Radiation Therapy and Breast Conservation: Cosmetic Results and Complications John M. Kurt~ and Raymond Miralbell

A lthough the oncologic results of breast-conserv- ing therapy are highly satisfactory, its possible

superiority to mastectomy as a treatment option depends to a great extent on offering the patient an esthetic and functional result superior to that ob- tained by total mastectomy and breast reconstruc- tion, while minimizing the risk of complications. It is the responsibility of the radiation oncologist to be aware of the cosmetic results and potential complica- tions associated with current techniques and to take into account the factors known to contribute to an unfavorable outcome. Only the well-informed radia- tion oncologist is in a position to tailor the technique of radiotherapy and its coordination with other treatment modalities to match the oncologic risk faced by the individual patient.

Cosmetic Results of Breast-Conserving Therapy

The most important factor influencing cosmetic results is the extent of the primary tumor excision and the surgical technique used. The unfavorable influence of quadrantectomy compared with tumor- ectomy, even in the most experienced hands, has been well documented.’ In addition, larger tumors require more generous excisions, leading to more marked asymmetry,* particularly in patients with relatively small breasts. Surgical guidelines for assur- ing optimal cosmetic results have been publishedP It is apparent that even the most scrupulous radiother- apeutic technique is unable to convert an unsightly surgical result into a satisfactory one.

Cosmesis is similarly affected by the dose and fractionation of whole-breast irradiation; the vol- ume, technique, and dose of boost treatment; the irradiation of peripheral nodal areas; and the use of adjuvant chemotherapy. Satisfactory results are gen-

From the Diuision ofRadiation Oncology, University Hospital, Geneva, &it&and.

No reprints available. Coptight 0 1992 iy W.B. Saunders Cornpay 1053-4296/92/0202-07$05.00/0

erally obtained with 45 to 50 Gy homogeneously applied to the whole breast in 23 to 28 fractions over 4.5 to 5.5 weeks. An unacceptable degree of fibrosis often results if higher total doses are applied,4X5 if daily fractions significantly greater than 2 Gy are given> or if only one field per day is treated6 (see below). Breast irradiation with a 4- to 6-MV linear accelerator, which generally results in a more homo- geneous dose distribution and a lower surface dose than telecobalt treatment, is likely to produce more favorable cosmesis, although this has not been objec- tively documented.

Although its contribution to local control is rela- tively modest, boost irradiation has the potential to exert a substantial adverse effect on cosmesis, through intense fibrosis or unsightly skin changes. Electron beam boost doses of 10 to 15 Gy seldom lead to visible sequelae, but higher doses lead to telangiectasias and induration in a significant percentage of cases. If higher boost doses are deemed necessary, interstitial implant therapy is recommended by some authors.“” Although interstitial boost therapy provides skin sparing with respect to electron beam treatment, the purported superiority of the former technique in this regard has not been convincingly shown. An adverse influence of implant volume on cosmesis has been reported.’

Regional nodal irradiation in conjunction with breast conservation is particularly problematic, in that it potentially endangers the esthetic result through possible overdosing at junctions between the nodal volumes and the breast volume. Such a match- line effect can result in parasternal fibrosis and skin changes if a separate internal mammary field is used, and a similar zone of fibrosis due to mismatch between supraclavicular-axillary and breast volumes can contribute to upward retraction of the breast.2,4 Sophisticated blocking techniques have been de- scribed that keep matchline problems to a mini- mum.g-”

Although quantitative scales based on breast re- traction have been devised,‘2,‘3 assessment of the esthetic aspects of therapy results remains largely

Seminars in Radiation Oncology, Vol 2, No 2 (April), 1992:# 125-131 125

126 Kurtz and Miralbell

subjective, based either on the observations of the treating physician, of the patient herself, or of a disinterested third party. Since the lasting sequelae due to radiotherapy generally become visible only after the first year and may progress significantly during the subsequent few years,6’14 an assessment regarding cosmesis is best performed on patients having a follow-up of at least 3 to 5 years. Using a three- or four-grade system ranging from excellent to unacceptable, there is considerable agreement in the literature with respect to overall long-term cosme- sis. The large majority of patients have good to excellent results, and 5% to 10% of patients have unsatisfactory results (Table 1). An unfavorable influ- ence of adjuvant chemotherapy on cosmesis has been reported by investigators from the Joint Center for Radiation Therapy, Harvard University,16 with excel- lent results at 5 years being observed in 71% of patients treated without and 40% of patients treated with chemotherapy. Simultaneous administration of radio- and chemotherapy appeared particularlydisad- vantageous in this regard.“j Although telangiectasias and breast retraction can progress in some instances between 5 and 10 years,6 long-term results from the Marseilles group indicate that the proportion of patients within each category remains quite stable at least for 20 years (Fig 1).

