The Role Of Radiation Therapy Post Mastectomy For Invasive Carcinoma Of The Breast: A Review

Marc S. Rudoltz, M.D.; Ryan S. Perkins, M.D.; Robert W. Luthmann, Ph.D.; Rick Croley, R.T.T.; Scot N. Ackerman, M.D.

Marc S. Rudoltz, M.D.; Ryan S. Perkins, M.D.; Robert W. Luthmann, Ph.D.; and Scot N. Ackerman, M.D. are with the Section of Radiation Oncology, St. Vincent's Medical Center. Rick Croley, R.T.T. is with First Coast Oncology.

Introduction

Historically, most patients with breast cancer have been treated with mastectomy. Until approximately 20 - 30 years ago, radical mastectomy, the removal of the breast and underlying pectoralis major and minor muscle, was the most commonly performed surgical procedure for breast cancer patients. In the 1970's, a landmark study showed that overall survival was equivalent in patients treated with simple mastectomy versus patients treated with radical mastectomy.¹ Based on this data, the modified radical mastectomy (MRM), removal of the breast, the pectoralis minor fascia, and at least a limited axillary lymph node dissection, became the surgical procedure most often performed. Later data showed overall survival was equivalent for patients with early stage breast cancer (Stage I and II - Table 1)² treated with lumpectomy and radiation therapy (RT) when compared to MRM.³

However, some patients with early stage breast cancer opt for mastectomy in the hope of precluding the need for radiation therapy. Other patients with more advanced disease are treated with MRM, with post-operative treatment tailored to the pathologic findings of the mastectomy specimen. Until the early 1980's, adjuvant locoregional radiation therapy was routinely utilized for these patients in order to decrease the risk of chest wall and regional lymph node recurrence. Since then, with new chemotherapeutic regimens and hormonal manipulation having been shown to benefit both axillary node negative and node positive breast cancer patients, and with dose-intensive regimens with bone marrow precursor cell reinfusion treatment being used more commonly, it has been presumed that adjuvant systemic therapy would eradicate distant micrometastatic disease and prevent locoregional recurrence. However, most studies of post-mastectomy chemotherapy have shown only a modest decrease in locoregional recurrence, with isolated locoregional recurrences (those which, if prevented, would theoretically have "cured" the patient) comprising 30 - 40% of all recurrences.⁴ Thus, interest in post-mastectomy RT has been renewed.

The goal of this review is to outline the role for post-mastectomy RT. The rationale for treatment, and the results of several clinical trials will be discussed. In addition, the technique utilized to deliver post-mastectomy RT will be described.

Rationale For Post-Mastectomy Radiation Therapy

The rationale for the use of post-mastectomy RT is to decrease locoregional recurrence and improve overall patient survival. In patients who develop a locoregional recurrence, the chest wall is the most common site, with 70% of all locoregional failures involving the chest wall.⁵ The mastectomy scar on the chest wall is the most common site of chest wall involvement.⁶ The supraclavicular / infraclavicular nodes are the next most common site (10-20%), with the axilla and internal mammary nodes being the least common (5 - 10%).⁷ The importance of initial locoregional control is that only 50% of locoregional recurrences are subsequently controlled. Thus, even with optimal radiotherapy, half of all patients who develop a locoregional recurrence will die with uncontrolled locoregional disease.

Indications For Post Mastectomy Radiation

Early Trials Of Mastectomy And Radiation

Prior to the routine use of adjuvant systemic therapy, several randomized trials evaluated the effect of RT post-mastectomy. These trials accrued patients during a 25 - 30 year span, from the 1940's through the 1970's; equipment and techniques from these trials are not comparable to what is done today. For example, some trials used orthovoltage (lower penetrating X-rays which deliver a high skin dose).^8-10 The regions treated have also been a source of criticism.¹⁰ Also, the total radiation doses and daily fraction size used are not considered standard today.

Despite these drawbacks, all of these trials showed a locoregional control benefit for patients who received RT. However, this did not translate into a benefit in overall survival. In fact, an early meta-analysis (statistical review of all randomized trials) of 10 year survival data from these trials showed a decrease in overall survival for patients who received RT when compared to patients in the observation arms.¹¹ An update of this meta-analysis demonstrated that this survival decrement was due to an increase in cardiac deaths in patients who received RT.¹² This increase in ischemic heart disease in patients treated with RT was secondary to the use of RT techniques which delivered a high dose to the heart. This negative effect on survival, however, was balanced by a reduction in breast cancer deaths in patients who received post-mastectomy RT.

