Developments in treatment of primary irresectable rectal cancer.

Abstract The treatment options for primary irresectable rectal cancers are discussed. Assessment of tumour stage is the first step for an appropriate choice of treatment. Following a diagnosis of rectal cancer, a vast array of diagnostic procedures is available to determine its stage, and thereby its best treatment options. From the many (new) diagnostic options the merits and drawbacks are discussed. If a diagnosis of irresectability is made, further treatment options should include radiotherapy in most cases, some aspects of timing and application, i.e. intra-operative treatment are discussed. Chemotherapy options are manifold, the results are discussed and some new options are explored.

Treatment of locally recurrent rectal cancer, results and prognostic factors.

PURPOSE: Assessment of the results and prognostic factors in patients with locally recurrent rectal cancer treated with curative intent. PATIENTS AND METHODS: Forty patients with an isolated pelvic recurrence of rectal cancer were studied retrospectively. The treatment consisted of radiotherapy alone or combined with chemotherapy and/or surgery performed between January 1992 and July 2001. Radiotherapy was given with a 3-4 fields technique (6-15 MV), five times a week. The median radiation dose was 50 Gy (range 25-66.6 Gy). Twenty-five patients underwent salvage surgery. Five patients were treated with concomitant chemotherapy (5-fluoro-uracil/leucovorin) (5FU/LV) during the 1st and 5th week of radiotherapy. RESULTS: Twenty-two of the 40 patients were male. The local recurrence free survival after 3 and 5 years, respectively, was 49 and 39%. Male gender was the only independent factor associated with failure of local control. The 3 and 5-year overall survival of the total group was 36 and 19%, respectively, with a median survival of 26 months. CONCLUSION: In a selection of patients in the treatment of locally recurrent rectal cancer valuable local palliation if not cure, can be reached. A multimodality approach seems to offer the best chances in this threatening situation.

5FU and oxaliplatin-containing chemotherapy in two dihydropyrimidine dehydrogenase-deficient patients.

Patients with a germline mutation leading to a deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme are at risk from developing severe toxicity on the administration of 5FU-containing chemotherapy. We report on the implications of this inborn genetic error in two patients who received 5FU and oxaliplatin. A possible co-medication effect of oxaliplatin is considered, as are the consequences of screening for DPD deficiency.

Late morbidity after treatment of breast cancer in relation to daily activities and quality of life: a systematic review.

AIMS: Breast cancer treatment may result in long-term upper limb morbidity: reduced range of motion of the shoulder, muscle weakness of the arm and hand, lymph edema, pain and numbness. Relationship of this late morbidity with activities of daily life (ADL) and quality of life (QOL) is infrequently described and the strength of this relationship is not clear. METHODS: A systematic review was performed to evaluate the results of studies, analyzing late morbidity of breast cancer treatment in relationship with ADL and/or QOL. A literature search over the last 20 years (1980-2000) was performed in the databases MEDLINE, EMBASE, PSYCHLIT and CANCERLIT. Methodological quality of selected articles was assessed and additional, aspects of treatment related late morbidity and the relationship to ADL and/or QOL were summarized. RESULTS: From the 1642 yielded articles 15 fulfilled our primary selection criteria. Only six articles could be selected due to the inappropriate methodological quality. There was high variation in prevalence of pain (12-51%), impairments in range of motion (2-51%), edema (6-43%) and decreased muscle strength (17-33%). Four articles reported significant relationships between late morbidity of the upper limb and perceived disabilities in ADL/QOL. The strength of these relationships was rather low. CONCLUSIONS: Few studies investigated the relationship between late morbidity of the upper limb after treatment of early breast cancer and ADL/QOL. Significant relationship between late morbidity and restrictions of daily activities and poorer QOL was reported, however, the strength of this relationship was rather low.

A favourable pathological stage after neoadjuvant radiochemotherapy in patients with initially irresectable rectal cancer correlates with a favourable prognosis.

