Serum prostate-specific antigen profile following radiotherapy for prostate cancer: implications for patterns of failure and definition of cure.

OBJECTIVES: A reference range of prostate-specific antigen (PSA) values compatible with cure following radiotherapy (RT) for prostate cancer (PCa) has yet to be established. Various thresholds, as low as 0.5 ng/mL, have been used to define biochemical disease-free status. We report PSA profiles in 118 patients who were systematically biopsied following standard RT, with a minimum 4-year follow-up. METHODS: One hundred eighteen patients were treated with standard external beam RT from May 1987 to October 1991, and were followed prospectively with transrectal ultrasound (TRUS)-guided biopsies and measurement of serum PSA levels. Stage distribution was as follows: T1b: 25 patients, T2a: 27 patients, T2b/c: 42 patients, T3: 23 patients, T4: 1 patient. Median follow-up for patients without clinical failure is 68 months (range 48 to 108). Treatment failures were categorized as biochemical (biochemical failure [chemF]: PSA level of 2.0 ng/mL or more and greater than 1 ng/mL over nadir), local (local failure [LF]: positive biopsy and PSA level greater than 2.0), and distant failure (DF). RESULTS: PCa recurred in 55% of patients: 38% LF (n = 45; 30 isolated and 15 with DF), 25% DF (n = 30; 15 isolated and 15 with LF), and 4% chemF (n = 5). Mean PSA nadir was 0.4 for patients with no evidence of disease (NED) and occurred at 33 months, 3.2 for LF at 17 months, 7.7 for DF at 12 months, and 1.4 for chemF at 24 months. After reaching the nadir, PSA in patients with recurrence followed first-order kinetics, rising exponentially over time. The mean PSA doubling time was 12.6 months for LF, 5.2 months for DF, and 21.8 months for chemF (P = 0.004). At last follow-up, the median PSA for patients without evidence of disease is 0.5 ng/mL. Four such patients had PSA values that rose to between 1 and 2 ng/mL for 5 to 38 months, but these eventually fell again to less than 1 ng/mL. Three patients had PSA values between 2 and 3 ng/mL, but 2 now have decreasing levels and the third has a rising level. All patients whose PSA levels rose to greater than 3 ng/mL exhibited a persistently rising pattern and ultimate tumor recurrence. CONCLUSIONS: There is a range of PSA values following RT for PCa that is compatible with cure. A definition of biochemical disease-free status at any absolute threshold of PSA level less than 3 ng/mL will overdiagnose failure in a significant proportion of patients. Patients with a PSA level between 1.5 and 3 ng/mL should be observed until there is unequivocal evidence of disease recurrence. In the absence of known biopsy status, PSA doubling time can be a useful indicator of whether failure is local or distant.

Radiotherapy for localized prostate carcinoma. The correlation of pretreatment prostate specific antigen and nadir prostate specific antigen with outcome as assessed by systematic biopsy and serum prostate specific antigen.

