Outcomes of complex colorectal polyps managed by multi-disciplinary team strategies-a multi-centre observational study.

PURPOSE: Team management strategies for complex colorectal polyps are recommended by professional guidelines. Multi-disciplinary meetings are used across the UK with limited information regarding their impact. The aim of this multi-centre observational study was to assess procedures and outcomes of patients managed using these approaches. METHOD: This was a retrospective, observational study of patients managed by six UK sites. Information was collected regarding procedures and outcomes including length of stay, adverse events, readmissions and cancers. RESULTS: Two thousand one hundred ninety-two complex polyps in 2109 patients were analysed with increasing referrals annually. Most presented symptomatically and the mean polyp size was 32.1 mm. Primary interventions included endoscopic therapy (75.6%), conservative management (8.3%), colonic resection (8.1%), trans-anal surgery (6.8%) or combined procedures (1.1%). The number of primary colonic resections decreased over the study period without a reciprocal increase in secondary procedures or recurrence. Secondary procedures were required in 7.8%. The median length of stay for endoscopic procedures was 0 days with 77.5% completed as day cases. Median length of stay was 5 days for colonic resections. Overall adverse event and 30-day readmission rates were 9.0% and 3.3% respectively. Malignancy was identified in 8.8%. Benign polyp recurrence occurred in 13.1% with a median follow up of 30.4 months. Screening detected lesions were more likely to undergo bowel resection. Colonic resection was associated with longer stays, higher adverse events and more cancers on final histology. CONCLUSION: Multi-disciplinary team management of complex polyps is safe and effective. Standardisation of organisation and quality monitoring is needed to continue positive effects on outcomes and services.

Use of risedronate to prevent bone loss following a single course of glucocorticoids: findings from a proof-of-concept study in inflammatory bowel disease.

SUMMARY: We performed a randomised controlled trial (RCT) to determine whether risedronate 35 mg once weekly prevents bone loss following an 8-week reducing course of prednisolone given for an exacerbation of inflammatory bowel disease (IBD). The greatest change in bone mineral density (BMD) was at Ward's triangle (WT), which fell by 2.2% in the placebo group, compared with a reduction of 0.8% in the risedronate group. INTRODUCTION: Whether bisphosphonates can prevent bone loss associated with intermittent glucocorticoid (GC) therapy is unknown, reflecting the difficulty in performing RCTs in this context. METHOD: To explore the feasibility of RCTs to examine this question, lumbar spine (LS; L2-4) and hip dual X-ray absorptiometry (DXA) scans were performed in 78 patients commencing a GC therapy course for a relapse of IBD. They were then randomised to receive placebo or risedronate 35 mg weekly for 8 weeks, after which the DXA scan was repeated. RESULTS: For LS BMD, there was no change in the placebo group (0.1 +/- 0.4, p = 0.9), but there was an increase after risedronate (0.8 +/- 0.4, p = 0.04; mean% +/- SEM by paired Student's t test). There were small decreases in both groups at the total hip (-0.5 +/- 0.3, p = 0.04; -0.5 +/- 0.3, p < 0.05, placebo and risedronate, respectively). At WT, BMD fell after placebo (-2.2 +/- 0.5, p = 0.001) but not risedronate (-0.8 +/- 0.5, p = 0.09; p = 0.05 for between-group comparison). CONCLUSION: RCTs can be used to examine whether bisphosphonates prevent bone loss associated with intermittent GC therapy, providing metabolically active sites such as WT are employed as the primary outcome.

Primary T-cell and activated macrophage response associated with tumor protection using peptide/poly-N-acetyl glucosamine vaccination.

The mode of peptide-based cancer vaccine administration critically affects the ability to achieve a clinically relevant tumor-specific response. We have previously shown (Cole et al., Clin. Cancer Res., 3: 867-873, 1997) that a specific formulation of the polysaccharide poly-N-acetyl glucosamine (p-GlcNAc, designated as F2 gel) is an effective vehicle for sustained cytokine and peptide delivery in vitro. The purpose of this study was to evaluate the efficacy of F2 gel/peptide vaccination in the murine EG.7-OVA tumor model and to elucidate potential mechanisms involved in the observed cell-mediated response. C57BL/6 mice were given injections of 200 microl in the base of tail/footpad using either F2 gel alone or 200 microg of: SIINFEKL minimal peptide (OVA) in PBS, OVA peptide/endoplasmic reticulum insertion signal sequence fusion (ESOVA) in PBS, OVA in F2 gel, or ESOVA in F2 gel. Splenocytes were tested 10 days later for a secondary response using a Cr51 assay as well as a primary CTL response using the lactate dehydrogenase cytotoxicity assay. Splenocytes from immunized mice were harvested at specific time points and assayed for cell surface and intracellular markers. On day 10 postvaccination, animals were challenged with EG.7-OVA murine thymoma cells. Tumor size and appearance were recorded. Vaccination with F2 gel/peptide (either OVA or ESOVA) resulted in a primary T-cell response (up to 25% tumor cell-specific lysis) and no tumor growth in 69% of the mice. By 48 h, the proportion of splenic T cells had increased 4-fold compared with B cells. Presence of an increased Th1 CD4 helper population was demonstrated by IFN-gamma production. CD4 cells were activated at 24 and 48 h as shown by IL-2 receptor alpha chain expression (from 2% basal expression to 15.4% at 48 h). Activated splenic macrophages increased from 3 to 8% within 10 h, and their level of B7-2 expression doubled. Depletion of macrophages before vaccine injection abolished any tumor-specific primary CTL response. F2 gel/peptide tumor vaccine can prime the immune system in an antigen-specific manner by generating a measurable primary T-cell response with minimal peptide; this process involves macrophage presence and activation as well as induction of Th1 CD4 cells. This is the first demonstration of a primary CTL response generated with minimal peptide vaccination using a noninfectious delivery system. These results justify additional studies to better define the mechanisms involved in F2 gel/peptide vaccination in preparation for clinical trials.

Distant metastases after irradiation alone in carcinoma of the uterine cervix.