Complications of Breast-Conserving Therapy Significant late complications are almost exclusively related to the treatment of the regional nodal areas and are thus not an inherent property of breast- conserving therapy. Complications clearly related to treatment of the breast itself are rare and of minor importance with current radiotherapy techniques. Acute skin reactions are virtually always self-limiting when megavoltage therapy is used. Significant breast

edema occurs almost exclusively in patients who had axillary surgery; its incidence is related to the extent of surgical dissection.‘g Although breast swelling can occasionally be psychologically disturbing and can adversely affect the early cosmetic results, it usually resolves within the first 1 to 3 years following irradia- tion16’lg and thus is seldom a long-term complication of treatment.

Since a portion of the chest wall must be included in the primary treatment volume, injury to the ribs and soft tissues underlying the breast is occasionally seen, especially if the boost technique results in a significant supplementary dose to the chest wall. During the first 2 years following treatment, patients may experience intermittent or fluctuating chest wall pain, the precise cause of which is unclear. Although this has been termed “myositis” by some authors,” such symptoms may also reflect irritation of the periosteum of the ribs. These complaints are seldom of importance and at any event are self- limiting. Rib fractures, or localized radionecroses of ribs, are often asymptomatic and have been reported in 1% to 2% of patients.7”5”8 Soft-tissue necroses should be extremely rare with the doses used in the treatment of early-stage breast cancer. However, localized fat necrosis has been observed in 1% to 8% of treated patients,7’2’ usually in the high-dose boost area. Although self-limiting and harmless, fat necro- sis is worthy of mention in that it may be confused with local tumor recurrence.

Complications related to irradiation of the supra- clavicular-axillary region include limitation of shoul- der motion, brachial plexus injury, as well as an increased risk of arm edema following axillary dissec- tion. Internal mammary nodal treatment may in rare instances provoke acute radiation pericarditis. With longer follow-up, excess deaths from myocar- dial infarction have been reported in patients irradi- ated to the heart using a direct parasternal photon

Table 1. Long-Term Cosmetic Scores in Selected Series of Stage I and II Patients Treated With Breast-Conserving Surgery and Megavoltage Radiotherapy

Institution Interval Results

N 0 Excellent Good Fair PWr

University of Pennsylvania” Harvard JCRT16 Gustave-Rous$ Curie” Marseilles Cl* Henri Mondor”

697 5 - 91% - 9% - 593 5 65% Gt% 7% 3% 592 5 58% 38% - 8% - 125 10 66% - 30% - 4% 491 10 55% 38% 5% 3% 112 15 66% 28% - 6% -

*SpitalierJ-M, KurtzJM: unpublished data, 1990.

Breast Conservation: Cosmesis and Complicatioru 127

% - 100 “~.-. A--

*-. :.

-90 \ ’ . #

\ j I \

-80

_ 70

_ 60 ABSENT/MILD

Figure 1. Sequelae of radio- therapy observed as a func-

-50 ____.

tion of time in stage I and II patients treated at the Mar-

- 4. -

seilles Cancer Institute and - associated clinics between 1963 - 30 and 1982 by conservative sur- - gery and megavoltage radio- _ 20 therapy. The numbers under _ the time axis indicate the _ 10 number of breasts evaluated at each 5-year interval. (Data A/ from Snitalier T-M and Kurtz

I I I I I I II 11 11 1 ” 1 ’ “1 5 10 15 2’. YEARS

JM, unpublished, 1990). 1120

field (see below). Symptomatic radiation-induced pulmonary reactions occur almost exclusively in pa- tients receiving nodal irradiation in addition to breast irradiation. Although such reactions may leave per- manent radiographic sequelae in the form of apical and paramediastinal fibrosis, they rarely require specific treatment and are generally self-limiting. The risk of significant arm edema due to radiother- apy alone is 1% or less for an undissected axilla if doses of 45 to 50 Gy are given.24 If radiotherapy is added after axillary dissection, the rate and severity of edema presumably depend on the extent of axillary surgery and the radiotherapeutic techniques used. In a large collaborative study, 78 of 907 (9%) patients treated by both staging axillary dissection and axillary radiation therapy developed edema of 2

491 142 36 NUMBER AT RISK

cm or more,24 a finding in agreement with the 7% incidence reported by Montague et a1.7 Complication rates from representative modern series are summa- rized in Table 2.

