Significant Improvement In Local Control Research Articles

Chemoradiotherapy for Cervical Cancer: What Next?

In this issue, Lanciano et al report the results of the Gynecologic Oncology Group’s most recent randomized study of concurrent chemoradiotherapy for cervical cancer (GOG-165). This trial, which compared the results of radiation therapy delivered concurrently with either weekly cisplatin or protracted venous infusion of fluorouracil (FU), was closed well before the planned accrual goal of 416 patients and 150 events because a scheduled interim analysis suggested that patients treated with FU were not likely to have a better outcome than those treated with the control regimen of radiation and weekly cisplatin. Although this negative study does not represent a major advance in the treatment of patients with cervical cancer, it does highlight many of the issues and challenges faced by investigators who seek to improve cervical cancer treatment in the modern era. GOG-165 is best understood in its historical context. The trial was designed and opened in 1997. In that year, the GOG published abstracts describing encouraging preliminary results from GOG trials of cisplatin-based concurrent chemoradiotherapy. However, the inclusion of hydroxyurea in the control arms of these trials and other perceived weaknesses, including problems with the quality of radiation therapy, prevented clinicians from reaching an early consensus about the trials’ importance. Therefore, in an effort to consolidate earlier findings, GOG-165 was designed. The study initially was planned with three arms: a control arm of modern radiation therapy alone, a second arm intended to confirm the value of adding weekly cisplatin, and a third, experimental arm that consisted of treatment with radiation and protracted venous infusion FU. This third arm drew on extensive data demonstrating the value of FU-based chemoradiotherapy in patients with gastrointestinal neoplasms and was intended to follow-up on an inconclusive but encouraging Canadian study of concurrent radiation and protracted venous infusion FU in patients with cervical cancer. However, in 1999, just 18 months after GOG-165 was opened, the near-simultaneous publication of results from five prospective randomized trials, all of which demonstrated significant improvements in local control and survival with cisplatin-based chemoradiotherapy, led to a National Cancer Institute alert establishing chemoradiotherapy as a standard treatment for patients with locoregionally advanced cervical cancer. At that point, the GOG felt compelled to drop the radiationonly control arm of GOG-165 but continued to accrue patients to the two concurrent chemoradiotherapy arms. The results of GOG-165 suggest that radiation plus protracted venous infusion FU was not a better treatment than radiation plus weekly cisplatin, but it does not prove that FU is ineffective as a radiation sensitizer in patients with cervical cancer. More importantly, the study does not answer the potentially more interesting question of whether FU can enhance the beneficial effects of adding cisplatin to radiation therapy. In fact, although randomized trials have demonstrated the benefit of concurrent cisplatin and of concurrent cisplatin with FU, no trial has yet compared the two regimens directly. Although the GOG regimen of radiation plus weekly cisplatin tends to be favored by gynecologic oncologists in the United States, data from the seven randomized trials suggest that radiation plus a combination of cisplatin and FU might be more effective. Of four randomized trials that included radiation therapy plus weekly cisplatin, only one, reported by Keys et al in 1999, demonstrated a benefit for radiation therapy plus cisplatin over radiation therapy alone. In that study, patients with bulky stage IB cancers were randomly assigned to prehysterectomy radiation therapy or chemoradiotherapy. Two other trials—the current trial and the GOG three-arm trial published in 1999—did not have a control arm of radiation therapy only; instead, they included chemotherapy of uncertain value in the noncisplatin-containing JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 33 NOVEMBER 2

Intensity modulated radiation therapy (IMRT) for nasopharynx cancer: Update of the Memorial Sloan-Kettering experience