This is a retrospective analysis of 1211 patients with invasive carcinoma of the uterine cervix treated with irradiation alone from 1959 through 1986, of whom 322 developed distant metastases during the course of the disease. The 10-year actuarial incidence of distant metastases was 3% in Stage IA (34 patients), 16% in Stage IB (384 patients), 31% in Stage IIA (128 patients), 26% in Stage IIB (353 patients), 39% in Stage III (292 patients), and 75% in Stage IVA (20 patients). A multivariate analysis of factors influencing the incidence of distant metastases showed clinical stage, endometrial extension noted by dilatation and curettage (D&C) prior to therapy, and pelvic tumor control within each stage to be significant indicators of distant dissemination; histology, volume of disease, and age of patient were not significant. The frequency of metastases in all stages except IVA was greater when endometrial tumor extension was detected by D & C before to definitive irradiation (Stage IB, 28%; Stage IIA, 48%; Stage IIB, 42%; Stage III, 72%; and Stage IVA, 75%). In contrast, with normal D & C findings, the incidence of distant metastases was 15% in Stage IB, 29% in Stage IIA, 25% in Stage IIB, 45% in Stage III, and 84% in Stage IVA. The incidence of metastases in patients with pelvic tumor control was 11% in Stage IB, 22% in Stage IIA, 21% in Stage IIB, 34% in Stage III, and 50% in Stage IVA; in contrast, the corresponding incidence in patients failing in the pelvis was 76% in Stage IB, 88% in Stage IIA, 62% in Stage IIB, 87% in Stage III, and 74% in Stage IVA. The frequency of metastases per histology was comparable in squamous cell carcinoma and other histologic types. The incidence of metastases to other organs was 56%: Most frequent sites were lung, abdominal cavity, liver, and gastrointestinal tract. The incidence of clinically apparent lymph node involvement was 22%, predominantly to paraaortic, supraclavicular, and inguinal nodes. Bone metastases occurred in 16% of the patients, most commonly to the lumbar and thoracic spine. Despite aggressive local therapy with excellent local control, the incidence of distant metastases in patients with invasive carcinoma of the uterine cervix is high. The management of these patients and their response to salvage therapy are discussed. The need for effective adjuvant systemic therapy in the management of patients with invasive carcinoma of the cervix is also discussed.

Technical factors affecting morbidity in definitive irradiation for localized carcinoma of the prostate.

PURPOSE: The impact of some technical factors on morbidity was analyzed in 738 patients with histologically confirmed carcinoma of the prostate treated with definitive irradiation. METHODS AND MATERIALS: The records of all patients were reviewed, and morbidity of irradiation was evaluated according to severity. All patients were followed up for a minimum of 3 years (median observation, 6.5 years). RESULTS: The most frequent Grade 2 (moderate) intestinal complication was proctitis, which was observed in 5% of the patients, followed by enteritis (1%) and anal-rectal fibrosis or stricture (about 1%). Incidence of Grade 3 (severe) proctitis was less than 1% and small bowel obstruction, 0.2%. One patient developed radiation-induced ileitis complicated with peritonitis, which was fatal. The most frequent Grade 2 urinary complication was urethral stricture (5%) and cystitis with significant symptoms or hematuria (2%). A vesicosigmoid and a rectovesical fistula (.4%) were noted, which required colostomy. One patient with hemorrhagic cystitis (.2%) required an ileal bladder, and two cases of ureteral stricture (.3%) required surgical correction. Most cases of Grade 2-3 intestinal or urinary morbidity appeared within 2-5 years after therapy (8% moderate and 3% severe cumulative intestinal morbidity at 10 years, and 9% and 3%, urinary). The actuarial incidence of rectosigmoid Grade 2 and 3 morbidity was 10% for patients treated to the pelvic lymph nodes and the prostate and 3% for those treated to the prostate only (p = 0.04). The difference in urinary morbidity in these two groups of patients was not statistically significant. There was also no significant correlation of morbidity with boost portal size for prostate irradiation. Patients treated with a stationary portal technique that delivered higher doses to the urinary bladder had a significantly greater incidence of urinary morbidity (18% cumulative) compared with patients treated with rotational techniques (5%) (p < 0.1). However, patients treated with pelvic fields and rotational techniques had a higher intestinal and rectosigmoid morbidity (11%) than patients treated to the prostate only (< or = 5%) (p = 0.05). No statistically significant difference in intestinal or urinary morbidity was related to doses of irradiation (60-70 Gy). CONCLUSION: Volume treated and, to a lesser extent, dose of irradiation at tolerance levels are important factors influencing significant morbidity in patients with carcinoma of the prostate treated with definitive irradiation. With recent advances in three-dimensional (3-D) treatment planning and conformal radiation therapy techniques, it is imperative to precisely determine optimal volumes and doses of irradiation required to achieve the highest local-pelvic tumor control while minimizing morbidity to enhance the role of irradiation in the management of localized carcinoma of the prostate.

Prognostic significance of pelvic recurrence and distant metastasis in prostate carcinoma following definitive radiotherapy.

This report is a retrospective analysis of 317 patients with recurrent prostate carcinoma, following definitive radiation therapy to 738 patients with histologically confirmed, clinical Stage T1b-T4(A2-D1) adenocarcinoma of the prostate. Seventy-four patients (10%) experienced pelvic recurrence only; 100 (13%) both pelvic recurrence and distant metastasis, while 143 (20%) developed distant metastasis only. The diagnosis of prostate recurrence was histologically confirmed in 92/174 (53%), while in the others diagnosis was based on clinical and radiographic evidence. Ninety percent of all recurrences occurred within 7 years of initial treatment. The median survival from time of recurrence for all patients was 27 months, with 5-, 8-, and 10-year survival rates of 24%, 12%, and 7%, respectively. In patients who experienced pelvic recurrence only, the 5-, 8-, and 10-year survival rates were 50%, 30%, and 22%, respectively (p < 0.0001). The 5-year survival rate from time of recurrence for patients who experienced pelvic recurrence with initial Stage T1b(A2) and T2(B) disease was 71% as opposed to 39% for patients with initial Stage T3(C) disease. The time of recurrence (i.e., the disease-free interval from initial treatment) significantly affected subsequent survival: the 5-year survival rates from time of recurrence for patients with pelvic recurrence were 20%, 49%, and 94% for those who recurred within 2 years, 2 to 5 years, and more than 5 years, respectively. Two-thirds of the patients with recurrence received hormonal therapy, including bilateral orchiectomy. Salvage therapy with hormones, including bilateral orchiectomy, has a favorable impact on patient survival: The 5-year survival rate from time of pelvic recurrence salvaged with hormones was 70% compared with 21% for patients not receiving hormonal therapy. In conclusion, the prognostic factors that affect subsequent patient survival after pelvic recurrence include initial stage, disease-free interval from initial treatment, and salvage therapy with hormones. Patients with distant metastasis with or without pelvic recurrence showed statistically worse survival and were apparently not influenced by initial tumor stage, or disease-free interval from initial treatment.

