Hyperbaric oxygen therapy for late sequelae in women receiving radiation after breast-conserving surgery.

PURPOSE: Persisting symptomatology after breast-conserving surgery and radiation is frequently reported. In most cases, symptoms in the breast resolve without further treatment. In some instances, however, pain, erythema, and edema can persist for years and can impact the patient's quality of life. Hyperbaric oxygen therapy was shown to be effective as treatment for late radiation sequelae. The objective of this study was to assess the efficacy of hyperbaric oxygen therapy in symptomatic patients after breast cancer treatment. PATIENTS AND METHODS: Forty-four patients with persisting symptomatology after breast-conservation therapy were prospectively observed. Thirty-two women received hyperbaric oxygen therapy in a multiplace chamber for a median of 25 sessions (range, 7-60). One hundred percent oxygen was delivered at 240 kPa for 90-min sessions, 5 times per week. Twelve control patients received no further treatment. Changes throughout the irradiated breast tissue were scored prior to and after hyperbaric oxygen therapy using modified LENT-SOMA criteria. RESULTS: Hyperbaric oxygen therapy patients showed a significant reduction of pain, edema, and erythema scores as compared to untreated controls (p < 0.001). Fibrosis and telangiectasia, however, were not significantly affected by hyperbaric oxygen therapy. Seven of 32 women were free of symptoms after hyperbaric oxygen therapy, whereas all 12 patients in the control group had persisting complaints. CONCLUSIONS: Hyperbaric oxygen therapy should be considered as a treatment option for patients with persisting symptomatology following breast-conserving therapy.

Effects of hyperbaric oxygen and normobaric carbogen on the radiation response of the rat rhabdomyosarcoma R1H.

PURPOSE: Hypoxic tumor cells are an important factor of radioresistance. Hyperbaric oxygen (HBO) and normobaric carbogen (95% oxygen, 5% carbon dioxide) increase the oxygen delivery to tumors. This study was performed to explore changes of tumor oxygenation during a course of fractionated irradiation and to determine the effectiveness of normobaric carbogen and HBO during the final phase of the radiation treatment. METHODS AND MATERIALS: Experiments were performed on the rhabdomyosarcoma R1H growing on WAG/Rij rats. After 20 X-ray fractions of 2 Gy within 4 weeks, oxygen partial pressure (pO2) was measured using the Eppendorf oxygen electrode under ambient conditions, with normobaric carbogen or HBO at a pressure of 240 kPa. Following the 4-week radiation course, a top-up dose of 10-50 Gy was applied in 2-10 fractions of 5 Gy with or without hyperoxygenation. RESULTS: HBO but not carbogen significantly increased the median pO2 in irradiated tumors. The radiation doses to control 50% of tumors were 38.0 Gy, 29.5 Gy, and 25.0 Gy for air, carbogen, and HBO, respectively. Both high oxygen content gas inspirations led to significantly improved tumor responses with oxygen enhancement ratios (OERs) of 1.3 for normobaric carbogen and 1.5 for HBO (air vs. carbogen: p = 0.044; air vs. HBO: p = 0.02; carbogen vs. HBO: p = 0.048). CONCLUSION: Both normobaric carbogen and HBO significantly improved the radiation response of R1H tumors. HBO appeared to be more effective than normobaric carbogen, both with regard to tumor oxygenation and response to irradiation.

Expense and benefit of neoadjuvant treatment in squamous cell carcinoma of the esophagus.

BACKGROUND: The effectiveness of neoadjuvant treatment (NT) prior to resection of squamous cell carcinoma of the esophagus (SCCE) in terms of prolonged survival has not been proven by randomized trials. Facing considerable financial expenses and with concerns regarding the consumption of the patient's remaining survival time, this study aims to provide rationales for pretreating resection candidates. METHODS: From March 1986 to March 1999, patients undergoing resection for SCCE were documented prospectively. Since 1989, NT was offered to patients with mainly upper and middle third T3 or T4 tumors or T2 N1 stage who were fit for esophagectomy. Until 1993, NT consisted of chemotherapy. Since that time chemoradiation has also been applied. The parameters for expense and benefit of NT are costs, pretreatment time required, postoperative morbidity and mortality, clinical and histopathological response, and actuarial survival. RESULTS: Two hundred and three patients were treated, 170 by surgery alone and 33 by NT + surgery. Postoperative morbidity and mortality were 52% to 30% and 12% to 6%, respectively (p = n.s.). The response to NT was detected in 23 patients (70%). In 11 instances (33%), the primary tumor lesion was histopathologically eradicated. Survival following NT + surgery was significantly prolonged in node-positive patients with a median survival of 12 months to 19 months (p = 0.0193). The average pretreatment time was 113 +/- 43 days, and reimbursement for NT to the hospital amounted to Euro 9.834. CONCLUSIONS: NT did not increase morbidity and mortality. Expenses for pretreatment, particularly time and costs, are considerable. However, taking into account that the results are derived from a non-randomized study, patients with regionally advanced tumor stages seem to benefit, as seen by their prolonged survival.

