HHS Public Access
`Author manuscript
`J Natl Compr Canc Netw. Author manuscript; available in PMC 2016 April 11.
`Published in final edited form as:
`J Natl Compr Canc Netw. 2016 January ; 14(1): 57–65.
`
`Prevalence and safety of off-label use of chemotherapeutic
`agents in older breast cancer patients: estimates from SEER-
`Medicare data
`
`Anne A. Eaton, MS1, Camelia S. Sima, MD, MS1, and Katherine S. Panageas, DrPH1
`1Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New
`York, NY
`
`Abstract
`Background—The practice of prescribing oncology drugs outside of the label indication is legal
`and may reflect standard practice. However, some off-label use is against practice guidelines and
`may be inappropriate. We aimed to measure the prevalence and safety of off-label use in
`accordance with NCCN guidelines and off-label use inconsistent with guidelines in older breast
`cancer patients.
`Patients and Methods—The SEER-Medicare dataset was used to identify women diagnosed
`with a first primary breast cancer between 2000-2007. Intravenous chemotherapy agents were
`identified using Medicare claims and classified as on-label, off-label/NCCN supported or off-
`label/unsupported using contemporary FDA approvals and NCCN guidelines. Off-label/
`unsupported regimens were matched to off-label/supported and on-label regimens using 1:1:1
`matching on patient factors, and hospitalization/ER admission rates were compared across
`indication categories using conditional logistic regression.
`Results—13,347 women were treated with 16,127 regimens (12% of women switched to a new
`regimen during followup). Sixty-four percent (10,391) of regimens were off-label/supported, 25%
`(3,987) were on-label and 11% (1,749) were off-label/unsupported. Drugs never supported for
`breast cancer accounted for 19% of off-label/unsupported use and 1% of total use.
`Hospitalization/ER admission occurred in 32% of off-label/unsupported regimens, compared to
`27% of off-label/supported and 25% of on-label regimens (p<.0001).
`Conclusions—Off-label use of chemotherapy without scientific support was not common in this
`cohort. Off-label/supported use accounted for 64% of use, reflecting the fact that widely-accepted
`indications are often not tested in registration trials. Off-label/supported use will likely increase as
`more drugs are expected to have activity across cancer sites, and understanding the safety
`implications of such use is critical.
`
`Corresponding Author: Anne A. Eaton, Memorial Sloan Kettering Dept of Epidemiology and Biostatistics, 485 Lexington Ave., 2nd
`floor, New York, NY 10017, 646-888-8334, 929-321-1516 (f), eatona@mskcc.org.
`This work was previously presented as a poster at the San Antonio Breast Cancer Symposium.
`Disclosures: Anne Eaton has no conflicts of interest to disclose.
`Camelia Sima is employed by Genentech.
`Katherine Panageas has received funding for travel, accommodations and expenses from AstraZeneca.
`
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`Introduction
`When a new drug is developed, the manufacturer must apply for approval from the Food and
`Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) before it can
`enter the market. The FDA grants approval for a specific setting (indication), including
`patient population, dosage, route of administration and other criteria, based on efficacy and
`safety data. Following approval, physicians may prescribe the drug for unapproved
`indications (‘off-label use’), and doing so may in fact be standard medical practice,
`especially in the oncology setting. 1,2
`
`A 2006 report describing prescribing patterns of 160 commonly used drugs found an
`estimated 150 million off-label mentions (21% of overall use) and that 73% of off-label
`prescriptions had little or no scientific support.1 Despite concerns about patient safety and
`costs to the health care system, little is known about the frequency of off-label use in
`oncology. A study conducted in 1991 by the United States General Accounting Office
`(GAO) based on a survey of 681 oncologists revealed that 33% of all anticancer drug
`administrations were off-label and 56% of patients received at least one off-label drug.3
`Twenty-eight percent of patients received a drug that did not have scientific support.
