Background and Methods Conservative surgery and radiotherapyhave become well-established treatments for breast cancer, andmany trials in progress are attempting to define the most acceptabletype of procedure. Between 1987 and 1989 we randomly assigned567 women with small breast cancers (<2.5 cm in diameter)to quadrantectomy followed by radiotherapy or to quadrantectomywithout radiotherapy. All patients underwent total axillarydissection. The median follow-up period was 39 months (range,28 to 54).
Results The incidence of local recurrence was 8.8 percent amongthe patients treated with quadrantectomy without radiotherapy,as compared with 0.3 percent among those treated with postsurgicalradiotherapy (P = 0.001). However, there was a substantial effectof age: patients more than 55 years old who did not receiveradiotherapy had a low rate of local recurrence (3.8 percent).The four-year overall survival was similar in the two treatmentgroups.
Conclusions Administering radiotherapy after quadrantectomyreduces the risk of local recurrence in women with small cancersof the breast, but radiotherapy may not be necessary in elderlywomen.
Twelve years ago we observed in a randomized trial that theresults of Halsted radical mastectomy might be equaled by thoseof more conservative treatment, such as quadrantectomy withaxillary dissection and radiotherapy1. These results were subsequentlyconfirmed by other investigators2,3,4. In recent years, additionalclinical trials have been undertaken to identify treatment programsthat would allow maximal local control of the disease and thebest cosmetic results5,6,7,8.
At the Milan Cancer Institute we tried two different approaches:one procedure reduced the extent of the surgical resection whileoptimizing the effect of radiotherapy, and the other maintainedthe extent of resection while reducing the intensity of radiotherapy.The first procedure was tested in a randomized trial in whichclassic quadrantectomy combined with radiotherapy was comparedwith a simple "tumorectomy" followed by intensive, partly interstitialradiotherapy5. Survival was similar in the two groups of patients,but there were significantly more local recurrences among thosetreated with tumorectomy and radiotherapy.
The second trial, reported here, was a controlled study in whichquadrantectomy combined with radiotherapy was compared withquadrantectomy alone. Patients treated with quadrantectomy aloneunderwent radiotherapy only if they had a recurrence; therefore,the ultimate comparison was between the results of immediate(prophylactic) radiotherapy after quadrantectomy and the resultsof delayed (therapeutic) radiotherapy after quadrantectomy.
Methods
Treatment Groups
Between 1987 and 1989, 579 women with carcinomas of the breastless than 2.5 cm in maximal diameter at pathological examinationwere randomly assigned to one of two treatments: 299 patientswere assigned to quadrantectomy combined with axillary dissectionand radiotherapy, and 280 to quadrantectomy combined with axillarydissection without immediate radiotherapy. Randomization toprophylactic radiotherapy or to therapeutic radiotherapy onlyin case of recurrence was performed immediately after surgery(quadrantectomy and axillary dissection). In 12 patients themargins of the resection were found to contain tumorous tissue(5 patients assigned to quadrantectomy with radiotherapy and7 assigned to quadrantectomy alone); consequently, these patientswere excluded, since they were candidates for a second operationor radiotherapy.
There was no significant difference between the two treatmentgroups in age, site and size of the primary carcinoma, histologiccharacteristics, and prevalence of axillary invasion (Table 1).Similarly, there was no significant difference between thegroups in the distribution of patients with nodal involvementaccording to the adjuvant treatments administered for this condition(Table 2). The two groups of patients were therefore comparable.
Table 2. Adjuvant Treatment Administered to Patients with Nodal Involvement.
Surgical Technique
Quadrantectomy consisted of extensive breast resection, includinga portion of the skin overlying the tumor and the underlyingfascia, generally performed with a radial incision. Axillarydissection always included total removal of all lymph nodesof the three levels up to the apex of the axilla. When the tumorwas located in the upper outer quadrant, the nodes were removeden bloc with the primary carcinoma. In other locations, thedissection was performed through a separate incision.
Pathological Examination
The specimen of breast tissue was examined, and the whole surfaceof the resected area was stained. The primary carcinoma andthe extent of the normal tissue removed around the tumor weremeasured on the cut surface. The minimal distance of the tumor(whether the carcinoma was infiltrating, intraductal, or both)from the inked margin was measured with the aid of a micrometricocular after at least five histologic sections 5 microm thickwere examined.