That cardiac events attributable to radiation can be associated with radiation technique was shown by investigators in the Stockholm Breast Cancer Trial.¹³ In this study, women with breast cancer received pre-operative RT, post-operative RT, or observation after MRM. In the early years of the trial the breast and regional lymph nodes, including the bilateral internal mammary (IM) nodes, were treated with an anterior cobalt-60 field, a technique which delivers a high dose of radiation to the heart. At a mean follow-up of 16 years the rate of locoregional recurrence was 4% for RT treated patients versus 20% for patients in the observation arm. This benefit in locoregional control was seen in both node-negative and node-positive patients. Additionally, in axillary node-positive patients, a reduction in the rate of distant metastases and an improvement in overall survival was noted. The authors also found that patients with left-sided cancers had a significant increase in ischemic heart disease when compared to patients with right-sided cancers.¹⁴ This suggests that a technique which limits the radiation dose to the heart may limit non cancer deaths and subsequently allow for an improvement in overall patient survival.

A later analysis of the Stockholm trial found that locally recurrent disease significantly predicted for the subsequent development of distant metastatic disease.¹⁵ Overall, the data from the Stockholm trial suggests that post-op RT to the chest wall and draining lymph noes should decrease the incidence of both locoregional recurrence and distant metastases. Additionally, a technique that limits the radiation dose to the heart may allow for an improvement in long term patient survival.

Trials Of Mastectomy And Adjuvant Systemic Therapy

In the early 1980's it was shown that systemic therapy improved disease free and overall survival in patients with stage II breast cancer. The effect of adjuvant systemic therapy on locoregional recurrence has also been evaluated.

There are no consistent findings with regard to the effect of chemotherapy on locoregional recurrence. The Guy's Hospital / Manchester trial of cyclophosphamide, methotrexate, and fluorouracil (CMF) in post-mastectomy node-positive patients showed, in pre-menopausal patients, a 5 year locoregional recurrence rate of 18%, versus 44% in untreated controls.¹⁶ No impact of CMF was noted in post-menopausal patients. An improvement in locoregional control was also seen in the NSABP B-05 trial of post-mastectomy melphalan in node-positive patients.¹⁷ On the other hand, the 20 year update of the Milan trial, in which patients with positive lymph nodes were randomized to receive or not receive CMF, did not show a significant improvement in locoregional control.¹⁸ A minimal effect of post-operative chemotherapy was also seen in the West Midlands Oncology Association trial which utilized a more intensive chemotherapy regimen of Adriamycin, Vincristine, Cyclophosphamide, Methotrexate, and Fluorouracil.¹⁹ These results suggest at best a modest improvement in locoregional control with chemotherapy, with the reduction in locoregional recurrences still being less than the effect of chest wall and regional RT.

What is the effect of endocrine therapy on locoregional control? Evidence from the Ludwig Breast Cancer Study Group suggests that it may reduce the risk of locoregional failure. In this trial, node-positive patients were randomized to receive post-mastectomy tamoxifen and prednisone (PT), CMF + prednisone and tamoxifen (CMFPT), or observation.²⁰ At a median follow-up of 13 years, locoregional recurrence as the first site of failure occurred in 34% of those observed, 21% of those receiving PT, and 14% in the CMFPT group. In a trial from Sweden, high risk patients (tumor > 3 cm. and/or positive axillary nodes) were randomized, after mastectomy, to one of four groups: RT, RT + tamoxifen for 2 years (RT + T), 12 cycles of adjuvant chemotherapy (C), or C + tamoxifen (C+T).²¹ At a mean follow-up of 6.5 years, locoregional recurrence rates were as follows: C - 32%, C + T - 20%, RT - 13%, RT + T - 12%. Thus, tamoxifen appeared to decrease the rate of locoregional recurrence in patients treated with chemotherapy, but not to the level seen with RT.

Risk Factors For Locoregional Failure After Mastectomy And Chemotherapy

Many patients who undergo mastectomy are felt to harbor more extensive or aggressive tumors. In light of this, most of these patients will receive chemotherapy. It is therefore important to identify the predictors for locoregional recurrence in these higher risk patients.