The risk of developing serious complications ap- pears to be significantly increased in patients receiv- ing adjuvant chemotherapy. In a study of 1,116 patients receiving breast and nodal irradiation at the Harvard Joint Center for Radiation Therapy be- tween 1968 to 1985, brachial plexus injury was observed in 4.6% of patients receiving chemotherapy versus 0.6% of patients treated without chemother- apy.** Symptomatic pneumonitis, observed in only 0.6% of patients treated without chemotherapy, was seen in 1.3% of patients receiving sequential and 8.7% of patients receiving concomitant chemother-

Table 2. Complications of Radiotherapy in Patients Treated With Breast Preservation and Irradiation of Both Breast and Nodal Areas

Institution Symptomatic Brachial

N Pneumonitis ,. Pericarditis Rib Fracture Plexopathy

University of Pennsylvania” Harvard JCRT2,23 M.D. Anderson7 Henri Mondor’*

697* 0.7% 0% 1.1% 0.3% 1,116 1.4% 0.3% NR 1.8%

263 7% NR 1.5% 1% 245 NR 0% 1.5% 0%

NR, not reported. *466 Patients received breast radiotherapy only. Note: As arm edema is primarily a surgical complication, this has not been included in the tabulation.

128 Kurt2 and Miralbell

apy.23 It is apparent that particular caution must be exercised in the use of breast and nodal irradiation in conjunction with adjuvant chemotherapy.

Radiobiologic Analyses of Clinical Complications

Although most of the studies cited previously are based largely on subjective assessments of the nor- mal tissue effects of breast cancer radiotherapy, a few authors have quantitatively analyzed these late effects with regard to dose, fractionation sensitivity, and latency time, using the endpoints of fibrosis, asymmetry, and telangiectasia. Studies published thus far have consistently suggested low o/p ratios characteristic of late-responding tissues, indicating a strong dependence on fraction size, with smaller fractions being associated with reduced complication rates. Van Limbergen et al4 analyzed the cosmetic endpoint of late fibrosis after breast irradiation in 161 patients and found that the best fit for the dose-response curves was obtained for an a/P ratio of 2.5 Gy. Bentzen et al,” assessing late effects in 229 breast cancer patients who had received postmastec- tomy irradiation in either two or five weekly frac- tions, obtained (Y/P ratios of 1.9 Gy and 3.7 Gy for fibrosis and telangiectasia, respectively. Turesson and Thame? evaluated the acute and late effects in 450 patients treated with 1,2, or 5 fractions per week and either 2 or 3 fractions per day. An o/p value of 2.8 Gy for late telangiectsia was determined.

The time-course of development of radiation- induced injuries is often prolonged. The concept of “latency time” is a fundamental issue in assessing the incidence of radiation injury and estimating parameters of repair kinetics. Many years may be needed after the initial latency period for all patients who will be affected to manifest the complication. Similarly, it may take years to see the full develop- ment of complications (ie, for them to reach their final degree of severity) in any single patient. Ignor- ing considerations of latency may lead to underesti- mation of the incidence and severity of late radiation sequelae, thus biasing estimates of radiobiologic parameters. Using actuarial methods, Turesson14 analyzed the time for development of telangiectasias in patients treated with postmastectomy radiother- apy. Progression of telangiectasias was observed for at least 5 to 10 years after treatment, the latency time being a decreasing function of dose. These data were also analyzed by Bentzen et alz7 according to a graded scoring system. They observed the longest

latency times and courses of progression in patients who had the lowest probability of developing telangi- ectasias. The time required to detect 90% of patients who would eventually develop severe telangiectasias was estimated to be beyond 15 years for the patient group having a low probability of developing this complication. The corresponding latency time for fibrosis was 3.2 years.

