Response to Comments: Luteinizing Hormone-Releasing Hormone (LHRH) Analogs

The National Comprehensive Cancer Network^® (NCCN^®) appreciates the opportunity to comment on the Proposed Local Coverage Determination (LCD) Luteinizing Hormone-Releasing Hormone (LHRH) Analogs (DL 39387) as it relates to NCCN's mission of improving and facilitating quality, effective, equitable, and accessible cancer care. NCCN will focus our comments on ways NCCN content can be used as a resource to inform coverage determinations to ensure LCDs remain evergreen as the science evolves facilitating Medicare beneficiary access to the highest standard of care possible.

NCCN Background

As an alliance of 32 leading academic cancer centers in the United States that treat hundreds of thousands of patients with cancer annually, NCCN^® is a developer of authoritative information regarding cancer prevention, screening, diagnosis, treatment, and supportive care that is widely used by clinical professionals and payers alike. The NCCN Clinical Practice Guidelines in Oncology^®(NCCN Guidelines^®) are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97% of cancers affecting patients in the United States.

NCCN Guidelines^® and Library of Compendia products help ensure access to appropriate care, clinical decision-making, and assessment of quality improvement initiatives. The NCCN Drugs & Biologics Compendium (NCCN Compendium^®) has been recognized by CMS and clinical professionals in the commercial payer setting since 2008 as an evidence-based reference for establishment of coverage policy and coverage decisions regarding off-label use of anticancer and cancer-related medications. NCCN was recognized by CMS in 2016 and renewed in 2021 as a qualified Provider Led Entity (PLE) for the Medicare Appropriate Use Criteria (AUC) Program for the development of AUC and the establishment of policy and decision-making for diagnostic imaging in patients with cancer.

NCCN Guidelines

NCCN develops authoritative information regarding cancer prevention, screening, diagnosis, treatment, and supportive care that is widely used by clinical professionals and payers alike. The NCCN Guidelines are a comprehensive set of 84 guidelines detailing the sequential management decisions and interventions across 218 algorithms that currently apply to 97% of cancers affecting patients in the United States. More than 1,700 panel members participate in Guideline development. In 2021, there were 13 million downloads of the Guidelines across web-based and mobile applications. NCCN Guidelines are developed by multidisciplinary expert panels from NCCN Member Institutions in an evidence-based process integrated with expert consensus. The NCCN Guidelines are updated at least annually, but quite often are updated more frequently, with 215 total version updates across all guidelines in 2021.

The NCCN Guidelines are considered the standard for clinical care and policy in oncology in the United States. The Guidelines are the most thorough and most frequently updated clinical practice guidelines in any area of medicine, are the most frequently referenced clinical practice guideline in oncology and are widely available free of charge for non-commercial use. Our Guidelines are also available through a multitude of health information technology vendors, used by payers representing more than 85% of covered lives in the United States, and form the basis for insurance coverage policy and quality evaluation.

NCCN imposes strict policies to shield the guidelines development processes from external influences. The "firewall" surrounding the NCCN Guidelines processes includes: financial support policies; panel participation and communication policies; guidelines disclosure policies; and policies regarding relationships to NCCN's other business development activities. The guidelines development is supported exclusively by the Member Institutions' dues and does not accept any form of industry or other external financial support for the guidelines development program.

Guideline Adherence as a Tool to Improve Outcomes, Reduce Costs, and Keep Coverage Evergreen

Numerous independent studies have found adherence to NCCN Guidelines improves care delivery and outcomes for patients with cancer. Improved health outcomes proven through concordance with NCCN Guidelines include: improved rates of survival for colon cancer, ovarian cancer, gastric cancer, nasopharyngeal cancer, and pancreatic cancer; decreased locoregional recurrence of melanoma; and improved pain control.

