B. O'Sullivan

Epidermoid anal cancer: Treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C

One hundred ninety-two patients with primary epidermoid cancer of the anal canal were treated by a series of prospectively designed, sequential non-randomized protocols of radiation alone (RT), radiation with concurrent 5-Fluorouracil and Mitomycin C (FUMIR), or radiation with concurrent 5-Fluorouracil only (FUR). The 5-year cause-specific survival rates were 69% overall, 68% RT, 76% FUMIR, 64% FUR. The primary tumor was controlled by radiation with or without chemotherapy in 68% (130/191) overall, 56% (32/57) by RT, 86% (59/69) by FUMIR, 60% (39/65) by FUR. The results with FUMIR were significantly better than with either RT alone or FUR, and except in tumors up to 2 cm in size, this superiority was found in all T stages. Regional lymph node metastases were controlled in 33 of 38 (87%) overall. The finding of clinically detectable regional lymph node metastases at presentation did not affect survival significantly in any treatment group. Anorectal function was preserved in 88% of the patients in whom the primary tumor was controlled, and in 64% overall. The delivery of 5FU and MMC concurrently with uninterrupted radical irradiation, 50 Gy in 20 fractions in 4 weeks, produced severe acute and late normal tissue morbidity. Split course treatment, and reduction of the daily fractional dose to 2 Gy, diminished the severity of normal tissue damage. Omission of Mitomycin C reduced acute hematological toxicity, but was associated with a decreased primary tumor control rate. The most effective treatment protocols as measured by survival rates, primary anal tumor control rates, and the likelihood of conservation of anorectal function included the administration of both Mitomycin C and 5-Fluorouracil concurrently with radiation therapy.

Caspase 3–mediated stimulation of tumor cell repopulation during cancer radiotherapy

In cancer treatment, apoptosis is a well-recognized cell death mechanism through which cytotoxic agents kill tumor cells. Here we report that dying tumor cells use the apoptotic process to generate potent growth-stimulating signals to stimulate the repopulation of tumors undergoing radiotherapy. Furthermore, activated caspase 3, a key executioner in apoptosis, is involved in the growth stimulation. One downstream effector that caspase 3 regulates is prostaglandin E2 (PGE2), which can potently stimulate growth of surviving tumor cells. Deficiency of caspase 3 either in tumor cells or in tumor stroma caused substantial tumor sensitivity to radiotherapy in xenograft or mouse tumors. In human subjects with cancer, higher amounts of activated caspase 3 in tumor tissues are correlated with markedly increased rate of recurrence and death. We propose the existence of a cell death–induced tumor repopulation pathway in which caspase 3 has a major role.

The surgical margin in soft-tissue sarcoma

In a retrospective review of 231 patients who were referred to Princess Margaret Hospital because of a soft-tissue sarcoma in an extremity, 100 patients were identified who had no metastases when they were first seen and who had been treated by local resection and adjuvant radiation therapy. Complete data were collected for each patient for the following variables: age; sex; location of the tumor and its size, grade, depth, and compartmental status; chemotherapy; and dose of radiation. The surgical margins were characterized as positive or negative for histological evidence of disease on the basis of an independent review of the pathological and operative reports by a surgeon and a radiation oncologist who were experienced in the management of sarcoma. Cox multivariate analysis was used to determine which of these variables contributed to local recurrence and evidence of systemic disease. Adequacy of the margin of resection was the only variable that was associated with local relapse (p = 0.0004). The size of the tumor (p = 0.0008) was the major determinant of the risk of systemic disease.

PREOPERATIVE AND POSTOPERATIVE IRRADIATION OF SOFT TISSUE SARCOMAS: EFFECT ON RADIATION FIELD SIZE

For the treatment of soft tissue sarcomas it has frequently been staged but not quantitatively demonstrated, that the volume irradiated is smaller when irradiation is given preoperatively as compared to postoperatively. In this study the field size used for preoperative irradiation was compared with that necessary in the same patient had the radiation been given postoperatively. Twenty-six patients with soft tissue sarcomas of the extremity, groin, and shoulder girdle who had received preoperative irradiation were resimulated following surgery to determine the size of the postoperative field. The simulation was performed by a physician not involved in the preoperative treatment planning. Preoperatively a radial margin of 5 cm around the tumor was used for low and intermediate grade and 7 cm for high grade sarcomas. Postoperatively the same margins were used but around the surgical field. Twelve patients underwent a wide resection and 14 patients a resection followed by vascularized tissue transfer to the surgical bed. The median follow-up was 22 months (range 13-46). No local recurrences and two cases of distant metastasis were observed. Independently of surgical procedure and tumor grade, the size of the preoperative radiation field and number of joints included in the field were significantly smaller than that of postoperative radiation (p less than 0.001). In two patients preoperatively and four patients postoperatively, the radiation field involved the whole circumference of the limb. Provided that equivalent radiation time-dose-fraction parameters are used and that the complication rate is proportional to the radiation field size, late complications may be less after preoperative irradiation than after post-operative irradiation.