The influence of inspiratory hyperoxia on ischemia-reperfusion-induced tumour growth delay.

We investigated the ischemia-reperfusion-induced tumour growth delay as a function of ischemic time, tumour temperature, and the amount of inspired oxygen during reperfusion. The rhabdomyosarcoma R1H growing on the right flank of male WAG/Rij rats was clamped for 2 or 4 h at 20 degrees C or 37 degrees C. Five minutes prior to and 10 min during reperfusion the animals respired air, pure oxygen or carbogen (95% O2, 5% CO2). Comparison of single treatment modalities with untreated controls revealed significant tumour growth delays after clamping times of 4 h at 37 degrees C for air and pure oxygen, but not for carbogen.

Induction chemotherapy and radiotherapy to avoid mastectomy in stage IIA-IIIA breast cancer.

The aim of the presented protocol was to investigate tumour remission and breast conservation rates with and without flap supported surgery after preoperative chemotherapy, radiotherapy and hyperthermia. 101 patients with stage IIA-IIIA breast cancers were initially treated with chemotherapy, radiotherapy and hyperthermia. 96 patients underwent salvage surgery. Complete pathologic response was not related to tumour diameter at diagnosis, the applied chemotherapy regime, number of chemotherapy cycles, overall radiation treatment time and time interval between radiotherapy and surgery. A breast conserving approach was possible in 55 patients (54%). After a median follow-up of 18 months no patient developed an isolated local recurrence.

Heterotopic calcification as a late radiation effect: report of 15 cases.

The LENT-SOMA scoring system for reporting late tissue effects following therapeutic radiation does not include heterotopic calcification as an end-point. Here we report on 15 long-term radiotherapy survivors with significant heterotopic calcifications. In all cases heterotopic calcification was linked to other radiation sequelae, e.g. ulceration, bone necrosis, nerve damage and fibrosis. The median time interval between radiotherapy and the occurrence of heterotopic calcification was 19 years (range 2-31 years). All patients received doses in excess of 40 Gy; overlap of adjacent fields played a role in some cases. It appears that heterotopic calcification can be regarded as end-stage damage following high dose radiotherapy. Heterotopic calcification in conjunction with local tissue breakdown is highly suggestive of previous radiation treatment.

Enhancement of radiosensitivity of rat rhabdomyosarcoma R1H with normobaric carbogen and hyperbaric oxygen (HBO) using conventionally fractionated irradiation.

Hypoxic clonogenic cells are an important contributory factor in tumour radioresistance. The objective of the present study was to evaluate whether hyperbaric oxygen enhances tumour radiosensitivity, using a conventionally fractionated irradiation schedule, and whether the radiosensitizing potential is different from carbogen. Experiments were performed using the rhabdomyosarcoma R1H model transplanted subcutaneously in the flank of WAG/Rij rats. A total of 30 X-ray fractions of 2 Gy were given either in air, normobaric carbogen or high pressure oxygen (HPO) (240 kPa, 2.37 atm) without anaesthesia. The time taken to achieve complete remission was 38.7 +/- 3.6 days, 36.7 +/- 2.7 days and 32.4 +/- 4.1 days for air, normobaric carbogen and HBO, respectively. The differences between air and HBO (p = 0.002) and carbogen and HBO (p = 0.015) were significant. Use of carbogen and HBO produced the same local control probability at 150 days and this was significantly higher than local control under ambient conditions (p < 0.0001). It was concluded that the time to achieve complete remission of the rat rhabdomyosarcoma R1H can be shortened by HBO. Furthermore, both HBO and carbogen give higher local control probabilities than treatment under ambient conditions when used with a conventionally fractionated radiation schedule.

Hyperbaric oxygen treatment for symptomatic breast edema after radiation therapy.

A 54-yr-old woman with a pT2pN0 breast cancer developed a long-standing symptomatic breast edema after lumpectomy and radiation therapy. The breast edema did not respond to non-steroidal anti-inflammatory drugs (NSAIDs) and manual lymph drainage of her arm. Three years after completion of radiation therapy, hyperbaric oxygen (HBO2) treatment was initiated. Fifteen HBO2 sessions were performed at a pressure of 240 kPa over 90 min in a multiplace chamber. At the end of treatment, breast discomfort had subsided completely, and 5 mo. after completing HBO2 therapy the patient is still free of complaints. We conclude from this observation that the value of HBO2 in the management of symptomatic radiation-induced breast edema should be investigated in a clinical study, because other effective treatment options are not available for this condition.