BACKGROUND: The objective of this study was to correlate the failure pattern of localized prostate carcinoma after radiotherapy (RT) with pretreatment (preTx) PSA and post-RT nadir PSA, using systematic biopsies and serum PSA in the assessment of outcome. METHODS: From January 1990 to February 1994, 207 patients treated with external beam RT were followed prospectively with systematic transrectal ultrasound-guided biopsies and measurements of serum PSA levels. Three hundred forty-three biopsies were performed, with 4-7 samples taken per session. The distribution of T classification was as follows: 19 patients had T1b, 15 had T1c, 34 had T2a, 79 had T2b/c, 53 had T3, and 7 had T4. Median follow-up was 36 months (range, 12-70 months). Failures were categorized as biochemical (chemF) (PSA > 2.0 ng/mL and > 1 ng/ mL over nadir), local (LF) (positive biopsy and PSA > 2), and distant (DF). The Cox proportional hazards model was used for multivariate analysis (MVA). RESULTS: Overall, failures were seen in 68 of 207 patients: 20 LF, 24 DF, 7 LF + DF, and 17 chemF. In univariate analysis, failures correlated significantly with preTx PSA, post-RT nadir PSA, T classification, and Gleason's score (GS). The total failure rate was 12% for T1b, T1c, and T2a; 39% for T2b and T2c; and 60% for T3 and T4 (P < 0.0001). By evaluation with preTx PSA, at 36 months the total failure rate was 3% for preTx PSA < or = 5 ng/mL 16% for 5.1-10 ng/mL, 32% for 10.1-15 ng/mL, 42% for 15.1-20 ng/mL, 63% for 20.1-50 ng/mL, and 88% for > 50 ng/mL (P < 0.0001). By evaluation with post-RT nadir PSA, at 36 months the total failure rate was 4% for nadir PSA < or = 0.5 ng/ mL, 26% for 0.6-1 ng/mL, 33% for 1.1-2 ng/mL, and 92% for > 2 ng/mL (P < 0.0001). In MVA, nadir PSA (P < 0.0001) and T classification (P < 0.0005) were independent predictors for any failure. LF occurred in 13% of patients (27 of 207). For these 27 patients, the categorization of T classification was: T1b/T1c/T2a, 7%; T2b/T2c, 16%; and T3/T4, 15% (P = not significant). In MVA, only nadir PSA (P = 0.0004) predicted for LF. DF occurred in 15% of patients (31 of 207). In MVA, nadir PSA (P < 0.0001) and T classification (P < 0.0001) predicted for DF, with pretreatment PSA of borderline significance (P < 0.05). To assess preTx predictors of outcome, post-RT nadir PSA was removed from the model. PreTx PSA then became the dominant variable to predict any failure (P < 0.0001), LF (P = 0.05), chemF (P = 0.0001), and DF (P < 0.003), while T classification also predicted for any failure (P = 0.03), chemF (P = 0.05), and DF (P < 0.0001). CONCLUSIONS: Systematic prostate biopsies, performed as part of the rigorous followup of prostate carcinoma after RT, define the patterns of failure and confirm the prognostic value of preTx PSA, post-RT nadir PSA, and T classification. Prior to treatment, preTx PSA is the overwhelming independent predictor of failure, but it is surpassed by post-RT nadir PSA when this is added to the model.

Evaluation of radiation effect, tumor differentiation, and prostate specific antigen staining in sequential prostate biopsies after external beam radiotherapy for patients with prostate carcinoma.

BACKGROUND: Sequential systematic biopsies after radiotherapy (RT) for prostate carcinoma were evaluated with respect to radiation effect, tumor differentiation, and prostate specific antigen (PSA) staining, and these histopathologic parameters were correlated with local outcome. METHODS: Since 1990, transrectal ultrasound-guided biopsies have been used to follow patients with localized prostate carcinoma after radical external RT at the General Hospital division of the Ottawa Regional Cancer Centre. Eighty-nine patients with residual tumor in 1 or more biopsies at 10-78 months of follow-up were selected for review. All patients had undergone biopsy on more than one occasion. The 198 biopsies were stained for PSA, high molecular weight keratin, and proliferative cell nuclear antigen (PCNA). Therapy effect was graded by nuclear and cytoplasmic changes. RESULTS: Of these 89 selected patients, 25 progressed to local failure (LF), 38 had delayed tumor clearance, and 26 remained biopsy positive without local or biochemical progression. In the 24- and 36-month biopsies, RT effect correlated with mean nadir serum PSA (Grade 4-6 RT effect: 0.7 ng/mL; Grade 0-3 RT effect: 1.3 ng/mL [P = 0.01]) and with local outcome (Grade 0-2 RT effect: 55% LF; Grade 3-4 RT effect: 30% LF; and Grade 5-6 RT effect: 0% LF [P = 0.003]). Of tumors with minimal RT effect, 61% were PCNA positive, compared with 34% for moderate and 17% for marked RT effect (P < 0.001). Adjacent areas within biopsies showed varied RT effect in 27 patients, of whom 41% had local failure, compared with 18% of patients with uniform RT effect (P = 0.03). Gleason score was assigned only if RT effect was minimal (36 patients/59 biopsies); 74% had the same Gleason score (+/-1) as the original, whereas 23% were 2 points lower. Only 1 biopsy lost PSA staining completely and 10% stained faintly, whereas 34% stained moderately and 55% strongly. CONCLUSIONS: PSA staining is apparently retained in residual tumor after RT, despite obvious RT effect. RT effect correlates with serum PSA nadir, PCNA staining, and local outcome. Varied RT effect is commonly observed in biopsies, and correlates with local failure. There is no convincing evidence for tumor dedifferentiation after RT.

