Ignacio Azinovic

Polymorphisms of the Repeated Sequences in the Enhancer Region of the Thymidylate Synthase Gene Promoter May Predict Downstaging After Preoperative Chemoradiation in Rectal Cancer

PURPOSE Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. TS gene promoter possesses regulatory tandemly repeated (TR) sequences that are polymorphic in humans, depending on ethnic factors. These polymorphisms have been reported to influence TS expression. TS expression levels affect tumor downstaging after preoperative fluoruracil (5-FU)-based chemoradiation. Tumor downstaging correlates with improved local control and disease-free survival. The aim of this study is to correlate TR polymorphisms with downstaging and disease-free survival. PATIENTS AND METHODS Sixty-five patients with rectal cancer underwent tumor resection after preoperative 5-FU-based chemoradiation. Tumor downstaging was evaluated by comparing the pretreatment T stage with the pathologic stage observed in the surgical specimen. TS polymorphism genotype was determined by polymerase chain reaction amplification of the corresponding TS promoter region, and products of amplification were electrophoresed, obtaining products of 220 bp (2/2), 248 bp (3/3), or both (2/3). The TS polymorphism genotype results were subsequently compared with the downstaging observed and with disease-free survival. RESULTS Patients who were homozygous for triple TR (3/3) had a lower probability of downstaging than patients who were homozygous with double TR or heterozygous patients (2/2 and 2/3): 22% versus 60% (P =.036; logistic regression). Furthermore, a trend toward improved 3-year disease-free survival was detected in the 2/2 and 2/3 groups, compared with that in the 3/3 group (81% v 41%; P =.17). CONCLUSION This preliminary study suggests that TS repetitive-sequence polymorphisms are predictive for tumor downstaging. TR sequences in TS promoter may be useful as a novel means of predicting response to preoperative 5-FU-based chemoradiation.

Combined treatment in superior sulcus tumors

January 1988 to August 1992, 18 patients (pts) with the established diagnosis of non-small cell lung cancer of the superior sulcus have been treated with a multidisciplinary approach, which includes 1–3 cycles of neoadjuvant chemotherapy (MVP or MCP regimens) followed by simultaneous preoperative chemotherapy and external beam irradiation. Radical surgery plus intraoperativc radiotherapy (IORT) was planned 4–5 weeks after the end of the preoperative protocol. Tumor stages were IIIA (9 pts) and IIIB (9 pts). Tumor characteristics included rib and vertebral involvement in 15 and 4 pts, respectively. Fatal toxicity was present in 3 pts (16.6%). Resectability rate was 76.4%. Pathologic findings disclosed complete response (pT0) in 70.5% of the surgical specimens and viable tumor (pT+) in 29.5%. With a median follow-up of 24+ months (2–52+), 4-year actuarial local control, and overall survival rates are 91% and 56.2%, respectively. Four-year actuarial overall survival according to pathologic response was 87.5% for pT0 patients and 20% for pT + patients. We conclude that this regimen promotes a high rate of pT0 as well as better than expected local control and survival rates. The presence of a pT0 specimen seems to correlate with the patient outcome.

Intraoperative radiotherapy electron boost followed by moderate doses of external beam radiotherapy in resected soft-tissue sarcoma of the extremities

PURPOSE To analyze the patterns of failure and the toxicity profile of intraoperative electron beam radiotherapy (IOERT) after resection of soft tissue sarcomas of the extremities (STS). PATIENTS AND METHODS Forty-five patients with extremity STS were treated with IOERT and moderate-dose postoperative radiotherapy (45-50 Gy). Twenty-six patients were treated for primary disease (PD) and 19 patients for an isolated recurrence (ILR). Tumor size was >5 cm (maximum diameter) in 36 patients (80%), and high-grade histology in PD patients was present in 14 patients (54%). In nine patients, IOERT was used alone, due to previous irradiation or patient refusal. Chemotherapy (neoadjuvant and/or adjuvant) was mainly given to high-grade tumors. RESULTS Nine patients relapsed in the extremity (20%), and 12 patients in distant sites (28%). Actuarial local control at 5 years was 88% for patients with negative/close margins and 57% for patients presenting positive margins (P=0.04). Five patients (11%) developed neuropathy associated with the treatment. Extremity preservation was achieved in 40 patients (88%). With a median follow-up of 93 months (range: 27-143 months) for the patients at risk, 25 patients remain alive (a 7-year actuarial survival rate of 75% for PD and 47% for ILR; P=0.01). CONCLUSIONS IOERT combined with moderate doses of external beam irradiation yields high local control and extremity preservation rates in resected extremity STS. Peripheral nerves in the IOERT field are dose-limiting structures requiring a dose compromise in the IOERT component to avoid severe neurological damage.

