The potential for dose dumping in normal tissues with IMRT for pelvic and H&N cancers.

The purpose of this study is to understand the potential for dose dumping in normal tissues (>85% of prescription dose) and to analyze effectiveness of techniques used in reducing dose dumping during IMRT. Two hundred sixty-five intensity modulated radiation therapy (IMRT) plans for 55 patients with prostate, head-and-neck (H&N), and cervix cancers with 6-MV photon beams and >5 fields were reviewed to analyze why dose dumping occurred, and the techniques used to reduce dose dumping. Various factors including gantry angles, depth of beams (100-SSD), duration of optimization, severity of dose-volume constraints (DVC) on normal structures, and spatial location of planning treatment volumes (PTV) were reviewed in relation to dose dumping. In addition, the effect of partial contouring of rectum in beam's path on dose dumping in rectum was studied. Dose dumping occurred at d(max) in 17 pelvic cases (85% to 129%). This was related to (1) depth of beams (100 SSD [source-to-skin distance]), (2) PTV located between normal structures with DVC, and (3) relative lack of rectum and bladder in beam's path. Dose dumping could be reduced to 85% by changing beam angles and/or DVC for normal structures in 5 cases and by creating "phantom structures" in 12 cases. Decreasing the iterations (duration of optimization) also reduced dose dumping and monitor units (MUs). Part of uncontoured rectum, if present in the field, received a higher dose than the contoured rectum with DVC, indicating that complete delineation of normal structures and DVC is necessary to prevent dose dumping. In H&N, when PTV extends inadvertently into air beyond the body even by a few millimeters, dose dumping occurred in beam's path (220% for 5-field and 170%, 7-field plans). Keeping PTV margins within body contour reduced this type of dose dumping. Beamlet optimization, duration of optimization, spatial location of PTV, and DVC on PTV and normal structures has the potential to cause dose dumping. However, these factors are an integral part of IMRT inverse planning. Therefore, understanding these aspects and use of appropriate technique/s would reduce or eliminate the dose dumping and minimize time to obtain optimum plan.

Patterns of failure after the multimodality treatment of uterine papillary serous carcinoma.

PURPOSE: Uterine papillary serous carcinoma (UPSC) is an aggressive variant of endometrial carcinoma. The majority of patients with clinical Stage I UPSC are found to have extrauterine disease at the time of surgery. Most authors report survival rates of 35-50% for Stage I-II and 0-15% for Stage III and IV UPSC. Surgical treatment as the sole therapy for patients with Stage I-IV UPSC is unacceptable because of high recurrence rates. Chemotherapy, radiotherapy, or both have been added after surgery in an attempt to improve survival. However, the survival benefit to patients from such multimodality therapy remains uncertain. This study analyzes the patterns of failure in patients with FIGO Stages I-IV UPSC treated by multimodality therapy. METHODS AND MATERIALS: Forty-two women with FIGO Stages I-IV UPSC who were treated by multimodality therapy were analyzed retrospectively between 1988 and 1998. Data were obtained from tumor registry, hospital, and radiotherapy chart reviews, operative notes, pathology, and chemotherapy flow sheets. All the patients underwent staging laparotomy, peritoneal cytology, total abdominal hysterectomy and salpingo oophorectomy, pelvic and para-aortic lymph node sampling, omentectomy, and cytoreductive surgery, when indicated followed by radiotherapy and/or chemotherapy. Therapy consisted of external beam radiation therapy in 11 patients (26%), systemic chemotherapy in 20 (48%), and both radiotherapy and chemotherapy in 11 (26%). The treatments were not assigned in a randomized fashion. The dose of external beam radiation therapy ranged from 45-50.40 Gy (median 45). Of the 31 patients (74%) who received chemotherapy, 18 received single-agent (58%), whereas 13 received multiagent chemotherapy (42%). RESULTS: Median follow-up for all patients was 19 months (range 4-72). Median follow-up for the surviving patients was 36 months (range 21-72). Their median age was 65 years. Six patients (14%) had Stage I, 8 patients (19%) had Stage II, 10 (24%) had Stage III, and 18 (43%) had Stage IV disease. Twenty-nine patients (69%) had suffered recurrence at the time of last follow-up. The actuarial failure rate at 2 and 5 years was 58% and 67%, respectively. The majority of the patients (19/29) recurred in the abdomen, vagina, or pelvis (66%). Metastases outside the abdomen were much less common as the first site of failure (17%). Twenty-five patients (60%) had died at the time of reporting; the observed survival rate at 2 years and 5 years was 52% and 43%, respectively. CONCLUSIONS: Our data suggest that, after multimodality therapy of FIGO Stage I-IV UPSC, most patients developed abdominopelvic (locoregional) failure, and the great majority of the failures occurred in the abdomen, vagina, and pelvis (66%). Abdominopelvic failure as a component of distant failure occurred in an additional 5 patients (17%). Distant failure alone occurred in 17% of the patients.We propose that future studies should combine whole abdominal radiotherapy (WART) with pelvic and vaginal boosts, in addition to chemotherapy for FIGO Stage I-IV UPSC, especially in patients with minimal residual disease, to attempt to improve the dismal prognosis of patients with UPSC.