Guideline adherent care has also been shown to decrease costs to both the payer and the patient. A peer-reviewed, published study by United, eviCore, and NCCN entitled "Transforming Prior Authorization to Decision Support" demonstrated mandatory adherence to NCCN Guidelines and NCCN Compendium^® using a real-time Clinical Decision Support Mechanism by United Healthcare significantly reduced total and episodic costs of care by 20% compared to trend while also reducing denials and increasing access to guideline-concordant care. A 2019 study "Guideline Discordance and Patient Cost Responsibility in Medicare Beneficiaries with Metastatic Breast Cancer" by Williams, et.al found median cost for metastatic breast cancer patients receiving guideline-discordant treatment was $7,421 versus $5,171 for those receiving guideline-concordant care. This study found an additional $1,841 in out-of-pocket cost savings for patients receiving guideline concordant care versus patients who received care that did not adhere to guidelines. These cost savings have also been found in studies evaluating the Medicare population. At this year's ASCO annual conference, CVS Health presented 2 abstracts looking at total costs of care beginning with the first treatment and for the subsequent 180 days for breast and colon cancer patients in relation to adherence to NCCN Guidelines. In both studies, there was a significant reduction in total cost of care with concordance with NCCN Guidelines. In the colon cancer study, this was most prominent and significant in the Medicare population. In the breast cancer study, significant reductions were observed across both commercially insured and Medicare patients, with the greatest reductions again seen in the Medicare population.

Nationally Recognized Guidelines as an Evergreening Mechanism for Coverage Determination

Public and commercial payers employ NCCN Guidelines within their coverage mechanisms to ensure evergreening of coverage while also reducing administrative burden. As noted above, adherence to NCCN Guidelines has been proven to improve quality across a variety of outcome measures, reduce costs to the payer and health care system, and reduce costs to the patient. The NCCN Compendium^® has been recognized by CMS and clinical professionals in the commercial payer setting since 2008 as an evidence-based reference for establishment of coverage policy and coverage decisions regarding off-label use of anticancer and cancer-related medications. NCCN was recognized by CMS in 2016 and renewed in 2021 as a qualified Provider Led Entity for the Medicare Appropriate Use Criteria (AUC) Program for the development of AUC and the establishment of policy and decision-making for diagnostic imaging in patients with cancer.

Recognizing the value of continuously updated evidence-based guidelines, numerous Medicare Administrative Contractors have cited NCCN Guidelines within their coverage policies as a mechanism for coverage. NCCN recommends that Palmetto consider the incorporation of nationally recognized guidelines into the proposed LCD coverage indications to ensure the LCD stays evergreen while also significantly reducing administrative burden.

NCCN Guideline Recommendations of Relevance to the Proposed LCD

Within the proposed LCD, Palmetto states that LHRH Analogs will be covered according to the FDA label in the following disease settings:

"Leuprolide Acetate is covered for endometriosis, uterine fibroids, advanced prostate cancer, head and neck cancer (salivary gland tumors), ovarian cancer/fallopian tube cancer/primary peritoneal cancer, premenopausal breast cancer, male breast cancer and central precocious puberty (CPP). Leuprolide mesylate is covered for advanced prostate cancer.

Goserelin implant is covered for prostate cancer in combination with flutamide, indicated for treatment of locally confined prostate cancer stage T2b-T4 (Stage B2-C), advanced breast cancer in premenopausal and perimenopausal women, endometriosis, to thin the endometrial lining of the uterus prior to endometrial ablation for dysfunctional uterine bleeding, advanced prostate cancer.

Triptorelin pamoate is covered for palliative treatment of advanced prostate cancer. It offers an alternative treatment for prostate cancer when orchiectomy or estrogen administration are either not indicated or unacceptable to the patient.

Histrelin acetate implant is covered for the palliative treatment of advanced prostate cancer, and CPP. "

NCCN publishes 4 guidelines of relevance to this proposed LCD: The NCCN Clinical Practice Guidelines in Oncology for Breast Cancer^®, The NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancers^®, The NCCN Clinical Practice Guidelines in Oncology for Ovarian Cancer^®, and The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer^®. NCCN is pleased to provide a list of recommendations for coverage across each of these disease settings.

Breast Cancer

In patients who are premenopausal, the NCCN Guidelines for Breast Cancer recommend endocrine treatment with or without ovarian suppression/ablation. Ovarian suppression utilizes the use of LHRH agonists including goserelin and leuprolide acetate for depot suspension. The NCCN Drugs and Biologics Compendium includes the use of leuprolide acetate for depot suspension and goserelin acetate for treatment of premenopausal patients with hormone receptor-positive invasive breast cancer or inflammatory breast cancer in combination with:

• adjuvant endocrine therapy
• endocrine therapy for recurrent unresectable (local or regional) or stage IV (M1) disease

Head and Neck Cancers

NCCN recommends the use of leuprolide acetate for recurrent or metastatic androgen receptor­ positive salivary gland tumors.

