Re: off-label drug 항암치료제로 사용될 수 있는 기존 약물들 review

[문형철]

beyond reason

미량원소 치유의학의 세계

클릭클릭

What is known and objective

The off‐label use of medicines is widespread in several diseases. This type of prescribing practice is particularly more acute in oncology. However, the suitability of anticancer medications for off‐label use remains an issue of controversy, due to uncertainty around the clinical benefits and potential toxicities, limited evidence to support clinical decision‐making, increased out‐of‐pocket costs for patients and ethical concerns around the lack of informed consent. Currently, data pertaining to the global preval‎ence of off‐label use in cancer therapy are lacking. The aim of this review was to provide an overview of off‐label drug use preval‎ence in oncology.

Methods

A systematic literature search was performed in PubMed as per the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines from 1975 to 2016. Studies assessing the preval‎ence of off‐label use of anticancer drugs were included.

Data synthesis

Of the 199 eligible papers retrieved, 23 studies were included in this systematic literature review. Off‐label drug use in inpatients ranged from 18% to 41%. Among adult patients with cancer, 13%–71% received a minimum of one off‐label chemotherapy. The main reasons for off‐label drug use were ‘drug unapproved for specific tumour’ and ‘modified drug applications’. Among adults, metastatic cancers and palliative care patients received the most off‐label drugs. The off‐label drug use unsupported by standard treatment guidelines or drug compendia was in the range of 7%–31%.

Conclusion

Off‐label drug use in cancer therapy is commonly practised but outcomes could vary significantly. Hence, greater scrutiny and robust clinical guidance is needed to establish the favourable benefit–risk ratio for patients at the time of prescribing at each level of oncology care to facilitate rational off‐label prescribing.

논문영향력지수 4점 논문

J Natl Compr Canc Netw. Author manuscript; available in PMC 2016 Apr 11.

Published in final edited form as:

J Natl Compr Canc Netw. 2016 Jan; 14(1): 57–65. 

Published online 2016 Jan 5. 

PMCID: PMC4827612

NIHMSID: NIHMS771443

PMID: 26733555

Preval‎ence and safety of off-label use of chemotherapeutic agents in older breast cancer patients: estimates from SEER-Medicare data

Anne A. Eaton, MS,1 Camelia S. Sima, MD, MS,1 and  Katherine S. Panageas, DrPH1

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The publisher's final edited version of this article is available at J Natl Compr Canc Netw

See other articles in PMC that cite the published article.

Associated Data

Supplementary Materials

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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.

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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

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.

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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.

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Figure 1

FDA Approval and NCCN Guideline Information by year for intravenous chemotherapies. Figure 1A shows approval timelines for the adjuvant treatment of early stage breast cancer (Stage I-III) and Figure 1B shows approval timelines for advanced stage breast cancer (stage IV metastatic). Dark blue indicates years during which the agent was FDA approved and NCCN supported, light blue indicates years during which the agent was FDA approved but not NCCN supported, and white indicates years during which the agent was NCCN supported but not FDA approved. Blank spaces indicate years during which the agent was neither approved nor supported. An asterisk next to an agent name indicates that the agent was never FDA approved for that stage of disease at any time during the study period.

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 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.

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Figure 2

The two sample scenarios below demonstrate the algorithm used to separate dated chemotherapy claims into regimen lines. A, B, and C represent different agents.

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, 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).

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Results

Figures 1A and ​and1B1B 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.

Table 1

Rates of off-label/unsupported, off-label/supported and on-label use, by stage and line of chemotherapy

	Off-label/unsupported	Off-label/supported	On-label	Total
All regimen-lines	1,749 (11%)	10,391 (64%)	3,987 (25%)	16,127
Stage 1	239 (9%)	1,661 (61%)	803 (30%)	2,732
Stage 2	775 (9%)	5,754 (67%)	2,014 (24%)	8,543
Stage 3	567 (16%)	2,000 (57%)	920 (26%)	3,487
Stage 4	168 (12%)	976 (70%)	250 (18%)	1,394
Stage I-III
Neoadjuvant	171 (15%)	577 (50%)	412 (36%)	1,160
Initial adjuvant	861 (7%)	7,985 (67%)	3,113 (26%)	11,959
Altered adjuvant*	549 (34%)	853 (53%)	212 (13%)	1,614
Stage IV
Line 1	133 (17%)	534 (70%)	96 (13%)	763
Line 2	19 (6%)	230 (70%)	78 (24%)	327
Line 3+	16 (5%)	212 (70%)	76 (25%)	304
Age
65-70	525 (10%)	3,534 (64%)	1,469 (27%)	5,528
70-75	546 (11%)	3,166 (65%)	1,165 (24%)	4,877
75-80	297 (10%)	1,940 (67%)	674 (23%)	2,911
80-85	162 (16%)	633 (62%)	231 (23%)	1,026
>85	47 (22%)	115 (53%)	53 (25%)	215
Charlson comorbidity index**
0	1,184 (11%)	7,194 (66%)	2,592 (24%)	10,970
1	246 (10%)	1,538 (62%)	704 (28%)	2,488
>1	133 (13%)	588 (60%)	266 (27%)	987