5541 Background: We previously demonstrated that IMRT significantly improves radiation dose distribution over 3-dimensional (3D) planning for nasopharynx cancer (NPC) and reported positive early clinical results. We now evaluate whether IMRT has resulted in improved outcomes for a larger cohort of NPC patients with longer follow-up. Methods: Since 1998, all 74 patients with newly diagnosed, nonmetastatic NPC were treated with IMRT using accelerated fractionation to 70 Gy; 59 received a hyperfractionated concomitant boost and more recently 15 received once daily treatment with dose-painting. With the exception Stage I disease (n=5) and patient refusing (n=1), 69 patients received concurrent and adjuvant platinum based chemotherapy similar to Intergroup 0099 trial. Results: Patient characteristics: median age 45; 32% Asian; 72% male; 65% WHO III; 51% Stage T3/4, 47% N2/3, and 47% Stage IV. Median follow up is 33 months. The 3-year actuarial rate of local control is 89% and regional control is 95%. Freedom from distant metastases, progression-free survival, and overall survival are 78%, 64% and 82% respectively. Six of the seven local failures were exclusively within the 70Gy volume and one was both within and outside the target volume. There is a trend for improved local control with IMRT when compared to local control of 79% for patients treated prior to 1998 with 3D planning and chemotherapy, but this is not statistically significant (p=0.18). Six months post-therapy, 21%, 13%, 15% and 0% of patients with follow-up audiograms (n=24 patients, 48 ears) had Grade 1, 2, 3, and 4 sensorineural hearing loss, respectively. For patients with >1 year follow-up (n=59), rates of long-term xerostomia were: 26% none, 42% grade 1, 32% grade 2, and zero grade 3. Conclusions: The lack of significant improvement in local control with IMRT and pattern of primary site failure within the target volume suggest a need for a higher biological dose to gross tumor. Rates of severe (grade 3–4) ototoxicity and xerostomia are low with IMRT due to normal tissue protection. Distant metastases are now the dominant form of failure emphasizing the need for improved systemic therapy. No significant financial relationships to disclose.

The role of radiotherapy in the treatment of endometrial carcinoma

The role of radiotherapy (RT) in the treatment of endometrial cancer is based on the presence of the prognostic factors, tumor stage, histological grade, depth of myometrial invasion and age. Pelvic RT is indicated in stage I endometrial carcinoma in the presence of at least 2 of 3 risk factors: deep myometrial invasion (50% or more of the myometrial width), grade 3 histology, and age 60 or over. Three randomized trials have shown that pelvic RT provides a highly significant improvement of local control, but without a survival advantage. The use of RT should be limited to those patients at sufficiently high risk of locoregional recurrence (15% or over) to warrant the risk of treatment associated morbidity in order to maximize initial local control and relapse-free survival. The ongoing PORTEC-2 trial randomizes between vaginal brachytherapy and external beam RT to evaluate vaginal control, survival, side effects and quality of life. For high risk and advanced disease, pelvic RT continues to be the most effective adjuvant treatment to ensure pelvic control. Further trials on the efficacy of concurrent RT and chemotherapy are needed.

Efficacy and treatment-related toxicity of radiotherapy for early-stage primary non-Hodgkin lymphoma of the parotid gland

To assess the efficacy of radiotherapy (RT) in the treatment of primary non-Hodgkin lymphoma (NHL) of the parotid gland. Data on 35 consecutive patients seen at Mayo Clinic between 1974 and 2000 with Ann Arbor Stage I and II NHL of the parotid gland were reviewed retrospectively. Radiotherapy was given to 23 patients, and 12 patients were observed. Eight patients received RT to local fields only. In addition to local fields, 9 patients received ipsilateral neck irradiation, and 6 patients received both ipsilateral and contralateral neck irradiation. Median follow-up was 6.5 years (range, 2 months-24 years). Local control was significantly improved in the RT group compared with the observation group (p = 0.03). Both overall survival and disease-specific survival were 90% at 5 years and 71% at 10 years. There was no significant difference in disease-specific survival or overall survival between the RT and observation groups. The overall prognosis for this rare presentation of NHL is excellent. Radiotherapy provided significant improvement in local control with minimal morbidity and should be considered in the treatment of these patients.

