Research ArticleClinical Studies

Long-term Outcome of Seropositive HIV Patients with Head and Neck Squamous Cell Carcinoma Treated with Radiation Therapy and Chemotherapy

WALEED F. MOURAD, KENNETH S. HU, DANIEL SHASHA, CATHERINE CONCERT, DAN ISHIHARA, WILSON LIN, MAURICIO E. GAMEZ, JOHN J. LUKENS, RANIA A. SHOURBAJI, MAGDALENA RYNIAK, ZUJUN LI, BRUCE E. CULLINEY, AZITA S. KHORSANDI, THERESA TRAN, ADAM JACOBSON, SPIROS MANOLIDIS, STIMSON SCHANTZ, MARK URKEN, MARK S. PERSKY and LOUIS B. HARRISON
Anticancer Research December 2013, 33 (12) 5511-5516;

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Abstract

Aim: To report the outcome of radiation therapy (RT) +/- chemotherapy in HIV-seropositive patients with Head and Neck Squamous Cell Carcinoma (HNSCC). Patients and Methods: This is the largest single-Institution retrospective study to date, consisting of 73 HIV patients with HNSCC treated from January 1997-2010. The median age at RT, HIV diagnosis and the duration of patients being HIV seropositive were 51, 34, and 11 years, respectively. Seventy patients had SCC and one had submandibular salivary duct carcinoma. Stages I-II, III and IVA/B were: 22%, 27% and 51%, respectively. Primary cancer sites comprised the larynx (37%), oropharynx (32%), oral cavity (13%), hypopharynx (7%), nasopharynx (4%), unknown primary (MUP) (4%), nasal cavity (3%), and submandibular salivary duct (1%). All patients had an ECOG performance scale of ≤1 and were treated with RT +/- chemotherapy. Fifty patients (70%) were on highly active anti-retroviral therapy (HAART) during treatment, and the median CD4 count was 290 (range: 203-1142). Median dose of 70, 63, and 54 Gy were delivered to the gross disease, high-risk neck, and low-risk neck respectively. Median duration of treatment was 52 (range: 49-64) days. Twelve patients (17%) underwent neck dissection for N3 disease. Results: After a median follow-up of 47 months (range: 7-140), the 4-year locoregional control (LRC) and overall survival (OS) were 69% and 55% respectively. Seven patients (10%) developed second primary sites within the first 5 years of completing RT (2 anal SCCs and 5 HNSCCs). The LRC for Stages III/IV larynx and oropharynx SCC (which represent the majority of the cohort) were 76% and 70%, respectively. Chemo/RT-related late toxicities were dysphagia of grade≤2, 3, and 4 found in 74%, 15% and 11% of patients, respectively. Hoarseness (grade 1) was reported in 10% of patients; no patient experienced grade ≥2. Xerostomia grade ≤2, and 3 was found in 77% and 23% of patients, respectively. A Chi-square test and univariate analysis showed statistically significant relationships between LRC and duration of RT (p<0.001), as well as positive trends for weight loss (<10%) and absence of second malignancy. Conclusion: Definitive RT +/- chemotherapy for HIV-seropositive patients with HNSCC appears to be less effective compared to the observed rates of LRC and OS of other HNSCC without HIV. Due to advances in the HAART which prolongs HIV patients' survival, it is extremely important to establish better treatment strategies to improve therapeutic ratio in this growing patient population.

The advent of highly active anti-retroviral therapy (HARRT) has significantly improved the life expectancy of patients infected with the human immunodeficiency virus (HIV) in the last two decades. While this remarkable progress has resulted in reductions in the incidence of acquired immune deficiency syndrome (AIDS)-defining malignancies, such as Kaposi's sarcoma and non-Hodgkin's lymphoma, an increasing proportion of patients are developing cancers that were previously not associated with AIDS (1, 2). These non-AIDS-defining cancers, such as squamous cell carcinoma (SCC) of the anus and of the head and neck, tend to present with a more aggressive behavior, more advanced disease at diagnosis and are less often cured than the HIV-negative patient population (3), which is responsible for poorer patient outcomes.