*Initial adjuvant was the first treatment given after surgery; altered adjuvant refers to treatment following a deviation from initial adjuvant regimen

**Only patients diagnosis at age 66+ are included as 1 year of pre-diagnosis claims were required to ascertain comorbidity score.

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 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.

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Figure 3

Percent of regimen lines off-label/unsupported versus total number of regimen lines, by agent. Only agents that were used in at least 24 regimen lines are included. Most agents were either used in very few regimen lines but with almost 100% of uses being off-label or used in many regimen lines with almost 100% of uses being on-label. For agents with 40-60% of uses off-label, the total number of regimen lines in which they were used is shown next to the agent name.

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.

Figure 4

Hospitalization and ER admission rates by indication category and stage, matched analysis

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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 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 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.

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Supplementary Material

Supplemental Table 1: Patient characteristics

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Acknowledgments

This work was partially supported by the Goldstein Fund and Core Grant (P30CA008748) awards.

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Appendix 1

J-codes representing IV chemotherapy

J-code	Agent
J9000	Injection, doxorubicin HCl, 10 mg
J9001	Injection, doxorubicin HCl, all lipid formulations, 10 mg
J9010	Injection, alemtuzumab, 10 mg
J9015	Injection, aldesleukin, per single use vial
J9017	Injection, arsenic trioxide, 1 mg
J9020	Injection, asparaginase, 10,000 units
J9025	Injection, azacitidine, 1 mg
J9027	Injection, clofarabine, 1 mg
J9031	BCG (intravesical) per instillation
J9033	Injection, bendamustine HCl, 1 mg
J9035	Injection, bevacizumab, 10 mg
J9040	Injection, bleomycin sulfate, 15 units
J9041	Injection, bortezomib, 0.1 mg
J9043	Injection, cabazitaxel, 1 mg
J9045	Injection, carboplatin, 50 mg
J9050	Injection, carmustine, 100 mg
J9055	Injection, cetuximab, 10 mg
J9060	Injection, cisplatin, powder or solution, 10 mg
J9062	Cisplatin, 50 mg
J9065	Injection, cladribine, per 1 mg
J9070	Cyclophosphamide, 100 mg
J9080	Cyclophosphamide, 200 mg
J9090	Cyclophosphamide, 500 mg
J9091	Cyclophosphamide, 1 g
J9092	Cyclophosphamide, 2 g
J9093	Cyclophosphamide, lyophilized, 100 mg
J9094	Cyclophosphamide, lyophilized, 200 mg
J9095	Cyclophosphamide, lyophilized, 500 mg
J9096	Cyclophosphamide, lyophilized, 1 g
J9097	Cyclophosphamide, lyophilized, 2 g
J9098	Injection, cytarabine liposome, 10 mg
J9100	Injection, cytarabine, 100 mg
J9110	Injection, cytarabine, 500 mg
J9120	Injection, dactinomycin, 0.5 mg
J9130	Dacarbazine, 100 mg
J9140	Dacarbazine, 200 mg
J9150	Injection, daunorubicin, 10 mg
J9151	Injection, daunorubicin citrate, liposomal formulation, 10 mg
J9155	Injection, degarelix, 1 mg
J9160	Injection, denileukin diftitox, 300 mcg
J9165	Injection, diethylstilbestrol diphosphate, 250 mg
J9170	Injection, docetaxel, 20 mg
J9171	Injection, docetaxel, 1 mg
J9175	Injection, Elliotts' B solution, 1 ml
