Bryan Fitzgerald, PharmD, BCOP

Oropharyngeal cancer (OPC) is a type of head and neck cancer that affects structures in the back of the throat, including the base of the tongue, the posterior pharynx, the soft palate, and the tonsils.

 In the United States, rates of OPC are increasing each year, with an estimated 54,010 new cases in 2021.

 Well-established risk factors include alcohol abuse; exposure to tobacco, including chewing tobacco, cigarettes, and pipes; and infection with human papillomavirus (HPV). 

With an estimated 43 million infections in 2018, HPV is the most common sexually transmitted infection in the United States.

 HPV infection is causally linked with cancers of the anogenital region, including anal, cervical, penile, vaginal, and vulvar cancers. When HPV is spread orally, infections can also lead to the development of OPC. In the United States, more than 70% of OPC cases are caused by HPV.

HPV is a group of more than 100 viruses, including certain high-risk strains associated with the development of cancer. The HPV-16 strain is responsible for causing the majority of HPV-positive (HPV+) OPC cases, with HPV-18, HPV-33, and HPV-35 also contributing, albeit significantly less than HPV-16.

 In these high-risk HPV strains, the viral genome encodes several oncogenic proteins that inhibit tumor suppressor proteins, leading to chromosomal instability and malignancy in infected cells.

HPV+ OPC is considered a genetically distinct form of OPC. Compared with HPV-negative (HPC–) OPC cases, HPV+ OPC is associated with a favorable prognosis with improved rates of response prognosis with improved rates of response to treatment and overall survival. Because of the difference in tumor biology, the National Comprehensive Cancer Network (NCCN) has adopted different staging criteria for HPV+ and HPV– disease and recommends that HPV status be used to stratify patients with OPC.

The treatment landscape for localized OPC typically involves a multidisciplinary approach consisting of chemotherapy, radiation, and/or surgery. For fit patients with locally advanced OPC who are able to tolerate intensive therapy, concurrent radiation with systemic high-dose cisplatin chemotherapy is the preferred treatment regimen.

 Unfortunately, treatment of OPC is associated with a high risk of treatment-related morbidity, which may leave patients cured of their malignancy but with lifelong complications, such as dysgeusia, dysphagia, and xerostomia, but also systemic complications from cisplatin chemotherapy, including hearing loss and neurotoxicity.

Because patients with HPV+ OPC are generally younger with more favorable prognoses, clinicians have hypothesized that less intensive treatment could result in fewer long-term complications from treatment but with continued favorable cancer-related outcomes.

 This concept, called deintensification, has become popular in recent years. Several strategies for treatment deintensification have been proposed, including reducing the dose of radiation; substituting cisplatin for an alternative agent with less toxicity, such as cetuximab; and surgical resection. Several phase 3 comparison trials have been conducted, and other trials are ongoing.

Aptly named De-ESCALaTE (NCT01874171), this phase 3 trial randomized patients with 334 HPV+ OPC to receive radiation plus cetuximab or cisplatin.

Unfortunately, the trial results did not favor substitution of cisplatin with cetuximab. At 2 years, the incidence of severe toxicities did not significantly differ between cetuximab and cisplatin (

 = .98), nor did rates of overall toxicities (

= .49). Significant differences in 2-year overall survival rates and recurrence rates were seen. However, these results favored cisplatin (HR, 5.0; 

RTOG-1016 (NCT01302834) was a second phase 3 trial published comparing cetuximab with cisplatin in HPV+ OPC patients.

 This trial analyzed 805 patients who were randomized to receive radiation plus cetuximab or cisplatin. Similar to the De-ESCALaTE trial, the RTOG-1016 trial results favored cisplatin over cetuximab, with 5-year overall survival rates of 84.6% versus 77.9%.

Because of the De-ESCALaTE and RTOG-1016 results, experts advise against the substitution of cisplatin for chemoradiation regimens for patients with localized HPV+ OPC, and cisplatin plus radiation continues to be the preferred systemic treatment option per the NCCN guidelines.

 Because cisplatin continues to be standard of care for the treatment of localized OPC, the role of deintensification for patients with HPV+ OPC may lie in adjustments to surgical strategies or radiation therapy. Treatment deintensification should be pursued only through clinical trials, and experts encourage clinicians to conduct and analyze phase 2 trials before moving on to phase 3 studies.