TREATMENT STRATEGIES FOR ESOPHAGEAL STRICTURE BEFORE OR AFTER CHEMORADIOTHERAPY FOR ADVANCED ESOPHAGEAL CANCER

ABSTRACTEsophageal stricture due to advanced cancer is one of the serious complications of esophageal cancer as it causes dysphagia. A self‐expandable metallic stent is easily inserted in such patients and provides immediate symptomatic relief of dysphagia. Alternatively, definitive chemoradiotherapy has demonstrated a significant improvement in local control and overall survival, and is now commonly used for not only unresectable esophageal cancer patients but also in resectable cases. However, little is known about its role in relief of dysphagia. Therefore, we reviewed our experience of patients with esophageal stricture who were treated with chemoradiotherapy. We expect that the findings in this article might be useful in future clinical practice.

Why a breast boost should remain a controversial aspect of routine breast conservation management in Australia and New Zealand in 2002.

Two randomized trials have recently shown a statistically significant improvement in local control when a boost is employed in the conservative treatment of early breast cancer. However, unresolved issues of cost effectiveness, potentially increased toxicity and the inability to automatically generalize these results to Australian and New Zealand practice remain. In view of these unresolved controversies, the St George and Wollongong hospitals breast boost trial (SGW trial) will continue to recruit.

Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate

Purpose: To test the hypothesis that androgen ablation before and during radiotherapy for locally advanced carcinoma of the prostate may, by reducing tumor bulk and enhancing tumor cell kill, improve locoregional control and ultimately survival. Methods and Materials: The study was conducted from 1987 to 1991. Eligible patients were those with bulky tumors (T2–T4) with or without pelvic lymph node involvement and without evidence of distant metastases. They were randomized to receive goserelin, 3.6 mg every 4 weeks; and flutamide, 250 mg t.i.d. for 2 months before radiation therapy and during radiation therapy (Arm I), or radiation therapy alone (Arm II). Of 471 randomized patients, 456 were evaluable: 226 on Arm I and 230 on Arm II. Results: As of November 1999, the median follow-up has reached 6.7 years for all patients and 8.6 years for alive patients. At 8 years, androgen ablation has been associated with an improvement in local control (42% vs. 30%, p = 0.016), reduction in the incidence of distant metastases (34% vs. 45%, p = 0.04), disease-free survival (33% vs. 21%, p = 0.004), biochemical disease-free survival = PSA <1.5 (24% vs. 10%, p < 0.0001), and cause-specific mortality (23% vs. 31%, p = 0.05). However, subset analysis indicates that the beneficial effect of short-term androgen ablation appears preferentially in patients with Gleason score 2–6. In that population, there is a highly significant improvement in all endpoints, including survival (70% vs. 52%, p = 0.015). In patients with Gleason 7–10 tumors, the regimen has not resulted in a significant enhancement in either locoregional control or survival. Conclusion: In patients with Gleason score 2–6 carcinoma of the prostate, a short course of androgen ablation administered before and during radiotherapy has been associated with a highly significant improvement in local control, reduction in disease progression, and overall survival.

Effect on local control and survival of electron beam intraoperative irradiation for resectable pancreatic adenocarcinoma

Purpose: To assess the impact on local control and survival of intraoperative radiotherapy (IORT) in resectable pancreatic adenocarcinoma. Methods and Materials: The outcome of 127 patients surgically treated with curative intent combined with IORT was compared with the therapeutic results of 76 patients treated with surgery as exclusive treatment. Results: Operative mortality and morbidity were similar in IORT and no-IORT patients. In 49 patients with locally limited disease (Stage I–II; LLD), IORT ( n = 30) reduced the local failure rate and significantly prolonged time to local failure (TTLF), time to failure (TTF), and overall survival (OS) with respect to surgery alone ( n = 19). The multivariate analyses, stratifying patients by age, tumor grade, resection margins, chemotherapy, and external-beam radiotherapy use, confirmed the independent impact of IORT on outcome. In patients with locally advanced disease (Stage III–IVA; LAD), IORT had an impact on local failure rate and on TTLF when combined with beam energies of greater than 6 MeV, whereas no effect on TTF and OS was observed. Conclusion: IORT did not increase operative mortality and morbidity and achieved a significant improvement in local control and outcome in patients with LLD. In patients with LAD, beam energies greater than 6 MeV prolonged TTLF.