While surgery is the mainstay of treatment in oral cavity carcinomas, adverse pathological features such as positive lymph nodes or close margins of excision indicate the need for adjuvant RT or concurrent chemoradiation (4). Nevertheless, previous studies have reported that RT is poorly-tolerated, particularly for those treated for anal cancer, and have recommended that modifications such as lower radiation doses and/or smaller field sizes to be considered in response to increased toxicity (5, 6). There is little information on RT of head and neck SCC (HNSCC) in HIV-positive patients (7) and specific therapeutic recommendations for HNSCC are lacking at present. Recent studies on RT management of HNSCC in this specific population, albeit small, have reported acceptable outcomes and toxicities compared to HIV-negative patients with HNSCC (8-13). Authors of these studies suggested that aggressive regimens commonly employed in HNSCC RT should be offered to HIV-positive patients with newly-diagnosed HNSCC. Therefore, we conducted a retrospective analysis of 71 HIV-seropositive patients treated at our cancer Center for HNSCC. Here we report the largest and longest single-Institution study, to date, on the treatment outcomes of RT for patients with HNSCC and co-existing HIV.

Patients and Methods

Patient population and eligibility. This study represents a single-Institution retrospective investigation and was fully-approved by our Institutional Review Board. Between 1997 and 2010, 70 HIV-seropositive patients who had pathologically-proven SCC and one HIV-seropositive patient with submandibular salivary duct carcinoma were treated. 49 patients (69%) were male with a median age of 51 years (range 32-72 years). The median age of HIV diagnosis and the duration of being HIV-seropositive were 34 years (range: 25-50 years) and 11 years (range: 6-20 years), respectively. While there was no acute RT-related fatality, two patients died before starting RT. One patient, with stage IVA base of tongue SCC, died from induction chemotherapy (TPF) while the other patient, with stage III tonsil SCC, died from bleeding after transoral robotic surgery (TORS). Both patients were not included in the current analysis of 71 patients. Tumor staging of AJCC 7th Edition (2009) was used to stage patients as follows: stages I, 6 patients (8%); stage II, 7 patients (10%); stage III, 17 patients (24%); stage IVA, 29 patients (41%) and stage IVB, 12 patients (17%). Various primary cancer sites and percentages of patients with each type of HNSCC are summarized in Table I. The median age of HIV diagnosis and the duration of these patients being HIV-seropositive were 34 years (range: 25-50 years) and 11 years (range: 6-20 years), respectively. Fifty patients (70%) were on HAART during treatment and the median CD4 count of the whole cohort was 290 (range: 203-1142).

Treatment. All patients were treated with curative intent using a continuous course, sequential boost, of once-daily RT. RT was delivered using either three-dimensional conformal RT (3DcRT) for 38 patients (54%) or intensity-modulated RT (IMRT) for 33 patients (46%). Patients were treated once daily receiving 1.8-2 Gy per fraction, to a total dose of 70 Gy (median 70 Gy; range: 66-70 Gy). Definitive RT was given as follows: 70, 63, and 54 Gy to the gross disease, high-risk ipsilateral involved neck, low-risk neck (uninvolved neck or low neck), respectively. The lateral retropharyngeal nodes (RPN) received elective dose of 54 Gy when clinically-indicated (e.g. SCC of the hypopharynx, oropharynx, MUP). Forty-six patients (65%) with stages III (n=5/17, 29.4%) and IVA/B (41/41, 100%) underwent concurrent chemo-RT. Cisplatin (CDDP) was the main chemotherapy regimen received by the patients, however, carboplatin or cetuximab were prescribed as a replacement for CDDP in cases of poor performance status or renal impairment. Twelve patients (17%) underwent neck dissection (ND) for N3 disease. Median duration of treatment was 52 days (49-64 days).

Follow-up. Each patient had follow-up appointments every 3 months during the first year, 4 months in the second, and every 6 months in years 3-5, then annually after 5 years. Each follow-up included a complete history and comprehensive physical examination, as well as a direct and indirect laryngoscope examination. All patients were followed for a minimum of 5 years, or until death. No patients were lost to follow-up. Flurodeoxyglucose (FDG) PET or CT was performed three months after completion of RT and every 6 months afterwards during the first three years, then once yearly. TSH levels were considered for all patients. Dental prophylaxis, rehabilitation and speech/swallowing evaluations were performed where needed. Complications were defined as per the RTOG toxicity scale. Patients who were unable to swallow during RT to the extent that a percutaneous endoscopic gastrostomy (PEG) tube was necessary were coded as grade 3 toxicity, while permanent PEG tube dependency was coded as grade 4 toxicity.