`Estimates from a more recent report on over 2 million administrations of ten intravenous
`chemotherapies were similar; 30% of use was off-label.4
`
`The option to use drugs off-label preserves the oncologists' autonomy to consider their
`patients' individual medical status, allows accumulation of real world efficacy and safety
`data, and makes novel drugs available in a timely manner and for cancer types with limited
`viable treatment options. However, off-label use can have negative consequences if the risk-
`benefit profile of the drug is not well established in the off-label setting, possibly resulting in
`increased toxicities.2 This problem may be exacerbated in older adults given the under-
`representation of this population in cancer registration trials, leading to lack of available data
`to guide treatment decisions.5 Furthermore, financial incentives for doctors to prescribe new
`and costly medications encourage the use of treatments that extrapolate the label
`indication.6,7 In the current economic environment where the need to control healthcare
`costs is universally recognized, utilization of off-label drugs without proven efficacy or
`comprehensive safety evaluation may be a target for cutting costs.
`
`The National Comprehensive Cancer Network (NCCN) is an alliance of twenty-six cancer
`centers in the United States whose mission is “to advance the quality, effectiveness, and
`efficiency of oncology care so that patients can live better lives.”8 The organization
`publishes clinical practice guidelines that serve as established measures for appropriate
`disease management in the oncology community. The guidelines also influence the Centers
`for Medicare and Medicaid Services (CMS) reimbursement of chemotherapy treatments;
`since 1993 Medicare has been required to cover off-label uses mentioned in accepted drug
`compendia (among which NCCN guidelines are central) or with scientific support in certain
`peer-reviewed journals.9 Even in the absence of FDA labeling, treatment in accordance with
`NCCN guidelines is widely regarded as ‘appropriate’, thus it is important to differentiate
`between NCCN supported and unsupported off-label use. In their 2013 report, Conti et al,
`found that about half of the off-label use identified was NCCN-supported.4
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`In this study, we set out to estimate the prevalence of off-label use of chemotherapies and to
`determine whether off-label use is associated with increased rates of hospitalization and
`emergency room (ER) admission, in a cohort of elderly Medicare beneficiaries diagnosed
`with breast cancer. To focus on use that could be considered ‘inappropriate,’ we differentiate
`between off-label utilization in agreement with NCCN guidelines, versus off-label use
`without scientific support.
`
`Methods
`Data Source and Cohort Definition
`The SEER-Medicare linked database (including cancer diagnoses through 2007 and
`Medicare claims through 2008) was utilized.10 Female Medicare beneficiaries 65 and older
`residing in geographic areas contained in the SEER registries and diagnosed with a first
`primary invasive breast cancer between 2000-2007 were identified. Patients were excluded
`for any of the following: diagnosis made at time of death, missing month of diagnosis, prior
`cancer diagnosis, enrollment in an HMO, lack of continuous Part B Medicare enrollment in
`the first 6 months following diagnosis. To restrict our analysis to patients whose treatment
`followed standard guidelines, we excluded patients with stage I-III disease who did not
`undergo surgical resection within 4 months of diagnosis (or within 4 months of completion
`of neoadjuvant therapy), as well as patients diagnosed with stage IV disease who underwent
`surgery.
`
`FDA Approval and NCCN Guideline Recommendation
`Drugs approved for breast cancer were identified and available labels were compiled.11,12
`Approval dates and breast cancer indications (adjuvant and/or metastatic; if metastatic, first
`line and/or after failure of another agent) were recorded for each label version. The same
`information was compiled from all versions of the NCCN Guidelines for Breast Cancer for
`the years 2000-2008.13 Drugs approved and/or NCCN supported in the adjuvant setting were
`also considered to be approved (supported) in the neoadjuvant setting, as separate approvals
`(support) specifically for the neoadjuvant setting were not standard in this era. FDA approval
`and NCCN guideline information is displayed in Figure 1.
