen

           

          1

          SCC, cervix T4N1M0, stage IVa

          29

          cisplatin

          189

          None

           

          2

          SCC, cervix, stage IIb

          34

          cisplatin

          189

          None

           

          3

          Cholangiocarcinoma, abdomen pT3N1M0

          53

          xeloda

          300

          efavirenz, emtricitabine, tenofovir

           

          4

          Adenocarcinoma, prostate TXNXM1, stage IV

          48

          None

          399

          None

           

          5

          Meningioma, CNS

          46

          None

          408

          None

           

          6

          Adenocarcinoma, prostate cT1cNXM0, GS

          62

          androgen

          1047

          None

           
           

          3+4, PSA 20.6, stage II

           

          deprivation

             

          7

          NSCLC, brain met, stage IV

          57

          None

          NR

          None

           

          8a

          DLBCL, brain met, stage IV

          46

          None

          214

          efavirenz, emtricitabine, tenofovir

           

          8b

          DLBCL, brain met recurrence, stage IV

          46

          None

          214

          efavirenz, emtricitabine, tenofovir

           

          8c

          DLBCL, testicular met, stage IV

          46

          None

          214

          efavirenz, emtricitabine, tenofovir

           

          9

          Adenocarcinoma, prostate cT2aNXM0, GS

          61

          None

          150

          efavirenz, emtricitabine, tenofovir

           
           

          3+4, PSA 1.1, stage II

               

          10

          SCC, cervix, stage IIIb

          57

          cisplatin

          116

          None

           

          11

          SCC, anal

          49

          mitomycin C and

          xeloda

          450

          efavirenz, emtricitabine, tenofovir

           

          Patients are uniquely identified by numbers, repeated treatments on a patient are distinguished by a letter after the number.

          NHL = non-Hodgkin lymphoma, DLBCL = diffuse large B-cell lymphoma

          cT = clinical tumor, pT = pathological tumor, GS = Gleason score, PSA = prostate specific antigen

          NR = not reported

          Radiation treatment

          For the 29 patients receiving radiation therapy, 15 patients were treated with definitive or adjuvant dose regimens (9 receiving PIs, 6 without PIs), while 14 patients received palliative radiation doses (9 receiving PIs, 5 without PIs). The exact definition of definitive/adjuvant versus palliative dose varied based on body site. Definitive/adjuvant dose was at least 5400 cGy for brain (conventional fractionation equivalent), 7000 cGy for head and neck, 5400 cGy for breast, 4500 cGy for pelvis, and 7800 cGy for prostate. Palliative doses also varied based on body site and disease histology, but were lower than definitive/adjuvant dose regimens.

          HIV medications and systemic chemotherapy

          Systemic chemotherapy regimens for these two groups of patients are presented (Table 1 and 2). Of the 32 treatments for cancer (19 with PIs, 13 without PIs), 13 included systemic chemotherapy regimens (7 [37%] with PIs; 6 [46%] without PIs). 21 of the 29 patients were receiving HIV medications (17 [94%] with PIs; 4 [36%] without PIs; p = 0.001).

          In the group receiving PIs, the most common PI was ritonavir (20 [95%]), followed by darunavir and lopinavir (7 [33%] each), atazanavir (5 [24%]), and only one [5%] patient received nelfinavir (Table 1 and 2).

          Toxicities

          Follow-up and observed toxicities are presented in Table 3 and 4. The median follow-up of all patients was 18 weeks [IQR 8-30], but the follow-up for patients not taking PIs (median 13 weeks [IQR 5-18]) was much shorter than the follow-up for patients taking PIs (median 21 weeks [IQR 10-38]). The limited follow-up in the group not taking PIs prevented comparison of long-term toxicities.
          Table 3

          Radiation regimen, follow-up and toxicities in patients receiving concurrent protease inhibitor

          #

          F/U

          [weeks]

          Region treated

          Dose (fractionation)

          [cgy]

          Complete RT regimen

          Acute toxicity and CTC grade

          1a

          75

          right breast

          5800 (200)

          yes

          dermatitis 2, pruritis 1, hyperpigmentation 2, fatigue 1, pain 1

          1b

          0

          pelvis

          3600 (180)

          no, prescribed 5400

          fatigue 2, pain 2, nocturia 2, anorexia 1, proctitis 2

               

          fatigue 1, pain 1, nocturia and urinary

          2

          9

          pelvis and left vulva

          4500 (180)

          yes

          frequency 1, dysuria 2, proctitis 1, diarrhea

               

          1, mucosal drainage 1

          3

          36

          right breast

          5130 (270)

          yes

          fatigue 2, pain 3, dermatitis 1, hyperpigmentation 2

          4

          18

          pelvis and anus

          3000 (200)

          yes

          dysuria 1

          5

          82

          prostate and SV

          6720 (320)

          yes

          dysuria and nocturia and urinary frequency 2, anorexia 1, diarrhea 1, hematochezia 1