The treatment landscape of cancer is ever-changing. Specifically in localized HPV+ OPC, the difference in tumor biology presents a unique clinical area where reducing the intensity of treatment may be warranted, particularly with long- and short-term toxicities associated with cisplatin. Interestingly, phase 3 data have shown evidence of harm in removing cisplatin from chemoradiation regimens for HPV+ OPC; therefore, cisplatin-based chemoradiation remains the standard of care for these patients. Future trials may support treatment deintensification in ways other than removing cisplatin.

1. NCCN. Clinical Practice Guidelines in Oncology. Head and neck cancers, version 3.2021. Accessed June 16, 2021. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf

2. Cancer stat facts: oral cavity and pharynx cancer. National Cancer Institute. Accessed June 16, 2021. https://seer.cancer.gov/statfacts/html/oralcav.html

3. Genital HPV infection – fact sheet. CDC. Updated January 19, 2021. Accessed June 17, 2021. https://www.cdc.gov/std/hpv/stdfact-hpv.htm

4. HPV and oropharyngeal cancer. CDC. Updated September 3, 2020. Accessed June 17, 2021. https://www.cdc.gov/cancer/hpv/basic_info/hpv_oropharyngeal.htm

5. Mehanna H, Rischin D, Wong SJ, et al. De-escalation after DE-ESCALATE and RTOG 1016: a head and neck cancer intergroup framework for future de-escalation studies. J Clin Oncol. 2020;38(22):2552-2557. doi:10.1200/JCO.20.00056

6. Mehanna H, Robinson M, Hartley A, et al; De-ESCALaTE HPV Trial Group. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet. 2019;393(10166):51-60. doi:10.1016/S0140-6736(18)32752-1

7. Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. 2019;393(10166):40-50. doi:10.1016/S0140-6736(18)32779-X

8. Gardasil 9. Prescribing information. Pfi zer; 2017. Accessed June 23, 2021. https://www.fda.gov/fi les/vaccines,%20blood%20&%20biologics/published/Package-Insert---Gardasil.pdf

Articles

Clinicians cite long-term complications and younger patients with better prognoses as reasons to pull back on oropharyngeal cancer therapy.

Calls Grow for Treatment Deintensification of HPV-Positive OPC

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases, with almost all cases attributed to tobacco smoke exposure.

SCLC is generally characterized by an aggressive, rapidly growing disease course with a high rate of metastasis. Although this rapid growth and proliferation translate into higher response rates to chemotherapy and radiation, patients relapse quickly with increased rates of disease progression.

Clinical staging for SCLC has historically been classified using the Veterans Administration Lung Study Group's 2-stage system to categorize patients to having either limited-stage SCLC (LS-SCLC) or extensive-stage SCLC (ES-SCLC) disease.

 This system differs from most solid tumor staging, which uses the American Joint Committee on Cancer TNM staging system. The National Comprehensive Cancer Network (NCCN) uses a combined approach for staging SCLC using the TNM staging criteria but ultimately classifies patients with SCLC as having LS-SCLC or ES-SCLC.

 Patients with ES-SCLC have a more advanced disease course. Therefore, the goal of treatment for these patients shifts from curative intent to an intent geared toward disease control and palliation.

For several decades, first-line treatment for ES-SCLC has consisted of systemic chemotherapy with a platinum agent (carboplatin or cisplatin) plus etoposide. Because of the favorable toxicity profile of carboplatin over cisplatin and comparable efficacy rates between the 2 platinum agents, carboplatin was preferred over cisplatin in ES-SCLC treatment regimens. Although response rates were reported as high as 80%, median overall survival rates for patients treated with carboplatin and etoposide were approximately 10 months.

In recent years, immune checkpoint inhibitors have revolutionized oncology treatment with 7 checkpoint inhibitors approved by the FDA to treat various types of cancer, including melanoma, non–small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and many others. By manipulating physiologic immune checkpoint pathways in place to reduce autoimmunity, cancer cells can evade recognition and targeting by cytotoxic T lymphocytes (CTLs). Immune checkpoint inhibitors target these pathways, either by inhibiting CTL antigen-4 (CTLA-4) or the interaction between PD-1 receptors and its ligands, PD-L1/L2.

Two immune checkpoint inhibitors, atezolizumab (Tecentriq; Genentech) and durvalumab (Imfinzi; AstraZeneca), were recently studied in the first-line setting for patients with ES-SCLC in combination with a platinum agent and etoposide. This addition of immunotherapy to chemotherapy represents the first change in ES-SCLC treatment since the 1990s. Both atezolizumab and durvalumab are humanized, IgG monoclonal antibodies targeting PD-L1 on the surface of tumor cells.