Ovarian Cancer

NCCN recommends leuprolide acetate as a treatment option for certain patients with ovarian, fallopian tube, or primary peritoneal cancers in both the primary and recurrence settings.

• In the primary setting for patients with grade 1 endometrioid or low-grade serous carcinoma (with stage IC-IV disease), leuprolide acetate is recommended as a maintenance hormonal therapy option following adjuvant chemotherapy and also as an adjuvant hormone therapy.
• For certain patients with ovarian, fallopian tube, or primary peritoneal cancer who experience recurrent disease (platinum-sensitive or platinum-resistant), leuprolide acetate is recommended as a hormone therapy option.
  • For patients with recurrent low-grade serous carcinoma, leuprolide acetate is recommended as a recurrence therapy option only if an aromatase inhibitor was given previously.
• Additionally, leuprolide acetate is recommended for patients with stage II-IV granulosa cell tumors as a recurrence therapy option.

Prostate Cancer

NCCN Guidelines recommend the option to use LHRH agonists in the following clinical scenarios:

• With radiation for patients with localized prostate cancer that is in the unfavorable­ intermediate-, high-, or very-high-risk groups (with or without other treatments, including first generation antiandrogens that include nilutamide, flutamide, and bicalutamide);
• With or without radiation for patients with regional prostate cancer (with or without other treatments);
• With radiation for patients with adverse features or recurrence after treatment with radical prostatectomy (with or without other treatments);
• Without radiation for patients with recurrence after treatment with radiation (with or without other treatments);
• Alone or with other treatments for patients with metastatic castration-sensitive disease;
• With other treatment for patients with metastatic castration-resistant disease;
• Alone as palliative treatment for patients with life expectancy ≤ 5.

Areas for Clarification and Requested Changes to LCD

NCCN would like to request clarification on several areas within the proposed LCD specific to Prostate Cancer. Specifically:

• The LCD covers to "advanced prostate cancer", but this is not precisely Many of the clinical scenarios for LHRH analog use outlined within the NCCN Guidelines for Prostate Cancer may be considered advanced, though likely not all. NCCN recommends further clarifying the clinical context in which coverage is granted, or alternatively citing to nationally recognized guidelines to accommodate specific clinical scenarios.
• The proposed LCD states that "Triptorelin is covered for palliative treatment of advanced prostate It offers an alternative treatment for prostate cancer when orchiectomy or estrogen administration are either not indicated or unacceptable to the patient." NCCN would like to respectfully note that estrogen is not recommended by NCCN. Additionally, within the NCCN Guidelines, no LHRH agonist is included as an alternative for orchiectomy, rather, they are equal options as alternative ways of suppressing or ablating androgen production.
• The proposed LCD states that "Goserelin implant is covered for prostate cancer in combination with flutamide, indicated for treatment of locally confined prostate cancer stage T2b-T4 (Stage B2-C)...". NCCN would like to respectfully note that within the NCCN Guidelines, this is recommended only with radiation in this disease setting. Additionally, within NCCN Guidelines, goserelin may be given with or without first generation antiandrogens nilutamide, flutamide, and bicalutamide, not just with flutamide as outlined in the LCD. NCCN encourages Palmetto to consider adding this specificity within the LCD or alternatively to consider citing to nationally recognized guidelines to accommodate specific clinical scenarios.
• NCCN respectfully notes that histrelin has been removed completely from the NCCN Guidelines for Prostate Cancer as the version that is FDA approved for prostate cancer has been discontinued. Since the LCD notes coverage to the FDA label, NCCN encourages the removal of coverage of histrelin for advanced prostate
• NCCN respectfully notes that the LHRH analogs goserelin, leuprolide, and triptorelin have identical recommendations within the NCCN Guidelines for Prostate Cancer and encourages a similar equivalency within this LCD.

NCCN would like to note that the most recent versions of our Guidelines are always available on our website. As NCCN Guidelines are continuously updated to stay current with the evidence, NCCN encourages Palmetto to consider the NCCN Guidelines as an evidence-based resource for coverage determinations. NCCN appreciates the opportunity to comment on the Proposed Local Coverage Determination Luteinizing Hormone-Releasing Hormone (LHRH) Analogs (DL 39387). NCCN is happy to serve as a resource and looks forward to working together to ensure Medicare beneficiary access to high-quality cancer care.

References were provided for review.

Thank you for your comments. We have reviewed and taken your comments into consideration and will respond to each concern individually.