          6

          18

          prostate and SV

          8000 (200)

          yes

          nocturia and urinary frequency 2

          7

          7

          prostate and SV

          7800 (200)

          yes

          pain 1, dysuria and urinary frequency and incontinence 2, constipation 1, diarrhea 1

          8

          8

          left lateral chest wall

          3600 (300)

          yes

          dermatitis 1

          9

          38

          brain

          2000 (2000)

          yes

          none

          10

          25

          head and neck

          7000 (200)

          yes

          dermatitis 3, fatigue 3, dysphonia 1, xerostomia 2

          11

          21

          brain

          3000 (300)

          yes

          fatigue 2, pain 2, nausea 2, insomnia 2, anorexia 2, vomiting 2, ataxia 2

          12

          23

          right neck and left axilla

          3000 (200)

          yes

          fatigue 1, pain 1, dermatitis 1, dysgeusia 1, dysphonia 1, xerostomia 1

          13a

          147

          right pelvis

          3000 (250)

          yes

          fatigue 1

          13b

          13

          right axilla and ulcerating skin lesion

          3060 (180)

          yes

          dermatitis 2, drainage 3, pruritus 1

          13c

          7

          right temple and subcutaneous skin lesion

          3060 (180)

          yes

          dermatitis 2

          14

          19

          brain

          3000 (300)

          yes

          fatigue 1

          15

          86

          right breast

          6000 (200)

          yes

          dermatitis 1

               

          fatigue 1, pain 2, nausea 1, nocturia and

          16

          85

          pelvis

          5040 (180)

          yes

          urinary frequency 1, anorexia 2, proctitis 1,

               

          diarrhea 2, dermatitis 2

          17

          10

          brain

          3000 (300)

          yes

          altered mental status in intensive care throughout treatment

          18

          31

          posterior scalp

          1600 (400)

          yes

          none

          Patients are uniquely identified by numbers, repeated treatments on a patient are distinguished by a letter after the number.

          F/U = follow-up

          Table 4

          Radiation regimen, follow-up and toxicities in patients not receiving concurrent protease inhibitor

          #

          F/U [weeks]

          Region treated

          Dose (fractionation) [cgy]

          Complete RT regimen

          Acute toxicity and CTC grade

          1

          6

          Pelvis

          5400 (180)

          yes

          fatigue 1, nocturia 1, proctitis 2, gastrointestinal bleed 3, dermatitis 2

          2

          6

          vaginal cuff brachytherapy

          4500 and 2500 HDR (180 and 500 HDR)

          yes

           

          3

          18

          Abdomen

          5040 (180)

          yes

          fatigue 1, anorexia 1, nausea 1

          4

          13

          thoracic spine

          3000 (300)

          yes

          fatigue 1

          5

          29

          Brain

          5400 (180)

          yes

          pain 2, edema 2

          6

          44

          prostate and SV

          7800 (200)

          yes

          nocturia and urinary frequency and urgency 2, urinary retention 1

          7

          20

          Brain

          5300 (250 and 18 Gy gamma-knife boost)

          yes

          memory impairment 1, concentration impairment 1

          8a

          0

          prostate and SV

          7800 (200)

          yes

          dysuria and nocturia 2, urinary retention 1, constipation 1

          8b

          13

          Pelvis

          3780 and 1400 HDR (180 and 700 HDR)

          no

          fatigue 2, anorexia 1, dermatitis 2

          8c

          4

          Pelvis

          3000 and 1200 IORT (200 and 1200 HDR)

          yes

          fatigue 1, pain 1, nocturia 1, anorexia 1, proctitis 1, diarrhea 1

          9

          13

          Brain

          2400 (200)

          yes

          fatigue 2, pain 2,

          10

          5

          brain (repeated)

          2400 (200)

          yes

          fatigue 2, anorexia 1, constipation 1, dermatitis 1,

          11

          0

          Testicles

          2700 (180)

          no, prescribed 4140

          pain 1, constipation 1, dermatitis 1

          Patients are uniquely identified by numbers, repeated treatments on a patient are distinguished by a letter after the number.

          F/U = follow-up

          HDR = high dose radiation

          There were 64 acute toxicities in the group receiving PIs (30 grade 1, 30 grade 2, 4 grade 3). In the group not receiving PIs, there were 36 acute toxicities (23 grade 1, 13 grade 2). The median number of toxicities experienced per patient was not different between the groups (3 [IQR 1-7] with PIs; 3 [IQR 2-3] without PIs). Chi-square analysis of the distribution of severity did not find statistically significant difference in the severity of toxicities between the two groups (p = 0.38). One radiation treatment in each group was stopped early, but neither of these was secondary to toxicity (no grade 3 toxicities in either patient).