Several studies have evaluated the predictors for locoregional failure in post-mastectomy patients following chemotherapy.^22-24 The results for some of these reports are listed in Table 2. In addition, Fowble and colleagues evaluated 627 women treated on Eastern Collective Oncology Group (ECOG) breast cancer protocols which evaluated treatment with mastectomy and adjuvant systemic therapy without chest wall and regional RT. This study reported that patients with 4 - 7 positive nodes and tumors > 5 cm. had a 31% risk of developing an isolated locoregional recurrence with no evidence of distant metastases.²⁵ This suggests that there is a subgroup of patients at higher risk of developing a locoregional recurrence as compared to systemic metastases; theoretically, prevention of locoregional recurrence in these patients would impact positively on their long term survival.

These studies suggest that the risk factors for locoregional failure following mastectomy and systemic therapy are the same as those previously identified in post-mastectomy patients in the absence of chemotherapy. In practice, RT is recommended for patients with tumors > stage T3, multiple positive axillary lymph nodes, gross extracapsular lymph node extension, clinical IM node involvement, pectoralis fascia involvement, or positive surgical margins.

Studies Of Post-Mastectomy RT In Patients Who Also Received Chemotherapy

Many studies have evaluated post-mastectomy RT in the setting of adjuvant chemotherapy^26-30, and until recently the results were similar; patients treated with RT had decreased rates of local recurrence, but overall survival was not affected. However two recently published trials reported improved overall survival in patients treated with MRM, chemotherapy, and RT. In the Danish Breast Cancer Cooperative Group Protocol 82b, high risk pre-menopausal women who had undergone mastectomy for pathologic stage II or stage III breast cancer were randomized to receive 8 cycles of CMF + RT versus 9 cycles of CMF alone.³¹ RT was delivered to the chest wall and draining lymphatics, including the IM nodes in the upper four intercostal spaces. IM irradiation was performed with electrons in order to limit the dose to the heart. The median follow-up was 9.5 years.

This study showed locoregional recurrence in 32% of patients treated with CMF versus 9% in patients treated with CMF + RT, p < 0.001. In addition, the 10 year disease free survival was significantly higher in radiotherapy treated patients (48%), than in patients treated with CMF alone (34%), p< 0.001. Most importantly, overall survival was improved in patients treated with RT as opposed to those not receiving radiation (Figure 1). Overall survival at 10 years was 54% in RT treated patients versus 45% among patients treated with CMF and no RT, p<0.001. On multivariate analysis, post-mastectomy RT improved disease-free and overall survival irrespective of tumor size, number of positive nodes, or histologic tumor grade.

Figure 1. Overall survival in the Danish Breast Cancer Group Protocol 82b. The numbers below the graph are the patients still at risk. The values in parentheses are overall survival at 10 years. (Reprinted with the permission of the New England Journal of Medicine)

In another report, Ragaz and colleagues from the British Columbia Cancer Agency published the results of a trial comparing MRM + CMF to MRM + CMF + RT in high risk pre-menopausal patients.³² RT consisted of 37.5 Gray (Gy) to the chest wall, 35 Gy to the supraclavicular and IM lymph nodes. All treatment was delivered with cobalt-60 photons. In a secondary randomization, patients with estrogen receptor positive tumors were treated with radiation induced ovarian ablation. The median follow-up was 12.5 years.

The results were similar to the Danish trial. Both the overall and local recurrence rates were significantly less in the group of patients treated with RT. Locoregional recurrence was 23% in patients treated with CMF versus 10% in those who received CMF + RT, p<0.003. Interestingly, locoregional RT also significantly decreased the rate of systemic metastases, 47% in RT treated patients compared to 61% in patients who did not receive RT, p<0.006. This decrease in distant metastases was observed in all patients, irrespective of the number of involved lymph nodes (Figure 2). In light of these findings, it is no surprise that patients treated with RT had a significant improvement in breast cancer specific survival, and an increase in overall survival that approached statistical significance (Figure 3). It should be noted that the total doses used in this trial are approximately 25% less than those which are commonly used in practice today, although the dose per fraction, a major determinant of radiation toxicity, was higher than that commonly used. Despite this, there were no deaths due to radiation induced ischemic heart disease in this trial.

		Figure 2 (Left). Survival free of distant metastases in the British Columbia Cancer Agency trial. (Reprinted with the permission of the New England Journal of Medicine) Figure 3 (Below). Overall survival in the British Columbia Cancer Agency trial. (Reprinted with the permission of the New England Journal of Medicine)

These results suggest that there is a subgroup of patients whose disease is predominantly locoregional and in whom distant metastases occur a result of persistent or recurrent locoregional tumor. When these patients are carefully selected for RT, and the treatment precisely delivered, the opportunity exists to not only improve locoregional control, but to increase the likelihood for long term survival.