Radiobiologic parameters for functional late ef- fects related to treatment of the axillary and supra- clavicular regions have also been studied. Bentzen et al’* estimated the repair capacity for impaired shoul- der motion after radiotherapy, using a scoring sys- tem to measure maximal flexion and abduction of the arm. The authors estimated the o/p ratio for this late effect to be 3.5 Gy, with 90% of cases appearing within 3.9 years. Powell et al” studied brachial plexus injury in 449 patients treated with postoperative radiotherapy, with either 45.9 Gy in 15 fractions or 54 Gy in 30 fractions delivered to the brachial plexus over 6 weeks. The actuarial incidence of plexopathy was higher (5.9%) in patients treated with the larger than with the smaller (1%) fraction sizes. With these data and others reported in the literature? the authors were able to estimate the o/p values for peripheral neuropathy to be in the range of 1.5 to 2 GY.

Does Radiotherapy for Breast Cancer Increase the Late Mortality Rate?

Recent meta-analysis of randomized studies of adju- vant postmastectomy irradiation has indicated a significantly increased mortality after 10 years in treated patients?’ Although there are alternative explanations for this observation,32 a true pejorative effect of radiotherapy cannot be excluded. As alluded to above, analysis of individual studies supports the notion that an excess of late cardiovascular deaths might be attributed to direct irradiation of the heart resulting from treatment of the internal mammary nodes in patients with left-sided breast cancers.33-35 In addition, data from the Cancer Registry in Sweden, where postoperative radiotherapy was used in about 50% of breast cancer patients, indicated a signifi- cantly higher risk of death due to myocardial infarc- tion in breast cancer patients with left-sided tumors than in patients with right-sided tumors.36

However, it should be pointed out that the radia- tion techniques used in these studies would not be considered acceptable today. The excess cardiovascu-

Breast Conservation: Cosmesis and Complications 129

lar mortality reported in the Manchester35 and Kings- Cambridge trials34 was associated with the use of orthovoltage irradiation techniques, and the Oslo study delivered 60 Gy in 2.5 Gy fractions with a direct anterior telecobalt field.33 Nonetheless, it is clear from these data that special attention must be paid to minimizing irradiation to the anterior aspect of the heart when treating the internal mammary lymph nodes, and that the possible risks of such treatment must be carefully weighed against the potential benefits for each individual patient.

The potential induction of second cancers repre- sents another possible source of increased late mortal- ity in irradiated patients. This might include con- tralateral breast cancers (from scatter irradiation due to treatment of the opposite breast), sarcomas or other malignant tumors (in volumes treated to high dose), and other malignancies, including acute leuke- mia. Available results have thus far been reassuring. Contralateral breast cancers are observed at a rate of 0.5% to 0.9% per year after the treatment of patients with unilateral cancer, with both hospital-based and population-based data suggesting equivalent rates for patients treated with local-regional radiotherapy or with surgery alone?’ Recently, data have been reported from trials in which patients were randomly assigned to receive local-regional radiotherapy or observation following surgery. In the Rings-Cam- bridge trial, a significant excess of contralateral cancers was observed for patients treated with ortho- voltage therapy, but no such effect could be observed for patients receiving megavoltage treatment?4 Nor has an excess of contralateral breast cancer rates been observed either in the first Stockholm tria1,38 or in the Milan QUART Trial, the only breast-conserva- tion trial with long-term follow-up.3g Although none of the available data implicate megavoltage treat- ment as a cause of contralateral breast cancer induc- tion, significant long-term risks in subgroups of patients (eg, very young patients) cannot be ex- cluded. Thus it is recommended that treatment techniques be used that minimize the radiation exposure of the opposite breast.40

Sarcomas occurring after local-regional irradia- tion for breast cancer have been described, including a few cases after breast-conserving therapy.37 As sarcomas are relatively rare tumors, their occurrence in an irradiated area after an appropriate latency period must be accepted as a complication of treat- ment. In one review of 344 post-irradiation sarcomas, 30.8% were found to have occurred after treatment of breast cancer.41 The risk of sarcoma induction is