`
`Characterization of Chemotherapy Use
`Medicare claims associated with intravenous chemotherapy administration following breast
`cancer diagnosis and prior to diagnosis with a second cancer were identified. The specific
`agent was identified using the HCPCS J-code (Appendix 1). Patients were considered to
`have received chemotherapy if at least one chemotherapy claim was identified within 4
`months of surgery (stage I-III) or diagnosis (stage IV).
`
`The Medicare claims data contains information on each agent administered (including the
`date of administration) but does not indicate whether the agent is part of a combination
`regimen or whether it is being used in the neoadjuvant, adjuvant, first line or later line
`setting, thus we developed an algorithm to separate claims into regimen-lines, which we
`defined as a period of time during which a patient was being treated with a specific single-
`agent or combination regimen. Each patient's first regimen line started on the first day
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`chemotherapy was administered. Any additional agents given in the next 15 days were
`considered to be part of a combination regimen. After 15 days, if a new agent was given, this
`was considered to indicate the start of the subsequent regimen line, except in the case of
`established sequential regimens (Appendix 2); in these cases a new agent was counted as
`part of the same regimen line since the regimen is designed to contain multiple phases.14
`(For example, if a patient received doxorubicin/cyclophosphamide followed by docetaxel,
`this would count as a single regimen line). The same algorithm was used to define each
`subsequent regimen line of intravenous chemotherapy. Examples demonstrating the
`algorithm are shown in Figure 2. In the metastatic setting, each change in regimen represents
`a higher line of treatment; in the adjuvant setting, the first treatment given after surgery is
`referred to as initial adjuvant and treatment following a deviation from initial adjuvant
`regimen is referred to as altered adjuvant. All agents administered preoperatively were
`considered to be part of a single neoadjuvant regimen line. For stages I-III, in order to limit
`our analysis to treatment for the primary tumor and to avoid capturing treatment after
`disease recurrence, the end of adjuvant therapy was identified when Medicare claims did not
`indicate chemotherapy administration for at least 120 days. We assumed that treatment
`breaks of up to 120 days could be due to toxicity or other delays, but that a longer break
`would indicate the completion of initial chemotherapy, and that additional treatment after
`such a break may be for metastatic or recurrent disease.
`
`Each regimen line was classified into one of the following indication categories based on the
`stage and line of chemotherapy:
`
`• On-label: All chemotherapies included in the regimen line were consistent with the
`FDA label indication.
`
`• Off-label/NCCN supported: All chemotherapies included in the regimen line
`were supported by NCCN guidelines, and at least one chemotherapy included in the
`regimen line was not consistent with the FDA label indication.
`
`• Off-label/Unsupported: At least one chemotherapy included in the regimen line
`was not consistent with the FDA label indication and was not supported by NCCN
`guidelines
`
`Indication category determinations were made based on the versions of FDA labels and
`NCCN guidelines in use 90 days following the date of administration, allowing for uses of a
`drug shortly prior to approval/support to be counted as approved/supported. For off-label/
`unsupported drug administrations, the reason the drug was not supported was classified as
`either: 1) drug was never NCCN-supported for breast cancer, 2) use was more than 90 days
`prior to NCCN support, or 3) drug was used in a stage or line outside of NCCN
`recommendations. To be conservative, J-Code J9999 (“Not otherwise classified
`antineoplastic drugs”) was considered on-label.
`
`Comparison of hospitalization and ER admission rates
`Each off-label/unsupported regimen line was matched with one off-label/supported regimen
`line and one on-label regimen line. Matching factors were age, line of chemotherapy,
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`number of prior comorbidities, stage at diagnosis, and history of prior hospitalizations/ER
`admissions, categorized as in Supplemental Table 1.15
`
`A hospitalization or ER admission was assigned to a regimen line if it occurred on or after
`day 16 of a regimen line (when all agents comprising a combination regimen would have
`been started) and before the start of a new regimen line (before date of surgery for
`neoadjuvant lines), or within 30 days of the last chemotherapy administration if no
`subsequent lines were initiated. Using the matched regimen lines, rates of hospitalization
`and/or ER admission and corresponding Wald 95% confidence intervals (CI) were compared
`between indication categories, overall and by stage. Wald type III p-values were obtained
`using conditional logistic regression. Analyses investigating the distribution of indication
`category by stage and line of chemotherapy were descriptive and tests were not conducted.