Results

Primary RT was the preferred treatment for HIV-positive patients with HNSCC treated at our Institution during the time of this study; therefore, all 71 (100%) patients received definitive RT. In the whole cohort, 49 (69%) patients were male. The median age was 51 years (range: 32-72 years). Twelve patients (17%) with N3 disease underwent ND. Our institutional ND experience has been previously reported (18). Chemo/RT-related late toxicities at median follow-up of 4 years were mainly dysphagia, hoarseness of voice and xerostomia. Dysphagia developed in 46% (grade 1), 28% (grade 2), 15% (grade 3) and 11% (grade 4) of patients, where as grade 4 dysphagia led to PEG dependence. Xerostomia grades ranging from 1 to 3 developed in 45% (Grade 1), 32% (grade 2) and 23% (grade 3) of patients. Seven patients (10%) developed second-primary within the first 5 years of completing RT (two patients with anal SCC and five patients with HNSCC) (Table I). All local and distant failures were observed within the first 3.5 years of treatment with a median time of 22 months (range: 3-43 months).The median overall survival (OS) for the group of patients that developed local recurrence (LR) was 10 months while the median OS for the group that developed distant metastasis (DM) was 5 months.

View this table:
Table I.

Primary sites of cancer and pattern of failure.

Locoregional control and survival. After a median follow-up of 47 months (range: 7-140 months), the four-year locoregional control (LRC) (Figure 1) and OS (Figure 2) for the whole cohort was 69% and 55%, respectively. The four-year actuarial LRF by primary tumor sites (Figure 3) were as follows: hypopharynx, 100%; nasal cavity, 50%; nasopharynx, 33%; oropharynx, 30%; larynx, 24%; oral cavity, 22%; metastatic SCC of unknown primary (MUP) and submandibular salivary duct tumor, 0%. The LRC for Stages III/IV larynx and oropharynx SCC (which represents >67% of the cohort) was 76% and 70% respectively. A Chi-square test and univariate analysis showed a statistically significant relationship between LRC and the duration of RT (p<0.001). A Chi-square test also showed significant relationship between lower CD4 counts and higher viral load (p=0.001). Positive trends were observed between weight loss ≤10% and LRC as well as between absence of second malignancy and OS (p=0.271).

Discussion

RT is a reputable treatment modality in the definitive management of HNSCC. The increase in the use of IMRT has significantly improved the outcomes associated with RT in the head and neck region (14, 15). HNSCC with co-existing HIV, however, remains a challenging clinical problem as there is very little information on the outcome and efficacy of RT for this population. Definitive RT+/- chemotherapy has been utilized for HNSCC in HIV-positive patients at our institution for over 14 years and our RT strategy was not modified with regard to dose and technique compared to immunocompetent patients with HNSCC. Given the varying CD4+ cell counts, end-points, diverse primary cancer sites and RT techniques, an exact comparison of toxicity with HNSCC in HIV-negative patients is difficult. However, a recent review article on the various published reports of outcomes using IMRT+/- concurrent chemotherapy for HNSCC in immunocompetent patients suggests HIV status does affect outcome of RT (16). In the present report, observed rates of LRC and OS for SCC of oropharyngeal, laryngeal/hypopharyngeal, nasopharyngeal and unknown primary site were (median 93%, 84%, 98% and 86.5%) and (92%, 83%, 89% and 75%), respectively (16). These data indicate significantly better outcome for HNSCC treated with RT+/- chemotherapy in immunocompetent patients compared to our observed rate of LRC (55%, Figure 1) and OS (69%, Figure 2) in HIV-positive patients with HNSCC. This finding is critical as there is no consensus on the best treatment modality for this population beyond what is commonly utilized for immunocompetent patients with HNSCC. Notably, a Chi-square test and univariate analysis showed a statistically-significant relationship between LRC and the duration of RT (p<0.001) in our patient population. Moreover, positive trends with weight loss <10% and absence of a second malignancy was noted. However, this analysis was limited as our multivariate analysis did not show any statistically-significant relationship, likely due to the relatively small sample size with diverse primary cancer sites. For example, we found all three patients with metastatic SCC of unknown primary did not experience Locoregional failure (LRF) whereas all five patients with stage IV disease of the hypopharynx developed LRF (Table I). Whether such difference in failure reflects the difference in behavior of primary cancer site require larger sample volume examination.

