The Influence Of Radiotherapy On Local Recurrence

As outlined above, radiotherapy given after surgery is very important to eradicate microscopic tumor left in the breast after lumpec-tomy, and thus to achieve acceptable LR rates. Randomized trials2-5,81,82 have demonstrated that adjuvant radiation therapy following conservative surgery reduces the risk of local recurrences remarkably compared to surgery alone.2-5,81,82 In the nonirradiated lumpectomy cohort in the National Surgical Adjuvant Breast Program (NSABP)-B06 trial, a local recurrence rate of 39% was found, compared to 14% in the irradiated patients at 20 years of follow-up.2 The local recurrence rates found in the other studies for the group of nonirradi-ated patients are similar to these results. A recent meta-analysis by the Early Breast Cancer Trialists' Collaborative Group, studied a group of 7300 patients that were treated with breast-conserving surgery in trials of radiotherapy. They showed a 5-year local recurrence risk of 7% versus 26% (absolute reduction 19%), and 15-year breast cancer mortality risks of 30.5% versus 35.9% (reduction 5.4%), all in favor of adjuvant radiotherapy following breast-conserving surgery.81

Studies have been performed in which radiotherapy was the only treatment for breast cancer. Pierquin et al83 used combinations of external megavoltage irradiation with interstitial implants of radioactive sources to raise the combined dose in the primary tumor mass to 90-100 Gy. Doses of this magnitude provided control of all primary breast carcinomas <5 cm in diameter. In a retrospective analysis of 463 breast tumors with radiotherapy alone, Arriagada et al84 demonstrated the independent influence of radiation dose for tumor control of primary breast cancer of various sizes. For tumors <4 cm a local control rate at 3 years of 25% was found when doses of 40-50 Gy were given. At 3 years, local control was obtained with 70-80 Gy in 81% of the cases, while doses >80 Gy resulted in local control for all breast carcinomas. For tumors of a larger size, the control rates were lower, but still a dose-effect on tumor control was seen. It should be noted, that high radiation doses on the breast will yield high risk for complications, especially severe fibrosis.65,85

Nowadays, following conservative surgery, radiation therapy is given to the whole breast to a total dose of 45-50 Gy in a period of 5 weeks. This is usually followed by a boost of 10-20 Gy to the original tumor bed. In this way, a moderate radiation dose is given, resulting in minimal adverse effects on the breast and surrounding tissues. Variations in the radiotherapy technique are found to have impact on the LR rate. Prolongations of the overall treatment time with <8 Gy/ week was found to be associated with high LR rates.86

Also, during the interval of surgery and radiotherapy, repopulation of residual tumor cells may occur. A long delay between surgery and radiation therapy may therefore increase the rate of LR. Delay of radiation treatment is mostly studied in patients who received chemotherapy given during this interval. Few studies have been published about the effect of surgery-radiotherapy interval without chemotherapy given during this interval, and although higher LR rates are reported with increasing interval,87,88 this has not been found in all studies.32,89

After radiation to the whole breast, usually a boost is given to the tumor bed. The treatment volume of the boost is determined by the diameter of the tumor with a safety margin of approximately 2-3 cm. Surgical clips placed in the tumor bed are very useful in accurately determining the boost localization. A radiation boost to the tumor bed can be given in different ways: by photons, electrons or iridium-192 implants. There is no correlation between the type of boost employed and the risk of LR.90-93

It has been demonstrated that for patients with unknown margins of tumor resection, the addition of a boost appears to decrease the risk of a breast recurrence.94 For patients with negative margins, the value of an additional boost had been a subject of debate, which was ended with the results of the EORTC 22881 trial.65 This prospective trial randomized patients with microscopically negative margins after tumor excision between a boost or no boost. In total, 5318 early stage breast cancer patients were randomized to an additional boost of 16 Gy or no boost following whole breast radiation of 50 Gy. At 10 years follow-up, the cumulative incidence of local recurrence was 10.2% versus 6.2% for the no boost and the boost group, respectively, resulting in a reduction of LR with a factor of 0.59. Also in this study, young age was the most important risk factor for LR. It was also shown that patients younger than 40 years of age show the largest absolute clinical benefit from the additional boost. The LR risk in this age group was reduced from 23.9% to 13.5% at 10 years. As a result, the number of salvage mastectomies has been reduced by 41%. The EORTC 22881 trial also randomized patients (n = 251) with a microscopically incomplete excision between a boost dose of 10Gy versus 26Gy.95 A higher boost dose of 26 Gy resulted in a nonsignificant trend towards a lower LR rate. At 10 years, the cumulative incidence of local recurrence was 17.5 % versus 10.8 %; however, at the cost of an increased risk of fibrosis.

