Brij Sood

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

PURPOSEnIn 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.nnnMETHODSnWe 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.nnnRESULTSnThe 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.nnnCONCLUSIONSnOur 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.

ACCELERATED REGRESSION OF BRAIN METASTASES IN PATIENTS RECEIVING WHOLE BRAIN RADIATION AND THE TOPOISOMERASE II INHIBITOR, LUCANTHONE

PURPOSEnTo determine if lucanthone crossed the blood-brain barrier in experimental animals; and to determine accelerated tumor regression of human brain metastases treated jointly with lucanthone and whole brain radiation.nnnMETHODS AND MATERIALSnThe organ distribution of 3H lucanthone in mice and 125I lucanthone in rats was determined to learn if lucanthone crossed the blood-brain barrier. Size determinations were made of patients brain metastases from magnetic resonance images or by computed tomography before and after treatment with 30 Gy whole brain radiation alone or with lucanthone.nnnRESULTSnThe time course of lucanthones distribution in brain was identical to that in muscle and heart after intraperitoneal or intravenous administration in experimental animals. Lucanthone, therefore, readily crossed the blood-brain barrier in experimental animals.nnnCONCLUSIONnCompared with radiation alone, the tumor regression in patients with brain metastases treated with lucanthone and radiation was accelerated, approaching significance using a permutation test at p = 0.0536.

Predictive value of linear-quadratic model in the treatment of cervical cancer using high-dose-rate brachytherapy

PURPOSEnTo determine whether a dose-response relationship exists between the biologic effective dose (BED) at Point A and the bladder and rectum and the clinical outcomes in our experience with external beam radiotherapy (EBRT) and high-dose-rate brachytherapy in the treatment of cervical carcinoma.nnnMETHODS AND MATERIALSnThis was a retrospective study. A total of 49 patients with cervical cancer were treated with a combination of EBRT (median 45 Gy, range 41.4-50.4) and high-dose-rate brachytherapy (median 18 Gy; range 18-19, in two fractions). Twenty-three patients received concomitant cisplatin-based chemotherapy. The cumulative BEDs were calculated at Point A (BED10) and at bladder and rectal reference points (BED3) using the linear-quadratic equation. The BED10 values, after incorporating a time factor (BED10tf) in the formula, were also calculated.nnnRESULTSnIn patients treated with RT alone, the local failure rate was 10% (1 of 10) and 19% (3 of 16) in patients receiving a BED10 >89 Gy10 or <89 Gy10 to Point A, respectively (p = 0.2). The corresponding local failure rates were 20% (3 of 15) and 0% (0 of 8) in patients treated with concomitant chemotherapy (p = 0.3). In patients treated with RT alone, the local failure rate was 7.7% (1 of 13) and 23% (3 of 13) in patients with a BED10tf >64 Gy10 or <64 Gy10 (p = 0.1), respectively. The median BED3 values at the rectal and bladder point was 95.5 Gy3 and 103.6 Gy3, respectively. Only 1 case of Grade 2 late rectal toxicity (2%) and no late bladder toxicity occurred.nnnCONCLUSIONnIn patients treated with RT alone, a BED10 >89 Gy and a BED10tf >64 Gy indicated a trend toward a better local control rate. This difference was not observed in patients receiving chemotherapy. A BED3 <100 Gy3 was associated with negligible late toxicity. Although the BED10 in our study was about 10-15 Gy10 less than that in the published data, the 4-year local control rate of 80% and 83% and disease-free survival rate of 75% and 70% with and without chemotherapy, respectively, compare well with the rates in other studies in the literature.

The relationship between dose heterogeneity ("hot" spots) and complications following high-dose rate brachytherapy.

PURPOSEnIt is generally believed that hot spots should be avoided in radiotherapy because they lead to complications. Dose homogeneity within the target volume is much more difficult to achieve during brachytherapy than during external beam irradiation, and implants are rarely geometrically perfect. To not underdose some parts of the target volume, therefore, it may be necessary to accept hot spots in other parts of the target volumes, but it is not at all clear from the literature how much dose heterogeneity should be considered excessive. We undertook this study in an effort to determine just how high a dose to a hot spot is associated with clinically significant complications.nnnMETHODS AND MATERIALSnWe studied 40 patients treated by high-dose rate brachytherapy with or without external irradiation. For each patient, we calculated the minimum dose to the hottest 1 cubic centimeter (cc) volume (Dmax1) and, for 18 patients, the minimum dose to the hottest 10 cc volume (Dmax10) as well.nnnRESULTSnConsiderable dose heterogeneity existed within the target volume. The Dmax1 ranged from 150-2000% (median 320%) of the minimum target dose (MTD). The median MTD/fraction was 2.50 Gy (range 1.50-25.00), and the median Dmax1/fraction was 10.00 Gy (range 3.75-150.00). The median Dmax1 from the entire course of brachytherapy was 75.00 Gy (range 25.00-550.00). Adding the doses from planned external irradiation, plus any prior irradiation to the same area, the median total Dmax1 was 112.50 Gy (range 30.00-580.00), yet the incidence of complications, even among those in the highest quartile of this dose range, was not greater than the lowest quartile. The total median Dmax10 was 85.00 Gy (range 32.00-130.00), but the incidence of complications was, again, similar whether the dose was in the lower or the upper half of this range (32.00-85.00 Gy, or 86.00-130.00 Gy, respectively).nnnCONCLUSIONSnWe had expected to find that the patients with the highest Dmax1 and/or Dmax10 would be the ones most likely to suffer complications, but the results did not support this hypothesis. Thus, dose heterogeneity, within the scope of our study, turned out to be rather unimportant with regard to complications. This finding contradicts the conventional wisdom and suggests that concerns about hot spots need not preclude optimization to ensure adequate dosage to all parts of the target volume.