presumably related both to treatment volume and total dose. The majority of bone sarcomas have been described after orthovoltage therapy:’ and a lesser risk is to be expected with the lower bone absorption associated with megavoltage treatment. However, soft-tissue sarcomas are observed in the range of doses routinely used in breast cancer therapy, 11 of 12 post-irradiation sarcomas in one series occurring after a dose of 45 GY:~ It is not apparent that post-irradiation soft-tissue sarcomas will become less frequent with megavoltage treatment. Mean latency periods for post-irradiation sarcomas have been re- ported to be 9.5 to 11 years.4”43 Although post- irradiation sarcomas rarely appear before the fifth post-treatment year, a shorter latency period does not exclude this diagnosis. As sarcomas have been described as long as 33 years following radiotherapy, it is unknown whether there is a maximum period at risk.4’ The few available data provide surprisingly consistent estimates of the risk of sarcoma induction. Data from the Connecticut Tumor Registry indi- cated an excess of 18.2 sarcomas in irradiated breast cancer patients per 100,000 patient-years of fol- low-up after the fifth year.% Similarly, in patients treated at the Marseilles Cancer Institute, two soft- tissue sarcomas were seen in 9,148 patient-years of observation after 5 years.37 Eleven sarcomas were observed in 7,620 irradiated breast cancer patients at the Institut Gustave-Roussy, an actuarial incidence of 0.2% at 10 years.43 Comparing this with age- specific incidence rates from the Danish Cancer Registry, an excess risk of 10 sarcomas per 100,000 patient-years was calculated.43 Thus, it appears that 1 to 2 soft-tissue sarcomas might be expected to arise in the irradiated volume per 1,000 patients per decade of follow-up after 4 or 5 years following primary treatment.

The question of leukemia risk following breast cancer radiotherapy has been studied and reviewed by Curtis et al.45 Although cohort studies provide conflicting data, the authors conclude that the weight of available evidence, particularly from carefully conducted case-control studies, excludes a clinically significant increase in leukemia associated with the use of radiation therapy. There are few studies concerning the possible influence of radiotherapy on other second malignancies in breast cancer patients, although there is some suggestion from Connecticut data that the frequency of non-Hodgkin’s lympho- mas and carcinomas of the kidney and esophagus might be increased.44

The hypothesis that breast cancer radiotherapy

130 Kurt< and Miralbell

might exert deleterious effects through immunologic mechanisms has been raised by Stjernsward,% with the implication that irradiated patients might be at greater risk of developing distant metastases. Extensive studies of lymphocyte subpopulations and immune parameters have subsequently been per- formed in patients treated in a randomized trial of postmastectomy irradiation in Stockholm. Radiation therapy resulted in both a long-term reduction in T-cell counts47 and a measurable impairment in certain parameters of immunologic reactivity.@ How- ever, irradiated patients in this trial developed signif- icantly fewer metastases than the surgical control patients and had a nonsignificant improvement in overall survival as we11.4g No increase in breast cancer mortality has been seen in irradiated patients in any of the other major trials of postmastectomy irradia- tion,33”5,50 indicating that the laboratory evidence of immunosuppression associated with breast cancer radiation therapy is not likely to be clinically relevant.

Conclusions Good to excellent cosmetic results can be achieved in a large majority of patients through the judicious use of conservative surgery and megavoltage breast irra- diation, if current guidelines of dose and fraction- ation are observed. Although such therapy is as- sociated with a virtual absence of significant complications, both the cosmetic result and the risk of complications can be unfavorably influenced by the addition of nodal irradiation and/or adjuvant chemo- therapy. If nodal areas are treated, techniques should be used to eliminate overlap between breast and nodal treatment fields, and direct irradiation of the heart should be minimized. The safest and most effective way of integrating radiotherapy and chemo- therapy remains to be defined.

Progression of radiation-related sequelae more than 5 years following treatment is uncommon, and the long-term stability of the cosmetic outcomes achieved by that point can be expected. Apart from a very small risk of sarcoma induction, there is no convincing evidence that megavoltage irradiation confined to the breast is associated with secondary malignancies or other serious late morbidity. How- ever, an increased risk of late cardiovascular mortal- ity has been observed after full-dose cardiac irradia- tion of left-sided breast cancers. It is apparent that indications for the irradiation of nodal areas should be carefully based on the individual oncologic risks,

and that scrupulous radiotherapeutic techniques must be employed.

References I. Veronesi U, Volterrani F, Luini A, et al: Quadrantectomy

versus lumpectomy for small size breast cancer. Eur J Cancer 2667 l-673,1990

2. Olivotto IA, Rose MA, Osteen RT, et al: Late cosmetic outcome after conservative surgery and radiotherapy: Analy- sis of causes of cosmetic failure. Int J Radiat Oncol Biol Phys 17:747-753, 1989

3. Fisher B, Wolmark N, Fisher ER, et al: Lumpectomy and axillary dissection for breast cancer: Surgical, pathological and radiation considerations. World J Surg 9:692-698, 1985

4. Van Limbergen E, Rijnders A, van der Schueren E, et al: Cosmetic evaluation ofbreast conserving treatment for mam- mary cancer. 2. A quantitative analysis of the influence of radiation dose, fractionation schedules and surgical treatment techniques on cosmetic results. Radiother Oncol 16253-267, 1989