Treatment Technique

As noted earlier, the initial trials of post-mastectomy RT often utilized techniques that are not considered adequate by today's standards. With better quality medical imaging, radiotherapy equipment, treatment planning computers, and software, RT today is more individualized than ever. Primarily due to computed tomography (CT) based treatment planning, the dose delivered to the heart and lung are much lower now than in the past. With the increasing use of three dimensional treatment planning, we are able to identify the volume of radiosensitive structures, such as the heart and lung, receiving a specific radiation dose (dose volume histogram, or DVH). This knowledge allows us to deliver the prescribed dose while limiting the dose received by radiosensitive structures.

The specific details of treating patients with post-mastectomy RT are too lengthy to discuss here, but are well described for interested readers.³³ Basic radiation physics is outlined by Khan.³⁴ In general, the goal of post-mastectomy RT is to deliver an adequate dose of radiation to the chest wall and draining lymphatics while limiting the dose to the aforementioned sensitive structures.

A modern radiation oncology facility should have a linear accelerator capable of producing both low energy (4 - 6 megavoltage (MV)) and high energy (10 - 25 MV) photons plus several energies of electrons. Many older RT facilities use machines which produce only one energy of photons, typically 4 MV or 6 MV, and either one energy of electrons or even no electrons. Many of these facilities also do not use CT based treatment planning, which allows for optimization of beam arrangements with respect to the target volumes and patient's anatomy.³⁵ Three-dimensional CT reconstruction based treatment planning can further help to reduce the dose volume of heart and lung treated with radiation; this is critical as more women are receiving potentially cardiac toxic adriamycin-based chemotherapy regimens. Not having these capabilities available hampers the ability to optimize post-mastectomy RT, with regard to treatment of the IM lymph nodes.

Treatment to the chest wall can be delivered using either photons or electrons. Photons provide for more uniform coverage of the target volume, but treat some of the lung; for left sided lesions, at least some of the heart is included within the treatment volume. Electrons spare more of these radiosensitive structures, but the dose distribution is not as uniform.

The borders for chest wall RT are the anterior midline (medial), the mid-axillary line (laterally), the inframammary fold (inferior), and the bottom of the head of the clavicle (superior). The supraclavicular, infraclavicular, and high axillary lymph nodes are treated with an anterior photon field; the inferior portion of this field is matched to the superior edge of the tangent fields, and there are several techniques which accomplish this.³⁶ In our practice, the gantry is angled approximately 15 degrees in order to exclude the spinal cord and pharyngeal / mediastinal structures from receiving unnecessary radiation. The head of the humerus is also shielded from the radiation beam. A small shaped posterior photon field can be added to adjust the dose to the upper axilla.

Treatment of the IM lymph nodes is controversial, primarily based on the fear of radiation induced cardiac and pulmonary toxicity.³⁷ However, with modern imaging and radiation treatment planning, the dose to the IM nodes can be optimized while limiting the dose to the lungs and the heart. The IM nodes, in most cases, lie in the para-sternal area, and the area felt to be most at risk for metastasis lies in the upper four intercostal regions. Treatment of the IM nodes is typically tailored to the clinical situation. If indicated, the IM nodes can be treated with either "deep tangent" fields to include the ipsilateral IM nodes, assuming the volume of heart and lungs can be limited, or with a combination of photons and electrons in order to limit the dose to the heart and lungs from the photons and the dose to the skin from the electrons.

The dose prescription is 45 - 50 Gy to areas of subclinical disease. The mastectomy scar, the area most often involved with tumor recurrence, is boosted for an additional 10 - 15 Gy.

Figure 4. Isodose plan from a post-mastectomy patient. The prescribed dose was 5040 cGy to the chest wall and draining lymph nodes. The ipsilateral IM nodes lie adjacent to the sternum and are seen to well covered by the 5040 isodose line (white arrow). The dose to the heart falls off rapidly (black arrow). See text for more details.

Isodoses from a post-mastectomy radiation treatment plan are shown in Figure 4. This patient had a left sided tumor, and the treatment was delivered to the chest wall, axilla, supraclavicular, and IM lymph nodes. The chest wall tangent, supraclavicular, and posterior axillary fields were treated with 6 MV photons. A combination of 6 MV photons and 12 MeV electrons were utilized to treat the IM lymph nodes. The electron field was angled slightly towards the left to decrease the chance for underdosage at the junction of the radiation fields. In Figure 4, a CT slice through the upper portion of the heart, it can be seen that a portion of the heart is receiving between 18 Gy (1 Gy = 100 centigray - (cGy)) and 27.8 Gy. For this patient, DVHs were performed for both the heart and the lung; only 7.3% of the heart received > 40 Gy while 11.6% of the lungs received > 20 Gy, both of which are well within acceptable radiation tolerance.