Nonrandomized evaluation of pelvic lymph node irradiation in localized carcinoma of the prostate.

PURPOSE: A great deal of controversy exists regarding the potential benefit of pelvic lymph node irradiation compared with treatment to the prostate only in patients with localized prostate cancer. Despite numerous reports, including a randomized study, this issue has not been completely elucidated. METHODS AND MATERIALS: A total of 963 patients with histologically proven localized adenocarcinoma of the prostate treated with definitive radiation therapy alone were analyzed. Median follow-up was 6.5 years (minimum: 2 years, maximum: 22 years). Pelvic lymph nodes received 40 to 55 Gy with anteroposterior/posteroanterior and sometimes lateral stationary portals in 1.8 Gy daily fractions; an additional dose was delivered to the prostate with 120 degrees bilateral are rotation to complete doses of 65 to 68 Gy for Stage A2 and B tumors and 68 to 71 Gy for Stage C tumors. The same total doses were delivered with smaller fields when the prostate only was treated. RESULTS: In Stage A2 (T1b,c) the 10-year clinical pelvic failure rate was 16% regardless of the volume irradiated or tumor differentiation. With Stage B (T2) well- or moderately differentiated tumors, the 10-year pelvic failure rates were 22% when pelvic lymph nodes were irradiated and 32% when prostate only was irradiated (p = 0.41). With Stage A2 (T1b,c) and B (T2) poorly differentiated tumors, the 10-year pelvic failure rates were 32% and 7%, respectively (p = 0.72). With clinical stage C (T3) well-differentiated tumors treated with 50 to 55 Gy to pelvic lymph nodes, the pelvic failure rate was 22% compared with 37% in those receiving 40 to 45 Gy (p < or = 0.07). A significant reduction in pelvic failures was noted with Stage C poorly differentiated tumors when the pelvic lymph nodes received doses higher than 50 Gy (23%) compared with lower doses (46%) (p < or = 0.01). Volume or doses of irradiation did not influence incidence of distant metastases in any stage or tumor differentiation group. Disease-free survival did not correlate with volume treated in any clinical stage or tumor differentiation group. In 317 patients on whom pretreatment prostate-specific antigen levels were available, there is a suggestion that those treated to the pelvic lymph nodes had a higher chemical disease-free survival than those receiving prostate irradiation only. Follow-up is short, and differences are not statistically significant in any of the groups. Morbidity of therapy was slightly higher in patients treated to the pelvic lymph nodes, but in Stages A2 (T1b,c) and B (T2) differences are not statistically significant (4 to 6%). Stage C patients treated to the pelvic lymph nodes with 50 Gy had a 12% incidence of Grade 2 rectosigmoid morbidity compared with 6% in those treated with 40 Gy (p = 0.26). CONCLUSIONS: In this retrospective analysis, pelvic lymph node irradiation did not influence local/pelvic tumor control, incidence of distant metastases, or disease-free survival in patients with clinical Stage A2 (T1b,c) or B (T2) localized carcinoma of the prostate. In patients with Stage C (T3) disease, irradiation of the pelvic lymph nodes with doses of 50 to 55 Gy resulted in a lower incidence of pelvic recurrences and improved disease-free survival. Morbidity of therapy was acceptable, although patients with Stage C disease had a somewhat higher incidence of Grade 2 rectosigmoid morbidity. Pelvic lymph node irradiation is being elucidated in properly designed prospective, randomized protocols.

Chemical disease-free survival in localized carcinoma of prostate treated with external beam irradiation: comparison of American Society of Therapeutic Radiology and Oncology Consensus or 1 ng/mL as endpoint.

PURPOSE: To compare postirradiation biochemical disease-free survival using the American Society of Therapeutic Radiology and Oncology (ASTRO) Consensus or elevation of postirradiation prostate-specific antigen (PSA) level beyond 1 ng/mL as an endpoint and correlate chemical failure with subsequent appearance of clinically detected local recurrence or distant metastasis. METHODS AND MATERIALS: Records of 466 patients with histologically confirmed adenocarcinoma of the prostate treated with irradiation alone between January 1987 and December 1995 were analyzed; 339 patients were treated with bilateral 120 degrees arc rotation and, starting in 1992, 117 with three-dimensional conformal irradiation. Doses were 68--77 Gy in 1.8 to 2 Gy daily fractions. Minimum follow-up is 4 years (mean, 5.5 years; maximum, 9.6 years). A chemical failure was recorded using the ASTRO Consensus or when postirradiation PSA level exceeded 1 ng/mL at any time. Clinical failures were determined by rectal examination, radiographic studies, and, when clinically indicated, biopsy. RESULTS: Six-year chemical disease-free survival rates using the ASTRO Consensus according to pretreatment PSA level for T1 tumors were: < or = 4 ng/mL, 100%; 4.1--20 ng/mL, 80%; and > 20 ng/mL, 50%. For T2 tumors the rates were: < or = 4 ng/mL, 91%; 4.1--10 ng/mL, 81%; 10.1--20 ng/mL, 55%; 20.1--40 ng/mL, 63%; and > 40 ng/mL, 46%. When postirradiation PSA levels higher than 1 ng/mL were used, the corresponding 6-year chemical disease-free survival rates for T1 tumors were 92% for pretreatment PSA levels of < or = 4 ng/mL, 58--60% for levels of 4.1--20 ng/mL, and 30% for levels > 20 ng/mL. For T2 tumors, the 6-year chemical disease-free survival rates were 78% in patients with pretreatment PSA levels of 4--10 ng/mL, 45% for 10.1--40 ng/mL, and 25% for > 40 ng/mL. Of 167 patients with T1 tumors, 30 (18%) developed a chemical failure, 97% within 5 years from completion of radiation therapy; no patient has developed a local recurrence or distant metastasis. In patients with T2 tumors, overall 45 of 236 (19%) had chemical failure, 94% within 5 years of completion of radiation therapy; 4% have developed a local recurrence, and 10%, distant metastasis. In patients with T3 tumors, overall, 24 of 65 (37%) developed a chemical failure, 100% within 3.5 years from completion of radiation therapy; 4% of these patients developed a local recurrence within 2 years, and 12% developed distant metastasis within 4 years of completion of irradiation. The average time to clinical appearance of local recurrence or distant metastasis after a chemical failure was detected was 5 years and 3 years, respectively. CONCLUSION: There was a close correlation between the postirradiation nadir PSA and subsequent development of a chemical failure. Except for patients with T1 tumors and pretreatment PSA of 4.1--20 ng/mL, there is good agreement in 6-year chemical disease-free survival using the ASTRO Consensus or PSA elevations above 1 ng/mL as an endpoint. Although the ASTRO Consensus tends to give a higher percentage of chemical disease-free survival in most groups, the differences with longer follow-up are not statistically significant (p > 0.05). It is important to follow these patients for at least 10 years to better assess the significance of and the relationship between chemical and clinical failures.