Initial treatments of locally advanced rectal cancers focus on local control, as local relapse of a rectal cancer is correlated with a high morbidity and mortality. We studied the effect of neoadjuvant radiochemotherapy on advanced rectal cancer patients in relation to downstaging, local relapse and survival. Post-treatment pathological staging, local relapse and survival were analysed in 66 patients from a single institution. 43 patients had irresectable cancer as determined by laparatomy (n=42) or rectal examination (n=1). These 43 patients received 45-56 Gy preoperatively with 5-fluorouracil (5-FU) and leucovorin (350/20 mg/m(2)x5 day (d)) in weeks 1 and 5 during the radiation therapy. 23 patients had primary resectable tumours with a T1-2 stage. Of the initially irresectable tumours 79% became macroscopically resectable, in 74% a R0 resection was performed. In 6 of 34 (18%) surgical specimens, no tumour was found (pT0), 7 patients had small tumour remnants (pT1-2). In these pT0-2 tumours, no local relapses occurred (observation period of median 4.5 years, range 18-87 months). In the 21 patients with pT3-4 tumours 3 local relapses were seen. In the 23 patients with primary resectable T1-2 tumours the relapse rate was 4%. Downstaging of an initially irresectable rectal tumour to pT2 or less results in a local relapse rate and overall survival that correspond with the rates in primary resectable cancer with the same T classification.

Comparison of three rat strains for development of radiation-induced lung injury after hemithoracic irradiation.

The purpose of this study is to define differences in radiation sensitivity among rat strains using breathing frequency and lung perfusion as end points of radiation-induced lung injury. The results have confirmed previous findings in mice showing that under stringently controlled iso-dose/volume irradiation conditions, substantial differences can be found in susceptibility to functional lung damage after radiation.

Liver tissue tolerance for irradiation: experimental and clinical investigations.

Radiation treatment of the liver for malignant disease has gained renewed interest due to newly developed treatment modalities. Still limited specific knowledge is available concerning liver damage following irradiation. Inconsistencies between reported animal experimental studies are largely due to differences in irradiation techniques and to varying observation periods. Following the introduction of Megavoltage irradiation and the development of more sophisticated irradiation techniques, clinical reports concerning more reliable studies became available. The reaction of the liver to irradiation depends specifically on parameters as type of irradiation, dose, dose rate, fractionation schedule, and irradiated volume. Also the use of cytotoxic agents and liver surgery are of importance for the ultimate therapeutic result. Radiation hepatitis in humans may develop following high-dose liver irradiation resulting in clinical and histopathological disorders resembling a veno-occlusive disease-like syndrome. These disorders may either totally or partially recover or be progressive in time resulting in hepatic failure. It is concluded that depending on the variables mentioned, ionizing radiation up to 35 Gy to the human liver, given to a limited volume, can be applied without major liver function disturbances.

Short- and long-term histopathological changes in the canine liver following single high-dose intraoperative radiation therapy (IORT).

PURPOSE: The histopathological changes in the canine liver following single high-dose intraoperative radiation therapy (IORT) were investigated in order to establish the tolerance of liver tissue to IORT, thus providing a framework for clinical IORT treatment of patients with metastatic disease to the liver. MATERIALS AND METHODS: Following partial resection of the liver, IORT in doses of 10, 20, 25, or 30 Gy was applied to the resection plane and a non-surgically manipulated part of the liver of 25 beagles. RESULTS: There were no postoperative complications, and no morbidity or mortality during a maximal follow-up of 5 years. Dogs were killed at 3 months, and 1, 2, 3 and 5 years following IORT. Light microscopic examination revealed capsular thickening, severe parenchymal fibrosis, liver cell atrophy, and bile duct proliferation at the irradiated area 1 2 years following IORT. At 3-5 years, however, only mild parenchymal changes were found that consisted of slight periportal fibrosis, an incidental portal-central fibrous septum and vascular changes with endothelial proliferation and focal arteriolar hyalinosis. CONCLUSIONS: This study demonstrated that following partial hepatic resection, IORT to the liver in the canine model can be applied safely, without short- or long-term treatment morbidity. Although doses up to 30Gy resulted in severe local tissue damage 1-2 years following IORT, these changes were largely reversible due to hepatic regeneration.