LOCAL RECURRENCE AFTER BREAST-CONSERVING THERAPY IS ASSOCIATED WITH POOR PROGNOSIS

LR after mastectomy has been known to be associated with poor prognosis even in the absence of synchronous distant metastases.96,97 It was considered in the initial period of BCT that prognosis after LR would be favorable because of the option of salvage mastectomy. In 1991, Fisher et al98 first described LR as a predictor for distant metastasis; this was later confirmed in other studies.29,99,100 It also appeared that after BCT a LR was found to be associated with poor prognosis. Whether LR is the cause of subsequent distant metastasis and poor prognosis or just an indicator of aggressive disease could not be resolved in these studies. Risk factors for distant metastasis after LR have only been studied in a few, very heterogeneous, studies.21,99,101-108 A short interval between BCT and time of LR, mostly defined as <2-3 years, is found to be a prognosticator for poor survival after LR.21,98-100,103-106 However, in most studies focusing on risk factors for survival after LR, patients are included who have distant metastasis diagnosed before or simultaneously with LR.

As already stated above, the results of the recently published Early Breast Cancer Trialists' Collaborative Group meta-analysis81 postulate that adequate local treatment reducing local recurrence rates would, in the hypothetical absence of any other causes of death, avoid about one breast cancer death over the next 15 years for every four local recurrences avoided.

THE INFLUENCE OF ADJUVANT SYSTEMIC THERAPY ON LOCAL RELAPSE IN BREAST-CONSERVING THERAPY

Adjuvant chemotherapy has been shown to have impact on LR. Lumpectomy withoutradi-ation has been associated with a significant risk of breast cancer recurrence also if chemotherapy is given with 5-year LR rates of 30-40%.7,82 However, when patients are treated with BCT including radiotherapy and adjuvant chemotherapy, a decreased incidence of LR is reported when compared to conservative surgery with radiation alone.7,64,109-111 In the NSABP B-13 trial,109 a total of 760 node-negative breast cancer patients with estrogen receptor-negative tumors were randomized between BCT followed by sequential methotrexate and fluorouracil or BCT alone. The risk for LR at 8 years among node-negative patients who had tumor-free margins after BCT was 2.6% for patients treated with adjuvant chemotherapy versus 13.4% for patients treated with BCT alone. Similar data were also found for adjuvant tamoxifen after BCT; in the NSABP-B-14 trial,112 at 7 years the LR rate was 2.2% for node-negative patients who were randomized to receive tamoxifen versus 5.5% of the patients randomized to receive placebo. Postmenopausal node-negative patients treated in the Stockholm Adjuvant Tamoxifen Trial,113 were randomized to receive either adjuvant tamoxifen or no further treatment. At 8 years follow-up, patients treated with BCT who received tamoxifen had an LR as first event of 3% versus 7% in patients who did not receive tamoxifen.

Thus, the use of adjuvant systemic therapy seems to potentiate the effects of breast irradiation after breast-conserving surgery for invasive breast cancer. It has also been shown that different chemotherapy regimes hold different effects on local control. In the NSABP B-19 protocol,109 node-negative breast cancer patients treated with BCT were randomized between sequential methotrexate and fluo-rouracil versus CMF (cyclophosphamide, methotrexate, fluorouracil). At 8 years, LR were detected in 2.6% of the patients treated with the sequential regimen versus 0.6% of the patients treated with CMF.

With the increasing use of chemotherapy as adjuvant treatment, also for node-negative patients it is important to note that sequencing of chemotherapy and radiotherapy may impact on local control. Options for sequencing of radiotherapy and chemotherapy include: the delivery of all chemotherapy prior to radiotherapy or all radiotherapy prior to chemotherapy (sequential regimens); the simultaneous initiation of both modalities (concurrent regimens); or the initiation of radiotherapy in the midst of the chemotherapy program (sandwich regimens). Concurrent regimens have the theoretical advantage of initiating both modality treatments (for local and systemic therapy) without a delay in either modality, and is thereby likely not associated with increased risk for LR. However, concurrent regimens may be associated with increased risk of toxicity. Concurrent chemotherapy is not associated with an increased risk of symptomatic pneumonitis in patients treated with tangential fields only. However, in one study treatment to the breast and regional nodes with concurrent chemotherapy, an incidence of 9% of symptomatic pneumonitis was found compared to 1% in patients who were treated with a sequential regimen.114 The concurrent use of chemotherapy has been associated with a less favorable cosmetic result in some series, but not in others.85,115

When using a sequential regimen there have been reports, mainly from nonrandom-ized studies, that delay of radiotherapy in favor of chemotherapy results in higher LR.116-118 There has been one randomized trial,119 unfortunately including only a relatively small number of patients, for which the initial analysis showed a 14% risk of local recurrence in the chemotherapy-first group versus 5% in the radiotherapy-first group at 5 years follow-up. However, systemic recurrence was more frequent when radiation therapy was given first. In subgroup analysis of this study, it was found that for patients with negative tumor margins no difference was found in local or distant recurrence rate whether they were treated with chemotherapy or radiotherapy first. Patients with close, positive or unknown tumor margins had higher incidence of LR in the chemotherapy-first regimen and the higher incidence of distant recurrences in the radiotherapy-first group persisted. An update of this study after a longer follow-up period failed to show any difference in disease outcome between the chemotherapy-first group and the radiotherapy-first group.120 Additional clinical trials of sufficient size are clearly required in this very important area.

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