NINTH EDITION, 2005 -2006
`
`Cancer
`Management:
`A Multidisciplinary
`Approach
`Medical, Surgical, & Radiation Oncology
`
`Edited by
`
`Richard Pazdur, MD
`US Food and Drug Administration
`
`Lawrence R. Coia, MD
`Saint Barnabas Health Care System
`
`William J. Hoskins, MD
`Curtis and Elizabeth Anderson Cancer Institute
`
`Lawrence D. Wagman, MD
`City of Hope National Medical Center
`
`And the publishers of the journal ONCOLOGY
`
`NOVARTIS EXHIBIT 2010
`Roxane v. Novartis, IPR 2016-01461
`Page 1 of 103
`
`

`
`NINTH EDITION, 2005-2006
`
`Cancer
`Management:
`A Multidisciplinary
`Approach
`
`Medical, Surgical, & Radiation Oncology
`
`Edited by
`
`Richard Pazdur, MD
`Director, Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`US Food and Drug Administration
`
`Lawrence R. Coia, MD
`Chairman, Department of Radiation Oncology
`Community Medical Center, Toms River, New Jersey
`An affiliate of Saint Barnabas Health Care System
`
`William J. Hoskins, MD
`Director, Curtis and Elizabeth Anderson Cancer Institute
`at Memorial Health University Medical Center
`Savannah, Georgia
`
`Lawrence D. Wagman, MD
`Chairman, Division of Surgery
`City of Hope National Medical Center
`
`And the publishers of the journal ONCOLOGY
`
`itii
`CMP
`
`united Business Media
`
`NOVARTIS EXHIBIT 2010
`Roxane v. Novartis, IPR 2016-01461
`Page 2 of 103
`
`

`
`Note to the reader
`The information in this volume has been carefully reviewed for accuracy of
`dosage and indications. Before prescribing any drug, however, the clinician
`should consult the manufacturer's current package labeling for accepted indica-
`tions, absolute dosage recommendations, and other information pertinent to the
`safe and effective use of the product described. This is especially important when
`drugs are given in combination or as an adjunct to other forms of therapy.
`Furthermore, some of the medications described herein, as well as some of the
`indications mentioned, had not been approved by the US Food and Drug
`Administration at the time of publication. This possibility should be borne in
`mind before prescribing or recommending any drug or regimen.
`
`The views expressed are the result of independent work and do not
`necessarily represent the views or findings of the US Food and Drug
`Administration or the United States.
`
`2005 by CMP Healthcare Media. All rights reserved. This book is
`Copyright (cid:9)
`protected by copyright. No part of it may be reproduced in any manner or by any
`means, electronic or mechanical, without the written permission of the publisher.
`
`Library of Congress Catalog Card Number 2005921293
`ISBN Number 1-891483-35-8
`
`For information on purchasing additional copies of this publication, contact us at this
`address, Cancer Management Handbook, CMP Media LLC, 4601 W. 6th St., Ste. B,
`Lawrence, KS 66049. Phone: 1-800-444-4881 or 1-785-838-7576; fax: 1-785-838-7566,
`or e-mail: orders@cmp.com. Single-copy price, $59.95.
`
`A 1.
`•• ••
`•• ••
`•
`CMP
`
`United Business Media
`
`Publishers of
`ONCOLOGY
`Oncology News International
`cancernetwork.com
`
`NOVARTIS EXHIBIT 2010
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`Page 3 of 103
`
`

`
`CHAPTER I I
`
`Stages III and IV
`breast cancer
`
`Lori Jardines, MD, Bruce G. Haffty, MD, Melanie Royce, MD, PhD,
`and Ishmael Jaiyesimi, MD
`
`This chapter addresses the diagnosis and management of locally advanced,
`locally recurrent, and metastatic breast cancer, ie, stages III and IV disease.
`
`Approximately 20%-25% of patients present with locally,advanced breast cancer.
`Inflammatory breast cancer is a particularly aggressive form of breast can-
`cer that falls under the heading of locally advanced disease and accounts for
`10/o-3% of all breast cancers.
`
`Locoregional recurrence of breast cancer remains a major clinical oncologic
`problem. Rates of locoregional recurrence may vary from < 10% to > 500/o,
`depending on initial disease stage and treatment.