Summary

Post-mastectomy RT reduces the incidence of locoregional recurrence. Initial trials of mastectomy plus RT showed a decrease in locoregional recurrence versus patients treated with mastectomy alone. Some of these trials also showed a decrease in breast cancer specific deaths. No improvement in overall survival was noted, however, primarily due to radiation related ischemic heart disease.

With the advent of systemic chemotherapy and endocrine therapy, trials were performed evaluating their effect in the post-mastectomy setting. The results of these trials showed at most a modest decrease in locoregional recurrence, but not to the levels in patients treated with RT. These studies did suggest, however, that a subset of patients exists who are at a higher risk of developing a locoregional recurrence than a systemic relapse, suggesting that optimal locoregional treatment combined with adjuvant systemic therapy in these selected patients may overall survival. Two recent trials have confirmed this hypothesis, finding an overall survival benefit in a selected group of high risk patients.

Recent advances in medical imaging and radiation oncology treatment planning have made it possible to treat the chest wall and IM regions while limiting the dose to the heart and the lungs. We currently recommend that post-mastectomy RT be utilized for patients who present with a primary tumor > stage T3, multiple positive lymph nodes, gross extracapsular lymph node extension, clinical IM node involvement, positive surgical margins, or pectoralis fascia involvement.

REFERENCES

1. Fisher B, Redmond C, Fisher E, et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med. 1985;312:674-681.

2. American Joint Committee on Cancer. AJCC Cancer Staging Manual. 5th ed. Philadelphia: Lippincott-Raven; 1997.

3. Fisher B, Redmond C, Poisson R, et al. Eight-year results of a randomised clinical trial comparing total mastectomy and lumpectomy with and without irradiation in the treatment of breast cancer. N Engl J Med. 1989;320:822-828.

4. Fowble B. Postmastectomy radiation: then and now. Oncology. 1997;11:213-239.

5. Halverson K, Perez C, Kuske R, et al. Isolated local-regional recurrence of breast cancer following mastectomy: radiotherapeutic management. Int J Radiat Oncol Biol Phys. 1990;19:851-858.

6. Donegan W, Perez-Mesa C, Watson F. A biostatistical study of locally recurrent breast carcinoma. Surg Obstet Gynecol. 1966;122:529-540.

7. Bedwinek J. Natural history and management of isolated local-regional recurrence following mastectomy. Semin Radiat Oncol. 1994;4:260-269.

8. Lythgoe J, Palmer M. Manchester regional breast study - 5 and 10 year results. Br J Surg. 1982;69:693-696.

9. Host H, Brennhovd I, Loeb M. Postoperative radiotherapy in breast cancer-long term results from the Oslo Study. Int J Radiat Oncol Biol Phys. 1986;12:727-732.

10. Jones J, Ribiero G. Mortality patterns over 34 years of breast cancer patients in a clinical trial of post-operative radiotherapy. Clin Radiol. 1989;40:204-208.

11. Cuzick J, Stewart H, Peto R, et al. Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer. Cancer Treat Rep. 1987;71:15-29.

12. Cuzick J, Stewart H, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol. 1993;12:447-453.

13. Rutqvist L, Cedermark B, Glas U, et al. Radiotherapy, chemotherapy, and tamoxifen as adjuncts to surgery in early breast cancer: a summary of three randomized trials. Int J Radiat Oncol Biol Phys. 1989;16:629-639.

14. Rutqvist L, Lax I, Fornander T, et al. Cardiovascular mortality in a randomized trail of adjuvant radiation therapy versus surgery alone in primary breast cancer. Int J Radiat Oncol Biol Phys. 1992;22:887-896.

15. Arriagada R, Rutqvist L, Mattson A, et al. Adequate locoregional treatment for early breast cancer may prevent secondary dissemination. J Clin Oncol. 1995;13:2869-2878.

16. Richards M, O'Reilly S, Howell A, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: an update of the Guy's / Manchester trial. J Clin Oncol. 1990;8:2032-2039.

17. Fisher B, Fisher E, Redmond C. Ten year results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial evaluating the use of L-phenylalanine mustard (L-PAM) in the management of breast cancer. J Clin Oncol. 1986;4:929-941.