Carcinoma of the prostate stage B and C: lack of influence of duration of radiotherapy on tumor control and treatment morbidity.

Between 1966 and 1985, 542 of 585 patients with histologically confirmed carcinoma of the prostate, Stages B and C, were treated with definitive radiation therapy to a minimum of 6300 cGy. There were 191 Stage B patients and 351 Stage C patients. The median tumor dose for Stage B patients was 6957 cGy and for Stage C patients 7020 cGy. Daily fractions of 180 to 200 cGy were given 4 or 5 times per week with occasional rest periods of several days, usually because of side effects of radiation therapy. The minimum follow-up time was 3 years; maximum follow-up was 16.0 years, and the median was 4.8 years. In this analysis, within each stage, patients were divided into four groups based on the number of treatment days: less than or equal to 56 days (8 weeks), 57 to 63 days (9 weeks), 64 to 70 days (10 weeks), and greater than 70 days. The distribution of Stage B and Stage C patients by histologic grade and duration of therapy is fairly even within each group. The influence of duration of radiotherapy on actuarial survival, progression-free survival, pelvic control, and incidence of complications was analyzed, and no statistical difference among the four groups of patients was found. The scatterplots of pelvic failure by radiation dose and duration of radiotherapy for both Stage B and C prostate carcinoma patients did not show a correlation between failure rate and duration of radiotherapy. Tumor histologic grade did not influence the incidence of pelvic failure. In summary, within the dose range used in this analysis the overall length of radiation treatment time did not seem to affect the clinical outcome of patients with Stage B and C prostate carcinoma.

Carcinoma of the uterine cervix. II. Lack of impact of prolongation of overall treatment time on morbidity of radiation therapy.

PURPOSE: Several reports document a negative impact of prolongation of overall treatment time in a course of irradiation on tumor control and survival. A correlation has been documented of incidence of significant treatment sequelae with increasing doses of irradiation, volume of the specific organ, and dose per fraction. However, no data were found on the potential correlation of overall irradiation treatment time with significant sequelae. METHODS AND MATERIALS: Records were reviewed of 1,269 patients with carcinoma of the cervix (Stage IB to HI) treated with definitive irradiation (combination of external beam and two intracavitary insertions). Follow-up was obtained in 97% of patients (median, 12 years; minimum, 3 years; maximum, 28 years). The relationships between overall treatment time and time of brachytherapy and incidence of treatment sequelae were analyzed for each stage. RESULTS: Overall incidence of Grades 2 (moderate) sequelae was 7% and of Grade 3 (severe) sequelae, 11%. There was no significant correlation of various incidences of Grade 2 and 3 sequelae with overall treatment times (8% in patients treated in less than 7 weeks, 9% in 7.1 to 9 weeks, and 12% when treatment time was longer than 9 weeks) (p = 0.08). In patients with Stage IB and IIA tumors, incidence of rectal toxicity (mostly proctitis) was comparable in patients treated in less than 7 or 7.1 to 9 weeks (4.1 and 6%, respectively) and slightly higher in those treated in longer periods (11.5%) (p = 0.24). In patients with Stage IIB and III, the incidence of Grade 2 and 3 small bowel morbidity was 2% in those treated in less than 7 weeks, 6% for 7.1 to 9 weeks, and 4.9% for longer times (p < or = 0.01). This increased morbidity was also correlated with total dose of irradiation to the lateral pelvic wall: 5 of 257 (2%) for less than 60 Gy and 21 of 438 (4.8%) for higher doses (p < or = 0.01). There was no significant correlation between the timing of brachytherapy (usually two low dose rate intracavitary insertions performed within 4.5 to 6.5 weeks of initiation of external beam therapy) and significant treatment sequelae. CONCLUSIONS: We observed a varied average incidence of Grade 2 and 3 morbidity in the bladder, rectum, and small intestine with different overall treatment times, without a definite pattern to suggest an impact of prolongation of treatment time on morbidity. Likewise, there was no significant correlation with the timing of intracavitary insertions and morbidity of therapy. Because prolongation of the overall treatment time has a well-documented detrimental effect on pelvic tumor control and survival in carcinoma of the cervix with no significant impact on morbidity, it is imperative to deliver radiation therapy in the shortest possible time and without schedule interruptions.

Tumor size, irradiation dose, and long-term outcome of carcinoma of uterine cervix.