Routine prostate biopsies following radiotherapy for prostate cancer: results for 226 patients.

OBJECTIVES: To determine the time course of histologic resolution of prostate cancer following radiotherapy (RT) and to correlate biopsy results with clinical outcome. METHODS: Since July 1990, all patients treated with radical external beam RT for prostate cancer at the General Division of the Ottawa Regional Cancer Centre have had systematic transrectal ultrasound (TRUS) and TRUS-guided biopsies beginning 12 months after RT and then every 6 months until negative or until clinical failure. Thus, 226 patients have had 375 TRUS with four to seven specimens per examination. Stage distribution was T1b: 32, T1c: 11, T2a: 45, T2b: 82, T3: 50, and T4: 6. Median follow-up was 33 months. RESULTS: Biopsy results were negative in 69.5% of patients by 30 months of follow-up. Thirty-two (14%) had local failure (T1b: 12.5%, T1c: 0%, T2a: 11%, T2b: 15%, T3: 18%, T4: 33%). Seven (3%) had chemical failure, and 47 (21%) had biopsy-only failure. Median follow-up for the biopsy-only failure group is only 19.5 months and mean prostate-specific antigen (PSA) is 1.0 ng/mL. Thirty-nine patients, initially with biopsy-only failure, have converted to negative biopsies at a median of 26 months. Nadir PSA for patients with local failure was 3.9 ng/mL at 14 months versus 0.7 ng/mL at 23 months for those without failure. Patients with late conversion to negative biopsy results had a later nadir PSA of 1.3 ng/mL at 27.3 months. CONCLUSIONS: Routine prostate biopsy specimens after RT in an unselected population show tumor clearance that is in agreement with long-term clinical follow-up, although tumor may take more than 30 months to resolve. Nadir PSA can be used to predict outcome.

A prospective study of ultrasound localization for renal shielding.

Accurate and reproducible shielding of sensitive tissues is essential in clinical radiotherapy. Renal localization is necessary when the kidneys are to be shielded during upper or whole abdominal radiotherapy. Despite extensive clinical experience with intravenous contrast media for renal localization, ultrasound has been proposed as a safer, more cost-effective alternative. In a prospective study, we assessed the accuracy of renal localization by ultrasound. Results show that ultrasound localization covers only 56.5 +/- 27.0% of the renal outline on average; moreover, the ultrasound designed shield results in 57.2 +/- 20.4% of its area being superfluous. Possible explanations and modifications are discussed. We urge others using ultrasound localization for renal shielding to assess its accuracy before using these shields in clinical practice.

Conservative treatment for lower gynecological tract malignancies in children and adolescents: the Institut Gustave-Roussy experience.