`All statistical analysis was performed in SAS 9.4 (SAS Institute, Cary, NC).
`
`Results
`
`Figures 1A and 1B list drugs FDA approved and/or NCCN supported for the treatment of
`breast cancer between 2000-2008, and their stage-specific and line-specific indications. It
`can be noted that more drugs are approved for advanced stage than early stage, and in the
`advanced stage setting, some drugs are only approved in line 2 or later.
`
`Study Cohort
`The initial cohort consisted of 78,824 women. Seventeen percent (n=13,347) received
`chemotherapy (5%, 33%, 50% and 21% for stages I-IV, respectively) and are included in the
`analyses. The breakdown by demographic and clinical factors is presented in Supplemental
`Table 1.
`
`Prevalence of off-label use
`Use by indication category is presented in Table 1. Overall, only 25% of all regimen lines
`consisted exclusively of on-label drugs. Most regimen lines (64%) were off-label/NCCN
`supported. Eleven percent of all regimens were off-label/unsupported, with higher rates of
`such use in patients with stage III (16%) or IV (12%) disease.
`
`Initial adjuvant regimens were rarely off-label/unsupported (7%). However, following a
`change in adjuvant regimen, prevalence of inappropriate use increases dramatically to 34%.
`The use of off-label/unsupported regimens in the neoadjuvant setting was 15%. Regimens
`used in advanced disease were more likely to be off-label/unsupported if used in the first line
`of chemotherapy (rate of off-label/unsupported use: 17% vs 6% in second line or higher),
`likely the reflection of the fact that a large number of agents are approved and/or NCCN
`supported for use as second line therapy, but not as first line (Figure 1B). Rates of off-label/
`unsupported and off-label/supported use by age and comorbidity index are shown in Table 1.
`
`For those chemotherapy drugs that were part of at least 24 regimen lines, Figure 3 presents
`the proportion of off-label/unsupported use, as a function of the total use. Six of the most
`commonly used agents (cyclophosphamide, doxorubicin, 5-FU, methotrexate, paclitaxel,
`epirubicin), accounting for 81% of the total drug use, were FDA approved and/or NCCN
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`supported for all stages and lines of chemotherapy. For docetaxel and trastuzumab (13% of
`total use), 14% and 16% of use respectively was off-label/unsupported. (Although both
`drugs were NCCN supported for all stages and lines by 2005, they were not supported for
`early stage breast cancer in the early part of the study period.) These two drugs alone
`accounted for 38% of the off-label/unsupported use. The remaining 60% of off-label/
`unsupported drug use was due to drugs that were rarely prescribed in this cohort, some of
`which have never been supported for breast cancer (e.g. vincristine, mitomycin, cytarabine,
`rituximab, fludarabine and irinotecan). The great majority of off-label/unsupported use
`(76%) was due to drug use outside of the recommended stage and/or line (including
`docetaxel and trastuzumab), while drugs never supported for breast cancer accounted for
`19% of the off-label/unsupported use and 1% of the total use. Use of drugs more than 90
`days prior to NCCN support was not common and accounted for only 5% of off-label/
`unsupported use.
`
`Hospitalization and ER admission
`In the matched analysis, a hospitalization or ER admission occurred in 32% (95% CI: 29-34)
`of off-label/unsupported regimen lines compared to 27% (95% CI: 25-29) of off-label/
`supported regimen lines and 25% (95% CI: 22-27) of on-label regimen lines (p<.0001).