`
`Metastatic disease is found at presentation in 9)/o-10% of patients with breast can-
`cer. The most common sites of distant metastasis are the lungs, liver, and bone.
`
`The optimal therapy for stage III breast cancer continues to evolve. Recently, the
`use of neoadjuvant chemotherapy has been effective in downstaging locally ad-
`vanced breast cancer prior to surgical intervention. The optimal neoadjuvant che-
`motherapeutic regimens continue to evolve, and studies are being performed to
`evaluate new agents and delivery methods.
`
`Diagnosis
`
`1,SV380 A1-1111 S3DV.I. •
`
`Locally advanced disease
`Patients with locally advanced breast cancer do not have distant metastatic
`disease and are in this group based on tumor size and/or nodal status. Such
`patients often present with a large breast mass or axillary nodal disease, which
`is easily palpable on physical examination. In some instances, the, breast is
`diffusely infiltrated with disease, and no dominant mass is evident.
`
`Patients with inflammatory breast cancer often present with erythema and edema
`of the skin of the breast (peau d'orange) and may not have a discrete mass
`within the breast. These patients often are treated with antibiotics unsuccessfully
`for presumed mastitis.
`Mammography is beneficial in determining the local extent of disease in the
`ipsilateral breast, as well as in studying the contralateral breast.
`
`CH
`
`STAGES III AND IV BREAST CANCER (cid:9)
`
`233
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`
`

`
`mar
`fror
`prir.
`
`Mai
`to t]
`dist
`skit.
`
`FN,
`dial
`sist(
`ope
`stat
`
`Tr
`
`TR
`Thy
`to 1:
`40
`anc
`wil
`50c
`
`Pat
`rar
`sta
`ME
`
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`rac
`sig
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`te
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`al
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`P[
`[5
`
`0.
`
`S-
`
`Fine-needle aspiration (FNA) or biopsy The diagnosis of breast cancer can
`be confirmed by either FNA cytology or core biopsy. Core biopsy is preferred
`to perform the wide variety of marker analyses.
`
`Search for metastasis The presence of distant metastatic disease should be
`ruled out by physical examination, chest radiography, CT of the liver, bone
`scan, and CT of the chest. "Fluorodeoxyglucose-positron emission tomogra-
`phy (FDG-PET) has moderate accuracy for detecting axillary metastasis. It is
`highly predictive for nodal tumor involvement when multiple intense foci of
`tracer uptake are identified but fails to detect small nodal metastasis. The addi-
`tion of FDG-PET to the standard workup of patients with locally advanced
`breast cancer may lead to the detection of unexpected distant metastases. Ab-
`normal PET findings should be confirmed to prevent patients from being de-
`nied appropriate treatment.
`
`Locoregional recurrence
`Biopsy or FNA Locoregional recurrence of breast cancer can be diagnosed by
`surgical biopsy or FNA cytology. Whichever modality is appropriate, material
`should be sent for hormone-receptor studies, since there is only an 80% con-
`cordance in hormone-receptor status between the primary tumor and recur-
`rent disease. When the suspected recurrent disease is not extensive, the biopsy
`procedure of choice is a negative margin excisional biopsy. For an extensive
`recurrence, an incisional biopsy can be used.
`
`Search for distant metastasis Prior to beginning a treatment regimen for a
`patient with locoregional recurrence, an evaluation for distant metastasis should
`be instituted, since the findings may alter the treatment plan.
`
`Distant metastasis from the breasts
`Metastatic breast cancer may be manifested by bone pain, shortness of breath
`secondary to a pleural effusion, parenchymal or pulmonary nodules, or neuro-
`logic deficits secondary to spinal cord compression or brain metastases. In some
`instances, metastatic disease is identified after abnormalities are found on rou-
`tine laboratory or radiologic studies.
`
`Assessment of disease extent by radiography, CT, and radionuclide scan-
`ning is important. Organ functional impairment may be determined by blood
`tests (liver/renal/hematologic) or may require cardiac and pulmonary function
`testing. Biopsy may be required to confirm the diagnosis of metastasis; this is
`especially important when only a single distant lesion is. identified.