5. Delouche G, Bachelot F, PrCmont M, et al: Conservation treatment of early breast cancer: Long-term results and complications. Int J Radiat Oncol Biol Phys 13:29-34, 1987

6. Dewar JA, Benhamou S, Benhamou E, et al: Cosmetic results following lumpectomy, axillary dissection and radiotherapy for small breast cancers. Radiother Oncol 12:273-280, 1988

7. Montague ED, Schell SR, Romsdahl MD, et al: Conservation surgery and irradiation in the treatment of breast cancer. Front Radiat Ther Oncol 17:76-83, 1983

8. Pierquin B, Owen R, Maylin C, et al: Radical radiation therapy of breast cancer. Int J Radiat Oncol Biol Phys 6: 17-24, 1980

9. Siddon RL, Buck BA, Harris JR, et al: Three-field technique for breast treatment using tangential field corner block. Int J Radiat Oncol Biol Phys 9:583-588,1983

10. Conte G, Nascimben 0, Turcato G, et al: Three-field isocen- tric technique for breast irradiation using individualized shielding blocks. Int J Radiat Oncol Biol Phys 14: 1299-1305, 1988

11. Chu JCH, Solin LJ, Hwang CC, et al: A nondivergent three field matching technique for breast irradiation. Int J Radiat OncolBiolPhys 19:1037-1040,199O

12. Pezner RD, Patterson MP, Hill LR, et al: Breast retraction assessment: An objective evaluation of cosmetic results of patients treated conservatively for breast cancer. Int J Radiat Oncol Biol Phys I 1:575-578, 1985

13. Van Limhergen E, van der Schueren E, van Tongelen K: Cosmetic evaluation of breast conserving treatment for mam- mary cancer. I. Proposal of a quantitative scoring system. Radiother Oncol 16159-167, 1989

14. Turesson I: The progression rate of late radiation effects in normal tissues and its impact on dose-response relationships. Radiother Oncol 15:217-226, 1989

15. Fowble B, Solin LJ, Schultz DJ, et al: Ten-year results of conservative surgery and radiation for Stage I and II breast cancer. Int J Radiat Oncol Biol Phys 2 1:269-277,199 1

16. Rose MA, Olivotto I, Cady B, et al: Conservative surgery and radiation therapy for early breast cancer. Long-term cosmetic results. Arch Surg 124: 153-157, 1989

17. Calle R: Experience with breast conserving approaches at the Curie Institute, in Tobias JS, Peckham MJ (eds): Primary

Breast Conmvation: Cometi and Complicatiotu 131

18.

19.

20.

21.

23.

24.

26.

27.

28.

29.

30.

31.

32

Management of Breast Cancer. London, Edward Arnold, 1985, pp 59-79 Pierquin B, Huart J, Raynal M, et al: Conservative treatment for breast cancer: Long-term results (15 years). Radiother Oncol20: 16-23, 1991 Clarke D, Martinez A, Cox RS, et al: Breast edema following staging axillary node dissection in patients with breast carci- noma treated by radical radiotherapy. Cancer 492295-2299, 1982 Ray GR, Fish VJ, Marmor JB, et al: Impact of adjuvant chemotherapy on cosmesis and complications in stages I and II carcinoma of the breast treated by biopsy and radiation therapy. Int J Radiat Oncol Biol Phys l&837-841, 1984 Boyages J, Bilous M, Barraclough B, et al: Fat necrosis of the breast following lumpectomy and radiation for early breast cancer. Radiother Oncol 13:69-74,1988 Pierce SM, Recht A, Lingos T, et al: Long-term radiation complications following conservative surgery (CS) and radia- tion therapy (RT) in early stage breast cancer. Int J Radiat OncolBiolPhys21:133-134, 1991 (abstr) (suppl 1) Lingos TI, Recht A, Vicini F, et al: Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 2 1:355-360, 1991

Pierquin M, Mazeron J-J, Glaubiger D: Conservative treat- ment of breast cancer in Europe: Report of the Groupe EuropCen de CuriethCrapie. Radiother Oncol6: 187-198, 1986 Bentzen SM, Thames HD, Overgaard M: Latent time estima- tion in late cutaneous and subcutaneous radiation reactions in a single follow-up clinical study. Radiother Oncol 15:267-274, 1989