Pelvic exenteration for cervix cancer: Would additional intraoperative interstitial brachytherapy improve survival?

OBJECTIVEnImproved local control with the addition of brachytherapy to pelvic exenteration for recurrent cervical cancer has been reported to improve survival. We examined the sites of recurrence after pelvic exenteration to determine if these patients might have been salvaged by the improved local control promised by interstitial brachytherapy. We sought to identify risk factors available intraoperatively or perioperatively which might predict decreased local control.nnnMETHODSnA retrospective review of 26 patients with recurrent cervical cancer who underwent total pelvic exenteration since 1988 at our institution was performed.nnnRESULTSnOverall, the mean follow-up was 29.5 months (range 6.1-81.6). Of the 26 patients, 14 had no evidence of disease (NED), 1 was alive with disease (AWD), 9 were dead of disease (DOD), and 2 died of unrelated causes (DOC). Seven of 26 patients (27%) had margins < or = 5 mm, of whom 2 were NED, 4 DOD, and 1 AWD. Seven of 26 (27%) patients had lymphovascular involvement (LVI) or perineural invasion (PNI) with clear margins. Three of the seven with LVI or PNI and clear margins were NED, and four DOD. Of the 10 failures, 9 (90%) had close margins, PNI, or LVI.nnnCONCLUSIONnOur data reveal that 9 of 14 (64%) patients with close margins, LVI, or PNI were DOD or AWD, and 6 of 9 of those patients suffered local regional failure alone. Brachytherapy has the potential to cure 6 of 14 (43%) patients with these risk factors. Further study of brachytherapy at the time of pelvic extenteration is warranted.

A novel second line chemotherapy treatment of recurrent thymoma

Thymoma is an uncommon malignancy which is initially treated with surgery. Combined modality treatment with radiation and chemotherapy is utilized in cases of unresectable or metastatic disease. In patients with relapse, a number of different chemotherapeutic regimens have been used with varying success. The case of a male with recurrent thymoma treated with carboplatin and paclitaxel is presented and the literature reviewed. The patient responded to this novel regimen with improvement in clinical symptoms and reduction in tumor mass. This novel regimen has shown activity as second line therapy and merits further investigation as a first line treatment for patients with invasive and or metastatic thymoma.

PHASE I CLINICAL TRIAL OF PARENTERAL HYDROXYUREA IN COMBINATION WITH PELVIC AND PARA-AORTIC EXTERNAL RADIATION AND BRACHYTHERAPY FOR PATIENTS WITH ADVANCED SQUAMOUS CELL CANCER OF THE UTERINE CERVIX

PURPOSEnOral hydroxyurea (HU) is a potent radiation sensitizer, but in vitro studies have suggested that prolonged exposure to HU by way of continuous parenteral infusion would enhance clinical efficacy. The objective of this study was to determine the maximal tolerated dose and identify the toxicities of continuous infusion HU in combination with pelvic and para-aortic external beam radiotherapy (RT) and intrauterine brachytherapy in patients with locally advanced carcinoma of the uterine cervix.nnnMETHODSnThis Phase I study of concomitant RT was designed with an escalating dose schedule of HU administered by continuous infusion. HU was administered parenterally as a continuous infusion, 5 d/wk, during the first 21 days of external radiation, during the final 5 days of external beam RT, followed by another 5-day infusion schedule bracketing the single fraction of brachytherapy. The maximal tolerated dose was defined as the highest dose level at which 3 of 3 or 5 of 6 patients could be treated without dose-limiting toxicity.nnnRESULTSnAt dose level 1 (0.25 mg/m(2)/min), 0 of 4 patients experienced Grade 4 toxicities and 2 patients experienced Grade 3 hematologic toxicities that were not considered dose-limiting. One of the first 4 patients at level 2 (0.375 mg/m(2)/min) had Grade 3 diarrhea, but the 3 subsequent patients tolerated the dose. At level 3 (0.5 mg/m(2)/min), 4 of 5 patients failed to complete therapy without a >7-day interruption in HU.nnnCONCLUSIONSnThe maximal tolerated dose of parenteral HU was 0.375 mg/m(2)/min when administered with concomitant RT. The most common toxicities were hematologic. A new trial, incorporating concurrent cisplatin, HU, and RT is planned.

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.