`
`Metastasis to the breasts
`The most common source of metastatic disease to the breasts is a contralateral
`breast primary. Metastasis from a nonbreast primary is rare, representing
`< 1.5% of all breast malignancies. Some malignancies that could metastasize to
`the breast include non-Hodgkin's lymphoma, leukemias, melanoma, lung can-
`cer (particularly small-cell lung cancer), gynecologic cancers, soft-tissue sarco-
`mas, and GI adenocarcinomas. Metastasis to the breasts from a nonbreast pri-
`
`236 (cid:9)
`
`CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH (cid:9)
`
`TAGES 11111-1V BREAS
`
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`

`
`MENI
`
`- can
`Bred
`
`d be
`)one
`)gra-
`It is
`ci of
`iddi-
`iced
`Ab-
`de-
`
`d by
`Trial
`am-
`cur-
`psy
`sive
`
`or a
`)uld
`
`?,,ath
`iro-
`>me
`-ou-
`
`;an-
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`don
`is is
`
`?sal
`:ing
`to
`:an-
`•co-
`Pri-
`
`\CH
`
`mary is more common in younger women. The average age at diagnosis ranges
`from the late 30s to 40s. Treatment depends on the status and location of the
`primary site.
`
`Mammographic findings Mammography in patients with metastatic disease
`to the breasts most commonly reveals a single lesion or multiple masses with
`distinct or semidiscrete borders. Less common mammographic findings include
`skin thickening or axillary adenopathy.
`
`FNA or biopsy FNA cytology has been extremely useful in establishing the
`diagnosis when the metastatic disease has cytologic features that are not con-
`sistent with a breast primary. When cytology is not helpful, core biopsy or even
`open biopsy may be necessary to distinguish primary breast cancer from meta-
`static disease.
`
`Treatment
`
`TREATMENT OF LOCALLY ADVANCED DISEASE
`The optimal treatment for patients with locally advanced breast cancer has yet
`to be defined, due to the heterogeneity of this group. There are approximately
`40 different substage possibilities with the different combinations of tumor size
`and nodal status. Between 66% and 90% of patients with stage III breast cancer
`will have positive lymph nodes at the time of dissection, and approximately
`50% of patients will have four or more positive nodes.
`
`Patients with locally advanced breast cancer have disease-free survival rates
`ranging from 0% to 60%, depending on the tumor characteristics and nodal
`status. In general, the most frequent type of treatment failure is due to distant
`metastases, and the majority of them appear within 2 years of diagnosis.
`
`With the increased utilization of multimodality therapy, including chemotherapy,
`radiation therapy, and surgery, survival for this patient population has improved
`significantly.
`
`Neoadjuvant systemic therapy
`Neoadjuvant therapy with cytotoxic drugs permits in vivo chemosensitivity
`testing, can downstage locally advanced disease and render it operable, and
`may allow breast-conservation surgery to be performed. Preoperative chemo-
`therapy requires a coordinated multidisciplinary approach to plan for surgical
`and radiation therapy. A multimodality treatment approach can provide im-
`proved control of locoregional and systemic disease. When neoadjuvant ther-
`apy is used, accurate pathologic staging is not possible.
`
`Active regimens Preoperative chemotherapy regimens reported to result in
`high response rates (partial and complete responses) include CAF (cyclo-
`phosphamide [Cytoxan, Neosar], doxorubicin [Adriamycin], and fluorouracil
`[5-FU]), FAC (5-FU, Adriamycin, and cyclophosphamide), CMF (cyclophos-
`phamide, methotrexate, and 5-FU), and CMFVP (cyclophosphamide, meth-
`otrexate, 5-FU, vincristine, and prednisone). Combination chemotherapy with
`
`STAGES III AND IV BREAST CANCER (cid:9)
`
`237
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`
`

`
`TABLE I: Doses and schedules of chemotherapy agents
`commonly used in patients with metastatic breast cancer
`
`Drug/combination (cid:9)
`
`Dose and schedule
`
`FAC
`
`5-FU (cid:9)
`Adriamycin (cid:9)
`Cyclophosphamide (cid:9)
`Repeat cycle every 3-4 weeks.
`
`TAC
`Taxotere (cid:9)
`Adriamycin (cid:9)
`Cyclophosphamide (cid:9)
`Repeat cycle every 2 I days.