`Figure 4 presents the event rates by indication category for each disease stage. On-label lines
`generally had the lowest event rate, with the exception of stage IV, where on-label lines had
`the highest rate (53%), although rates of hospitalization/ER admission were not significantly
`different (p=0.241). Of 138 on-label regimen lines used in the stage IV setting, 54 (39%,
`compared to 9% of all use) consisted of single-agent trastuzumab and 33 (24%, compared to
`3% of all use) consisted of the combination regimen cyclophosphamide, fluorouracil and
`methotrexate (CMF). Both of these regimens were observed to have high rates of
`hospitalization and ER admission (trastuzumab=61%; CMF=55%), which drove up the event
`rate for on-label lines in the stage IV setting.
`
`Discussion
`We evaluated the prevalence of off-label chemotherapy use among Medicare beneficiaries
`diagnosed with breast cancer and the rate of ER visits/hospitalizations among patients
`receiving this type of treatment. Overall 11% of the lines of therapy included one or more
`drugs whose use was not in agreement with their FDA label indication and not NCCN
`supported. The low prevalence of off-label/unsupported use confirms prior reports and
`provides reassurance regarding the appropriateness of the therapeutic decisions made in the
`medical community.4
`
`We found that the majority of therapy regimens (64%) were prescribed in a setting outside
`the FDA label indication, but supported by NCCN. This reflects the fact that registration
`trials tend to be undertaken in well-defined, specific populations that maximize the chance
`of therapeutic success, leading to narrow label indications. In contrast, once the drug enters
`the market, the opinion of leaders in the medical community, reflected in professional
`guidelines and the scientific literature, is more influential on drug utilization than the label.
`Since off-label use in accordance with professional guidelines is generally covered by
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`insurance, there is little incentive for drug manufacturers to go through a cumbersome FDA
`approval process to update the label indications. Furthermore, performing well-controlled
`trials for the all the settings in which a drug may be active (i.e. site, stage, and disease
`combinations), is not feasible, and with good-quality retrospective data, not necessary.
`Interestingly, the rate of off-label/supported use was much lower in the Conti report (14% of
`administrations), possibly reflecting the fact that that analysis excluded agents whose patent
`had expired.4
`
`In the adjuvant setting, we found small but non-negligible increases in the risk of
`hospitalization and ER admission as we moved from on-label to off-label/supported to off-
`label/unsupported regimen lines. To our knowledge, this is the first comparative evaluation
`of outcomes following treatment with off-label chemotherapy. We hypothesize that the lack
`of rigorous scientific scrutiny that accompanies off-label/unsupported use translates into
`limited, but real added toxicity burden. An alternative explanation is that use of off label/
`unsupported drugs could be a marker for suboptimal care.
`
`In contrast, among stage IV patients, we observed the highest hospitalization and ER
`admission rates for on-label regimens, more than half of which consisted of trastuzumab
`monotherapy or CMF, regimens usually associated with milder toxicity profiles. This could
`be due to doctors selecting safer regimens for patients more prone to adverse events. Stage I-
`III patients at an increased risk of adverse events may also tend to be treated with less toxic
`regimens; this would lead to conservative estimates of the excess toxicity associated with
`off-label/unsupported regimens since safer regimens with better-understood toxicity profiles
`would tend to be on-label.
`
`Our analysis has several limitations. The generalizability of results is limited to older
`Medicare beneficiaries with breast cancer. The rates of off-label use might be higher in
`younger, commercially insured patients or in other cancers, where a more limited number of
`FDA approved and NCCN supported drugs may lead to more therapeutic experimenting.