          Discussion

          Our retrospective review of HIV-positive patients receiving radiation therapy found no increased toxicity in patients receiving concurrent PIs. The number and severity of toxicities experienced per patient were not found to be different in patients who were concurrently taking PIs compared to those who were not. There were differences in the baseline characteristics and medication regimens of the two groups. First, there were no cases of AIDS-defining malignancies in the group treated with PIs. This difference coincided with a difference in all HIV treatment and CD4 count. Significantly more patients in the non-PI group did not receive any medication to manage HIV, and significantly more patients in the non-PI group had CD4 counts below 500. This difference may reflect the efficacy of PIs and ART in controlling HIV, and a resulting decrease in opportunistic malignancies that has been observed with progressive generations of ART[9]. Although ART is typically initiated if the CD4 count is below 500, there are a number of other factors that contribute to the decision to initiate therapy, such as patient preference, adherence to prescriptions, and HIV strain. There was no association between CD4 count and adverse events.

          There have been a number of case reports and small case series documenting seve re toxicities in HIV patients receiving radiation therapy. A meta-analysis of case reports and case series found severe toxicities in HIV patients receiving radiation therapy for Kaposi sarcoma and cervical carcinoma, but not in other malignancies[10]. Our results are in accordance with the only published study evaluating toxicities from interaction between PIs and radiation therapy [11]. Plastaras et al. reviewed 14 patients with concurrent PIs and 28 patients in the absence of PI, and found no difference in toxicity from radiation therapy. Although this group found no increase in toxicity from radiation therapy, the patient series was treated between 1993-2007 for the control group and 1997-2006 for the PI group. Inclusion of patients from this time period may have been reflected in the distribution of PIs and the distribution of malignancies treated. Nearly all patients in the Plastaras et al. study were treated with nelfinavir, three were treated with saquinavir (the oldest available PI), and one was treated with amprenavir (no longer available). 29 (69%) of 42 malignancies were AIDS-defining or strongly associated with HIV. These results may be limited by the baseline characteristics: AIDS-defining and HIV-associated malignancies are more heavily represented than in the current HIV+ population and PI regimens are evolving rapidly. Although not related to the years from which the patients were sampled, only 6 of the 14 patients from the PI group had documented CD4 count: one was <50, two were <200, and three <500. No association was observed between CD4 count and radiation toxicity, but the data is limited.

          Our study characterizes the safety of radiation therapy combined with the newer generation of PIs in treatment of non-AIDS defining malignancies which are increasingly common in the era of improved ART. The series included only patients treated from January 1, 2009 onwards: of the 18 patients receiving PIs, 16 (89%) were receiving a dual-PI regimen; only two were taking a mono-PI regimen (one ritonavir and one nelfinavir). The case series included more malignancies not associated with HIV or AIDS (ductal carcinoma of the breast, renal cell carcinoma, cholangiocarcinoma, and meningioma), and two non-malignancies (dural AVM, and keloid scar) that were treated with radiation. Half of the patients in this case series received definitive or adjuvant radiation dose regimens (45-78 Gy). These patients were distributed equally in the group with PIs and in the group without PIs, and combination of definitive/adjuvant doses of radiation with PIs did not increase toxicities over definitive/adjuvant radiation doses alone. The present study more than doubles the reported number of patients treated with HIV PIs and radiation from 14 to 32.

          The limitations of this study include the small size, short follow-up, heterogeneous nature of our cohort, and the differences between the control group and the PI treatment group. As discussed before, in addition to not taking PI, the control group also received less non-PI HIV medications and had a lower median CD4 count. The factors that underlie these two differences may confound the results. In addition, although we collected data on late toxicities, there was insufficient follow-up (21 weeks [IQR 10-38] with PIs, 13 [IQR 5-18] without PIs) to assess differences in late toxicities. Extended follow-up is necessary to determine the impact on long term toxicities. In addition, the majority of the cases received ritonavir combined with a second PI. Ritonavir does not inhibit Akt, which is a proposed mechanism of radiosensitization by PIs [27]. However, there are no published studies evaluating the radiosensitizing effect of darunavir, atazanavir, or lopinavir, which were used in combination with ritonavir by the majority of the patients. Prior studies on radiosensitization by PIs have not found a defining structural characteristic which would predict whether a PI will increase radiosensitivity. In spite of these limitations, this retrospective review provides valuable information about the acute toxicity of combining radiation with current PI therapies. Review of this contemporary series of patients did not find an increase in acute toxicity from the combination of the newest generation of HIV PIs and radiation therapy to treat diverse pathologies.

          Conclusions

          Preclinical data has suggested that PIs used in the treatment of HIV may radiosensitize cancer cells, but case reports have suggested that PIs may exacerbate radiotoxicity in normal tissue. Review of a set of HIV-positive radiation therapy patients did not reveal increased toxicity in patients taking PIs during radiation therapy. Our cohort doubles the number of patients in the current literature on the acute safety profile of combining PIs and radiation therapy. These data suggest that clinical trials of PIs as radiosensitizers will not encounter increased acute toxicity.

          Declarations

          Authors’ Affiliations

          (1)
          Department of Neurosurgery, The Johns Hopkins Hospital
          (2)
          Department of Radiation Oncology and Molecular Radiation Sciences, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital
          (3)
          Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital

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          This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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