PURPOSE: To assess the impact of tumor size and extent, and dose of irradiation on pelvic tumor control, incidence of distant metastases, and disease-free survival in carcinoma of the uterine cervix. METHODS AND MATERIALS: Records were reviewed of 1499 patients (Stages IA-IVA) treated with definitive irradiation (combination of external beam plus two intracavitary insertions to deliver doses of 65-95 Gy to point A, depending on stage and tumor volume). Follow-up was obtained in 98% of patients (median 11 years, minimum 3 years, maximum 30 years). The relationship between outcome and tumor size was analyzed in each stage. Pelvic tumor control was correlated with total doses to point A and to the lateral pelvic wall. RESULTS: The 10-year actuarial pelvic failure rate in Stage IB was 5% for tumors <2 cm, 15% for 2.1-5 cm, and 35% for tumors >5 cm (p = 0.01); in Stage IIA, the rates were 0%, 28%, and 25%, respectively (p = 0.12). Stage IIB unilateral or bilateral nonbulky tumors <5 cm had a 23% pelvic failure rate compared with 34% for unilateral or bilateral bulky tumors >5 cm (p = 0.13). In Stage IIB, pelvic failures were 18% with medial parametrial involvement only, compared with 28% when tumor extended into the lateral parametrium (p = 0.05). In Stage III, unilateral parametrial involvement was associated with a 32% pelvic failure rate versus 50% for bilateral extension (p < 0.01). Ten-year disease-free survival rates were 90% for IB tumors <2 cm, 76% for 2.1-4 cm, 61% for 4.1-5 cm, and 47% for >5 cm (p = 0.01); in Stage IIA, the rates were 93%, 63%, 39%, and 59%, respectively (p < or = 0.01). Patients with Stage IIB medial parametrial involvement had better 10-year disease-free survival (67%) than those with lateral parametrial extension (56%) (p = 0.02). Stage III patients with unilateral tumor extension had a 48% 10-year disease-free survival rate compared with 32% for bilateral parametrial involvement (p < or = 0.01). The presence of endometrial extension or tumor only in the endometrial curettings had no significant impact on pelvic failure. However, in patients with Stage IB disease, the incidence of distant metastases was 31% with positive curettings, 15% with negative curettings, and 22% with admixture (p < or = 0.01). In Stage IIA, the corresponding values were 51%, 33%, and 18% (p = 0.05). The 10-year disease-free survival rates in Stage IB were 67% with positive curettings, 81% for negative curettings, and 77% for admixture (p = 0.02); in Stage IIA, the rates were 45%, 66%, and 67%, respectively (p = 0.14). Because this is not a prospective Phase II dose-escalation study, the correlation of doses of irradiation with pelvic tumor control in the various stages and tumor size groups is not consistent. Nevertheless, with Stage IB and IIA tumors <2 cm in diameter, the pelvic failure rate was under 10% with doses of 70-80 Gy to point A, whereas for larger lesions even doses of 85-90 Gy resulted in 25% to 37% pelvic failure rates. In Stage IIB with doses of 70 Gy to point A, the pelvic failure rate was about 50% compared with about 20% in nonbulky and 30% in bulky tumors with doses > 80 Gy. In Stage III unilateral lesions, the pelvic failure rate was about 50% with < or =70 Gy to point A versus 35% with higher doses, and in bilateral or bulky tumors it was 60% with doses <70 Gy and 50% with higher doses. CONCLUSIONS: Clinical stage and size of tumor are critical factors in prognosis, therapy efficacy, and evaluation of results in carcinoma of the uterine cervix. The doses to point A suggest that for lesions <2 cm, doses of 75 Gy result in < or =10% pelvic failures, whereas in more extensive lesions, even with doses of 85 Gy, the pelvic failure rate is about 30%; and in Stage IIB-III tumors, doses of 85 Gy result in 35-50% pelvic failures. Refinements in brachytherapy techniques and/or use of agents to selectively sensitize the tumors to irradiation will be necessary to improve the present results in invasive carcinoma of t

Cervical stump carcinoma.

Although supracervical hysterectomy is becoming a vanishingly rare procedure, there are still many women with a retained cervical stump. We have reviewed 70 patients treated at the Radiation Oncology Center, Mallinckrodt Institute of Radiology for carcinoma of the cervical stump. The average time between the hysterectomy and the diagnosis of cancer in the stump was 26.6 years. The median age at diagnosis of 63.5 years is 8.5 years older than the median age at diagnosis of patients with cancer of the cervix with an intact uterus. Patients were treated with external beam radiation and/or intracavitary implants. Sixteen patients underwent surgery as well. The 5- and 10-year overall actuarial survival for all patients was 60% and 40%, respectively. The 5- and 10-year progression-free survival for all patients was 77% and 70%, respectively. Ten-year progression-free survival by stage was: 0--100%, 1A--100%, 1B--79%, 2A--100%, 2B--66%, and 3B--39%. Poor histologic differentiation correlated with a decreased long-term progression-free survival. Black patients, and those receiving prolonged courses of external beam irradiation, had a trend toward a worse prognosis. Neither non-squamous histology nor gross appearance affected outcome. With a median follow-up time of 12.9 years, there were only three isolated local failures and four combined with distant metastases. Complications were few, with twice as many occurring in the gastrointestinal system as in the genitourinary tract. We conclude that carcinoma of the cervical stump effectively treated by radiation therapy yields results equivalent to those seen in patients with an intact uterus.

The effect of volume of disease in patients with carcinoma of the uterine cervix.

This is a retrospective study of 635 consecutively treated patients with FIGO Stage IIB or IIIB carcinoma of the uterine cervix. All patients were treated definitively with radiation therapy. The effect of volume of disease on outcome was studied. The 5-, 10-, and 15-year disease-free survivals (DFS) for the 346 Stage IIB patients were 64%, 61%, and 58%, respectively. Corresponding DFS for the 289 Stage IIIB patients were 40%, 38%, and 34%, respectively. The presence of bilateral parametrial invasion did not alter the 10-year DFS in Stage IIB patients (61% vs 64%, p = 0.60) but did decrease it in Stage IIIB patients (34% vs 50%, p = 0.006). Patients with both Stage IIB and IIIB cancers and central bulky disease (greater than or equal to 5 cm in diameter) had decreased DFS when compared to those without central bulky disease. Stage IIB patients with the lateral half of the parametrium involved had a decreased 10-year DFS in comparison with medial half involvement (52% vs 68%, p = 0.004). The total pelvic failure rate was 23% for Stage IIB and 41% for Stage IIIB patients. Central bulkiness increased the pelvic failure rate by about 11% for all patients. Bilateral parametrial disease increased the pelvic failure rate in Stage IIIB patients but not in patients with Stage IIB disease. The total pelvic failure rate for Stage IIB patients was greater in those whose disease extended into the lateral parametrium. Multivariate analysis was done using stage, lateral pelvic wall dose, parametrial disease, central bulkiness, age, and total dose to point A as variables. With local control as the endpoint, only stage (IIB vs IIIB) was significant (p = 0.008). Using DFS as the endpoint, stage (p = 0.0001) and central bulkiness of tumor (p = 0.026) were significant. Complications were not increased in patients with bulky or bilateral disease. We conclude that there is justification for subdividing FIGO Stage IIIB patients into those with unilateral or bilateral disease; however, these data do not support such a division for FIGO Stage IIB patients. These latter patients would be better analyzed with reference to medial versus lateral parametrial extension because of the difference in pelvic control and survival.