Turesson I, Thames HD: Repair capacity and kinetics of human skin during fractionated radiotherapy: Erythema, desquamation, and telangiectasia after 3 and 5 years’ follow- up. Radiother Oncol 15:169-188, 1989 Bentzen SM, Turesson I, Thames HD: Fractionation sensitiv- ity and latency of telangiectasia after post-mastectomy radio- therapy: A graded response analysis. Radiother Oncol l&95- 106,199O Bentzen SM, Overgaard M, Thames HD: Fractional sensitiv- ity of a funtional endpoint: Impaired shoulder movement after post-mastectomy radiotherapy. Int J Radiat Oncol Biol Phys 17:53 l-537, 1989 Powell S, Cooke J, Parsons C: Radiation-induced brachial plexus injury: Follow-up of two different fractionation sched- ules. Radiother Oncol 18:213-220,199O Basso-Ricci S, della Costa C, Vaganotti G, et al: Report on 42 cases of post-irradiation lesions of the brachial plexus and their treatment. Tumori 66:117-122, 1980 Cuzick J, Stewart H, Peto R, et al: Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer. Cancer Treat Rep 71:15-29, 1987 Levitt SH, Potish RA, Lindgren B: Assessing the role of adjuvant radiation therapy in the treatment of breast cancer. Int J Radiat Oncol Biol Phys 15:787-790,1988

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

34. Haybittle JL, Brinkley D, Houghton J, et al: Postoperative radiotherapy and late mortality: Evidence from the Cancer Research Campaign trial for early breast cancer. Br Med J 298:1611-1614,1989

35. Jones JM, Ribeiro GG: Mortality patterns over 34 years of

36.

37.

38.

39.

40.

41.

42.

43.

44

45

46

breast cancer patients in a clinical trial of post-operative radiotherapy. Clin Radio1 40:204-208, 1989 Rutqvist LE, Johansson H: Mortality by laterality of the primary turnour among 55,000 breast cancer patients from the Swedish Cancer Registry. BrJ Cancer 61:866-868, 1990 KurtzJM, Amalric R, Brandone H, et al: Contralateral breast cancer and other second malignancies in patients treated by breast-conserving therapy with radiation. Int J Radiat Oncol Biol Phys 15:277-284, 1988 Wilking N, Rutqvist LE: The risk of contralateral breast cancer after adjuvant radiation of patients with early breast cancer: Results from a randomized clinical trial. Proc Am Sot Clin Oncol8: 149, 1989 Veronesi U, Banfi A, Salvadori B, et al: Breast conservation is the treatment of choice in small breast cancer: Long-term results of a randomized trial. EurJ Cancer 26:668-670, 1990 Fraass BA, Robcrson PL, Lichter AS Dose to the contralateral breast due to primary breast irradiation. Int J Radiat Oncol Biol Phys 11:485-497, 1985 Robinson E, Neugut AI, Wylie P: Clinical aspects ofpostirradi- ation sarcomas. J Nat1 Cancer Inst 80:233-240, 1988 Doherty MA, Rodgers A, Langlands AO: Sarcoma of bone following therapeutic irradiation for breast carcinoma. Int J Radiat Oncol Biol Phys 12:103-106, 1986 Taghian A, de Vathaire F, Terrier P, et al: Long-term risk of sarcoma following radiation treatment for breast cancer. Int J Radiat Oncol Biol Phys 19:186, 1990 (abstr) (suppl 1) Harvey EB, Brinton LA: Second cancer following cancer of the breast in Connecticut. Nat1 Cancer Inst Monogr 68:9-112, 1985

Curtis ME, Boice JD, Stovall M, et al: Leukemia risk following radiotherapy for breast cancer. J Clin Oncol7:21-29,1989 Stjernsward J: Decreased survival related to irradiation postop eratively in early operable breast cancer. Lancet 2:1285-1286, 1974

47. Rotstein S, Blomgren H, Petrini B, et al: Long term effects on the immune system following local radiation therapy for breast cancer. I. Cellular composition of the peripheral blood lymphocyte population. Int J Radiat Oncol Biol Phys 11:921- 925,1985

48. Wasserman J, Wallgren A, Blomgren H, et al: Prognostic relevance of postirradiation lymphocyte reactivity in breast cancer patients. Cancer58:348-351,1986

49. Rutqvist LE, 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 16:629-639, 1989

50. Fisher M, Redmond C, Brown A, et al: Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 312:674-681, 1984