Tubo-ovarian abscess in virginal adolescents: exposure of the underlying etiology.

Tubo-ovarian abscesses (TOA) are acute complications of pelvic inflammatory disease (PID). PID is an infection of the upper genital tract that is usually caused by an ascending sexually transmitted infection. We present two cases of TOA in patients who deny any history of sexual activity or sexual abuse. In our first case a TOA was the primary manifestation of Crohn's disease. The TOA in our second case was attributed to a combination of obesity, constipation, recurrent urinary tract infections, and poor hygiene. In both cases the laparoscopic evaluation revealed purulent fluid collections in the fallopian tubes that were not evident on imaging. These cases support the use of laparoscopy for diagnosis in atypical cases.

The treatment of late radiation effects with hyperbaric oxygenation (HBO).

BACKGROUND: Late radiation injuries may impose a negative influence on the quality of life in the affected patients. In several entities, standardized treatment protocols are lacking. Hyperbaric oxygenation (HBO) has been shown to have beneficial effects in the treatment of late radiation sequelae. MATERIAL AND METHODS: The basic principles of HBO are reviewed as well as clinical issues. Current study protocols are presented. RESULTS: During HBO-therapy the patient breathes pure oxygen at pressures above 100 kPa. The oxygen solubility within the fluid phase of the blood is largely increased. Biological effects include an increased oxygen diffusibility, improved collagen synthesis and neoangiogenesis as well as an enhancement of antimicrobial defenses. By decreasing the capillary filtration pressure a reduction of edema becomes possible. HBO has been shown to prevent complications following surgery in irradiated tissues. Its efficacy as an adjunct in the treatment of osteonecroses in radiation patients could be demonstrated. In addition, the loss of osseointegrated implants in the maxillofacial bones of these patients could be significantly reduced. Further indications include soft tissue necroses, hemorrhagic cystitis and proctitis in tumor patients that have been treated by radiotherapy as part of a multimodality approach. CONCLUSIONS: HBO in the treatment of late radiation effects is still subject of investigation, but remarkable results have been reported. Optimized treatment protocols need to be determined in various entities. The rate of side effects is acceptable low.

[Short-term hypofractionated radiotherapy followed by total mesorectal excision]. / Kleinvolumige hypofraktionierte Radiotherapie vor totaler mesorektaler Exzision.

PURPOSE: Is preoperative short-term radiotherapy of operable rectal carcinoma feasible with regard to early side effects and perioperative complications? PATIENTS AND METHODS: As of December 1996 to March 1999, 34 patients with locally advanced rectal cancer have been irradiated preoperatively with 5 times 5 Gy. After CT-planning, radiotherapy was administered using a 3-field or 4-field box technique with 2 anterior-posterior fields or a posterior field of 9 +/- 2 cm x 11.5 +/- 2.4 cm and 2 opposed bilateral fields of 9 +/- 1.5 cm x 11.5 +/- 2 cm with 6- to 25-MV photons. Surgery was performed 14 +/- 6 days after irradiation in 33/34 patients (82% anterior resection with total mesorectal excision, 18% abdomino-perineal resection). Patients with a positive lymph node status or pT3/4 lesions underwent adjuvant chemotherapy with 5-Fluorouracil (5-FU). The median follow-up period is 189 days (range: 15 to 548 days). RESULTS: The following early side reactions were registered: increased bowel movements (4/34), fatigue (2/34), pain in the groins (1/34), nausea and perianal smart (1/34), vertigo (1/34), temporary urinary obstruction (1/34). One patient with heart failure NYHA Grade III died of a heart attack after 21 days. Preoperative T and N categories showed a distribution of 3, 29 and 2 for T4, T3 and unknown and 20, 11 and 3 for N+, N- and unknown; postoperative T and N categories showed a distribution of 3, 19 and 11 for T4, T3 and T2 and 19 and 14 for N+ and N-. In 32 of 33 patients tumor-free margins were achieved. One patient with peritoneal metastases had a R1 resection. In 3 patients metastases were detected intraoperatively. Perioperative complications were: 2 cases of leaking anastomosis and postoperative bowel atonia, 1 case with bowel obstruction, delayed wound healing, wound dehiscence and temporary renal dysfunction. CONCLUSION: Preoperative radiotherapy is feasible with moderate toxicity and is able to induce down staging despite the short time interval between radiotherapy and surgery.

