Lung Cancer

Introduction

Lung cancer is the most common non-AIDS defining malignancy (non-ADM) and the leading source of non-ADM mortality in persons living with HIV/AIDS (PLWHA)1. Lung cancer incidence in HIV patients is 0.79 [0.66-0.92]/1000 PY2. It appears that the incidence of non-small cell lung cancer (NSCLC) is increased in people living with HIV infection but there is no evidence of an increased incidence of small cell lung cancer (SCLC) for some authors3, 4. Nevertheless other authors consider that the risk of lung cancer in the setting of HIV infection is elevated for all major lung cancer subtypes (adenocarcinoma, squamous cell carcinoma and small cell carcinoma) and has not been significantly modified by the introduction of HAART5. Engels et al6 reported that the relative risk (RR) of lung cancer occurring during the pre-HAART era [2.5 (95% CI 1.9-3.3)] was similar to that described in the early [3.3 (95% CI 2.9-3.8)] and recent HAART era [2.6 (95% CI 2.1-3.1)].

Cumulative mortality estimates were particularly high in the 140 individuals
diagnosed with lung cancer in the D:A:D Study (57.2% [48.4-65.9] and 77.0% [67.3-86.8] at 1 and 2.5 years, respectively. HCV co-infection and disseminated cancer at time of diagnosis were predictors of mortality among patients with lung cancer. No association was seen in univariate analyses between the latest CD4 count and mortality from lung cancer (relative hazard per 50 cells/mm3 higher: 0.99 [95% confidence interval 0.95-1.03], p = 0.70)2. Nevertheless, in a French cohort with more than 52.000 HIV-positive individuals7, a RR of 2.2 (95% CI 1.3-3.6) for lung cancer has been reported in patients with current CD4 cell count between 350 and 500 cells/µl and 8.5 (95% CI 4.3-16.7) in patients with current CD4 counts <50 cells/µl, when compared to HIV-positive patients with current CD4 cell count >500 cells/µl.

Considering that smoking is the major etiologic agent of lung cancer, heavier smoking exposure has been considered as the main explanation for higher rates of lung cancer observed in the setting of HIV. In fact, among HIV-infected individuals smoking rates range from 35% to 70%, compared to approximately 20% in the general US population. However, HIV infection has been associated with increased lung cancer incidence even after controlling for smoking history data. The incidence rate ratio (IRR) of lung cancer associated with HIV infection remains significant even after multivariable adjustment for major confounders, including smoking and age (IRR 1.7; 95% CI 1.5-1.9)5.

The most recent studies demonstrated similar survival rates among HIV-positive lung cancer patients as compared with HIV-negative8.

Patients with HIV-related NSCLC present at a younger age and with more advanced disease than their HIV-negative counterparts. The rise in incidence of adenocarcinoma in the HIV-negative population has also been seen in people living with HIV/AIDS9.


Signs and Symptoms

More than 80% of lung cancer patients refer symptoms for less than 3 months. Most frequent symptoms are: cough (75%), asthenia (50%), weight loss (57%), chest pain (50%), haemoptysis (20-50%), dyspnoea (40%), dysphonia (15%), bone pain (9%), dysphagia (3%).

 

Diagnostic Tools

NSCLC [10]: CT chest and upper abdomen, including adrenals; pulmonary function tests (PFTs); consider PET/CT scan; patients with a strong clinical suspicion of stage I or II lung cancer (risk factors and radiologic appearance) do not require a biopsy before surgery. Bronchoscopy should preferably be performed during the planned surgical resection. Invasive mediastinal staging is recommended before surgical resection for most patients with clinical stage I or II lung cancer. Brain MRI is also recommended. Smoking cessation counseling and intervention are recommended.

For T, N, M definitions, Anatomic Stages and Prognostic Groups see NCCN Guidelines for NSCLC, version 2.2014, pages 59-61.

SCLC11: chest/liver/adrenal CT with intravenous contrast whenever possible; brain MRI (preferred) or CT scan with intravenous contrast whenever possible; PET/CT scan if limited stage is suspected; smoking cessation counseling and intervention. If pleural effusion is present consider thoracentesis; if thoracentesis is inconclusive, consider thoracoscopy.

For T, N, M definitions, Anatomic Stages and Prognostic Groups see NCCN Guidelines for SCLC, version 2.2014, pages 20-21.


Treatment Overview

NSCLC:

  • Operable disease9: Those with operable disease should be offered curative surgery (lobectomy or pneumonectomy, with mediastinal lymphadenectomy). Chemotherapy should consist of standard regimens (based in cisplatin) and doses. HAART should continue throughout treatment. If surgery is not possible due to concomitant medical problems, radical radiotherapy is recommended (stereotactic RT).
  • Locally advanced disease: chemo-radiation according to HIV-negative guidelines. Patients should therefore continue/commence HAART and antifungal prophylaxis where appropriate.
  • Metastatic disease: The presence of activating mutations within the epidermal growth factor receptor (EGFR) gene of lung cancer cells makes these tumours highly sensitive to EGFR-targeting tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib. The incidence of such mutations in HIV-associated lung cancer is not known. In the absence of an activating EGFR mutation, standard chemotherapy regimens are indicated in the first-line setting.

