Randomized Prospective Study of the Benefit of Adjuvant Radiation Therapy
Reviewers: John Han-Chih Chang, MD and Kenneth Blank, MD
Source: Journal of Clinical Oncology 1998; Volume 16 (Number 1): pages 197 - 202
Surgery remains the mainstay of treatment for soft tissue sarcomas of the extremity. Radical surgery such as amputation optimize cure rates but, obviously, have high functional morbidity. The radical extent of surgical resection has been called into question since the dawn of adjuvant radiation therapy. Limb sparing surgery (LSS) can allow for a functional extremity, but local control rates are reportedly less than 50%. High dose radiation therapy (XRT) adjuvantly added to LSS achieves local control rates of approximately 80% retrospective studies. Similar disease free and overall survivals have been demonstrated in randomized prospective trials comparing LSS with adjuvant XRT and amputation. Adjuvant XRT is not without its drawbacks. Function morbidity of the extremity can occur after therapy. With this in mind, as previously mentioned, nearly 50% of those patients with such a malignancy may not need adjuvant treatment. Also, local control has not been causally linked to overall survival (though retrospective data supports improved overall survival with increasing local control).
The question of chemotherapy in high grade lesions has been addressed by many an institution with a prospective randomized trial. Few, if any, have shown a truly significant survival advantage. In an attempt to procure an survival benefit from such data, the Sarcoma Meta-analysis Collaboration published their data (meta-analysis of 14 prospective randomized trials), which demonstrated a significant increase in recurrence free intervals and survival along with a trend towards improved overall survival with a doxorubicin (adriamycin) - based chemotherapy regimen.
Based upon the above mentioned background, the investigators at National Cancer Institute devised this prospective randomized trial comparing LSS with or without adjuvant XRT in patients with soft tissue sarcomas of the extremity. Chemotherapy was given adjuvantly to patients with high grade lesions.
Materials and Methods
One hundred and forty-one patients were randomized between 1983 - 1991. All patients received a LSS with margins of 1 - 2 cm (close/positive margin were allowed when more extensive local resection would result in functional impairment of the extremity). Those that were randomized to XRT received 4500 rads to a wide field followed by a boost of another 1800 rads to the gross tumor. Ninety-one patients had high grade lesions for which they all received doxorubicin (70mg/m2) and cyclophosphamide (700mg/m2) concurrent with the XRT for the first cycle and then every 28 days for 4 more cycles. Fifty patients with low grade lesions were adjuvantly treated with radiation or no further adjuvant treatment.
Overall, only 1 patient of those that had received XRT, failed locally. Seventeen local recurrences were noted in the no XRT group. Median follow up was nearly ten years. Among the 91 patients that were enrolled as high grade lesions, the actuarial local failure rate was 22% at 10 years for those who received only adjuvant chemotherapy versus 0% for those who received adjuvant XRT. In the low grade group, only 1 local recurrence was found in the XRT arm, while 8 have locally recurred in the no adjuvant therapy arm. The patient who recurred after adjuvant XRT did so in the margins of the radiation field. No further information on what type of salvage or outcome was documented in the article. Local failure differences as demonstrated in figures 2 and 5 in the article were statistically significant.
Of the nine high grade patients with local recurrence, salvage was attempted with amputation or a wide local excision with adjuvant XRT. Four had synchronous metastases. Two did not receive any further therapy and died of disease. Of the 4 that got a wide local excision with XRT, 3 are without evidence of disease 6 - 8 years from recurrence, while the other is alive with disease at 7 years out from recurrence. General information on the nine patients (8 in the no XRT arm and 1 in the XRT arm) with local recurrence in the low grade group revealed salvage attempts with local re-excision and XRT in 6 patients who are without evidence of local recurrence 14 - 84 months from their recurrence.
The metastatic disease free survival was not significantly different in the high grade group with both being approximately 70% at 10 years based on figure 3 in the article. Four deaths (2 in each arm) from metastatic disease occurred in the low grade patients. Metastases rates were not stated for the low grade group.
The 10 year overall survival rates in the high grade population were 75% for those that received XRT comparable to 74% for those that got just adjuvant chemotherapy. Overall survival in the low grade group was not discussed nor depicted graphically.
In the high grade sarcoma patients, table 2 reveals that there are 39% of the patients that had close (< 1 cm) or positive margins in the no XRT group, while only 25% had the same poor margin status in the XRT group. Similarly, in the low grade group, table 4 demonstrates that 54% of patients who received no adjuvant therapy had poor margin status contrasted to 30% of the adjuvant XRT group.
Quality of life assessments compared XRT group to those who did not initially receive XRT in the areas of muscle strength, joint motion, edema and functional living index at baseline, 6, 12, 24 and 36 months post treatment. The only significant quality of life differences were seen in the joint motion at and beyond 6 months and edema at 6 months only. But subjectively, patients' functional living index questionnaires revealed that they felt no different as far as what their functional capacity for daily living.
Overall survival and distant metastatic rates were similar for both arms of the trial is the claim of the article, which is believable but without documented data for the low grade group. The impact of XRT on local control is undoubtedly significant, with one confounding factor (above mentioned discrepancy in poor margin status between the two arms in both groups). The contention of the article is that XRT is seemingly unnecessary, because in 75% - 80% of patients they do not fail locally after LSS. If one looks at the data, only 1 local failure was seen in patients with adjuvant XRT, while others who failed locally eventually got an amputation or wide re-excision and XRT for salvage. LSS was done very aggressively at the NIH with very high local control rates compared to historical controls. Thus, the results from their LSS cannot safely be extrapolated to the community setting. Overall quality of life is not subjectively hindered with radiation therapy, despite the joint motion differences. Usually the effects of radiation on extremity function is transient and not debilitating. Dr Joel Tepper in his discussions on the International Journal Club states, "Except for the small low grade lesions that can be resected with wide margins, I think the value of (XRT) in soft tissue sarcomas has been comfirmed."