Treatment of radiation proctitis with hyperbaric oxygen: what is the optimal number of HBO treatments?

AIM: Our objective was to investigate the effectiveness of hyperbaric oxygenation (HBO) in the treatment of radiation proctitis. The current literature was reviewed with regard to the necessary number of HBO treatments. PATIENTS AND METHODS: Two patients with proctitis after pelvic irradiation were treated with 40 and 38 HBO treatments, respectively. Hyperbaric oxygenation was delivered at 240 kPa over 90 min. RESULTS: In one patient, proctosigmoidoscopy showed a significant improvement after 40 HBO sessions. The other patient interrupted therapy after 38 HBO treatments without subjective change. The reported number of HBO sessions for a successful treatment of radiation proctitis ranges from 12 to 90. CONCLUSION: HBO should be considered before more invasive treatment modalities are performed for radiation proctitis.

[Changes in hemoglobin concentrations in combined radio- and chemotherapy in locally advanced ORL tumors]. / Anderungen der Hämoglobinkonzentration bei kombinierter Radio- und Chemotherapie lokal fortgeschrittener HNO-Tumoren.

BACKGROUND: Despite multimodality treatment strategies of locally advanced head and neck cancers long-term results leave much to be desired. There is evidence that oxygenation status of head and neck tumors is directly influenced by the hemoglobin concentration. The aim of this study was to verify changes in the hemoglobin level during combined radio-chemotherapy of locally advanced head and neck tumors. PATIENTS AND METHODS: Sixty-eight patients with locally advanced head and neck cancer had primary or adjuvant radiotherapy with doses of 60 to 74 Gy in combination with cisplatin- (+/- 5-FU) or carboplatin chemotherapy in the first and fifth week of treatment. Hemoglobin levels were analyzed before and at the end of radiotherapy. RESULTS: In 41% of all patients the initial hemoglobin concentration was below normal levels. The mean hemoglobin values in all patients dropped significantly from 12.9 +/- 1.7 g/dl before to 11.6 +/- 1.6 g/dl at the end of treatment. In 12 cases (18%) allogeneic erythrocytes had to be transfused during treatment. At the end of treatment 76% of all patients had anemic hemoglobin levels. In the groups of patients with cisplatin and carboplatin chemotherapy a significant decrease in hemoglobin levels was seen without meaningful statistical difference between these 2 groups. CONCLUSIONS: In patients with locally advanced head and neck cancer a high initial rate of anemia was registered (41%): This rate was nearly doubled during chemoradiation (76%). Since several studies have shown a correlation between hemoglobin levels and local tumor control, there is evidence, that this group might benefit from correcting anemia before combined radio-chemotherapy.

Remission rates following preoperative chemotherapy and radiation therapy in patients with breast cancer.

PURPOSE: To evaluate remission and breast-conservation rates after preoperative chemotherapy or chemo-radiotherapy (CT-RT). PATIENTS AND METHODS: Seventy-three patients with 74 biopsy-proven invasive breast cancers prospectively entered the protocol. Eighteen patients were treated by neoadjuvant chemotherapy followed by surgery and adjuvant irradiation (chemotherapy group). Fifty-five patients with 56 tumors were treated with combined neoadjuvant chemo-radiotherapy, followed by surgery (chemo-radiotherapy group). Most patients of both treatment groups received 4 cycles of EC chemotherapy. In some patients with large tumors 3 cycles of CMF were added. Chemotherapy was followed by hormonal treatment with tamoxifen or LHRH agonists in case of positive hormone-receptor status. Preoperative radiotherapy was administered using 2 Gy fractions up to a total dose of 50 Gy, followed by a tumor boost of 6 to 11 Gy. The median overall treatment time was 41 days (range: 35 to 55 days). The median time interval between end of neoadjuvant therapy and surgery was 11 weeks (range: 10 to 22 weeks) and 27 weeks (range: 11 to 41 weeks) for the chemotherapy- and chemo-radiotherapy group. The median time interval between end of chemotherapy and the beginning of irradiation ranged between 2 and 8 weeks (median 4 weeks) in the chemo-radiotherapy group. RESULTS: Side-effects due to chemo- or radiotherapy were moderate and reversible. In the chemotherapy group 17/18 patients (94%) achieved a partial (pPR) and 1/18 patients (6%) a complete histopathological response (pCR). In the chemo-radiotherapy group 32/56 (57%) showed a pPR and 24/56 (43%) a pCR. The difference in complete remission is significant (Fisher's Exact Test: p = 0.004). In 45/74 cases (61%) the breast was preserved, immediate breast reconstructions with rectus myocutaneous flaps (TRAM) after mastectomy were performed in 8/74 cases (11%) and modified radical mastectomies without reconstruction were required in 21/74 cases (28%). The breast conservation rates were similar in both treatment groups. CONCLUSIONS: Even though the small number of patients in the present protocol does not permit definite conclusions, the results of combined modality treatment seem promising with regard to tumor remission within the treated breast and as a tool for breast conservation in advanced stage disease. On the basis of these encouraging data a prospective Phase-III study has been initiated.