Selective use of preoperative radiotherapy in the treatment of cancer in the lower two thirds of the rectum.

PURPOSE: The authors review the result of the selection of patients with a low rectal cancer for pre-operative radiotherapy. METHODS: The selection was based on the findings of digital examination eventually combined with surgical staging consisting of bimanual palpation during a staging laparotomy or "trial" operation. This selection was used to divide the patients into three groups: one where local radicality could be expected from primary surgery (group 1), one with deeply infiltrating, but mobile tumours requiring 10 x 3 Gy pre-operative radiotherapy (group 2) and one with fixed or borderline resectable tumours requiring protracted pre-operative radiotherapy with 55-59 Gy (group 3). One hundred and one patients were eligible for this study. A resection aiming for pelvic radicality was carried out in 94 patients: primary resection in 38 (group 1), surgery subsequent to 10 x 3 Gy pre-operative radiotherapy in 20 (group 2) and 55-59 Gy in 36 (group 3). RESULTS: The calculated risk of local recurrence at 5 years was 15% (95% C.I. 4-27) for group 1, 8% (95% C.I. 0-20) for group 2 and 30% (95% C.I. 16-44) for group 3. The calculated 5 years survival for the 3 groups was respectively 60%, 49% and 39%. CONCLUSION: The overlap in local recurrence rate between the three groups suggests a substantial downgrading by this approach of selective use of pre-operative radiotherapy in the patients with the most advanced tumour. Notwithstanding recent improvements of imaging techniques there still is a place for the staging laparotomy in the selection of the treatment strategy for advanced rectal cancers.

Pelvic exenteration for advanced primary rectal cancer in male patients.

Between November 1987 and January 1996 pelvic exenteration for primary rectal cancer was carried out in 11 male patients. Two underwent a primary resection with subtotal cystectomy. In the remaining nine patients, the treatment commenced with a staging laparotomy and the fashioning of an end colostomy of the descending colon, followed by preoperative radiotherapy (50-56 Gy in 5 weeks). Total exenteration with uretero-ileo-cutaneostomy was carried out 4-6 weeks later. In two patients, the exenteration was performed despite the detection of hepatic metastases during the second laparotomy. The pathological staging was T4 in six and T3 in five patients. The immediate postoperative course was uneventful in eight patients and their hospital stay averaged 20 days. Serious postoperative complications prolonged the hospital stay of three patients. Three died during the first 6 months. Recurrent disease caused the death of three of the eight remaining patients: one locoregional (7.5 years after surgery), one from pre-existing hepatic metastases (18 months after surgery) and one from the combination of locoregional and distant recurrence (15 months after surgery). Four patients are on follow-up without evidence of disease, 96, 43, 23 and 22 months after surgery. One patient is alive 20 months after exenteration, with two pulmonary metastases having been recently excised. We conclude that, notwithstanding the morbidity rate, total pelvic exenteration is an acceptable option for advanced primary rectal cancer in male patients. Preoperative radiotherapy should be administered for cancers seated in the lower two-thirds of the rectum and perioperative chemotherapy should be considered seriously.

Feasibility of tumor imaging using L-3-[iodine-123]-iodo-alpha-methyl-tyrosine in extracranial tumors.