`
`500 mg/m2 IV on days I and 8
`50 mg/m2 IV on day I
`500 mg/m2 IV on day I
`
`75 mg/m2 IV on day I
`50 mg/m2 IV on day I
`500 mg/m2 IV on day 1
`
`FEC
`5-FU
`Epirubicin (cid:9)
`Cyclophosphamide (cid:9)
`Repeat cycle every 21 days.
`Note:An absolute granulocyte count < 1,500/mm3 and/or platelet count <100,000/mm3 on
`day 21 will cause a treatment delay of at least I week. Treatment wil be terminated if
`hematology recovery takes more than 3 weeks.
`
`on day I
`500 mg/m2
`(cid:9) IV
`100 mg/m2 IV on day I
`500 mg/m2 IV on day I
`
`Docetaxel (cid:9)
`
`Paclitaxel (cid:9)
`
`175 mg/m2 by 3-h IV infusion every 3 weeks
`or 80-100 mg,/m2/week
`60-100 mg/m2 by I -h IV infusion every 3
`weeks or 40 mg/m2/week
`Repeat if hematologic recovery has occurred (ie, absolute granulocyte count > 1,500/pL and
`platelet count > 100,000/µL).
`
`Capecitabine
`
`Repeat cycle every 21 days.
`
`Capecitabine + docetaxel
`Capecitabine
`
`Docetaxel
`Repeat cycle every 3 weeks.
`
`Vinorelbine + trastuzumab
`Vinorelbine (cid:9)
`Trastuzumab (cid:9)
`
`2,000 to 2,500 mg/m2 PO bid (divided dose,
`AM and PM) for 14 days, followed by I -week
`rest
`
`1,000 to 1,250 mg/m2 orally twice daily on
`days 1 to 14, followed by I -week rest
`75 to 100 mg/m 2 IV infusion over I hour
`
`25 mg/m2 IV on day I every week
`4 mg/kg IV loading dose, then 2 mg/kg IV
`every week
`
`is used most often. Recently
`an anthracycline-based regimen—FAC or AC (cid:9)
`published data suggest that the AT regimen of Adriamycin and docetaxel
`(Taxotere) given concomitantly may produce equivalently high response rates.
`Combination agents for metastastic breast cancer also include paclitaxel plus
`trastuzumab (Herceptin) with carboplatin (Paraplatin), gemcitabine (Gemzar)
`
`238 (cid:9)
`
`CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH
`
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`
`

`
`n
`
`NMI
`
`y
`
`Drug/combination (cid:9)
`
`Dose and schedule
`
`Paclitaxel (cid:9)
`
`Docetaxel or paclitaxel + carboplatin + trastuzumab (every-3-week dosing)
`75 mg/m2 IV on day I every 21 days
`Docetaxel (cid:9)
`OR
`175 ring/m2 IV on day I every 21 days
`PLUS
`AUC of 5 to 6 on day I every 21 days
`PLUS
`4 mg/1<g IV loading dose on day 1, followed by
`2 mg/kg weekly
`Note: Patients must be premeditated with dexamethasone prior to docetaxel.
`
`Carboplatin (cid:9)
`
`Trastuzumab (cid:9)
`
`Trastuzumab
`
`4 mg/kg IV loading dose, then 2 mg/1<g weekly
`8 mg/kg IV loading dose, then 6 mg/kg
`every 3 weeks
`
`Docetaxel (cid:9)
`
`Paclitaxel or docetaxel + carboplatin + trastuzumab (weekly dosing)
`80 mg/m2 IV on day I every week
`Paclitaxel (cid:9)
`OR
`35 mg/m2 IV on day I every week'
`PLUS
`AUC 2 IV on day I every week
`PLUS
`4 mg/kg IV loading dose, then 2 mg/kg every week
`
`Carboplatin (cid:9)
`
`Trastuzumab (cid:9)
`
`Gemcitabine + paclitaxel
`Gemcitabine
`
`Paclitaxel
`
`1,250 mg/m2 IV on days I and 8 (as a 30-minute infusion)
`every 21 days
`175 mg/m2 IV on day I (over 3 hours) every 21 days
`
`Note: Standard paclitaxel premedications should be given.