Comparison of our treatment outcome with previous smaller size single-institutional reports on RT for HNSCC in HIV-positive patients is also alarming (Table II). Sanfilipo et al. reviewed treatment results of 13 HIV-positive patients with head and neck cancer who underwent RT, where 6 patients (46%) also received concurrent chemotherapy (9). Analysis from this study revealed higher OS rates compared to our study (83% vs. 69%), while a similar control rate (66% disease-free vs. 55% LRC patients) was found. Similarly, Klein et al. reviewed treatment results of 12 HIV-positive patients with HNSCC and also reported higher OS rates compared to our study (78% vs. 69%), however, a much higher rate of LRC was reported compared to our study (92% vs. 55% LRC) (8). While the authors of these studies concluded that the outcomes of RT for HNSCC in HIV-positive patients were relatively good, our study found poorer LRC and OS. Given the similar patient population, RT modalities employed and treatment duration between the studies, it is possible that the difference in the rates of LRC and OS could be attributed to the difference in the median follow-up duration as these studies had a shorter median follow-up duration of 2 years (9) and 3 years (8) compared to our study. Accordingly, we found that approximately 25% of all patients developed late Grade 3 to 4 RT toxicities, which is much higher than the reported late events by other studies with shorter follow-up (Table II). Additional consideration in the comparison of efficacy and outcome of RT includes varying CD4+ cell count between the studies. Interestingly, local control and disease-specific survival rates in HIV-positive patients receiving RT are worse than in immunocompetent patients when CD4 counts are less than 200 cells/μl (16). Additionally, Hoffman et al. has reported identifying a CD4 count of less than 200 cells/μl as a predisposing factor to hospitalization with an increased likelihood of experiencing RT-related toxicities compared to those without HIV (17). An excellent LRC rate of 92% was found in Klein et al.'s study, where the median CD4 cell count was above 400 cells/μl, which was higher than either Sanfillipo et al.'s study or our study (Table II). While none of our patients had a CD4 count below 200 cells/μl and an univariate analysis found that only the duration of RT was associated with LRC, it remains a possibility that with larger patient volumes and longer follow–up, significant differences may emerge. Given the small number of patients in our study, however, it is not surprising that relatively few statistical conclusions could be drawn regarding the possible prognostic factors and variables.

Figure 1.
Figure 1.

The 4-year locoregional failure rate for the entire patient post RT +/- chemotherapy.

Figure 2.
Figure 2.

The 4-year overall survival rate for the entire patient post RT +/- chemotherapy.

Figure 3.
Figure 3.

The 4-year locoregional failure rate per primary cancer site post RT +/- chemotherapy. HPX; Hypopharynx, NPX; nasopharynx, OPX; oropharynx, LX; larynx, SMD; submandibular, and salivary duct carcinoma.

Finally, the strengths of our study include: largest single-Institution experience with the longest median follow-up, reported in the literature. All RT were designed by two radiation oncologists (LBH and KSH) and all statistical analyses being performed by an independent statistician uninvolved with data abstraction. The caveats include: a non-randomized retrospective analysis, relatively small number of patients, dependence upon accuracy of documentation, vulnerability to selection bias, as well as poorly-documented smoking history. Nevertheless, our data strongly suggest the need for modification of the current regimen in the management of HNSCC for HIV-positive patients to improve outcome.

View this table:
Table II.

A detailed comparison of studies for tolerance and RT-induced side-effects of HNSCC in HIV-seropositive patients receiving definitive RT.