UNLABELLED: L-3-[123I]-Iodo-alpha-methyl-tyrosine (IMT) is a modified amino acid. It is reported to be avidly taken up in brain tumors, reflecting amino acid transport and is suitable for SPECT. METHODS: To determine whether tumors outside the brain can also accumulate this tracer, we injected 300-450 MBq IMT into 20 patients with different tumors [5 breast cancers, 4 lung tumors (1 benign), 2 carcinoid liver metastases, 4 soft-tissue tumors (1 benign), 3 malignant lymphomas and 2 primary brain tumors]. Tumor size ranged from 1-12 cm. Imaging was repeated after radiotherapy in two patients with breast cancer. Histology was available in all cases. Dynamic scans, whole-body imaging and SPECT were performed during the first hour and 3 hr after injection. Plasma samples were analyzed for IMT, free 1231 and other metabolites. RESULTS: All primary tumors were visualized. Tumor-to-background ratios ranged from 1.1 to 3.8 on planar and from 1.3 to 6.2 on SPECT images. Tumor uptake peaked in the first hour. Two carcinoid lesions in the liver tumors exhibited no IMT uptake above liver background. Tumor-to-background ratios in a benign bone inflammatory process and a focal pulmonary vasculitis were less than 1.2 (planar) and 1.9 (SPECT) and could be differentiated from uptake in all malignant nonbrain tumors. IMT was rapidly cleared from the plasma [3.6% +/- 0.6% (mean +/- s.d.) injected dose/liter at 10 min postinjection]. Minor in vivo deiodination was present (<1% of injected dose 1 hr postinjection). No other metabolites were found. Normal distribution consists of some uptake in the brain, liver, spleen, muscles, pancreatic region and intestinal structures and massive uptake and excretion in the kidneys and bladder. CONCLUSION: IMT has potential as a metabolic tracer in tumors outside the brain.

Internal hemipelvectomy with intraoperative and external beam radiotherapy in the limb-sparing treatment of a pelvic girdle chondrosarcoma.

The case of a patient with an extensive pelvic girdle chondrosarcoma treated with internal hemipelvectomy and intraoperative radiotherapy, followed by adjuvant high-dose external beam radiotherapy, with a successful attempt in achieving long-term local tumor control and limb-sparing treatment is described.

Radiological and functional assessment of radiation-induced lung injury in the rat.

The purpose of this study is to develop an experimental model to measure localized radiation-induced lung injury using multiple end-points including breathing frequency, high-resolution computed tomography (CT), and radionuclide perfusion. The rats were anesthetized and the right lung irradiated with a single dose of 18 Gy using 200-kVp x-rays. The lung function of the animals was measured every 2 weeks after irradiation with the breathing rate assay. CT scanning and radionuclide lung perfusion assay were performed prior to and 2, 4, 10, 16, and 34 weeks after irradiation. Significant elevation in breathing rate occurred after 16 weeks, with a maximal increase between 22 and 28 weeks. An increase in the right lung density started 4 weeks after irradiation. Regional measurements indicated a relatively uniform increase in density at 4 and 10 weeks, while foci of high-density areas were observed at the later time points. Changes in rat lung volume indicated shrinkage of the irradiated right lung and accompanying compensatory hypertrophy of the shielded left lung. Radionuclide perfusion assay showed significant decrease in relative blood flow in the irradiated right lung 4 weeks after hemithoracic irradiation. Changes in breathing rate provide an index of overall lung function while changes in lung density, volume, and perfusion are of particular importance for evaluating loco-regional differences in lung sensitivity. This study is the first demonstration that CT can be used to measure volume changes after thoracic irradiation in rats.

Plasma TGFbeta level in rats after hemithoracic irradiation.

Changes in TGF-beta plasma levels were observed 18 weeks after hemithoracic irradiation in rats. This coincides with an increase in the breathing frequency. being most pronounced between 22 and 28 weeks after irradiation. The correlation suggests a potential role of the circulating TGF-beta in the monitoring of localized radiation-induced lung injury.

Pulmonary function after high-dose chemotherapy with autologous bone marrow transplantation and radiotherapy in patients with advanced loco-regional breast cancer.