`
`Pegylated doxorubicin
`Doxil (cid:9)
`
`30 to 50 mg/m2 IV on day I every 21 to 28 days
`
`and paclitaxel, and capecitabine (Xeloda) and docetaxel (Table 1). Although
`not yet definitive, recent data indicate that enhancing dose density may in-
`crease the pathologic complete response rate for women with locally advanced
`disease. The doses of these combination chemotherapy regimens are given in
`Table 1, chapter 10.
`
`There seems to be no difference in survival in women with locally advanced
`disease who receive chemotherapy before or after surgery. Neoadjuvant che-
`motherapy results in complete response rates ranging from 20%-53% and par-
`50% reduction in bidimensionally measurable disease)
`tial response rates (cid:9)
`ranging from 37%-50%, with total response rates ranging from 80%-90%. Pa-
`tients with large lesions are more likely to have partial responses. Pathologic
`complete responses (pCRs) do occur and are more likely to be seen in patients
`with smaller tumors. A pCR in the primary tumor is often predictive of a corn-
`
`STAGES III AND IV BREAST CANCER (cid:9)
`
`239
`
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`
`

`
`plete axillary lymph node response. Patients with locally advanced breast can-
`cer who have a pCR in the breast and axillary nodes have a significantly im-
`proved disease-free survival rate compared with those who have less than a
`pCR. However, a pCR does not entirely eliminate the risk for recurrence.
`
`Patients should be followed carefully while receiving neoadjuvant systemic
`therapy to determine treatment response. In addition to clinical examination,
`it may also be helpful to document photographically the response of ulcerated,
`erythematous, indurated skin lesions. Physical examination, mammography,
`and breast ultrasonography are best for assessing primary tumor response,
`whereas physical examination and ultrasonography are used to evaluate re-
`gional nodal involvement.
`The role of MRI in evaluating response to preoperative chemotherapy is still
`evolving. Dynamic contrast-enhanced MRI performed at baseline, during che-
`motherapy, and before surgery has yielded more than 90% diagnostic accu-
`racy in identifying tumors achieving a pCR and can potentially provide func-
`tional parameters that may help to optimize neoadjuvant chemotherapy strate-
`gies. However, despite its high sensitivity, a large number of patients still may
`have either false-negative or false-positive results on MRI scanning.
`
`Multimodality approach
`A multimodality treatment plan for locally advanced breast cancer (stage IIIA
`and IIIB, M1 supraclavicular nodes) is shown schematically in Figure 1. This
`approach has been shown to result in a 5-year survival rate of 840/0 in patients
`with stage IIIA disease and a 44% rate in those with stage IIIB disease. The
`most striking benefit has been seen in patients with inflammatory breast cancer,
`with 5-year survival rates of 35%-50% reported for a multimodality treatment
`approach including primary chemotherapy followed by surgery and radiation
`therapy and additional adjuvant systemic therapy. The same chemotherapy
`drugs, doses, and schedules used for single-modality therapy are employed in
`the multimodality approach.
`Surgery Traditionally, the surgical procedure of choice for patients with locally
`advanced breast cancer has been mastectomy. In recently published studies,
`some patients with locally advanced breast cancer who responded to treatment
`with neoadjuvant chemotherapy became candidates for breast-conservation
`therapy and were treated with limited breast surgery and adjuvant breast
`irradiation. Patients who have been downstaged using neoadjuvant chemo-
`therapy should be evaluated carefully before proceeding with conservative treat-
`ment. It may be helpful to mark the site of the primary tumor with the place-
`ment of a clip during the course of percutaneous biopsy prior to beginning
`adjuvant therapy. There can sometimes be a complete clinical and/or radio-
`graphic response after neoadjuvant chemotherapy or hormonal therapy, and
`this may facilitate a wide local incision.
