Research Issues in Patients with Breast Disorders

Research Issues in Patients with Breast Disorders

Output of students from UPCM circa 1999

Case

This is the case of Delia Sanchez, 53 y.o. female, Filipino, married, housewife, right-handed, currently resideing in Potrero, Malabon, who was admitted for the first time in PGH last February 8, 1999 for the chief complaint of tender breast mass with bloody nipple discharge.

Three weeks PTA, patient palpated a 2×1.5 cm, hard, fixed, tender lump in the upper outer quadrant of the left breast.  Two days PTA, patient had bloody nipple discharge, thus prompting consult oat PGH-OPD.  No evidence of nodal involvement and distant mass were noted.  Fine needle aspiration biopsy revelaed solid nature of the mass, gritting on needling, and positive cells considered cells consistent with malignancy.  patient was diagnosed to have ductal carcinoma in situ (DCIS) and was advised to undergo segmental resection with adjuvant radiation therapy.

Research Issue

Patient agrred to invasive procedrue but declined radiation therapy due to fear of side effcts, thus the issue: Is the 10-year survival rate of DCIS patietns undergoing local excision with adjuvant radiation therapy significantly grater than those undergoing local excision alone?

Significance of the research

Current treatment for breast cancer range from simple tumor excision to various forms of wider excision (segmental resection, quadrant resection) to mastectomy with or without reconstruction.  All  tratments less than mastectomy may be followed by radiation therapy.  Since breast cancer is a heterogeneous group of lesions, and because patietns have a variety of personal agendas that must be considered when selecting treatment, no single approach will be appropriate for all forms of the disease.  Methods must be develped to determine the best treatment for each patietn.  Clinicians need to know which lesions, if untreated, will become invasive breat cancer. We need to know which lesions, if treated con=servatively, will have high recurrence rates such that mastectomy will be the preferred treatment.  We also need to know which patients in the group who do not need mastectomy can be treated by tumor excision alone or with post-operative radiotherapy.

Several studies have shown that post-operative radiotherapy increases the survival rate of patients with breast cancer.  A study by Solin et al in 1993 demonstrated important differnences in recurence rate based on the pathologic characteristics of primary tumor in patietns with ductal carcinoma in situ (DCIS) treated with breast-conservation ssurgery and definitive radiotherapy.  A study by Fisher et al in 1995 showed an increased five-year event-free survival rate in all breast cancer patient who received post-operative radiotherapy.  It also indicated that through 3 years of follow-up, lumpectomy with radiotherapy was more beneficial than lumpectomy alone fro women with localized DCIS.

However, clinicans cannot deny the fact that radiation does carry risk ot the patient. Even “controlled” doses are not 100% safe.  Radiation causes DNA mutation in cells that can possibly lead to another form of cancer.  Moreover,, radiotherapy is expensive and, in some cases, accmpaneied by side effects such as cardiac toxicity and pulmonaryfibrosis.  The latter is a more common side effect particular with older radiotherapy techniques developed during the 1980s.  This complication changes the texture of the reast, makes mammographic follow-up more difficulty, and may result in delayed diagnosis in cases of recurrence.

We believe that there is still a need to evaluate if the benefits of post-operative radiotherapy, in terms of improved ten-year survival rate and decreased recurrence rate, do singnificantly outweight its side effects, complications, inconvenience and costs.

1. Methodology

Selection and Screening of Subjects

From a compound list of about 3,000 -5,000 women breast cancer patients taken from selected participating hosptials only those aged 40-50 years shall be included in the study. This is narrowed down to those found with ductal carcinoma-in-situ of the large tumro type, limited to breast disease. Diagnosis will be based on the presence of a clinically palpable or mamographically detected mass of >/=2 cm diamter, with confirmation of true DCIS without invasion (no multifocal or multicentric lesions, no axillarynodal metastases, no distant metastases) by microscopic analysis of multiple, step sections of paraffin blocks of the biopsied tissue.  Also, patietns whose similar diagnoses of DCIS were incidental details at the time a biopsy was performed for another reason are eligible for the study. Cases of synchronous bilateral DCIS will not be excluded.  If possible, the stratification of the diagnosses of DCIS into theri morphological subtypes and/or grades would facilitate a more thorough assessment of the recurrence rate of the leasions following treatment.

Patietns suitable to the criteria cited will then be invited to participate.  They will be informed as to the nature and objectives of the study, its methods, benefits and risks, and their right to withdraw from it should they wish to. A sample size of 600-1,500 freely consenting subjects would be most ideal.  They will be randomly assigned to 2 categories of treatment: modified radical mastectomy alone and modified radical mastectomy with adjuvant radiotherapy.

Operative Procedure and Radiotherapy

Unilateral modified mastectomy is the gold standard treatment for large DCIS. Both gourps of subjects will undergo the mastectomy process specifically the Patey Modified Radical mastectomy (PMRM). The PMRM necessitates en bloc resection of the breast, the axillary lymphatics and overlying skin near the rim with a 3 cm to 5 cm margin that ensures histologic clearance of the tumor.  This method acknowledges the importance of complete axillary dissection and the anatomic necessity for preservations of the medial and lateral pectoral (anterior thoracic) nerves, which may provide dual innervation to the pectoralis major muscle.  With the removal of the pectoralis minor muscles, this allows acccess to level III nodes.  The PMRM is intended for lesins that cannot be removed with clear margins by segmental mastectomy and for lesions of large size in which cosmetic reconstruction and regional control can’t be accomplished.