Under the Covered Indications section of Leuprolide Acetate and Goserelin implant, the NCCN Clinical Practice Guidelines in Oncology have been added as a reference for recommendations for coverage.

Additionally, under the Covered Indications section of Leuprolide Acetate, the NCCN Clinical Practice Guidelines in Oncology for Breast Cancer^®, The NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancers^®, The NCCN Clinical Practice Guidelines in Oncology for Ovarian Cancer^®, and The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer® have been added and are cited to nationally recognized guidelines to accommodate specific clinical scenarios.

We have added the statement “only with radiation in this disease setting” for the Goserelin implant. Under the Covered Indications section of Goserelin implant, the NCCN Clinical Practice Guidelines in Oncology for Breast Cancer^®, has been added and is cited to nationally recognized guidelines to accommodate specific clinical scenarios. The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer^® has been added and is cited to nationally recognized guidelines to accommodate specific clinical scenarios for “advanced prostate cancer”.

Under the Covered Indications section of Triptorelin we removed the sentence, “It offers an alternative treatment for prostate cancer when orchiectomy or estrogen administration are either not indicated or unacceptable to the patient.” The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer^® has been added and is cited to nationally recognized guidelines to accommodate specific clinical scenarios for “advanced prostate cancer”.

The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer^® for specific clinical scenarios for “advanced prostate cancer” has been added under the Covered Indications section.

We have removed coverage of Histrelin acetate implant for palliative treatment of advanced prostate cancer.

We have added “palliative treatment of advanced prostate cancer” to the LHRH analogs goserelin, leuprolide, and triptorelin so the recommendation is identical to the NCCN Guidelines for Prostate Cancer^®. Additionally, the NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer^® is referenced to accommodate specific clinical scenarios.

Under the Bibliography section, the NCCN Clinical Practice Guidelines in Oncology for Breast Cancer^®, The NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancers^®, The NCCN Clinical Practice Guidelines in Oncology for Ovarian Cancer^®, and The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer^® have been added.

Thank you for the opportunity to provide some brief comments regarding this draft LHRH analogs LCD and billing/coding article. This organization appreciates Palmetto GBA’s updates to this LCD and companion article and the inclusion of the most recently approved LHRH analog, leuprolide mesyslate Camcevi^®, approved by the FDA on May 25, 2021.

Recommended edits to draft LHRH analog LCD (DL39387):

1. Page 5 of 7 – “Bibliography” Include the Camcevi^® prescribing information in the bibliography, along with the other LHRH analog’s prescribing information, already listed.

Recommended edits to draft LHRH analog billing/coding article (DA59160):

1. Page 20 of 22 – “Group 7 Paragraph”: This organization agrees with the listing of: C61-Malignant neoplasm of prostate. In order to align the Palmetto GBA LHRH billing/coding article with the LHRH billing/coding article located on the cms.gov website, and to encourage providers to be as specific as possible in their coding, we respectfully recommend the addition of the following ICD-10-CM codes to this section:
   • D07.5 - Carcinoma in situ of prostate
   • Z85.46 – Personal history of malignant neoplasm of prostate
2. Page 20 of 22 – “Group 7 Paragraph”: In order to align the Palmetto GBA LHRH billing/coding article with the LHRH billing/coding article located on the cms.gov website, please include this statement from that article:
   • “Effective for dates of service after 1/1/2022, leuprolide mesyslate, Camcevi^® should be reported with HCPCS code J1952.”
   • “Effective for dates of service 5/26/2021 to 12/31/2021, leuprolide mesyslate, Camcevi^® should be reported with HCPCS code J3590.”

Thanks for your review and consideration of our comments on this draft LHRH analog LCD and companion billing/coding article. Should you have any questions about our comments or Camcevi^®, please feel free to contact us.

Thank you for your comments. We have reviewed and taken your comments into consideration.

Camcevi^® prescribing information has been added to the bibliography.

The ICD-10-CM code Z85.46 Personal history of malignant neoplasm of prostate has been added to the “Group 7 Codes”. We reviewed the FDA prescribing information for Camcevi^®, “CAMCEVI is a gonadotropin-releasing hormone (GnRH) agonist indicated for the treatment of adult patients with advanced prostate cancer.” As such, we were unable to add ICD-10-CM code D07.5 Carcinoma in situ of prostate to the “Group 7 Codes”. The HCPS code J1952 has been added to the LHRH Billing and Coding article under the “Group 7 Codes”.