`
`The role of sentinel node biopsy in the treatment of breast cancer after
`neoadjuvant chemotherapy has yet to be defined. Studies have shown that patho-
`logically positive axillary lymph nodes can be sterilized when neoadjuvant che-
`
`240 (cid:9)
`
`CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH
`
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`
`

`
`can-
`• im-
`an a
`
`bon,
`tted,
`phy,
`mse,
`re-
`
`still
`che-
`ccu-
`unc-
`rate-
`may
`
`[IIA
`This
`ents
`The
`leer,
`nent
`ition
`rapy
`d in
`
`:ally
`dies,
`vent
`.tion
`'east
`mo-
`reat-
`ace-
`Laing
`iclio-
`and
`
`after
`itho-
`che-
`
`ACH
`
`FAC 4 courses
`
`Adequate response
`for negative
`margin surgery
`
`Inadequate response
`for negative
`margin surgery
`
`Su rgerya
`
`Switch to
`taxane-based
`chemotherapy
`
`Additional systemic therapy
`(4-6 cycles of FAC)
`
`1
`
`Radiation therapy
`
`Adequate
`response
`for
`negative
`margin
`surgery
`
`Inadequate
`response
`for
`negative
`margin
`surgery
`
`urgery
`
`Radiation
`therapy
`
`Radiation
`
`Surgery if
`operable
`
`therapy z
`
`For women with hormone-
`receptor-positive tumors
`(ER and/or PR positive):
`endocrine therapy
`
`°The extent of surgery Is determined by response, but always Includes axillary lymph node dissection.
`
`FIGURE I : Multimodality approach to locally advanced breast cancer
`
`motherapy is utilized. There are other biologic concerns with sentinel node
`biopsy after neoadjuvant chemotherapy. The lymphatics may undergo fibrosis
`or may become obstructed by cellular debris, making the mapping procedure
`unreliable, with false-negative rates of up to 250/0. The rate of conversion from
`positive to negative nodes can be enhanced when four cycles of a doxorubicin-
`based regimen are followed by four cycles of docetaxel. Sentinel node biopsy
`will only be accurate then if all the metastatic deposits within the axilla respond
`
`STAGES III AND IV BREAST CANCER (cid:9)
`
`241
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`

`
`in a similar fashion to chemotherapy. Preliminary data from the National Sur-
`gical Adjuvant Breast and Bowel Project (NSABP) B-27 trial demonstrated an
`11% false-negative rate in women who underwent sentinel node biopsy after
`receiving four cycles of doxorubicin and cyclophosphamide followed by four
`cycles of docetaxel. However, patients with clinically positive nodes prior to
`neoadjuvant chemotherapy should have full node dissection.
`
`Radiation therapy remains an integral component of the management of
`patients with locally advanced breast cancer. For patients with operable breast
`cancer undergoing mastectomy, radiation therapy to the chest wall and/or
`regional lymph nodes (to a total dose of 5,000-6,000 cGy) is usually employed,
`as discussed in chapter 10. Recent randomized trials suggest that postmastectomy
`patients with any number of positive nodes derive a disease-free and/or overall
`survival benefit from postmastectomy irradiation.
`
`Available data do not suggest a problem in delaying radiation therapy until the
`completion of systemic chemotherapy. Even in patients undergoing high-dose
`chemotherapy with autologous bone marrow or stem-cell transplantation, irra-
`diation is generally indicated following mastectomy for patients with locally
`advanced disease (primary tumors 5 cm and/or four positive axillary nodes).
`
`For patients whose disease is considered to be inoperable, radiation therapy
`may be integrated into the management plan prior to surgery.
`
`High-dose chemotherapy Patients with locally advanced breast cancer and
`those with multiple positive nodes may be candidates for protocol treatment
`with high-dose chemotherapy plus autciiogous stem-cell support. Preliminary
`results from three prospective, randomized trials of high-dose chemotherapy
`with autologous stem-cell support in women with high-risk primary breast can-
`cer were recently presented. All three trials are summarized in Table 2, and two
`of the trials are discussed in more detail below.
`
`In the largest trial yet reported, investigators from all of the bone marrow trans-
`plant centers in the Netherlands randomly assigned 885 women with stages II
`and III breast cancer with four or more tumor-positive nodes to a standard
`therapy arm of five courses of FEC (5-FU, epirubicin [Ellence], and cyclophos-
`phamide) followed by radiation therapy and tamoxifen or an investigational
`treatment arm of four cycles of FEC followed by high-dose chemotherapy with
`cyclophosphamide, thiotepa, and carboplatin with peripheral blood stem-cell
`support followed by radiation therapy and tamoxifen. After a median follow-
`up of 57 months, there was a trend for improved 5-year relapse-free survival
`rates in the high-dose group, but it was not statistically significant (hazard ratio
`[HR] = 0.83; P= .09). In the subgroup of patients with 10 or more positive
`nodes, however, the relapse-free survival rate reached statistical significance
`(HR = 0.71; P= .05). There was also a suggestion that the benefit seen in the
`high-dose group may be confined to patients with HER-2/neu-negative tumors.