Radiotherapy
Patients treated with both quadrantectomy and radiotherapy receivedradiation therapy from a cobalt unit or a 6-MeV linear accelerator,starting four to six weeks after surgery. The breast was treatedwith two opposing tangential fields (a total of 50 Gy givenover a five-week period, with a daily target dose of 2 Gy) andthen with a boost dose to the tumor bed with an orthovoltageunit (10 Gy in five fractions).
Follow-up
Follow-up was strict and included routine clinical examinationevery four months and mammography, chest radiography, bone scanning,and ultrasonography of the liver every year. If a local recurrencewas suspected, mammography and a fine-needle biopsy were performed.The median length of follow-up was 39 months (range, 28 to 54).
Adjuvant Treatment
Patients with positive axillary nodes (nodal involvement) weretreated with adjuvant medical therapy: premenopausal patientsand postmenopausal patients negative for estrogen receptorsreceived chemotherapy (a regimen of cyclophosphamide, methotrexate,and fluorouracil), and postmenopausal patients positive forestrogen receptors received tamoxifen. Nine patients with positivenodes declined adjuvant treatment (six patients in the grouptreated with quadrantectomy and radiotherapy and three in thegroup treated with quadrantectomy).
Statistical Analysis
Life tables were constructed by the Kaplan-Meier method, andP values calculated with the log-rank test, on the basis ofoverall follow-up9,10.
Results
As in our previous trials, we defined a local recurrence asthe appearance of any new tumor in the breast within 2 cm ofthe surgical scar, and a second primary carcinoma as the appearanceof any new tumor in other quadrants of the breast more than2 cm from the scar.
We observed a considerable difference in the rate of local recurrencebetween the two treatment groups (Table 3). Only 1 of the 294patients treated with quadrantectomy and radiotherapy (0.3 percent)had a local recurrence, as compared with 24 of 273 patientstreated with quadrantectomy (8.8 percent) (Figure 1).
Figure 1. Cumulative Incidence of Local Recurrences among 567 Women with Breast Cancer, According to Treatment Group.
The values in parentheses are the number of recurrences, followed by the number of patients in the treatment group.
Although the analysis of risk factors for local recurrence wasnot the primary objective of the study, we found that amongthe many variables evaluated (Table 4 and Figure 2), age wasthe most important. In the quadrantectomy group, the recurrencerate was 17.5 percent among patients 45 years of age or youngerand 3.8 percent among those over 55. Since a difference betweensubgroups in the rate of distant recurrence might obscure therisk of local recurrence, we analyzed the rate of occurrenceof distant metastases. There were no differences among the variousage groups. We also found no differences in recurrence ratesamong subgroups defined according to tumor size or the statusof the axillary nodes (positive or negative) (Figure 3). Patientswith an extensive intraductal component had a much higher rateof local recurrence (7 of 42, or 16.7 percent) than patientswithout this histologic feature (17 of 231, or 7.4 percent)(Figure 4). There was no difference between the rate of localrecurrence among 184 estrogen-receptor-positive patients (16recurrences, or 8.6 percent) and the rate among 48 estrogen-receptor-negativepatients (5 recurrences, or 10.4 percent).
Table 4. Local Recurrences among 273 Patients Treated with Quadrantectomy Alone, According to Tumor Diameter, Age, Nodal Status, and Presence or Absence of Extensive Intraductal Component.
Figure 4. Cumulative Incidence of Local Recurrences among 273 Patients Treated with Quadrantectomy Alone, According to the Presence or Absence of an Extensive Intraductal Component.
Second primary carcinomas of the ipsilateral breast developedin four of the patients treated with quadrantectomy, but innone of those treated with quadrantectomy and radiotherapy.