A phase II study of Biotene in the treatment of postradiation xerostomia in patients with head and neck cancer

Abstractu2002One of the major side effects of radical radiation therapy for head and neck malignancies is xerostomia, or dryness of the mouth. There is no clearly effective treatment for this condition, but we have observed that patients in our practice believe that their symptoms improve significantly when using two over-the-counter oral comfort products – Biotene (toothpaste, mouthwash and chewing gum) and Oralbalance gel. We decided to study these agents in a formal phase II study to evaluate their usefulness in patients with postirradiation xerostomia. Twenty-eight patients with post-irradiation xerostomia were entered on the study. All had biopsy-proven carcinoma of the nasopharynx, oropharynx, oral cavity, hypopharynx or larynx, and had received primary radiotherapy with curative intent (≥50u2009Gy in 20 fractions) more than 4u2009months before study entry. More than 75% of both parotid glands were included in the primary radiation field. There was no clinical evidence of recurrent disease. Patients were provided with a 2-month supply of Biotene mouthwash, toothpaste, chewing gum and Oralbalance gel. Response was evaluated 1 and 2u2009months after study entry using a patient-completed visual analogue scale to assess the severity of xerostomia and its effects on quality of life. For analysis, the scored baseline was subtracted from the later scores to assess change. Patients with an increase of 10u2009mm from their baseline score on the visual analogue scale were classified as having responded to the treatment intervention, and those with an increase of ≥25u2009mm from their baseline score were classified as having experienced a major improvement in their symptoms. After 2u2009months of treatment, 15 patients (54%) reported an improvement in intraoral dryness and 10 of these patients (36%) reported a major improvement. Similar proportions of patients (46% some improvement, 25% major improvement) reported an improvement in their ability to eat normally. Seventeen patients (61%) reported an improvement in oral discomfort, and 12 of these (43%) had a major improvement in their symptoms. The results of this study suggest that the use of Biotene (mouthwash, toothpaste and chewing gum) and Oralbalance gel can improve many of the symptoms of radiation-induced xerostomia. A placebo effect could account for many of the observed improvements in symptoms, and in order to assess the role of these agents in the management of patients with postirradiation xerostomia a randomised phase III study is needed.

Controversies in the management of non-small cell lung cancer: the results of an expert surrogate study

Four hundred and sixty-one doctors who treat lung cancer in Canada and the United States answered a questionnaire in which they were asked how they would wish to be managed if they developed non-small cell lung cancer (NSCLC). There was no evidence of a consensus as to preferred treatment in either of two clinical situations described. Personal treatment preferences were significantly influenced by specialist training and each discipline showed a preference for its own modality of treatment. The personal treatment preferences of American and Canadian doctors differed significantly. In the United States, the role of surgery in NSCLC with extensive mediastinal disease was controversial, whereas in Canada, the major controversy was whether any active treatment was desirable in this situation if symptoms were absent. The role of chemotherapy in the treatment of NSCLC with painful bone metastases was controversial in the United States, but the vast majority of Canadian doctors would not wish any form of chemotherapy in this situation. Respondents were also asked what treatment they usually recommended for patients with NSCLC in the two situations described. Almost all these doctors recommended for their patients exactly the same treatment which they would choose for themselves. It was concluded that the personal treatment preferences of doctors are an important factor in determining how patients with NSCLC are treated. Doctors were also asked (a) if they would be willing to participate as patient-subjects in a number of clinical trials for which they would be eligible if they developed NSCLC, and (b) if they would be willing to ask their patients to participate in the same trials. There were significant differences in the perceived acceptability of the trials studied, but in each case a higher proportion of doctors would be willing to ask their patients to participate than would be prepared to consent themselves.

Combined radiation therapy, mitomycin C, and 5-fluorouracil for locally recurrent rectal carcinoma: Results of a pilot study

Twenty-two patients underwent combined radiation therapy (XRT), mitomycin C (MMC), and 5-fluorouracil (5FU) for rectal carcinoma, locally recurrent following either abdominoperineal or anterior resections. All patients presented with symptomatic unresectable pelvic cancer. The protocol XRT doses were 45-50 Gy/20/4-6 weeks. Chemotherapy consisted of MMC 10 mg/m2 on day 1, and 5FU 15 mg/kg/day on days 1, 2, and 3 of XRT, both given by intravenous bolus injection. Only 2 of 22 patients remained NED at 5 years following treatment. All but four patients eventually experienced progression of pelvic disease. Ten of 22 patients were unable to complete the treatment protocol because of excessive acute hematological and gastrointestinal toxicity. Five patients developed neutropenic sepsis, one of whom died. Combined XRT, MMC, and 5FU as used in this study had no apparent advantage over XRT alone in terms of pelvic disease or survival, and produced significant toxicity.