Between 1972 and 1986, 37 patients with lower genital tract malignancies were treated with intracavitary or interstitial brachytherapy. Thirteen patients presented with clear cell adenocarcinoma, 14 patients with embryonal rhabdomyosarcoma, 6 patients with endodermal sinus tumor, 3 patients with sarcoma, and 1 patient with an undifferentiated tumor. FIGO classification was: Stage I, 16%; Stage II, 47%; and Stage III, 37%. Treatment policy included initial exploratory laparotomy with lymph node biopsy and ovarian transposition, chemotherapy (except in clear cell adenocarcinoma) and/or external radiotherapy prior to interstitial brachytherapy. Chemotherapy consisted of a combination of VAC-Ad (V = vincristine, A = D actinomycin, C = cyclophosphamide, Ad = adriamycin) in rhabdomyosarcoma and sarcomas, and MAC-Ad (M = methotrexate) in endodermal sinus tumor. External radiotherapy was used in seven patients: in one to reduce a bulky clear cell adenocarcinoma (20 Gy) and in six for pelvic nodal involvement (45 Gy). Brachytherapy techniques depended on tumor site and extent, and on the anatomy of the patients. Vulvar tumors were implanted with iridium-192 wires by an afterloading plastic tube technique. Cervical and vaginal tumors were treated with individually tailored moulded vaginal applicators loaded with either cesium-137 or iridium-192, with or without interstitial implants by plastic tube or guide gutter technique. Computerized dosimetry allowed calculation of treatment volumes and doses delivered on the tumor and adjacent critical organs. The prescribed dose (including external radiotherapy) was 60-75 Gy with 1-3 brachytherapy applications of a low dose rate (0.2 Gy/hr). Six patients are dead: one from chemotherapy complication, three of metastases (two sarcomas, one endodermal sinus tumor) and two of pelvic failures and metastases (two clear cell adenocarcinoma). The overall disease free 5-year survival is 72%. Actuarial 5-year local control is 84%, but including salvage is 94%: three (two rhabdomyosarcoma, one clear cell adenocarcinoma) of the five local failures were salvaged by surgery, chemotherapy and/or brachytherapy. Metastases occurred in six patients, one (sarcoma) salvaged by chemotherapy and external radiotherapy. Complications requiring surgery occurred in five patients: two hydronephroses, one urethral stricture, one ileo-cecal obstruction, and one vesicovaginal fistula. Twelve of the 17 patients (71%) over 12 years of age are normally menstruating. Two patients have produced three normal children. This multidisciplinary management of lower gynecological tract tumors including brachytherapy is both conservative and effective.

Interstitial and external radiotherapy in carcinoma of the soft palate and uvula.

Forty-three patients, all male, with limited epidermoid carcinoma of the soft palate and uvula were treated by interstitial implant usually associated with external radiotherapy. Most patients received 50 Gy external irradiation to the oropharynx and neck followed by 20-35 Gy by interstitial iridium-192 wires using either guide gutters or a plastic tube technique. Twelve primary tumors and two recurrences after external irradiation alone had implant only for 65-75 Gy. Total actuarial local control is 92% with no local failures in 34 T1 primary tumors. Only one serious complication was seen. Overall actuarial survival was 60% at 3 years and 37% at 5 years but cause-specific survivals were 81% and 64%. The leading cause of death was other aerodigestive cancer, with an actuarial rate of occurrence of 10% per year after treatment of a soft palate cancer. Interstitital brachytherapy alone or combined with external irradiation is safe, effective management for early carcinoma of the soft palate and uvula but second malignancy is a serious problem.

Dosimetric methods in the optimization of radiotherapy for carcinoma of the uterine cervix.

Pelvic failures and late radiation sequelae were analyzed using the dosimetric parameters of ICRU Report 38 for 338 patients with Stage I-III carcinoma of the uterine cervix treated by radiation alone and followed for a minimum of 2 years. The pelvic recurrence rates were: Stage IB 5.1% (N = 118, 1% pelvis alone), Stage IIA 15.1% (N = 53, 9.4% pelvis alone), Stage IIB 15.8% (N = 76, 9.2% pelvis alone) and Stage IIIB 28.9% (N = 76, 17.1% pelvis alone). For Stages I and II pelvic failure was unrelated to cumulated lateral parametrial dose (CDPW) or reference volumes, but for Stage IIIB was higher for CDPW above 65 Gy. Overall complication rates were: grade 3-10.1% and grade 2-18.1% but were much lower for 176 patients treated with stem and ovoids (S + O: grade 3-5.7%, grade 2-15.7%) than for 43 receiving vaginal cylinders (grade 3-37.2%, grade 2-28%). Grade 3 rectal complications associated with cylinders were related to a maximal vaginal application over 1.50 cGy X m2 of total reference air kerma (or 2080 mgh) and cumulated rectal reference doses (CDRref) above 75 Gy. For the S + O group, grade 2 and 3 rectal complications increased with increasing reference volumes (hwt and HWT) and showed dose thresholds for CDRref and CDRmean (grade 3: 75 Gy). Prospective use of zones of risk defined graphically on a dose-volume plot (CDRref vs HWT) has reduced our severe complication rate without reducing local control. This technique requires individualization of patient therapy, rapid access to computerized dosimetry and the establishment of center- and applicator-specific risks of complications.