Radiotherapy for epithelial skin cancer.

PURPOSE: To retrospectively review patterns of failure, cosmesis, and outcomes according to treatment modality of patients with histologically confirmed epithelial skin cancer. METHODS AND MATERIALS: The records of 468 patients having 531 lesions were analyzed; 389 basal cell carcinomas and 142 squamous cell carcinomas were treated, 167 of which were recurrent tumors. Median follow-up was 5.8 years. Electron beam irradiation was used in 19%, superficial x-rays in 60%, a combination of electron beam and superficial x-rays in 20%, and megavoltage photons in <2%. RESULTS: The overall local tumor control rate was 89%; it was 93% for previously untreated lesions and 80% for recurrent lesions. Patients with basal cell carcinoma had a 92% overall control rate; patients with squamous cell carcinoma 80%. Multivariate analysis showed that local failure was related to the daily dose fractionation. The maximal diameter of the lesion and pathologic tumor type were also significant (p 0.01). Treatment type, patient age, and treatment duration were not significant. Overall, 92% of the treated population with cosmesis data had excellent or good results. The overall complication rate was 5.8%, consisting primarily of soft-tissue necrosis. CONCLUSIONS: Radiotherapy remains an excellent treatment modality for epithelial skin cancer. Local tumor control, cosmesis, and complications are related to the size of the primary lesion. Recurrent lesions fared worse, and therefore treatment at the earliest possible stage is strongly recommended.

Radiation therapy morbidity in carcinoma of the uterine cervix: dosimetric and clinical correlation.

PURPOSE: To quantitate the impact of total doses of irradiation, dose rate, and ratio of doses to bladder or rectum and point A on sequelae in patients treated with irradiation alone for cervical cancer. METHODS AND MATERIALS: Records were reviewed of 1456 patients (Stages IB-IVA) treated with external-beam irradiation plus two low-dose rate intracavitary insertions to deliver 70 to 90 Gy to point A. Follow-up was obtained in 98% of patients (median, 11 years; minimum, 3 years; maximum, 30 years). The relationships among various dosimetry parameters and Grade 2 or 3 sequelae were analyzed. RESULTS: In Stage IB, the frequency of patients developing Grade 2 morbidity was 9%, and Grade 3 morbidity, 5%; in Stages IIA, IIB, III, and IVA, Grade 2 morbidity was 10% to 12% and Grade 3 was 10%. The most frequent Grade 2 sequelae were cystitis and proctitis (0.7% to 3%). The most common Grade 3 sequelae were vesicovaginal fistula (0.6% to 2% in patients with Stage I-III tumors), rectovaginal fistula (0.8% to 3%), and intestinal obstruction (0.8% to 4%). In the bladder, doses below 80 Gy correlated with less than 3% incidence of morbidity and 5% with higher doses (p = 0.31). In the rectosigmoid, the incidence of significant morbidity was less than 4% with doses below 75 Gy and increased to 9% with higher doses. For the small intestine, the incidence of morbidity was less than 1% with 50 Gy or less, 2% with 50 to 60 Gy, and 5% with higher doses to the lateral pelvic wall (p = 0.04). When the ratio of dose to the bladder or rectum in relation to point A was 0.8 or less, the incidence of rectal morbidity was 2.5% (8 of 320) vs. 7.3% (80 of 1095) with higher ratios (p < or = 0.01); bladder morbidity was 2.3% (7 of 305) and 5.8% (64 of 1110), respectively (p = 0.02). The incidence of Grade 2 and 3 bladder morbidity was 2.9% (10 of 336) when the dose rate was less than 0.80 Gy/h, in contrast to 6.1% (62 of 1010) with higher dose rates (p = 0.07). Rectal morbidity was 2% to 5% in Stage IB, regardless of dose rate to the rectum; in Stages IIA-B and III, morbidity was 5.2% (28 of 539) with a dose rate of 0.80 Gy or less and 10.7% (37 of 347) with higher dose rates (p < 0.01). Multivariate analysis showed that dose to the rectal point was the only factor influencing rectosigmoid sequelae, and dose to the bladder point affected bladder morbidity. CONCLUSIONS: Various dosimetric parameters correlate closely with the incidence of significant morbidity in patients treated with definitive irradiation for carcinoma of the uterine cervix. Careful dosimetry and special attention to related factors will reduce morbidity to the lowest possible level without compromising pelvic tumor control.

Carcinoma of the uterine cervix. I. Impact of prolongation of overall treatment time and timing of brachytherapy on outcome of radiation therapy.