`Furthermore, while SEER-Medicare files allow identification of chemotherapy use with high
`accuracy, identification of specific agents has been shown to have sensitivity in the range of
`70%-80%; drugs used off-label and outside of professional guidelines might be especially
`underreported.15 Together, these suggest that the rates observed are conservative estimates of
`off-label/unsupported use. The results are also not generalizable to endocrine and oral
`therapies as these were not covered prior to the passage of Medicare Part D and thus
`reimbursement data was not available. Relatedly, such therapies were not accounted for
`when determining line of therapy; however, we believe that the amount of previous
`intravenous chemotherapy still captures an important patient characteristic that may affect
`our outcomes. Furthermore, SEER does not collect information on cancer recurrence, so it is
`possible that some non-metastatic patients progressed to metastatic disease and were treated
`with a drug that was off-label (not recommended) for their initial disease but on-label
`(recommended) for their current disease at the time of treatment. In order to capture only
`initial treatment and exclude treatment after recurrence, we stopped following stage I-III
`patients when they had a period of 120 days without chemotherapy administration. The
`detection of adverse events using claims data is difficult and it is impossible to definitively
`attribute toxicities to chemotherapy, especially in advanced stage disease. Hence we focused
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`on events (hospitalizations and ER admissions) that are serious and can be reliably identified
`and we carefully matched off-label and on-label regimens by factors that may influence the
`risk of toxicity. Finally, we were not able to account for different toxicity profiles inherent to
`different agents as the sample size prevented matching on specific agent administered or for
`varying propensity to receive off-label treatment.
`
`Overall, we found that off-label/unsupported use was uncommon and that use of
`chemotherapy regimens that are off-label but have scientific support was surprisingly
`common, representing 64% of all use. We found slightly increased rates of hospitalization
`and ER admission in off-label/supported regimens. While off-label/unsupported use has
`traditionally been an obvious target for cost-containment and quality of care improvement,
`the high prevalence of off-label/supported use should not be ignored.17 This large segment
`of use likely consists of therapies that fall across a spectrum in terms of safety. With the
`recent paradigm shift towards treatments directed at molecular targets and immunotherapies,
`which are expected to have activity across different cancer sites (and are extremely
`expensive), the off-label/supported share of use will likely increase. Given that the NCCN
`guidelines appear to be central in chemotherapy utilization, safety evaluation of the off-label,
`guideline recommended indications is critical. 17 In fact, although the NCCN has
`traditionally based its guidelines on efficacy without explicitly addressing toxicity or cost,
`plans were recently announced to incorporate both of these into future guidelines.18 The