Radiotherapy combined with other treatments in rectal cancer.

Since the first reports in the late 1950's, a large amount of data have been collected. The analysis of the main evidence from the major randomized trials will be analyzed in this paper according to preoperative, postoperative and chemoradiation approaches. Fifteen randomized preoperative trials were reported; they have been grouped according to the fractionation schedule. In the hypofractionation group (5 Gy for fraction), all five studies that delivered 3-5 doses in one week had a significant improvement in local control and one of them also showed improvement in survival. Operative mortality was higher in the radiotherapy arm if inadequate techniques had been applied. In 3 out of 8 studies with conventional fractionation there was a significant improvement in local control, but no impact in survival was detected. No studies with total dose lower than 34 Gy had an improvement in local control. None of the six randomized postoperative studies showed an improvement in local control or survival. In all trials the local control rate was uniform; ranging from 76% to 84%. Toxicity was higher in the radiotherapy arm. One preoperative and five postoperative randomized studies that used chemoradiation were analyzed. One postoperative chemoradiation study showed a significant improvement in survival in comparison to the surgery arm, and another showed the same advantage compared to the postoperative arm. Protracted infusional administration of 5FU concomitant to radiotherapy showed better survival than bolus administration. No advantages were shown in using MeCCNU or Levamisole in two studies. Toxicity was high and related to the dose and the modality of administration of the drugs in order to adequately treat the different stages of rectal cancer, patients must be carefully selected in order to prescribe the most effective and the least toxic treatment for the individual stage; organ preservation should be an essential goal for its impact on quality of life, and the cost estimates should be taken into account.

Developments in radiotherapy

There is a rather negative attitude towards the role of radiotherapy in breast cancer and over the years it has acquired a somewhat poor image despite 50 years of clinical research. Historically, the first randomized trial to assess radiotherapy was the ovarian ablation study performed at the Christie Hospital in Manchester (1). The second study assessing post-mastectomy radiotherapy (1) was also from the Christie where percentage mortality up to the fifth year was 42% in the control group (n = 305), and 35% in treated (n = 293) patients. A significant improvement in local control was demonstrated although the overall message was that long-term radiotherapy was harmful. This trial has had an inordinate influence in the U.K. over the years and is still influencing perception of adjuvant radiotherapy. Despite this, data from the Scottish Cancer Therapy Network, who have audited all patients diagnosed with breast cancer in Scotland, in 1987 and in 1993 indicate that radiotherapy is being used increasingly frequently (2). Following wide local excision (lumpectomy) or mastectomy the numbers of patients that received radiotherapy were found to have increased by 20% and 38%, respectively, between these two years.

External beam radiation therapy and retinoblastoma: Long-term results in the comparison of two techniques

Purpose : This study compares the long-term actuarial local control, eye conservation rate, survival, and ocular complications in children with retinoblastoma treated with two different external beam treatment techniques. Methods and Materials : From 1979–1991, 182 eyes in 123 children (104 bilateral) received primary external beam radiation therapy. An anterior lens-sparing electron beam technique delivering 38 to 50 Gy in 2.5 Gy fractions was used in 67 eyes from 1979–1984 and a modified lateral beam technique, delivering 42 to 46 Gy in 2 Gy fractions, was used in 113 eyes from 1984–1991. These groups were balanced with respect to known prognostic variables. Results : For Group I–III eyes, the 5- and 8-year local control was significantly improved using the modified lateral beam technique (84%) compared to (38%) using the anterior lens sparing technique ( p p ≤ 0.0001). For Group IV–V eyes, the 5- and 8-year local control rates were not statistically different, despite a trend favoring the modified lateral beam technique. Survival endpoints including eye survival (no enucleation), cause-specific survival, and overall survival comparing the two treatment techniques were not significantly different. Overall, 22% of eyes developed cataracts. There was no difference between the two treatment groups in terms of cataract development. No eyes required enucleation for ocular complications. Conclusion : There is a significant improvement in local control using the modified lateral beam technique compared to an anterior lens-sparing approach for Group I–III eyes. However, there was no difference in survival end points between the two treatment techniques. The incidence of ocular complications using these two external beam techniques is acceptable.