J9178	Injection, epirubicin HCl, 2 mg
J9179	Injection, eribulin mesylate, 0.1 mg
J9180	Epirubicin HCl, 50 mg
J9181	Injection, etoposide, 10 mg
J9182	Etoposide, 100 mg
J9185	Injection, fludarabine phosphate, 50 mg
J9190	Injection, fluorouracil, 500 mg
J9200	Injection, floxuridine, 500 mg
J9201	Injection, gemcitabine HCl, 200 mg
J9202	Goserelin acetate implant, per 3.6 mg
J9206	Injection, irinotecan, 20 mg
J9207	Injection, ixabepilone, 1 mg
J9208	Injection, ifosfamide, 1 g
J9209	Injection, mesna, 200 mg
J9211	Injection, idarubicin HCl, 5 mg
J9212	Injection, interferon alfacon-1, recombinant, 1 mcg
J9213	Injection, interferon, alfa-2a, recombinant, 3 million units
J9214	Injection, interferon, alfa-2b, recombinant, 1 million units
J9215	Injection, interferon, alfa-N3, (human leukocyte derived), 250,000 IU
J9216	Injection, interferon, gamma 1-b, 3 million units
J9217	Leuprolide acetate (for depot suspension), 7.5 mg
J9218	Leuprolide acetate, per 1 mg
J9219	Leuprolide acetate implant, 65 mg
J9225	Histrelin implant (Vantas), 50 mg
J9226	Histrelin implant (Supprelin LA), 50 mg
J9228	Injection, ipilimumab, 1 mg
J9230	Injection, mechlorethamine HCl, (nitrogen mustard), 10 mg
J9240	MEDROYPROGESTERONE ACETATE, 100 MG
J9245	Injection, melphalan HCl, 50 mg
J9250	Methotrexate sodium, 5 mg
J9260	Methotrexate sodium, 50 mg
J9261	Injection, nelarabine, 50 mg
J9263	Injection, oxaliplatin, 0.5 mg
J9264	Injection, paclitaxel protein-bound particles, 1 mg
J9265	Injection, paclitaxel, 30 mg
J9266	Injection, pegaspargase, per single dose vial
J9268	Injection, pentostatin, 10 mg
J9270	Injection, plicamycin, 2.5 mg
J9280	Mitomycin, 5 mg
J9290	Mitomycin, 20 mg
J9291	Mitomycin, 40 mg
J9293	Injection, mitoxantrone HCl, per 5 mg
J9295	POLYESTRADIOL PHOSPHATE 40 MG
J9300	Injection, gemtuzumab ozogamicin, 5 mg
J9302	Injection, ofatumumab, 10 mg
J9303	Injection, panitumumab, 10 mg
J9305	Injection, pemetrexed, 10 mg
J9307	Injection, pralatrexate, 1 mg
J9310	Injection, rituximab, 100 mg
J9315	Injection, romidepsin, 1 mg
J9320	Injection, streptozocin, 1 g
J9328	Injection, temozolomide, 1 mg
J9330	Injection, temsirolimus, 1 mg
J9340	Injection, thiotepa, 15 mg
J9350	Injection, topotecan, 4 mg
J9351	Injection, topotecan, 0.1 mg
J9355	Injection, trastuzumab, 10 mg
J9357	Injection, valrubicin, intravesical, 200 mg
J9360	Injection, vinblastine sulfate, 1 mg
J9370	Vincristine sulfate, 1 mg
J9375	Vincristine sulfate, 2 mg
J9380	Vincristine sulfate, 5 mg
J9390	Injection, vinorelbine tartrate, 10 mg
J9600	Injection, porfimer sodium, 75 mg
J9999	Not otherwise classified, antineoplastic drugs

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Appendix 2

Established sequential adjuvant chemotherapy regimens for breast cancer

Phase 1	Phase 2	Phase 3
Doxorubicin/Cyclophosphamide	Docetaxel
Doxorubicin/Cyclophosphamide	Docetaxel + Trastuzumab followed by Trastuzumab
Doxorubicin/Cyclophosphamide	Paclitaxel followed by Trastuzumab
Doxorubicin/Cyclophosphamide	Paclitaxel
Docetaxel + Trastuzumab	Fluorouracil/Epirubicin/Cyclophosphamide
Doxorubicin /Cyclophosphamide	Paclitaxel
Doxorubicin	Paclitaxel	Cyclophosphamide
Fluorouracil/Epirubicin/ Cyclophosphamide	Docetaxel
21 day cycle of Trastuzumab for 1 year following at least four courses of approved adjuvant chemotherapy

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Footnotes

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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