`integration of this additional important information will help doctors and patients navigate
`the heterogenous space of off-label/supported therapy and make optimal treatment decisions.
`
`Supplementary Material
`Refer to Web version on PubMed Central for supplementary material.
`
`Acknowledgments
`This work was partially supported by the Goldstein Fund and Core Grant (P30CA008748) awards.
`
`Appendix 1
`
`J-codes representing IV chemotherapy
`
`J-code
`
`Agent
`
`J9000
`
`J9001
`
`J9010
`
`J9015
`
`J9017
`
`J9020
`
`J9025
`
`J9027
`
`J9031
`
`Injection, doxorubicin HCl, 10 mg
`
`Injection, doxorubicin HCl, all lipid formulations, 10 mg
`
`Injection, alemtuzumab, 10 mg
`
`Injection, aldesleukin, per single use vial
`
`Injection, arsenic trioxide, 1 mg
`
`Injection, asparaginase, 10,000 units
`
`Injection, azacitidine, 1 mg
`
`Injection, clofarabine, 1 mg
`
`BCG (intravesical) per instillation
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`J-code
`
`Agent
`
`J9033
`
`J9035
`
`J9040
`
`J9041
`
`J9043
`
`J9045
`
`J9050
`
`J9055
`
`J9060
`
`J9062
`
`J9065
`
`J9070
`
`J9080
`
`J9090
`
`J9091
`
`J9092
`
`J9093
`
`J9094
`
`J9095
`
`J9096
`
`J9097
`
`J9098
`
`J9100
`
`J9110
`
`J9120
`
`J9130
`
`J9140
`
`J9150
`
`J9151
`
`J9155
`
`J9160
`
`J9165
`
`J9170
`
`J9171
`
`J9175
`
`J9178
`
`J9179
`
`J9180
`
`J9181
`
`Injection, bendamustine HCl, 1 mg
`
`Injection, bevacizumab, 10 mg
`
`Injection, bleomycin sulfate, 15 units
`
`Injection, bortezomib, 0.1 mg
`
`Injection, cabazitaxel, 1 mg
`
`Injection, carboplatin, 50 mg
`
`Injection, carmustine, 100 mg
`
`Injection, cetuximab, 10 mg
`
`Injection, cisplatin, powder or solution, 10 mg
`
`Cisplatin, 50 mg
`
`Injection, cladribine, per 1 mg
`
`Cyclophosphamide, 100 mg
`
`Cyclophosphamide, 200 mg
`
`Cyclophosphamide, 500 mg
`
`Cyclophosphamide, 1 g
`
`Cyclophosphamide, 2 g
`
`Cyclophosphamide, lyophilized, 100 mg
`
`Cyclophosphamide, lyophilized, 200 mg
`
`Cyclophosphamide, lyophilized, 500 mg
`
`Cyclophosphamide, lyophilized, 1 g
`
`Cyclophosphamide, lyophilized, 2 g
`
`Injection, cytarabine liposome, 10 mg
`
`Injection, cytarabine, 100 mg
`
`Injection, cytarabine, 500 mg
`
`Injection, dactinomycin, 0.5 mg
`
`Dacarbazine, 100 mg
`
`Dacarbazine, 200 mg
`
`Injection, daunorubicin, 10 mg
`
`Injection, daunorubicin citrate, liposomal formulation, 10 mg
`
`Injection, degarelix, 1 mg
`
`Injection, denileukin diftitox, 300 mcg
`
`Injection, diethylstilbestrol diphosphate, 250 mg
`
`Injection, docetaxel, 20 mg
`
`Injection, docetaxel, 1 mg
`
`Injection, Elliotts' B solution, 1 ml
`
`Injection, epirubicin HCl, 2 mg
`
`Injection, eribulin mesylate, 0.1 mg
`
`Epirubicin HCl, 50 mg
`
`Injection, etoposide, 10 mg
`
`J Natl Compr Canc Netw. Author manuscript; available in PMC 2016 April 11.
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`Eaton et al.
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`J-code
`
`Agent
`
`J9182
`
`J9185
`
`J9190
`
`J9200
`
`J9201
`
`J9202
`
`J9206
`
`J9207
`
`J9208
`
`J9209
`
`J9211
`
`J9212
`
`J9213
`
`J9214
`
`J9215
`
`J9216
`
`J9217
`
`J9218
`
`J9219
`
`J9225
`
`J9226
`
`J9228
`
`J9230
`
`J9240
`
`J9245
`
`J9250
`
`J9260
`
`J9261
`
`J9263
`
`J9264
`
`J9265
`
`J9266
`
`J9268
`
`J9270
`
`J9280
`
`J9290
`
`J9291
`
`J9293