Conclusion

HNSCC treatment in HIV-positive patients remains a challenging clinical problem. Our data show that definitive RT +/- chemotherapy for HIV-positive patients with HNSCC appears to be less effective compared to the observed rates of LRC, and OS of other HNSCC in patients without HIV. As HIV-positive patients' survival and life expectancy continues to improve, the likelihood to non-AIDS-defining malignancy increases. Hence, it is extremely important to establish better effective regimens to improve outcomes of treatment for HNSCC.

Footnotes

  • Presented at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by AHNS, ASCO, ASTRO and SNM. January 2012. Phoenix, AZ, U.S.A.

  • Funding

    None.

  • Conflicts of Interest

    None of the Authors report conflicts of interest or have financial disclosures to make. This article contains no copyrighted information.

  • Received October 21, 2013.
  • Revision received November 6, 2013.
  • Accepted November 8, 2013.

References

  1. ↵
    1. Hessol NA,
    2. Pipkin S,
    3. Schwarcz S,
    4. Cress RD,
    5. Bacchetti P,
    6. Scheer S
    : The impact of highly active antiretroviral therapy on non-AIDS-defining cancers among adults with AIDS. Am J Epidemiol 165(10): 1143-1153, 2007.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Clifford GM,
    2. Polesel J,
    3. Rickenbach M,
    4. Dal Maso L,
    5. Keiser O,
    6. Kofler A,
    7. Rapiti E,
    8. Levi F,
    9. Jundt G,
    10. Fisch T,
    11. Bordoni A,
    12. De Weck D,
    13. Franceschi S
    : Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst 97(6): 425-432, 2005.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Spano JP,
    2. Costagliola D,
    3. Katlama C,
    4. Mounier N,
    5. Oksenhendler E,
    6. Khayat D
    : AIDS-related malignancies: state of the art and therapeutic challenges J Clin Oncol 26(29): 4834-4842, 2008.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Bernier J,
    2. Cooper JS,
    3. Pajak TF,
    4. van Glabbeke M,
    5. Bourhis J,
    6. Forastiere A,
    7. Ozsahin EM,
    8. Jacobs JR,
    9. Jassem J,
    10. Ang KK,
    11. Lefèbvre JL
    : Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 27(10): 843-850, 2005.
    OpenUrlCrossRefPubMed
  5. ↵
    1. Chadha M,
    2. Rosenblatt EA,
    3. Malamud S,
    4. Pisch J,
    5. Berson A
    : Squamous-cell carcinoma of the anus in HIV-positive patients. Dis Colon Rectum 37(9): 861-865, 1994.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Holland JM,
    2. Swift PS
    : Tolerance of patients with human immunodeficiency virus and anal carcinoma to treatment with combined chemotherapy and radiation therapy. Radiology 193(1): 251-254, 1994.
    OpenUrlPubMed
  7. ↵
    1. Kao GD,
    2. Devine P,
    3. Mirza N
    : Oral cavity and oropharyngeal tumors in human immunodeficiency virus-positive patients: acute response to radiation therapy. Arch Otolaryngol Head Neck Surg 125(8): 873-876, 1999.
    OpenUrlPubMed
  8. ↵
    1. Klein EA,
    2. Guiou M,
    3. Farwell DG,
    4. Luu Q,
    5. Lau DH,
    6. Stuart K,
    7. Vaughan A,
    8. Vijayakumar S,
    9. Chen AM
    : Primary radiation therapy for head-and-neck cancer in the setting of human immunodeficiency virus. Int J Radiat Oncol Biol Phys 79(1): 60-64, 2011.
    OpenUrlPubMed
  9. ↵
    1. Sanfilippo NJ,
    2. Mitchell J,
    3. Grew D,
    4. DeLacure M
    : Toxicity of head-and-neck radiation therapy in human immunodeficiency virus-positive patients. Int J Radiat Oncol Biol Phys 77(5): 1375-1379, 2010.