PURPOSE: Some studies have described decreased pelvic tumor control and survival rates in invasive carcinoma of uterine cervix when the overall time in a course of definitive irradiation is prolonged. We attempt to confirm or deny these observations and evaluate the impact of timing of brachytherapy on outcome. We also explore the hypothesis that more extensive tumors technically require prolongation of the course of irradiation; thus, decreased tumor control and survival in these patients may not necessarily be the result of time/dose factor. METHODS AND MATERIALS: Records of 1,224 patients (Stage IB to III) treated with definitive irradiation (combination of external beam and two intracavitary insertions to deliver doses of 70 to 90 Gy to point A) were reviewed. Follow-up was obtained in 97% of the patients (median, 12 years; minimum, 3 years; maximum, 28 years). The relationship between outcome and overall treatment time and time of intracavitary insertions was analyzed in each stage and according to tumor size/extent. RESULTS: There was strong correlation between overall treatment time (OTT) and tumor stage (< or = 7 weeks: 81% for Stage IB; 74% for Stage IIA; 52% for Stage IIB; and 47% for Stage III). Interruptions of therapy accounting for prolongation of treatment time occurred in 25-30% of patients, most frequently because of holidays and weekends and side effects of therapy. Overall treatment time had a major impact on pelvic tumor control in Stages IB, IIA, and IIB; in Stage IB 10-year actuarial pelvic failure rates were 7% with OTT < or = 7 weeks, 22% with 7.1 to 9 weeks, and 36% with > 9 weeks (p < or = 0.01). For Stage IIA the corresponding values were 14%, 27%, and 36% (p = 0.08), and in Stage IIB pelvic failure rates were 20%, 28%, and 34%, respectively (p = 0.09). In Stage III, pelvic failure was 30%, 40%, and 50%, respectively (p = 0.08). There was also a strong correlation between OTT and 10-year cause-specific survival (CSS); in Stage IB rates were 86% with OTT of < or = 7 weeks, 78% for 7.1 to 9 weeks, and 55% for > or = 9 weeks (p < 0.01). The corresponding rates in Stage IIA were 73%, 41%, and 48% (p < or = 0.01). For patients with Stage IIB, CSS rates were 72% for OTT < or = 7 weeks, 60% for 7.1 to 9 weeks, and 70% for > 9 weeks (p = 0.01). Patients with Stage III disease had 45% 10-year CSS when treatment was delivered in 9 weeks or less and 36% for longer overall times (p = 0.16). In multivariate analysis of patients with Stage IB and IIA, OTT and clinical stage were the most important prognostic factors for pelvic tumor control, disease-free survival, and CSS. Tumor size was a prognostic factor for CSS. In Stages IIB and III, OTT, clinical stage, unilateral or bilateral parametrial invasion, and dose to point A were significant prognostic factors for pelvic tumor control, disease-free survival, and CSS. Prolongation of time had a significant impact on pelvic tumor control and CSS regardless of tumor size, except in Stage IB tumors < or = 3 cm. Regression analysis confirms previous reports that prolongation of OTT results in decreased pelvic tumor control rate of 0.85% per day for all patients, 0.37% per day in Stages IB and IIA, 0.68% per day in Stage IIB, and 0.54% for Stage III patients treated with > or = 85 Gy to point A. Performance of all intracavitary insertions within 4.5 weeks from initiation of irradiation yielded decreased pelvic failure rates in some groups of patients (8.8 vs. 18% in Stage IB and IIA tumors < or = 4 cm and 12.3 vs. 35% in Stage IIB) (p < or = 0.01). CONCLUSIONS: Prolongation of treatment time in patients with Stage IB, IIA, IIB, and III carcinoma of the uterine cervix has a significant impact on pelvic tumor control and CSS. The effect of OTT was present regardless of tumor size except in Stage IB tumors < or = 3 cm.

Brachytherapy or electron beam boost in conservation therapy of carcinoma of the breast: a nonrandomized comparison.

PURPOSE: The results of breast-conservation therapy using breast irradiation and a boost to the tumor excision site with either electron beam or interstitial 192Ir implant are reviewed. METHODS AND MATERIALS: A total of 701 patients with histologically confirmed Stage T1 and T2 carcinoma of the breast were treated with wide local tumor excision or quadrantectomy and breast irradiation. The breast was treated with tangential fields using 4 or 6 MV photons to deliver 48 to 50 Gy in 1.8 to 2 Gy daily dose, in five weekly fractions. In 80 patients the regional lymphatics were irradiated. In 342 patients with Stage T1 and 107 with Stage T2 tumors, boost to the primary tumor excision site was delivered with 9 MeV and, more frequently, with 12 MeV electrons. In 91 patients with Stage T1 and 38 patients with Stage T2 tumors an interstitial 192Ir implant was performed. Tumor control, disease-free survival, cosmesis, and morbidity of therapy are reviewed. Minimum follow-up is 4 years (median 5.6 years; maximum, 24 years). RESULTS: The overall local tumor recurrence rates were 5% in the T1 and 11% in the T2 tumor groups. There was no significant difference in the breast relapse rate in patients treated with either electron beam or interstitial 192Ir boost. Regional lymph node recurrences were 1% in patients with T1 and 5% with T2 tumors. Distant metastases were recorded in 5% of the T1 and 23% of the T2 groups. The 10-year actuarial disease-free survival rates were 87% for patients with T1 and 75% with T2 tumors. Disease-free survival was exactly the same in patients receiving either electron beam or interstitial 192Ir boost. Cosmesis was rated as excellent/good in 84% of patients with T1 tumors treated with electron beam and 81% of patients treated with interstitial implant, and 74 and 79% respectively, in patients with T2 tumors. CONCLUSIONS: Breast-conservation therapy is an effective treatment for patients with T1 and T2 carcinoma of the breast. There is no difference in local tumor control, disease-free survival, cosmesis, or morbidity in patients treated with either electron beam or interstitial 192Ir implant boost. Clinical trials in progress will further elucidate this controversial subject.

Factors affecting long-term outcome of irradiation in carcinoma of the vagina.

OBJECTIVE: This report evaluates prognostic and technical factors affecting outcome of patients with primary carcinoma of the vagina treated with definitive radiation therapy. METHODS AND MATERIALS: A retrospective analysis was performed on records of 212 patients with histologically confirmed carcinoma of the vagina treated with irradiation. RESULTS: Tumor stage was the most significant prognostic factor; actuarial 10-year disease-free survival was 94% for Stage 0 (20 patients), 80% for Stage I (59 patients), 55% for Stage IIA (63 patients), 35% for Stage IIB (34 patients), 38% for Stage III (20 patients), and 0% for Stage IV (15 patients). All in situ lesions except one were controlled with intracavitary therapy. Of the patients with Stage I disease, 86% showed no evidence of vaginal or pelvic recurrence; most of them received interstitial or intracavitary therapy or both, and the addition of external-beam irradiation did not significantly increase survival or tumor control. In Stage IIA (paravaginal extension) and IIB (parametrial involvement) 66% and 56% of the tumors, respectively, were controlled with a combination of brachytherapy and external-beam irradiation; 13 of 20 (65%) Stage III tumors were controlled in the pelvis. Four patients with Stage IV disease (27%) had no recurrence in the pelvis. The total incidence of distant metastases was 13% in Stage I, 30% in Stage IIA, 52% in Stage IIB, 50% in Stage III, and 47% in Stage IV. The dose of irradiation delivered to the primary tumor or the parametrial extension was of relative importance in achieving successful results. In patients with Stage I disease, brachytherapy alone achieved the same local tumor control (80-100%) as in patients receiving external pelvic irradiation (78-100%) as well. In Stage II and III there was a trend toward better tumor control (57-80%) with combined external irradiation and brachytherapy than with the latter alone (33-50%) (p = 0.42). The incidence of grade 2-3 complications (12%) correlated with the stage of the tumor and type of treatment given. CONCLUSION: Radiation therapy is an effective treatment for patients with vaginal carcinoma, particularly Stage I. More effective irradiation techniques, including optimization of dose distribution combining external irradiation and interstitial brachytherapy in tumors beyond Stage I, are necessary to enhance locoregional tumor control. The high incidence of distant metastases emphasizes the need for earlier diagnosis and effective systemic cytotoxic agents to improve survival in these patients.