`
`The second-largest trial evaluating high-dose chemotherapy was conducted by
`the Cancer and Leukemia Group B (CALGB) in patients with stage II or III
`breast cancer involving 10 or more axillary lymph nodes. This trial examined
`the value of consolidation high-dose therapy with cyclophosphamide, cisplatin,
`
`242 (cid:9)
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`

`
`ir-
`an
`ter
`cur
`to
`
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`"or
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`rail
`
`the
`o se
`-ra-
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`
`aPY
`
`and
`Lent
`iary
`apy
`an-
`two
`
`ans-
`II
`lard
`hos-
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`with
`-cell
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`i the
`C1OTS.
`
`,d by
`ir III
`tined
`latin,
`
`DACH (cid:9)
`
`TABLE 2: Randomized studies of high-dose chemotherapy in
`primary breast cancer
`
`Number
`of patients
`
`Follow-up
`(median)
`
`Survival
`benefit?
`
`885
`
`783
`
`525
`
`36 mo
`
`36 mo
`
`20 mo
`
`Yes
`
`No
`
`No
`
`P value
`
`P < .05
`
`NS
`
`NS
`
`Investigators
`
`Rodenhuis et al
`
`Peters et al
`
`Scandinavian Breast
`Cancer Study Group
`
`NS = not significant
`
`and carmustine (BiCNU) with autologous stem-cell support following adjuvant
`therapy with cyclophosphamide, doxorubicin, and 5-FU. Preliminary results
`of this study, with 783 participants, showed a reduction in relapse frequency of
`over 30% in patients receiving high-dose chemotherapy; a 3-year survival rate
`of 68% was observed in patients treated with high-dose chemotherapy, vs a
`640/o rate in those who received intermediate-dose consolidation therapy with
`the same drugs. However, follow-up is not yet long enough to define the ulti-
`mate benefit of this approach. Moreover, toxicity to date has been significantly
`higher and the relapse rate significantly lower in the high-dose group.
`
`Nonrandomized studies of high-dose chemotherapy plus autologous stem-cell
`support have shown a disease-free survival of - 70%, as compared with historic
`data showing a 30% 5-year disease-free survival rate with conventional-dose
`chemotherapy.
`
`To date, the results of available clinical trials have not all shown improved
`disease-free and overall survival in patients treated with dose-intensive regi-
`mens. However, trial design, power, and strategy have all been questioned.
`Outside the context of a clinical trial, high-dose chemotherapy cannot be rec-
`ommended for patients with primary or metastatic breast cancer.
`
`TREATMENT OF LOCOREGIONAL RECURRENCE AFTER
`EARLY INVASIVE CANCER OR DCIS
`When a patient develops a local failure after breast-conservation treatment for
`early invasive cancer or ductal carcinoma in situ (D CIS), it is generally in the
`region of the initial primary tumor. The risk of ipsilateral breast tumor recur-
`rence after conservative treatment in patients with early invasive cancer ranges
`from 0.5%-2.0% per year, with long-term local failure rates plateauing at about
`15%-20%. Local failure rates after wide excision alone for DCIS vary from
`10%-63%, as compared with rates between 7% and 21% after wide excision
`plus radiation therapy. Most patients whose disease recurs after conservative
`treatment for DCIS can be treated with salvage mastectomy. In one study, 140/0
`of patients who developed local recurrence had synchronous distant metastatic
`disease.