Uroporphyrinogen Decarboxylase Is a Radiosensitizing Target for Head and Neck Cancer

Uroporphyrinogen decarboxylase inhibition sensitizes head and neck cancer to both radiotherapy and chemotherapy. xa0A Lightning UROD for Head and Neck Cancer They say lightning never strikes the same place twice—unless, of course, that place is a lightning rod. This metal conductor draws damaging bolts to itself and away from sensitive and important structures. Cancer therapies would benefit from similar specificity. The ability to direct radiation and chemotherapy selectively toward cancer cells would decrease treatment side effects and improve patient prognosis. Ito et al. have found that uroporphyrinogen decarboxylase (UROD) can act as a lightning rod for cancer cells, sensitizing them to radiotherapy. Head and neck cancer (HNC) comprises a diverse group of tumors of the upper respiratory and digestive tracts. Alcohol and tobacco use are strongly associated with risk for developing HNC. Using a high-throughput RNA interference screen, the authors identified UROD, an enzyme involved in heme biosynthesis, as a target for enhanced radiosensitization of these tumor types. Knockdown of UROD gene expression with a specific small inhibitory RNA molecule increased cancer cell death both in vitro and in vivo, likely through the production of reactive oxygen species and the resultant rise in oxidative stress. Moreover, elevated amounts of UROD were observed in HNC specimens, and low amounts of cancer-associated UROD correlated with improved patient survival. The sensitizing effects of UROD down-regulation extended to other cancer types and were applicable to both radiation and chemotherapy. These findings suggest that UROD represents a new target for drugs that help cell-killing agents attack tumors and spare normal cells. Head and neck cancer (HNC) is the eighth most common malignancy worldwide, comprising a diverse group of cancers affecting the head and neck region. Despite advances in therapeutic options over the last few decades, treatment toxicities and overall clinical outcomes have remained disappointing, thereby underscoring a need to develop novel therapeutic approaches in HNC treatment. Uroporphyrinogen decarboxylase (UROD), a key regulator of heme biosynthesis, was identified from an RNA interference–based high-throughput screen as a tumor-selective radiosensitizing target for HNC. UROD knockdown plus radiation induced caspase-mediated apoptosis and cell cycle arrest in HNC cells in vitro and suppressed the in vivo tumor-forming capacity of HNC cells, as well as delayed the growth of established tumor xenografts in mice. This radiosensitization appeared to be mediated by alterations in iron homeostasis and increased production of reactive oxygen species, resulting in enhanced tumor oxidative stress. Moreover, UROD was significantly overexpressed in HNC patient biopsies. Lower preradiation UROD mRNA expression correlated with improved disease-free survival, suggesting that UROD could potentially be used to predict radiation response. UROD down-regulation also radiosensitized several different models of human cancer, as well as sensitized tumors to chemotherapeutic agents, including 5-fluorouracil, cisplatin, and paclitaxel. Thus, our study has revealed UROD as a potent tumor-selective sensitizer for both radiation and chemotherapy, with potential relevance to many human malignancies.

Preoperative radiotherapy is effective in the treatment of fibromatosis.

The use of preoperative radiation is well-established for soft tissue sarcoma, but its use in fibromatosis is not well-characterized. The purpose of this study was to examine the impact of preoperative radiotherapy on the local control of fibromatosis and to assess treatment-related morbidity in this setting. In particular we assessed complication rates in comparison with soft tissue sarcoma treatment. All patients with fibromatosis referred to this unit who received preoperative radiotherapy (50 Gy in 25 fractions) from 1988 to 2000 and who had at least 2 years of followup were included in this study. The rate of recurrence in this group was ascertained. Similarly constructed datasets from all patients with soft tissue sarcomas of the extremities who received preoperative radiation from 1986 to 1997 also were analyzed. The rates of complications in the two groups were compared. Fifty-eight patients were treated with preoperative radiation for fibromatosis and the median followup was 69 months. There were 11 local recurrences (19%). Major wound complications manifested in two patients (3.4%). Wound-related complications arose in 89 of 265 patients with soft tissue sarcomas (33.5%). There was a significant difference in the rate of major wound complications observed in the two groups. The use of radiotherapy before surgery is effective in the combined treatment of fibromatosis.

Fractures following limb-salvage surgery and adjuvant irradiation for soft-tissue sarcoma.

In a prospective study, consecutive patients were treated for soft-tissue sarcoma (STS) by wide resection and adjuvant irradiation. Twelve patients had resection of bone to achieve a tumor free margin; five of these patients were left with lower extremity open segmental cortical defects in the high-dose radiation field. Four of the five patients with cortical defects suffered a fracture through the defect more than six months after surgery. Only one of 71 patients not treated with bony resection suffered a late fracture. Patients requiring bony cortex resection for STS of the lower extremity should be considered at risk for late fracture if adjuvant irradiation is prescribed.