Extended-field radiotherapy and high-dose-rate brachytherapy in carcinoma of the uterine cervix: clinical experience with and without concomitant chemotherapy.

BACKGROUND: It has long been recognized that many patients with locally advanced carcinoma of the cervix harbor occult paraaortic metastases. A randomized study demonstrated that elective paraaortic irradiation improved survival and reduced distant metastases. More recently, concomitant chemotherapy with pelvic irradiation has improved survival among patients with locally advanced carcinoma of the cervix. This has led to a reexamination of the role of extended-field irradiation. An important issue is the toxicity of concomitant chemotherapy and extended-field radiotherapy. The authors report a retrospective analysis of their experience with extended-field radiotherapy and high-dose-rate brachytherapy with or without concomitant chemotherapy. METHODS: The authors treated 54 women with biopsy-confirmed carcinoma of the cervix using extended-field radiotherapy and high-dose-rate brachytherapy with or without concomitant chemotherapy. The histology was squamous cell carcinoma in 49 patients (91%) and nonsquamous cell carcinoma in 5 patients (9%). The median size of the primary tumor was 7 cm (range, 3-10 cm). Each patient received 45 grays (Gy) of external beam radiotherapy to the pelvis and the paraaortic region, followed by a parametrial boost (9 Gy) in the patients with disease extension to the parametrium or the pelvic side wall(s). Each patient also underwent two applications of high-dose-rate brachytherapy, 1 week apart. The median dose delivered to Point A from each application was 9 Gy. Forty-four of the 54 patients (81%) received concomitant chemotherapy (cisplatin, 20 mg/m(2)/day for 5 days) during the first and the fourth weeks of external beam radiotherapy, and once after the second high-dose rate application. Chemotherapy was not assigned randomly. RESULTS: One of the 10 patients (10%) treated without chemotherapy experienced acute toxicity, whereas 41 of 44 patients (93%) who received chemotherapy suffered from acute toxicity, including hematologic toxicity, gastrointestinal toxicity, and deep venous thrombosis. During a median follow-up period of 28 months (range, 12-70 months), 6 of the 54 patients have died (11%). The actuarial rate of local control at 3 years is 100% among the patients treated without chemotherapy, compared with 85% among those receiving chemotherapy. No one failed in the paraaortic region. The actuarial rates of freedom from distant metastases are 90% and 95% among the patients treated without and with chemotherapy, respectively. The actuarial incidence of late toxicity is 10% among the patients treated without chemotherapy and 6% among those receiving chemotherapy. CONCLUSIONS: The regimen of extended-field radiotherapy with concomitant cisplatin and high-dose-rate brachytherapy produced substantial acute toxicity, but its long-term toxicity is low and the preliminary tumor control excellent, albeit with limited follow-up. Only prospective, randomized trials can evaluate whether these results are truly better than those of pelvic radiotherapy with concomitant chemotherapy, or those of other regimens of extended-field radiotherapy with concomitant chemotherapy. Cancer 2003;97:1781-8.

Microsatellite dinucleotide (T-G) repeat: a candidate DNA marker for breast metastasis.