Intraoperative and external radiotherapy in resected gastric cancer: Updated report of a phase II trial

From September 1984 to August 1991, 48 evaluable patients with resected gastric cancer and apparent disease confined to locoregional area were treated with intraoperative electron beam boost to the celiac axis and peripancreatic nodal areas (15 Gy) and external irradiation (40 to 46 Gy in 4 to 5 weeks) including the gastric bed and upper abdominal nodal draining regions. At the time of evaluation for IORT, the disease was primary in 38 cases, recurrent but resectable in four (anastomosis), and unresectable in four (nodal). Post operative complications were reversible. Acute tolerance to the complete treatment program was acceptable. Late complications included life-threatening events: Six episodes of gastro intestinal bleeding (three of them had an arteriographic documentation of arterioenteric fistula) and nine with severe enteritis (five required reoperation). Other long-term treatment related complications were six cases of vertebral collapse. The median follow-up time for the entire group is 22 months. Locoregional recurrence/persistence of disease has been identified in five patients (three with residual and/or recurrent postsurgical tumor). Systemic tumor progression has been detected in 15 patients (11 in intra-abdominal sites). Overall actuarial survival for patients with positive or negative serosal involvement was 33% versus 56%. It is concluded that the treatment program described is able to induce a high locoregional tumor control rate (100%) when used strictly in an adjuvant setting and might control long term, a small portion of patients not amenable for curative surgery (2 out of 8 patients with confirmed residual post-surgical disease). Gastrointestinal bleeding and enteritis are findings that indicate treatment intensity at the upper limits of tissue tolerance. Assessment of long term tolerance of pancreatic parenchyma and large blood vessels (tissues included in the IRORT field) are pending for longer follow-up and the appropriate selective studies.

Long-term normal tissue effects of intraoperative electron radiation therapy (IOERT) : Late sequelae, tumor recurrence, and second malignancies

PURPOSE To evaluate long-term survivors treated with intraoperative electron radiation therapy (IOERT) as a component, with particular emphasis on analyzing late normal tissue toxicity, second malignancies, and patterns of delayed tumor recurrence. METHODS AND MATERIALS From September 1984 to December 1991, 739 patients were treated with IOERT. One hundred ninety-five patients were alive at least 5 years after IOERT (26%). Patient information regarding late complications related symptoms, incidence of second tumors, and delayed relapses were analyzed. Normal tissue changes were categorized by a modified LENT/SOMA scale (Grade 0-1, Grade 2, and Grade 3-4). Risk of late toxicity was grouped by type and number of cancer treatment modalities employed in each patient: surgery + IOERT alone (17 patients, 9%); IOERT + external radiotherapy +/- chemosensibilization (90 patients, 46%); IOERT +/- external radiotherapy +/- neoadjuvant chemotherapy (+/- previous radiotherapy) (88 patients, 45%). Biologic effective doses (BED) were calculated for alpha/beta = 3.5 for late fibrosis. RESULTS With a mean follow-up time of the surviving patients of 94 months (range: 55-162 months), 99 patients (51%) had Grade 0-1 toxicity, 52 (27%) had Grade 2, and 44 patients (23%) presented Grade 3-4 late normal tissue complications. Risk groups by treatment intensity did correlate with severity of observed toxicity (p < 0.001). BED estimations did not correlate with late normal tissue damage. The tumor type with higher toxicity scores was bone sarcoma (28/46, 60%), in which the estimated BED = 100.5 Gy. Peripheral neuropathy was the dominant IOERT-specific toxicity present in 24 patients (12%). Second malignancies were identified in 8 patients (4%), none inside the IOERT field (3 questionable to be marginal to the external beam radiotherapy volume). In 36 patients (18%), recurrence of the originally treated tumor was detected, including 11 (7%) local relapses. CONCLUSIONS The incidence of late normal tissue complications (50%) and severity (23%) is significant in a cohort of patients surviving more the 5 years after IOERT. The understanding of the contribution of IOERT to late tissue damage requires specific analysis. Peripheral neuropathy is a characteristic finding in IOERT trials. Second malignancies inside the IOERT field were not identified during the study period. The risk of recurrences, including local failures, requires an intensive follow-up of long-term survivors from IOERT trials.

Intraoperative radiotherapy for recurrent and/or residual colorectal cancer

Intraoperative radiotherapy (IORT) is an attractive boosting modality in the combined treatment of recurrent and/or residual colorectal cancer. Twenty seven patients treated with IORT are analysed. Residual disease following resection of the primary tumor was treated in 11 cases (group I). Localized recurrent disease without previous radiotherapy was treated in 11 cases (group II). IORT was used in five additional patients with local recurrences in previously irradiated areas (group III). The treatment program consisted of maximal tumor resection, IORT (10-30 Gy) to the area of residual disease and external beam radiotherapy (46-50 Gy). The median follow-up time for the entire series of patients is 11 months. Local tumor control rates are 90% in group I, 63% in group II and 60% in group III. Toxicity and complications related to IORT observed in this initial experience have been pelvic pain (29%) and lower extremity neuropathy (3%). These early clinical results suggest that the IORT combined with surgery and external beam radiotherapy is feasible in primary and recurrent disease. Local control rates obtained in patients not suitable for curative surgery are encouraging.