Cost benefit of emerging technology in localized carcinoma of the prostate.

PURPOSE: In a health care environment strongly concerned with cost containment, cost-benefit studies of new technology must include analyses of loco-regional tumor control, morbidity, impact on quality of life, and financial considerations. METHODS AND MATERIALS: This nonrandomized study analyzes 124 patients treated with three-dimensional conformal radiation therapy (3D CRT) and 153 with standard irradiation (SRT) between January 1992 and December 1995, for histologically proven adenocarcinoma of prostate, clinical Stage T1 or T2. Mean follow-up is 1.4 years. Three-dimensional CRT consisted of six or seven coplanar oblique and lateral and, in some patients, AP fields designed to treat the prostate with a 1 to 1.7 cm margin. SRT consisted of 120 degrees bilateral arc rotation. Total doses to prostate were 67 to 70 Gy when pelvic lymph nodes were irradiated or 68.4 to 73.8 Gy when prostatic volume only was treated; dose per fraction was 1.8 Gy. Patients were interviewed weekly for severity of 12 acute intestinal and urinary pelvic irradiation side effects (0 to 4+ grading). Time and effort for 3D RTP and daily treatment with 3D CRT and SRT were recorded. Dose-volume histograms (DVHs) were calculated for gross tumor volume, planning target volume, bladder, and rectum. Actual reimbursement to the hospital and university was determined for 41 3D CRT, 43 SRT, and 40 radical prostatectomy patients treated during the same period. RESULTS: Average treatment planning times (in minutes) were: 101 for 3D conformal therapy simulation, 66 for contouring of target volume and sensitive structures, 55 for virtual simulation, 39 for plan preparation and documentation, 65 for physical simulation, and 20 for approval of treatment plan. Daily mean treatment times were 19 min for 3D CRT with Cerrobend blocking, 16 with multileaf collimation, and 10 with bilateral arc rotation. Dosimetric analysis (DVHs) showed a reduction of 50% in volume of bladder or rectum receiving doses higher than 65 Gy. Acute side effects included dysuria, moderate difficulty in urinating, and nocturia in 25-39% of both SRT and CRT patients; loose stools or diarrhea in 5-12% of 3D CRT and 16-22% of SRT patients; moderate proctitis in 3% of 3D CRT and 12% of SRT patients (p = 0.01). Chemical disease-free survival (prostate-specific antigen < or =2 ng/ml) at 3 years was 90% with 3D CRT and 80% with SRT (p = 0.01). Average initial treatment reimbursements were $13,823 (3D CRT), $10,864 (SRT), and $12,250 (radical prostatectomy). Average total treatment reimbursement and projected cost of management of initial therapy failures per patients were $15,173, $16,264, and $16,405, respectively. CONCLUSIONS: Three-dimensional CRT irradiated less bladder and rectum volume than SRT; CRT initial reimbursement was 28% higher than SRT and 12% higher than radical prostatectomy. Because of projected better local tumor control, average total cost of treating a patient with 3D CRT or radical prostatectomy is equivalent to cost of SRT. Treatment morbidity was lower with 3D CRT. Our findings reflect an overall benefit with 3D CRT as a new promising technology in treatment of localized prostate cancer. Dose-escalation studies may enhance its efficacy and cost benefit.

Carcinoma of the tonsillar fossa: prognostic factors and long-term therapy outcome.

PURPOSE: To identify prognostic parameters and evaluate the therapeutic outcomes for patients with carcinoma of the tonsillar fossa treated with three treatment modalities. METHODS AND MATERIALS: The results of therapy are reported in 384 patients with histologically proven epidermoid carcinoma of the tonsillar fossa; 154 were treated with irradiation alone (55-70 Gy), 144 with preoperative radiation therapy (20-40 Gy), and 86 with postoperative irradiation (50-60 Gy). The operation in all but four patients in the last two groups consisted of an en bloc radical tonsillectomy with ipsilateral lymph node dissection. RESULTS: Treatment modality and total irradiation doses had no impact on survival. Actuarial 10-year disease-free survival rates were 65% for patients with T1 tumors, 60% for T2, 60% for T3, and 30% for T4 disease. Patients with no cervical lymphadenopathy or with a small metastatic lymph node (N1) had better disease-free survival (60% and 70%, respectively) at 5 years than those with large or fixed lymph nodes (30%). Primary tumor recurrence (local, marginal) rates in the T1, T2, and T3 groups were 20-25% in patients treated with irradiation and surgery and 31% for those treated with irradiation alone (difference not statistically significant). In patients with T4 disease treated with surgery and postoperative irradiation, the local failure rate was 32% compared with 86% with low-dose preoperative irradiation and 47% with irradiation alone (p = 0.03). The overall recurrence rates in the neck were 10% for N0 patients, 25% for N1 and N2, and 35-40% for patients with N3 cervical lymph nodes, without significant differences among the various treatment groups. The incidence of contralateral neck recurrences was 8% with the various treatment modalities. On multivariate analysis the only significant factors for local tumor control and disease-free survival were T and N stage (p = 0.04-0.001). Fatal complications were noted in 7 of 144 (5%) patients treated with preoperative irradiation and surgery, 2 of 86 (2%) of those receiving postoperative irradiation, and 2 of 154 (1.3%) patients treated with radiation therapy alone. Other moderate or severe nonfatal sequelae were noted in 30% of the patients treated with preoperative irradiation and surgery, in 53% treated with postoperative irradiation, and in 19% receiving radiation therapy alone. CONCLUSION: Primary tumor and neck node stage are the only significant prognostic factors influencing locoregional tumor control and disease-free survival. Treatment modality had no significant impact on outcome. Radiation therapy remains the treatment of choice for patients with stage T1-T2 carcinoma of the tonsillar fossa. In patients with T3-T4 tumors and good general condition, combination surgery and postoperative irradiation offers better tumor control than single-modality and preoperative irradiation procedures, but with greater morbidity.