A dinucleotide (T-G) repeat sequence was isolated by comparing DNA from metastatic lymph node and matched normal breast samples from a ductal mammary carcinoma patient using representational difference analysis (RDA) method. Our present study used this metastasis associated DNA sequence (MADS) as a diagnostic probe to screen five patient samples by slot blot method. A new approach to isolate single cells by microdissection, namely single cell microdissection (SCM) was developed to obtain homogeneous population of tumor cells (approximately 1000) from matched primary tumors and corresponding positive lymph nodes of five patients. We isolated DNA from these homogeneous tumor cells and used for the RDA and DNA slot blot experiments. The screening of patient samples showed loss of this MADS in the transition from primary to metastasis in four out of five cases (80%) suggesting its possible role in breast metastasis.

Two fractions of high-dose-rate brachytherapy in the management of cervix cancer: clinical experience with and without chemotherapy.

PURPOSE: In recent years, high-dose-rate brachytherapy has become popular in the management of carcinoma of the uterine cervix, because it eliminates many of the problems associated with low-dose-rate brachytherapy. However, the optimum time-dose-fractionation remains controversial. Two fractions of high-dose-rate brachytherapy are convenient for patients, but most radiation oncologists in the United States do not use them, because of fear that they could lead to excessive rectal or bladder toxicity. Here we present our experience, which suggests that a two-fraction regimen is indeed safe and effective. METHODS: We treated 49 patients with Stages I-III biopsy-proven carcinoma of the uterine cervix by external beam radiation therapy (EBRT), plus two fractions of high-dose-rate brachytherapy. The histology was squamous cell carcinoma in 43 patients (88%) and nonsquamous in 6 (12%). The median size of the primary tumor was 6 cm (range: 3-10 cm). Each patient received EBRT to the pelvis to a median dose of 45 Gy (range: 41.4-50.4 Gy), followed by a parametrial boost when indicated. Thirty patients (61%) also received irradiation to the para-aortic lymph nodes to a dose of 45 Gy. After EBRT, each patient underwent two applications of high-dose-rate brachytherapy, 1 week apart. The dose delivered to point A was 9 Gy per application for 49 applications (50%) and 9.4 Gy for 43 applications (44%), and it varied from 7 to 11 Gy for the rest (6%). The total dose to the rectum from both high-dose-rate brachytherapy applications ranged from 4.7 to 11.7 Gy (median: 7.1 Gy), and the total dose to the bladder from 3.8 to 15.5 Gy (median: 10.5 Gy). Twenty-five of the 49 patients (51%) received concomitant chemotherapy (cisplatin 20 mg/m(2)/day for 5 days) during the first and fourth weeks of EBRT and once after the second high-dose-rate brachytherapy application. Chemotherapy was not assigned in a randomized fashion. The use of chemotherapy increased during the time period spanned by this study as increasing evidence supporting the use of chemotherapy began to appear. RESULTS: The observed survival rates after 2, 3, and 5 years were 83%, 78%, and 78%, respectively. The surviving patients have been followed up for a median of 3 years (range: 2-6 years). Eight of the 49 patients suffered local failures. Among patients treated without chemotherapy, the 3-year local control rate was 77%; it was 88% among those receiving chemotherapy. There have been no regional failures. Four patients developed distant metastases. At 3 years, 91% of the patients in each group were free of distant metastases. Ten of the 49 patients (20%) suffered Grade 3 acute toxicity; 11 (22%) had Grade 4. Among the 24 patients treated without chemotherapy, only 1 (4%) suffered Grade 3 toxicity. Among the 25 patients receiving chemotherapy, in contrast, 8 (32%) suffered Grade 3 and 12 (48%) Grade 4 acute toxicity. Only 2 patients suffered late toxicity: One suffered Grade 2 and the other Grade 3 late toxicity. The actuarial risk of Grade 2 or worse late toxicity was 5%, with or without chemotherapy. CONCLUSIONS: Our experience suggests that two fractions of high-dose-rate brachytherapy are safe and effective in the management of cervix cancer, even in conjunction with concomitant cisplatin. The fears that the use of two fractions would lead to excessive rectal or bladder toxicity proved unfounded. Guidelines for ensuring a low complication rate are discussed.