Intraoperative radiotherapy during lung cancer surgery: Technical description and early clinical results

A phase I-II study of intraoperative radiotherapy (IORT) for Stage III lung cancer was performed in 34 patients during a period of 58 months. Loco-regional treatment included tumor resection if technically feasible, IORT boost of electron beams using moderate single doses (10-15 Gy) to tumor bearing areas and external photon beam irradiation (46-50 Gy in 5 weeks) using conventional fields. Indications for this study were unresectable hiliar tumors (14, 41%), and mediastinal, hiliar and/or chest wall residual disease following resection (20, 59%). Thirty-four procedures, with 40 IORT fields, have been analyzed to describe the relevant technical aspects and the toxicity. IORT was delivered using acrylic transparent cones of different diameters. Surgical approach consisted in a lateral thoracotomy in all patients (21 right side and 13 left side). Tissues included within the IORT field were: tumor or residual tumor tissues (34, 100%), collapsed lung parenchyma and main bronchus not surgically manipulated (14, 41%), bronchial stump and vascular suture following resection (19, 55%), mediastinal structures (20, 58%), and brachial plexus (1, 3%). The bronchial suture was covered with pleural or pericardial flap after IORT in 10 cases (29%). Life threatening toxicity related to IORT consisted in broncho-pleural fistula (1, 3%) and massive hemoptysis (1, 3%). Other reversible toxic events were acute pneumonitis (12, 85%) and esophagitis (10, 50%). Long term asymptomatic lung fibrosis was detected in 11 cases (32%). Median survival time for the entire group has been 12 months. With a median follow-up time of 12 months the freedom from thoracic recurrence rate is 30% (65% in cases with tumor resection). Projected actuarial survival rates at 4 years were 28% for resected group and 7% for unresected cases. This experience supports IORT as a feasible alternative modality to be used in the management of locally advanced lung cancer. Tolerance of thoracic organs to moderate doses of IORT appeared to be adequate and local control is achieved in certain patients. These results deserve further investigation and confirmation trials.

Patterns of failure and long-term results in high-risk resected gastric cancer treated with postoperative radiotherapy with or without intraoperative electron boost

To evaluate the possible role of adjuvant radiotherapy in the management of high‐risk resected gastric carcinoma.

Intraoperative radiotherapy in recurrent gynecological cancer

A retrospective analysis to assess the feasibility and clinical tolerance of intraoperative radiotherapy (IORT) in the treatment of recurrent gynecologic cancer is reported. From February 1985 to September 1992, 26 patients with recurrent gynecologic tumors entered this trial. The clinical experience comprises two different categories of disease situations: tumors relapsing after full dose radiation therapy (group I) and recurrent disease to previous surgery (group II). Cervical carcinoma was the initial tumor site of involvement in 18 patients (69%). Treatment consisted in maximal surgical resection + IORT boost (10-25 Gy) to the high-risk areas for recurrence. Non previously irradiated patients also received external beam irradiation (EBRT) (+/- chemotherapy) pre- or postoperatively. IORT-related toxicity was one episode of motor neuropathy. Local control rates have been 33% and 77%, respectively in groups I and II. The 4-year actuarial overall survival in Group I is 7% and 6-year actuarial overall survival in Group II is 33%. The addition of IORT to surgical debulking achieves modest local control and long-term survival rates if tumor-free margins cannot be obtained in previously irradiated patients. Combined EBRT (+/- chemotherapy) maximal surgical resection plus IORT could render some long-term survivors among those surgical recurrent patients not candidates for radical surgery with curative intent.

Induction platinum-based chemotherapy followed by radical hyperfractionated radiotherapy with concurrent chemotherapy in the treatment of locally advanced non-small-cell carcinoma of the lung.

This study evaluated tolerance, local control, and short-term survival in patients with locally advanced non-small-cell lung carcinoma treated with induction chemotherapy followed by radical hyperfractionated radiotherapy with concurrent chemotherapy. Thirty-one patients with stage IIIa (N2) or IIIb tumors were treated with cis-platinum-based induction chemotherapy for 1 to 4 courses followed by radical hyperfractionated radiotherapy (69.6 Gy) with concurrent chemotherapy given at the beginning and end of radiotherapy. Induction chemotherapy produced no complete responses and 18 (58%) partial responses. After completion of radiotherapy, 4 patients had complete response (13%) and 23 patients (74%) partial response. The patterns of failure were as follows: intrathoracic, 6 patients (22%); intrathoracic + distant metastasis, 6 patients (22%); distant metastasis without thoracic failure, 5 patients (19%). Six patients of the 12 with intrathoracic failure experienced in-field radiotherapy pure local failure. At the time of this analysis, 10 patients were alive and well (4 complete and 6 partial responders). Actuarial survival projected at 39 months is 35%. No benefit was observed for those patients responding to induction chemotherapy. Toxicity was as follows: grade III neutropenic fever in 4 patients (13%), grade IV neutropenia in 13 patients (42%), pneumonia in 6 patients (19%), grade III esophagitis in 4 patients (13%) and severe clinical pneumonitis in 1 patient (3%). Induction chemotherapy followed by chemoradiotherapy is feasible, and the preliminary results are encouraging. Complete response after radiotherapy appeared to be related to short-term disease-free survival, and decisions based on the response to chemotherapy may be equivocal.