`
`J9295
`
`Etoposide, 100 mg
`
`Injection, fludarabine phosphate, 50 mg
`
`Injection, fluorouracil, 500 mg
`
`Injection, floxuridine, 500 mg
`
`Injection, gemcitabine HCl, 200 mg
`
`Goserelin acetate implant, per 3.6 mg
`
`Injection, irinotecan, 20 mg
`
`Injection, ixabepilone, 1 mg
`
`Injection, ifosfamide, 1 g
`
`Injection, mesna, 200 mg
`
`Injection, idarubicin HCl, 5 mg
`
`Injection, interferon alfacon-1, recombinant, 1 mcg
`
`Injection, interferon, alfa-2a, recombinant, 3 million units
`
`Injection, interferon, alfa-2b, recombinant, 1 million units
`
`Injection, interferon, alfa-N3, (human leukocyte derived), 250,000 IU
`
`Injection, interferon, gamma 1-b, 3 million units
`
`Leuprolide acetate (for depot suspension), 7.5 mg
`
`Leuprolide acetate, per 1 mg
`
`Leuprolide acetate implant, 65 mg
`
`Histrelin implant (Vantas), 50 mg
`
`Histrelin implant (Supprelin LA), 50 mg
`
`Injection, ipilimumab, 1 mg
`
`Injection, mechlorethamine HCl, (nitrogen mustard), 10 mg
`
`MEDROYPROGESTERONE ACETATE, 100 MG
`
`Injection, melphalan HCl, 50 mg
`
`Methotrexate sodium, 5 mg
`
`Methotrexate sodium, 50 mg
`
`Injection, nelarabine, 50 mg
`
`Injection, oxaliplatin, 0.5 mg
`
`Injection, paclitaxel protein-bound particles, 1 mg
`
`Injection, paclitaxel, 30 mg
`
`Injection, pegaspargase, per single dose vial
`
`Injection, pentostatin, 10 mg
`
`Injection, plicamycin, 2.5 mg
`
`Mitomycin, 5 mg
`
`Mitomycin, 20 mg
`
`Mitomycin, 40 mg
`
`Injection, mitoxantrone HCl, per 5 mg
`
`POLYESTRADIOL PHOSPHATE 40 MG
`
`J Natl Compr Canc Netw. Author manuscript; available in PMC 2016 April 11.
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`IPR2017-01122
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`Eaton et al.
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`Page 11
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`J-code
`
`Agent
`
`J9300
`
`J9302
`
`J9303
`
`J9305
`
`J9307
`
`J9310
`
`J9315
`
`J9320
`
`J9328
`
`J9330
`
`J9340
`
`J9350
`
`J9351
`
`J9355
`
`J9357
`
`J9360
`
`J9370
`
`J9375
`
`J9380
`
`J9390
`
`J9600
`
`J9999
`
`Injection, gemtuzumab ozogamicin, 5 mg
`
`Injection, ofatumumab, 10 mg
`
`Injection, panitumumab, 10 mg
`
`Injection, pemetrexed, 10 mg
`
`Injection, pralatrexate, 1 mg
`
`Injection, rituximab, 100 mg
`
`Injection, romidepsin, 1 mg
`
`Injection, streptozocin, 1 g
`
`Injection, temozolomide, 1 mg
`
`Injection, temsirolimus, 1 mg
`
`Injection, thiotepa, 15 mg
`
`Injection, topotecan, 4 mg
`
`Injection, topotecan, 0.1 mg
`
`Injection, trastuzumab, 10 mg
`
`Injection, valrubicin, intravesical, 200 mg
`
`Injection, vinblastine sulfate, 1 mg
`
`Vincristine sulfate, 1 mg
`
`Vincristine sulfate, 2 mg
`
`Vincristine sulfate, 5 mg
`
`Injection, vinorelbine tartrate, 10 mg
`
`Injection, porfimer sodium, 75 mg
`
`Not otherwise classified, antineoplastic drugs
`
`Appendix 2
`
`Established sequential adjuvant chemotherapy
`regimens for breast cancer
`
`Phase 1
`
`Doxorubicin/Cyclophosphamide
`
`Doxorubicin/Cyclophosphamide
`
`Phase 2
`
`Docetaxel
`
`Docetaxel + Trastuzumab followed by
`Trastuzumab
`
`Phase 3
`
`Doxorubicin/Cyclophosphamide
`
`Paclitaxel followed by Trastuzumab
`
`Doxorubicin/Cyclophosphamide
`
`Paclitaxel
`
`Docetaxel + Trastuzumab
`
`Fluorouracil/Epirubicin/Cyclophosphamide
`
`Doxorubi