`
`STAGES III AND IV BREAST CANCER (cid:9)
`
`243
`
`NOVARTIS EXHIBIT 2010
`Roxane v. Novartis, IPR 2016-01461
`Page 12 of 103
`
`

`
`Low-risk hormone
`receptor-positive
`patientsa
`
`Aromatase inhibitor or
`fulvestrant for
`postmenopausal women;
`tamoxifen, LHRH against
`+/- aromatase inhibitor
`for premenopausal women
`
`If partial or complete
`response, continue therapy
`until progressive disease
`
`Progressive disease
`
`Megestrol acetate
`or tamoxifen
`
`If partial or complete
`response, continue therapy
`until progressive disease
`
`Progressive disease
`
`Trial of third-line hormone
`
`Hormone-refractory disease
`
`Intermediate- or high-risk
`hormone receptor-negative
`patientsb
`
`No prior anthracycline:
`pegylated doxorubicin,
`FA/EC, CA/EF, A/ET
`Prior anthracycline:
`taxane (paclitaxel or docetaxel)
`single agent or in combination
`(such as paclitaxel/gemcitabine
`or docetaxel/capecitabine)
`
`If partial or complete
`response, continue 2 cycles
`past best response or until
`disease progression or
`unacceptable toxicity
`
`Progressive disease
`
`Trial of paclitaxel or docetaxel:
`if taxane-resistant, use single-agent
`vinorelbine or capecitabine
`
`If partial
`or complete
`response,
`continue 2
`cycles past
`best
`response
`or until
`disease
`progression or
`unacceptable
`toxicity
`
`If no
`response,
`consider
`referral
`for inves-
`tigational
`trial
`
`41- (cid:9)
`
`Trastuzumab +
`taxane +/- platinum
`until partial
`response or
`complete response
`Maintain on
`trastuzumab until
`disease
`progression
`Change chemo
`(eg, vinorelbine,
`gemcitabine)
`+/- continue
`trastuzumab
`
`If no response to two consecutive
`chemotherapy regimens +
`poor performance status, give
`symptomatic/supportive care
`
`'Low-risk patients include those with a long disease-free interval, tumors that are positive for
`hormone receptors (estrogen and progesterone), or bone-only disease, as well as those without
`extensive visceral involvement
`
`bIntermediate- or high-risk patients include those with rapidly progressive disease, visceral
`involvement, hormone-refractory disease, or tumors that are negative for hormone receptors
`
`FIGURE 2: Treatment approach to metastatic breast cancer
`
`244 (cid:9)
`
`CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH
`
`NOVARTIS EXHIBIT 2010
`Roxane v. Novartis, IPR 2016-01461
`Page 13 of 103
`
`

`
`The optimal treatment of a local or regional recurrence after mastectomy has
`yet to be defined. Locoregional recurrences are associated with initial nodal
`status and primary tumor size. Appropriate treatment may result in long-term
`control of locoregional disease. In many instances, these patients develop si-
`multaneous distant metastasis, or distant disease develops some time after the
`locoregional recurrence manifests itself.
`
`Recurrence of invasive cancer after breast conservation
`Recurrence after wide excision and breast irradiation For patients with
`early invasive cancer who have undergone conservative surgery followed by
`irradiation and whose cancer recurs in the ipsilateral breast, salvage mastec-
`tomy is the most common treatment modality. The same is true for ipsilateral
`recurrence (of invasive or in situ disease) after conservative treatment for DCIS,
`when there is no evidence of distant metastatic disease.
`
`Some studies with limited follow-up have reported acceptable results with re-
`peated wide local excision for ipsilateral breast tumor relapses following
`conservative surgery and radiation therapy. Selection criteria for this approach
`are unclear, however, and use of this salvage procedure remains controversial.
`Although the use of limited-field reirradiation has been reported, selection cri-
`teria for this management option and long-term follow-up data are lacking.
`
`Recurrence after wide excision alone In patients initially treated with wide
`local excision alone who sustain an ipsilateral breast tumor recurrence, small
`series with limited follow-up suggest that wide local excision followed by radia-
`tion therapy to the intact breast at the time of local recurrence may be a reason-
`able treatment alternative. In this situation, standard radiation doses would be
`employed.
`
`Recurrent disease in the chest wall after mastectomy
`In general, patients who develop minimal recurrent disease in the chest wall
`after a long disease-free interval may be treated by excision alone, although
`this approach is controversial and may not be, ideal. Locoregional control ob-
`tained by radiation therapy alone is related to the volume of residual disease
`and may not be durable. When possible, disease recurring in the chest wall or
`axillary nodes should be resected and radiation therapy should be delivered to
`aid in local control.
`
`Radiation treatment techniques are generally similar to those employed for
`patients treated with standard postmastectomy irradiation and consist of photon-
`and/or electron-beam arrangements directed at the chest wall and adjacent
`lymph node regions. Treatment planning should strive for homogeneou