    OpenUrlPubMed
    1. Mourad WF,
    2. Hu KS,
    3. Ishihara D,
    4. Shourbaji RA,
    5. Lin W,
    6. Kumar M,
    7. Jacobson AS,
    8. Tran T,
    9. Manolidis S,
    10. Urken M,
    11. Persky M,
    12. Harrison L
    : Tolerance and toxicity of primary radiation therapy in the management of seropositive HIV patients with squamous cell carcinoma of the head and neck. Laryngoscope 123(5): 1178-1183, 2013.
    OpenUrlPubMed
    1. Mourad WF,
    2. Hu KS,
    3. Shourbaji RA,
    4. Lin W,
    5. Kaplan-Marans E,
    6. Li Z,
    7. Culliney B,
    8. Urken M,
    9. Persky M,
    10. Harrison LB
    : The Role of Chemoradiation Therapy (CRT) in the Management of Patients With Squamous Cell Carcinoma of the Head and Neck (SCCHN) ± HPV With Coexisting HIV. Int J Radiat Oncol Biol Phys 84(3): S506, 2012.
    OpenUrl
    1. Mourad WF,
    2. Hu K,
    3. Shourbaji RA,
    4. Li Z,
    5. Culliney B,
    6. Harrison LB
    : Outcomes of HIV patients treated with chemoradiotherapy (CRT) for squamous cell carcinoma of the head and neck (SCCHN). JCO 30: s15, 2012.
    OpenUrlCrossRef
  13. ↵
    1. Mourad WF,
    2. Hu KS,
    3. Shourbaji RA,
    4. Harrison LB
    : Management of sarcomatoid salivary duct carcinoma of the submandibular gland duct with coexisting seropositive human immunodeficiency virus. J Laryngol Otol 127(6): 621-624, 2013.
    OpenUrlPubMed
  14. ↵
    1. Butler EB,
    2. Teh BS,
    3. Grant WH 3rd.,
    4. Uhl BM,
    5. Kuppersmith RB,
    6. Chiu JK,
    7. Donovan DT,
    8. Woo SY
    : Smart (simultaneous modulated accelerated radiation therapy) boost: a new accelerated fractionation schedule for the treatment of head and neck cancer with intensity modulated radiotherapy. Int J Radiat Oncol Biol Phys 45: 21-32, 1999.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Bhide SA,
    2. Newbold KL,
    3. Harrington KJ,
    4. Nutting CM
    : Clinical evaluation of intensity-modulated radiotherapy for head and neck cancers. Br J Radiol 85(1013): 487-494, 2012.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Mallik S,
    2. Talapatra K,
    3. Goswami J
    : AIDS: a radiation oncologist's perspective. J Cancer Res Therapeutics 6: 432-441, 2010.
    OpenUrl
  17. ↵
    1. Hoffman R,
    2. Welton ML,
    3. Klencke B,
    4. Weinberg V,
    5. Krieg R
    : The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIV-positive patients with anal cancer. Int J Radiat Oncol Biol Phys 44: 127-131, 1999.
    OpenUrlCrossRefPubMed
  18. ↵
    1. Frank DK,
    2. Hu KS,
    3. Culliney BE,
    4. Persky MS,
    5. Nussbaum M,
    6. Schantz SP,
    7. Malamud SC,
    8. Holliday RA,
    9. Khorsandi AS,
    10. Sessions RB,
    11. Harrison LB
    : Planned neck dissection after concomitant radiochemotherapy for advanced head and neck cancer. The Laryngoscope 115: 1015-1020, 2005.
    OpenUrlCrossRefPubMed
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Long-term Outcome of Seropositive HIV Patients with Head and Neck Squamous Cell Carcinoma Treated with Radiation Therapy and Chemotherapy
WALEED F. MOURAD, KENNETH S. HU, DANIEL SHASHA, CATHERINE CONCERT, DAN ISHIHARA, WILSON LIN, MAURICIO E. GAMEZ, JOHN J. LUKENS, RANIA A. SHOURBAJI, MAGDALENA RYNIAK, ZUJUN LI, BRUCE E. CULLINEY, AZITA S. KHORSANDI, THERESA TRAN, ADAM JACOBSON, SPIROS MANOLIDIS, STIMSON SCHANTZ, MARK URKEN, MARK S. PERSKY, LOUIS B. HARRISON
Anticancer Research Dec 2013, 33 (12) 5511-5516;
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