Brachytherapy and function preservation in the localized management of soft tissue sarcomas of the extremity

Over the past 20 years, it has become evident that limb preservation is possible in the management of soft tissue sarcomas of the extremities. Amputation has been generally replaced by more conservative operations that preserve limb function, followed by radiation therapy. Although external beam irradiation has been the most commonly applied adjuvant, there has been increasing interest in using brachytherapy instead of external beam therapy. The reasons for this tren include the apparent equivalence of local control for properly selected patients using brachytherapy, improved patient convenience, shorter treatment time, and lower cost. A recently published report of a prospective randomized trail shows statistically significant improvement in local control when brachytherapy is added to surgery for high grade sarcomas. The treatment concepts used when using brachytherapy challenge many of the orginal teachings for external beam irradiation with regard to field size, volume irradiated, and the tissues that require treatment in the postoperative setting. This article addresses thse controversies, as well as reviews the evolving role of brachytherapy in the management of soft tissue sarcomas. Issues such as patient selection, integration with other local therapies, and complications are highlighted, and special situations are discussed.

Preoperative radiation therapy for rectal cancer. An effective therapy in need of a clinical trial.

Sixty patients with locally advanced adenocarcinoma of the rectum have been treated with preoperative high-dose pelvic irradiation in an attempt to improve operability and increase local control. Fifty-six patients showed no evidence of distant metastases at surgery and their records have been analyzed with respect to recurrence patterns, survival, and complications. The results have been compared with those of a similar analysis of 106 patients treated with curative surgery alone. There was a statistically significant improvement in local control between groups, with 16% of patients in the radiotherapy group having a component of local failure compared with 40% in the surgery group. A dose response was observed, with 67% local control at 4000 rad (4000 cGy) and 91% local control at 5000 rad (5000 cGy). Despite the more advanced clinical stage of the irradiated patients, no significant difference in survival was seen between groups, with a five-year survival rate of 52% in the irradiated patients and 48% in patients treated by surgery alone. Preoperative high-dose radiotherapy was well tolerated, with a 5% incidence of major complications in both groups.

Guidelines for comprehensive quality assurance in brachytherapy

Brachytherapy treatment techniques can provide significant improvement in local control and overall survival, but only when quality assurance can be guaranteed. In the absence of well-trained personnel and inadequate equipment undesirable results usually follow. To establish brachytherapy quality assurance, basic requirements for three predetermined subdivisions of clinical institutions will be forwarded. These are: (1) centers having minimum requirements to provide brachytherapy, (2) intermediate centers such as regional or community hospitals, and (3) optimal centers such as university hospitals and cancer centers. A minimum center would have no board certified radiation personnel, would make use of services of a gynecologist or surgeon, be limited to afterloading or remote afterloading techniques for uterus cancer, and quality control would be guaranteed by using simple treatment protocols with fixed intrauterine applicators. Additional quality assurance such as leak testing, etc. would be provided by a parent organization (W.H.O. or Optimal Center). An intermediate center would have at least one certified radiation personnel with expansion of brachytherapy techniques to interstitial implants with several isotopes. Like the minimum center, no teaching would be provided but some quality assurance policies would be performed at the center (e.g., autoradiographs). The optimal center would have a full complement of personnel, have total brachytherapy capabilities, have teaching programs for its staff and possibly the minimum and intermediate centers and be able to provide its own quality assurance. This presentation will highlight personnel needs, equipment requirements, academic activities, clinical experience with these systems and proposed quality assurance guidelines.