According to the protocol, patients in the quadrantectomy groupwho had a local recurrence were to be treated with radiotherapyafter reexcision. However, of the 24 patients with recurrences,only 15 received this treatment. The other nine patients underwenttotal mastectomy, performed either because the recurring carcinomawas too large and the breast too small (four patients) or becausethe patient asked that the breast be removed (five patients).Of the 15 patients treated with reexcision and radiotherapy,1 patient had a second local recurrence and 1 had a new carcinomain another quadrant. Of four patients with second primary carcinomas,three underwent a second excision and radiotherapy and one underwenta mastectomy.
There was no difference between the two treatment groups insurvival four years after the beginning of the trial (actuarialsurvival curves were calculated according to the product-limitmethod of Kaplan and Meier10; data not shown).
Discussion
The results of this trial show clearly that postoperative radiotherapyadministered directly after quadrantectomy has a protectiveaction against local recurrences and new primary carcinomas.This was not unexpected, but the difference between the outcomeswas marked (24 local recurrences and 4 new carcinomas afterquadrantectomy alone, as compared with 1 recurrence and no newtumors after quadrantectomy combined with radiotherapy). Inthe quadrantectomy group, local recurrences occurred mainlyin patients under 55 years of age and rarely in patients beyondthis age. The presence of an extensive intraductal componentwas confirmed as an important predictor of the risk of a localrecurrence11.
In the quadrantectomy group, the patients who had positive nodestreated with adjuvant therapy and those who had negative nodesdid not differ in the incidence of local recurrence. This findingcontradicts our previous data, which showed a low rate of recurrenceamong patients with positive nodes that was ascribed to theprotective effect of adjuvant therapy12. The results of thepresent study suggest an alternative explanation: patients withpositive axillary nodes may be a selected subgroup with tumorsthat are more radiosensitive than those of patients with negativenodes. This might explain the absence of a difference in therate of local recurrence in the present trial between node-positiveand node-negative patients in the quadrantectomy group, sincethe node-positive patients received adjuvant therapy but noradiotherapy to the breast.
In fact, the degree of influence of nodal status on the riskof local relapse is uncertain. The many reports in the literaturethat consider the problem of local recurrence after conservativetreatments do not include nodal involvement in their lists ofrisk factors13,14,15,16,17. In contrast, according to Rose etal.18 the use of adjuvant chemotherapy lowered the incidencerate from 15 percent to 4 percent for relapses during the fiveyears after treatment of the primary tumor.
The limited number of local recurrences among postmenopausalwomen treated with quadrantectomy without radiotherapy may reflectthe difference between the structure of the mammary glands inwomen in this age group and that in young women. After menopause,the complex structure of the mammary gland disappears and thebreast is reduced to a fatty organ with scattered islands offibroepithelial tissue, without connections between them.
This trial confirms that quadrantectomy combined with axillarydissection and radiotherapy is an effective treatment that doesnot appear to expose patients to a significant risk of localrecurrence. An important issue in weighing our findings is thedifference between our results and the long-term results ofthe National Surgical Adjuvant Breast and Bowel Project previouslyreported by Fisher et al. (trial B-06)19. In the latter trial,among patients treated with lumpectomy without radiotherapythere was little difference between age groups in the incidenceof local recurrence: there were 89 recurrences among the 236patients 49 years of age or younger (37.7 percent), but 104recurrences among the 336 patients 50 years of age or older(30.9 percent)19.
The difference between the data of Fisher et al.19 and our resultsmay be explained by the difference in surgical procedures. Intheir study, the operation consisted of a simple excision ofthe primary carcinoma (lumpectomy) without removal of the skinand the pectoral fascia. In our study, the operation was muchmore extensive, removing 2 to 3 cm of normal breast tissue aroundthe tumor, the corresponding portion of overlying skin, andthe underlying muscular fascia.
Regardless of such differences, the results of both these studieslead us to conclude that in young women, even an extensive surgicalresection offers only incomplete protection against local recurrenceand that postsurgical radiotherapy is essential. In contrast,in older women a more extensive operation such as quadrantectomymay be sufficient to prevent local recurrence without a needfor radiotherapy, whereas this may not be true of a simple operationsuch as lumpectomy.
Source Information
From the Istituto Nazionale per lo Studio e la Cura dei Tumori, Via G. Venezian 1, 20133 Milan, Italy, where reprint requests should be addressed to Dr. Veronesi.
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