18. Bonadonna G, Valagussa P, Molitern A, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995;332:901-906.

19. Morrison J, Howell A, Kelly K, et al. West Midlands Oncology Association trials of adjuvant chemotherapy in operable breast cancer: results after a median follow-up of 7 years. I. Patients with involved axillary lymph nodes. Br J Cancer. 1989;60:911-918.

20. Castiglione-Gertsch M, Johnsen C, Goldhirsch A, et al. The international (Ludwig) breast cancer study group trials I-IV: 15 years follow-up. Ann Oncol. 1994;5:717-724.

21. Rutqvist L, Cedermark B, Glas U, et al. Randomized trial of adjuvant tamoxifen combined with postoperative radiation therapy or adjuvant chemotherapy in postmenopausal breast cancer. Cancer. 1990;66:89-96.

22. Stefanik D, Goldberg R, Byrne P, et al. Local-regional failure in patients treated with adjuvant chemotherapy for breast cancer. J Clin Oncol. 1985;3:660-665.

23. Sykes H, Sim D, Wong C, et al. Local-regional recurrence in breast cancer after mastectomy and adriamycin-based adjuvant chemotherapy: evaluation of the role of postoperative radiotherapy. Int J Radiat Oncol Biol Phys. 1989;16:641-647.

24. Pisansky T, Ingle J, Schaid D, et al. Patterns of tumor relapse following mastectomy and adjuvant systemic therapy in patients with axillary lymph node-positive breast cancer. Cancer. 1993;72:1247-1260.

25. Fowble B, Gray R, Gilchrist K, et al. Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy. J Clin Oncol. 1988;6:1107-1117.

26. McArdle C, Crawford D, Dykes E, et al. Adjuvant radiotherapy and chemotherapy in breast cancer. Br J Surg. 1986;73:264-266.

27. Griem K, Henderson I, Gelman R, et al. The 5-year results of a randomized trial of adjuvant radiation therapy after chemotherapy in breast cancer patients treated with mastectomy. J Clin Oncol. 1987;5:1546-1555.

28. Blomqvist C, Tiusanen K, et al. The combination of radiotherapy, adjuvant chemotherapy (cyclophosphamide-doxorubicin-ftorafur) and tamoxifen stage II breast cancer: long-term follow-up results of a randomised trial. Br J Cancer. 1992;66:1171-1176.

29. Velez-Garcia E, Carpenter J, Moore M, et al. Postsurgical adjuvant chemotherapy with or without radiotherapy in women with breast cancer and positive axillary nodes: a South-Eastern Cancer Study Group (SEG) trial. Eur J Cancer. 1992;28A:1833-1837.

30. Buzdar A, Blumenshein G, Smith T, et al. Adjuvant chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide, with or without Bacillus Calmette-Guerin and with or without irradiation in operable breast cancer. A prospective randomized trial. Cancer. 1984;53:384-389.

31. Overgaard M, Hansen P, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med. 1997;337:949-955.

32. Ragaz J, Jackson S, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med. 1997;337:956-962.

33. Pierce L, Lichter A, Archer P. Indications, integration, and technical aspects of local-regional irradiation in the management of advanced breast cancer. Sem Radiat Oncol. 1994;4:242-253.

34. Khan F. The physics of radiation therapy. 2nd ed. Baltimore: Williams and Williams; 1994.

35. Danoff B, Galvin J, Cheg E, et al. The clinical application of CT scanning in the treatment of primary breast cancer. Current Controversies in Breast Cancer. Austin: University of Texas Press; 1984:391-397.

36. Taylor M, Perez C, Levitt S. Breast: locally advanced (T3 and T4), inflammatory, and recurrent tumors. In: Perez C, Brady L eds. Principles and practice of radiation oncology. 3rd ed. Philadelphia: Lippincott-Raven; 1998:1415-1448.

37. Harris J, Hellman S. Put the "hockey stick" on ice. Int J Radiat Oncol Biol Phys. 1988;15:497-499.

Jacksonville Medicine / March, 1998

What's New · Northeast Florida Medicine Journal · Know Your Physician · Legal & Legislative
· DCMS Alliance · Academy of Medicine · Member Websites · Community Health
About the DCMS · Meetings Calendar · Member Benefits · Employment Connection · Home

Duval County Medical Society   ·   555 Bishopgate Lane  ·   Jacksonville, FL  32204
Phone: (904) 355-6561   ·     FAX:  (904) 353-5848   
General Email: dcms@dcmsonline.org    ·   Webmaster's Email: mdoran@dcmsonline.org
Privacy Policy and Disclaimers