As a significant increase in myelosuppression has been reported for patients also taking protease inhibitors, it may be worth interrupting HAART prior to chemotherapy if the patient’s HIV is well controlled9.

SCLC: cisplatin and etoposide for all stages. Associated concomitant chest RT for limited disease is recommended. All patients who achieve complete remission should undergo whole-brain RT.

 

Screening and Prevention

The evidence is insufficient to recommend for or against screening asymptomatic persons for lung cancer. Clinicians with access to high-volume, high-quality lung cancer screening and treatment centers may initiate a discussion about screening with apparently healthy PLWHA aged 55–74 years who have at least a 30 pack-year smoking history and who currently smoke or have quit smoking within the past 15 years12.

The importance of stopping smoking is a crucial message during clinical encounters. A recent cohort study13 from Denmark, where HIV care is well organized and antiretroviral therapy is free, showed that HIV-infected smokers lose more life-years to smoking than to HIV (12.3 vs. 5.1 years). Lung cancer screening must not be viewed as an alternative to smoking cessation12.

 

Drug-Drug Interactions14

Cisplatin and dolutegravir: in vitro data indicate that dolutegravir is a moderate inhibitor of cisplatin renal elimination so it is recommended to monitoring for cisplatin related side effects.

Cisplatin and cobicistat: in vitro data indicate that cobicistat is a moderate inhibitor of cisplatin renal elimination so it is recommended to monitoring for cisplatin related side effects.

Cisplatin and tenofovir: coadministration may increase the risk of nephrotoxicity (closely monitor renal function).

Cisplatin and fenitoin: cisplatin decreases fenitoin plasma concentrations.

Efavirenz or Etravirine and erlotinib: EFV or ETV could potentially decrease erlotinib concentrations.

Any PI (with or without ritonavir) and erlotinib: coadministration of a potent CYP3A4 inhibitor like any PI and erlotinib should be avoided.

Any PI or EVG/COBI may increase etoposide exposure.

NNRTI except rilpivirine could potentially decrease etoposide exposure.

 

When to Refer15

An urgent referral for a chest X-ray should be made when a patient presents with: haemoptysis, or any of the following unexplained persistent (that is, lasting more than 3 weeks) symptoms and signs: chest and/or shoulder pain, dyspnoea, weight loss, hoarseness, finger clubbing, cervical and/or supraclavicular lymphadenopathy, cough with or without any of the above features suggestive of metastasis from a lung cancer (for example, in brain, bone, liver or skin). A report should be made back to the referring primary healthcare professional within 5 days of referral.

An urgent referral should be made for either of the following: persistent haemoptysis in smokers or ex-smokers who are aged 40 years and older or a chest X-ray suggestive of lung cancer (including pleural effusion and slowly resolving consolidation).  Immediate referral should be considered for the following: signs of superior vena caval obstruction (swelling of the face and/or neck with fixed elevation of jugular venous pressure) or stridor.

References

  1. Shiels M, Pfeiffer R, Gail M, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst 2011; 103:753–762.
  2. SW Worm, M Bower, P Reiss, et al. Non-AIDS defining cancers in the D:A:D Study - time trends and predictors of survival: a cohort study. BMC Infectious Diseases 2013, 13:471.
  3. Engels EA, Brock MV, Chen J et al. Elevated incidence of lung cancer among HIV-infected individuals. J Clin Oncol 2006; 24: 1383-1388.
  4. Bower M, Powles T, Nelson M et al. HIV-related lung cancer in the era of highly active antiretroviral therapy. Aids 2003; 17: 371-375
  5. Pinzone MR, Fiorica F, Di Rosa M, Malaguarnera G, Malaguarnera L, Cacopardo B, Zanghì G, Nunnari G. Non-AIDS-defining cancers among HIV-infected people. Eur Rev Med Pharmacol Sci. 2012 Oct;16(10):1377-1388.
  6. Engles EA, Pfeiffer RM, Goedert JJ, et al., Trends in cancer risk among people with AIDS in the United States. 1980-2002. AIDS 2006; 20: 1645-1654.
  7. Guiguet M, Boue F, Cadranel J, et al.,. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study. Lancet Oncol 2009; 10:1152-1159.
  8. D’Jaen G, Pantanowitz L, Bower M, et al., Human immunodeficiency virus– associated primary lung cancer in the era of highly active antiretroviral therapy: a multi-institutional collaboration. Clin Lung Cancer 2010; 11: 396-404.
  9. British HIV Association guidelines for HIV-associated malignancies 2013. Version 1. 25 July 2013.
  10. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. Version 2.2014.
  11. NCCN Clinical Practice Guidelines in Oncology. Small Cell Lung Cancer. Version 2.2014
  12. Mani D. and Aboulafia DM. Screening guidelines for non-AIDS defining cancers in HIV-infected individuals. Curr Opin Oncol. 2013 Sep;25(5):518-525.
  13. Helleberg M, Afzal S, Kronborg G, et al. Mortality attributable to smoking among HIV-1-infected individuals: a nationwide, population-based cohort study. Clin Infect Dis 2013; 56:727–734.
  14. Drug Interactions. University of Liverpool. Updated October 2013.
  15. NHS National Institute for Health and Clinical Excellence. Referral Guidelines for Suspected Cancer. Clinical Guideline 27. June 2005.