Atezolizumab was studied in combination with carboplatin and etoposide for first-line treatment in ES-SCLC in the phase 1/3 IMpower133 trial.

 In a 1:1 fashion, 403 patients with untreated ES-SCLC were randomized to receive treatment with carboplatin, etoposide, and atezolizumab or a matching placebo every 21 days for 4 cycles. After the initial 4-cycle induction phase of treatment, patients received maintenance therapy with atezolizumab or a placebo every 21 days until loss of clinical benefit, disease progression, or unacceptable toxicity.

After a median follow-up of 13.9 months, patients in the atezolizumab arm had a longer median overall survival (12.3 months) compared with the placebo arm (10.3 months).

=.007), suggesting a 30% lower risk of death with the addition of atezolizumab to standard carboplatin-etoposide therapy. In February 2021, an updated analysis was published after a median follow-up of 22.9 months, supporting the original results of the IMpower133 trial.

 The update reported a median overall survival of 12.3 months in the atezolizumab arm compared with 10.3 months in the placebo arm (HR, 0.76; 95% CI, 0.60-0.95; 

Durvalumab was the second PD-L1 inhibitor approved by the FDA based on the results of the CASPIAN trial.

 In this trial, 805 patients with untreated ES-SCLC were randomized 1:1:1 to receive treatment with a platinum agent (carboplatin or cisplatin) and etoposide; platinum-etoposide plus durvalumab; or platinum-etoposide plus durvalumab and tremelimumab, a CTLA-4 inhibitor. Initial treatment was given for 4 cycles (up to 6 cycles in the platinum-etoposide arm), followed by maintenance durvalumab every 4 weeks until disease progression or unacceptable toxicity. 

The published results of the CASPIAN trial included analysis of the platinum-etoposide and platinum-etoposide-durvalumab arms.

 After a median follow-up of 25.1 months, updated results were published showing that the median overall survival was longer in the platinum-etoposide-durvalumab arm (12.9 months) compared with the platinum-etoposide arm (10.5 months).

=.0032), similar to the results from the IMpower133 trial. 

As with other checkpoint inhibitors, treatment with both atezolizumab and durvalumab is associated with a unique immune-mediated toxicity profile, ranging from mild toxicities to potentially life-threatening toxicities. With a heterogeneous clinical presentation, immune-mediated toxicities can affect any organ system, most commonly the gastrointestinal tract, liver, skin, and thyroid gland. Immune-mediated toxicities should be identified as early as possible for close monitoring, prompt initiation or high-dose corticosteroids, and supportive care.

Based on the results of both the CASPIAN and IMpower133 trials, the addition of atezolizumab or durvalumab to platinum-etoposide therapy is considered the standard of care for patients with untreated ES-SCLC, as recommended by the NCCN guidelines. Pharmacists should recognize the role of adding atezolizumab and durvalumab to first-line treatment for ES-SCLC, along with the unique toxicities with which these patients may present.

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2. Pesch B, Kendzia B, Gustavsson P, et al. Cigarette smoking and lung cancer-relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer. 2012;131(5):1210-1219. doi:10.1002/ijc.27339

3. Jett JR, Schild SE, Kesler KA, Kalemkerian GP. Treatment of small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(suppl5):e400S-e419S. doi:10.1378/chest.12-2363

4. Recently updated guidelines. National Comprehensive Cancer Network. Accessed April 28, 2021. https://www.nccn.org/guidelines/recently-published-guidelines

5. Socinski MA, Smit EF, Lorigan P, et al. Phase III study of pemetrexed plus carboplatin compared with etoposide plus carboplatin in chemotherapy-naive patients with extensive-stage small-cell lung cancer. J Clin Oncol. 2009;27(28):4787-4792. doi:10.1200/JCO.2009.23.1548

6. Horn L, Mansfield NS, Szczesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064

7. Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630. doi:10.1200/JCO.20.01055

8. Paz-Ares L, Dvorkin ML, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6

9. Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):51-65. doi:10.1016/S1470-2045(20)30539-8

 is an oncology clinical pharmacy specialist at University of Rochester Medical Center in New York.

Addition of atezolizumab and durvalumab to chemotherapy is a win for patients with extensive-stage small cell lung cancer