Our aim was to study the extent of pulmonary toxicity after high-dose chemotherapy and radiotherapy in breast cancer patients. In a retrospective study the pulmonary symptoms and chest X-rays were analyzed before, during and after treatment in 17 patients, treated with loco-regional radiotherapy to the breast/chest wall and the regional lymph nodes after the completion of high-dose chemotherapy and autologous bone marrow transplantation for locally advanced breast cancer. Lung function was evaluated between 15 and 46 months after completion of the irradiation. Nine patients (53%) had pulmonary symptoms during and/or within two months from irradiation. Radiographic changes were seen in twelve patients (71%) and a decreased diffusion capacity occurred in nine patients (53%). The spirometric values (VC and FEV1) were abnormal in two patients (12%). There is a high incidence of radiation pneumonitis, although no consistent correlation between the various parameters (pulmonary symptoms, chest X-rays and lung function tests) could be found.

The anatomical substrate for a difference in surgical approach to rectal cancer in male and female patients.

This review emphasizes' gender related anatomical differences warranting a difference in surgical approach to the problem of rectal cancer in men and women. Differences in the anatomy of the bony pelvis, the pelvic viscera and the lymphatics of the rectum, inspired the authors to extend the margins of the rectal resection in the anterior plane in female patients. Between 1978 and 1992 a rectal resection was carried out for cancers confined to the pelvis in 158 patients. Of these patients 152 were available for review, 95 male and 57 female. In 24 out of 57 female patients extension of the rectal resection towards the genital tract by en bloc excision of posterior vaginal wall and/or uterus was considered necessary to be confident about obtaining tumour free margins. After a median follow-up of 8 years the risk of local recurrence and cancer related death were significantly lower in female patients.

Concurrent chemo- and radiotherapy in patients with locally advanced carcinoma of the cervix.

BACKGROUND: The feasibility of concurrent chemotherapy and radiotherapy for advanced primary carcinoma of the cervix was evaluated and the results were compared to historical controls. PATIENTS AND METHODS: In a single institution study, patients (n = 74) with primary cervical carcinoma received 3 cycles carboplatin/5-fluorouracil concurrent with radiotherapy followed by salvage hysterectomy (group I). Treatment results were compared with those of a historical control group (n = 39) (group II), treated similarly but without chemotherapy. RESULTS: In group I median follow-up is 28 months (12-68+) and in group II 23 months (14-90+ months). The 5-year overall survival, progression-free survival and local recurrence free survival for group I and II are, respectively, 69% versus 38% (P < 0.003), 67% versus 38% (P < 0.005) and 84% versus 43% (P < 0.0001). Two patients in each group developed posttreatment enteritis. CONCLUSIONS: Radiotherapy with concurrent carboplatin and 5-fluorouracil resulted in a better overall survival, disease free survival and local disease free survival compared to historical controls. The toxicity of this schedule did not exceed that of radiation alone in historical controls.

Hemipelvectomy and intraoperative radiotherapy for bone and soft tissue sarcomas of the pelvic girdle.

Current treatment of locally advanced bone and soft tissue sarcomas of the pelvic girdle are associated with a high local and distant failure rate, and local tumor control after hemipelvectomy can be a significant problem. IORT has been used in conjunction with hemipelvectomy, both conventional (seven patients) and limb-sparing internal hemipelvectomy (one patient), in seven males and one female, median age 27 (range 24-57) years with locally extensive high grade bone (seven patients) or soft tissue (one patient) sarcomas. IORT (15-30 Gy, 8-16 MeV) was delivered to sacral resection margins and surrounding soft tissues considered likely to harbor microscopically residual disease. Four patients received 46-54 Gy postoperative radiotherapy in addition to IORT. During a median follow-up of 33 months (range 6-131 months) two patients developed a local recurrence (25%), and five patients distant metastases (62%). Three patients with pelvic girdle sarcomas remained free of tumor (37%) with a mean follow-up of 100 (range 49-131) months. There was no treatment-related mortality. Two patients developed radiation-induced necrosis of the coccyx (25%). On the basis of this preliminary experience, it appears that IORT may substantially help to control local recurrence and survival in patients with marginally resectable sarcomas of the pelvic girdle after hemipelvectomy. Since the majority of the patients die from metastatic disease, there is a need for adjuvant systemic treatment.