Post-Operative Radiotherapy of the Rhabdomyosarcoma R1H of the Rat.

Purpose. Post-operative radiotherapy (RT) is routinely applied in the treatment of several human tumours. The aim of the present study was to investigate the value of post-operative RT in a rat model.Methods. Experiments were performed using the rhabdomyosarcoma R1H of the WAG/Rij rat. Animals were randomized to different treatment schedules: surgery, RT or a combination of both. Tumours were excised at different sizes (0.1-4.5 g) aiming for complete macroscopic resection. RT (60 Gy in 30 daily fractions over 6 weeks) was applied either primarily or to the former turnout site from the third post-operative day. Tumour growth delay, time to recurrence and local tumour control were used as endpoints.Results. Pre-operative tumour size determined the time and rate of recurrence. The larger the tumour, the shorter the time to relapse and the higher the recurrence rate. The 50% local control rate (LCR(50)) for surgery was found in tumours with a mass of 0.8 g. For post-operative RT a LCR(50) was achieved for tumours with a mass of 1.1 g. For larger turnouts (> 1.1 g), however, the rate and time course of relapse were similar for both the group receiving RT alone and the group receiving post-operative RT.Discussion. In this model the tumour mass at excision governs the prognosis. Relatively small R1H turnouts may recur despite complete macroscopical resection. With regard to the LCR, the outcome for larger tumours is improved with post-operative RT (60 Gy/6 weeks) than compared with surgery alone. The factor is 1.3. Within a certain range of tumour sizes, combined treatment (surgery + RT) can improve the outcome considerably.

[Preoperative irradiation and interstitial radiotherapy-hyperthermia boost in breast tumors > or = 3 cm. The Düsseldorf experience]. / Präoperative Bestrahlung mit interstitiellem Radio-hyperthermie-Boost bei Mammatumoren > or = 3 cm. Düsseldorfer Ergebnisse.

AIM: The aim of this protocol was to investigate breast conservation rates with and without flap-supported surgery after preoperative chemotherapy, radiotherapy and hyperthermia. PATIENTS AND METHODS: One hundred and fifty-eight patients with stage IIA-IV breast cancers were initially treated with chemotherapy, radiotherapy and hyperthermia. Radiation treatment consisted of an interstitial boost of 10 Gy 192Ir-afterloading therapy and a course of external beam radiotherapy of 50 Gy, using 5 x 2 Gy/week. Local hyperthermia with 43.5-44.5 degrees C over 60 minutes was delivered immediately before interstitial radiotherapy. RESULTS: One hundred and forty-two patients underwent salvage surgery. A breast-conserving approach was possible in 74 patients (52%). Fifty-three patients (37%) underwent flap-supported surgery. After a median follow-up of 20 months, one patient developed isolated local recurrence. In 14 cases, locoregional recurrences occurred in combination with distant metastases. CONCLUSION: In about 50%, breast conservation was achieved by chemotherapy, radiotherapy and hyperthermia. The low isolated local recurrence rate of 0.6% (1/158) has to be substantiated by further follow-up.

Radiosensitizing effect of carbogen breathing during pulsed irradiation of the rat R1H tumor.

The objective of the present study was to investigate the radiosensitizing effect of carbogen breathing during pulsed x-ray irradiation in an experimental tumor model. Rat R1H rhabdomyosarcoma tumors were irradiated with 36 Gy total dose in 1 Gy high dose rate pulses, either hourly repeated, or in an 'office hours' protocol with irradiation-free overnight intervals. With the hourly, pulsed irradiation scheme, tumor growth delay (TGD) was significantly increased from 24.4+/-0.7 days in air-breathing animals to 29.0+/-0.9 days in animals breathing carbogen during irradiation. With irradiation during office hours, the TGD was shortened, and carbogen was less effective. The data show that carbogen acts as a radiosensitizer when applied during pulsed irradiation. Translation of the experimental data to clinical practice indicates that hyperoxygenation of the tumor during pulsed dose rate (PDR) or high dose rate (HDR) brachytherapy might enhance the tumor response of patients.