Regardless of the skin incisions chose, the limits of themastectomy are limited laterally by the anterior margin of the latissimus dorsi, medially by the middle of the sternum, superiorly by the subclavius muscle, and inferiorly, by the caudal extensiion of the breast some 2-3 cm inferior to the mammary fold.  Ths surgeon should be cognizant of the thoracodorsal nerve, where origin is medial to the throracodorsal artery and vein, otherwise, permanent disability with a winged scapula and shoulder apraxia will follow denervation of the serratus anterior.

One group of subjects will receive radiotherapy as adjuvant therapy following the mastectomy.  The skin flaps, axilla and supraclavicular and internal mammary areas will be treated with either orthovoltage or supervoltage radiotherapy.  For orthovoltage, the maximum recommended deep tissue dosage on the chest wall, at themidpoint of axilla and the estimated depth of the supraclavicualr and internal mammary nodes is within the range of 2850 rads in three weeks to 4050 rads in six weeks at three fractions per week or 3250 rads in three weeks to 4600 rads in six weeks at five fractions per week.  These figures will be multiplied by 1.1 for supervoltage treatment.

Postoperative Surveillance of  Subjects

For the group treated with mastectomy alone, the first clinical history and physical examinatin will be scheduled in 4 months.  This is repeated 4 months later, and continued regularly at similar intervals.  The subjects (including those in the other treatment group) will be taught how to perform the breast self-examination, and will be expected to do it habitually so that any abnormal finding may be checked outside scheduled appointments.  The first follow-up mammogram of the involved breast will be performed in 6 months, that of both breasts in the next 6 months and subsequent mammograms annually therafter, except for recurrences when it si permissible to perform the mammogram after only 3-6 months.  The appearance of a new breast mass is recorder and consequently brought up for immediate diagnostic work-up.

As regards to the masttectomy plus radiotherapy group, clinical history and phhysicial examination will be done in the same vein as the one in the first group. The initial follow-up mammogram, on the other hand, will be done 6 months after the last radiotherapy session.  The succeeding pattern in the previous group will also be applied for this group.

Monitoring will be doe for 10 years and duration of event-free periods, periods of recurrence, losses to follow-up and deaths due to surgery or recurrent breast malignancy are noted within this time.  Deaths caused by extraneous factors and/or unrelated diseases/malignancies are eliminated from the tally. Finally, statistical analysis will be employed to determine the significance of the discrepancies in survival rates between the two treatment groups.

 

References

Fisher B, Constantino J, Redmond C, Fisher E, Margolese R, Dimitrov N. 1993 Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer.  N Engl J Med 328 1581-1586.

Fisher B, Constantino J, Fisher E, Palekar A, Paik S, Suarez C 1995 Pathologic finding from the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17: Intraductal carcinoma (ductral carcinoma in situ) Cancer 75: 1310-1319.

Fisher B, Dignam J, Wolmark N, Mamounas E, Constantino J, Poller W 1998 Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: Findings from the National Surgical Adjuvant Breast Project Protocol B-17. J Clin Oncol 16: 441-452.

Lagios M, Page D 1993 Radiation therapy for in situ or localized breast cancer. N Engl J Med 21:1577-1578.

Landis S, Murray T, Bolden S, Wingo P. 1998 Cancer statistics of 1998.  Cancer J Clin 48:6-29.

Nemoto T, Vana J, Bedwani R, Baker H, McGregor F, Murphy G. 1980. Management and survival of female breast cancer: results of a national survey by the American College of Surgeons Cancer 45:2917-2924.

Schwartz S et all 1994 Principles of Surgery 6th ed McGraw Hill New York

Schwartz GF, Finkel GC, et al Subclinical ductal carcinoma in situ of the breast: Treatment by local excision and surveillance alone.  Cancer 70:2468, 1992

Silverstein M, Barth A, Poller D, Colburn W, Waisman J, Gierson E.  1995 Ten-year results comparing mastectomy to excision and radiation therapy for ductal carcinoma in situ of the breast.  Eur J Cancer  31: 1425-1427.

Silverstein M, Lagios M, craig P, Waisman J, Lewinsky B, Colburn W 1996  A prognostic index for ductal carcinoma in situ of the breast.  Cancer  77:2267-2274.

Silverstein M, Gamagami P, Colburn W.  1997 Coordinated biopsy team: surgical. pathological, and radiologic issues.  In Ductal Carcinoma in Situ of the Breast Silverstein M et al (Eds) Williams & Wilkins, Baltimore 333-342.

Solin L, Yet I, Kurtz J, Fourquet A, Recht A, Kuske R.  1993  Ductal carcinoma in situ (intrductal carcinoma) of the breast treated with breast-conserving surgery and definitive irradiation: correlation of pathologic parameters with outcome of treatment.  Cancr 71:2532-2542.

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ROJ@17nov14