Reference volume, milligram-hours and external irradiation for the Fletcher applicator.

The ICRU Report 38 recommends the use of reference point doses and reference volumes for the reporting of intracavitary gynecologic therapy. The reference volume enclosed by the 60 Gy isodose for intracavitary therapy alone (which can be represented by hwt) and for combined external and intracavitary therapy (HWT) has no conceptual counterpart in the standard intracavitary systems. We report the relationship of the reference volumes (hwt and HWT) to milligram-hours (mgh) radium equivalent and to dose of external irradiation (XRT) for the Fletcher system. HWT and hwt are directly proportional to mgh, the proportionality constant depending on XRT but not appreciably on moderate changes in source geometry. HWT increases slowly with increasing XRT to about 30 Gy, then increases dramatically with even small increases in XRT. The reasons for this behavior and the possible clinical significance are discussed.

Dose-volume analysis and the prevention of radiation sequelae in cervical cancer.

We report a 9 year (1975-1983) experience of treatment of carcinoma of the uterine cervix by radiation alone. Computerized dosimetry conforming to the ICRU 38 recommendations was performed for all 348 patients analyzed. Late sequelae were graded as mild (grade 1), moderate (grade 2) and severe (grade 3). The overall rates were grade 3: 9.8%, grade 2: 18%, and grade 1: 19.5%. Of the moderate to severe sequelae, 48% were rectal, 15% rectosigmoid and 21% urinary. The complication rate was highly dependent on the type of intracavitary applicator: lowest for patients treated by two insertions of a standard Fletcher-Suit applicator (grade 3: 5.4%, grade 2: 14.4%) and highest for those receiving uterine stem plus vaginal line sources (grade 3: 29.5%, grade 2: 26%). For 183 patients treated with stem and standard ovoids, moderate and severe rectal and bladder sequelae were analyzed according to critical organ reference doses and reference treatment volumes as defined by ICRU 38, with the addition of a mean rectal dose. Zones of low, moderate and high risk could be defined on dose-volume plots using these parameters. Modification of treatment plans at the Cancer Institute G. F. Leclerc (CGFL) of Dijon according to these concepts produced a reduction in moderate and severe sequelae (grade 3: 14.4-3.4%) without a concurrent increase in pelvic failures. Although the zones of risk proposed can be used directly only with standard Fletcher-Suit applicators and comparable computer dosimetry, the concept can be applied to other systems.

Cutaneous malignant lymphoma.

The skin as the first site of non-Hodgkin's lymphoma is uncommon. Between 1967-1982 only 61 evaluable patients were seen; lymphoma was confined to the skin in 43. Most histological subtypes of non-Hodgkin's lymphoma were represented with diffuse histiocytic tumors accounting for 28 (46%). Overall, there was a 5-year survival rate of 52% with a median of 75 months. For patients with disseminated lymphoma involving the skin, the median survival was 18 months and there were no 10 year survivors. Patients with disease confined to the skin had 5 and 10-year survival rates of 62 and 57%, and a median survival of 159 months. Significant prognostic indicators included the site and bulk of tumor, but not the histological subtype. For small bulk localized tumors radiotherapy achieved local control in all patients and an over 80% five-year relapse-free rate. We conclude that lymphomas confined to the skin can be adequately treated by radiotherapy, whereas disseminated tumors require systemic therapy in addition. The management of bulky cutaneous lymphoma remains controversial.