Early PSA level decline is an independent predictor of biochemical and clinical control for salvage postprostatectomy radiotherapy.

BACKGROUND: To improve the early detection of responders to salvage external beam radiotherapy (RT) after radical prostatectomy (RP). METHODS: Between 2002 and 2007, in a single institution, 136 consecutive patients received salvage RT to a dose of 66 Gy without androgen-deprivation therapy after RP for a rising prostate-specific antigen (PSA) level. PSA measurements were systematically performed before RT (PSART), at the fifth week of RT (PSA5), and in the follow-up at least twice a year (every 6 mo). The PSA level decline during RT was expressed as PSA ratio (PSA5/PSART). Two different definitions of biochemical failure after salvage RT were considered: PSA level>0.4 ng/ml and PSA>PSA nadir post-RT +0.4 ng/ml. Statistical analyses included univariate and multivariate Cox regression models. RESULTS: The median follow-up was 60 months. The 5-year freedom from biochemical and clinical failure rates were 57% (95% CI: 48%-66%) and 92% (95% CI: 87%-97%), respectively. The mean PSA5 was 0.61 ng/ml (range: 0-7) and the mean PSA ratio was 0.67 (0-1.7). A PSA ratio<1 was a significant prognostic factor in multivariate analysis for both definitions of biochemical failure (P = 0.01 for both) and for clinical failure (P = 0.005). CONCLUSIONS: For patients undergoing salvage RT after RP for a rising PSA level, the absence of PSA level decline during RT is predictive of biochemical and clinical failure and may be used to rapidly identify poor responders.

A risk-adapted strategy of radiotherapy or cisplatin-based chemotherapy in stage II seminoma.

OBJECTIVES: Indications for radiotherapy and chemotherapy in stage II seminoma are currently debated. MATERIALS AND METHODS: Since 1980, the policy at Institut Gustave Roussy was to treat patients with stage IIA-B disease with external radiotherapy and patients with stage IIB-C with cisplatin-based chemotherapy. In stage IIB disease, 3 cm was the usual tumor size threshold above which individual patients were considered for chemotherapy. RESULTS: During the period 1980-2001, 67 patients with stage II seminoma were treated: stage IIA (n = 5), stage IIB (n = 31), and stage IIC (n = 31). The median age was 40 years (range: 23-64). Among 37 patients who received radiotherapy, 5, 28, and 4 had a stage IIA, IIB, and IIC, respectively. Among 30 patients who received chemotherapy, 27 had a stage IIC. With a median follow-up of 9.4 years, 19 relapses (28%) occurred, including 11 and 8 cases treated with radiotherapy (30%) and chemotherapy (27%), respectively. The 5-year relapse-free survival was 71% (95% CI: 59-80). All but three relapses were salvaged with chemotherapy followed in selected cases by surgical resection of residual masses. Only 3 patients died of seminoma. The 5-year overall survival rate is 97% (95% CI: 89-99). Five patients subsequently developed a non-germ-cell second cancer, which occurred within the radiation field in 3 cases. CONCLUSION: With an overall survival rate of 97%, the overall outcome of patients with stage II seminoma managed according to this risk-adapted strategy is good. The possibility of extending the indications for chemotherapy to selected stage IIB seminoma patients needs to be further evaluated as potentially beneficial in terms of relapse risk.

Accelerated radiotherapy and concomitant high dose chemotherapy in non resectable stage IV locally advanced HNSCC: results of a GORTEC randomized trial.

BACKGROUND: The objective was to evaluate the efficacy of a strong increase of the dose-intensity of concomitant radio-chemotherapy (RT-CT) in patients with far advanced non metastatic HNSCC. METHODS: Eligible patients had N3 disease (UICC 1997) and the primary tumor and/or the node(s) had to be strictly unresectable. Patients with palpable N2B-C were also eligible if massive nodal involvement was present. 109 patients were included, with 53 randomized to RT-CT and 56 to accelerated RT. In the RT-CT arm, the RT regimen consisted of 64Gy in 5weeks and the CT regimen consisted of synchronous CDDP 100mg/m(2) on days 2, 16, and 30 and 5FU 1000mg/m(2) on days1-5 and 29-33 of the RT course. After RT-CT, two adjuvant cycles of CDDP-5FU were delivered in good responders. A control arm was using a very accelerated RT, delivering 64Gy in 3weeks. RESULTS: The most common tumor sites were oropharynx and hypopharynx. Most of the patients had T4 disease (70%) and 100% had a massive nodal involvement (mainly N3 with a mean nodal size >7cm in both arms). A significant difference was observed in favor of the RT-CT arm (p=0.005) in terms of cumulative incidence of local regional failure or distant metastases. However, the overall survival and event free survival rates were not significantly different between the two arms (p=0.70 and 0.16, respectively). The lack of survival benefit in favor of the RT-CT was partly due to an excess of initial early treatment related death in the RT-CT arm. CONCLUSION: The very intense RT-CT schedule was more efficient on disease control, but was also more toxic than accelerated RT alone, pointing out that there was no clear improvement of the therapeutic index. This study shows the limits of dose-intensification, with regard to concomitant RT-CT.

Long-term results of brachytherapy for carcinoma of the penis confined to the glans (N- or NX).

PURPOSE: To analyze the results of exclusive interstitial low-dose-rate brachytherapy (BT) for squamous cell carcinoma (SCC) of the penis, strictly confined to the glans. METHODS AND MATERIALS: A total of 144 patients with SSC of the glans penis were treated with BT. Inguinal nodal dissection was performed in 19% of patients (all N-). After circumcision, BT was performed using the hypodermic needle technique. Median iridium length per patients was 24 cm (range, 4-108) and median dose was 65 Gy (range, 37-75). Median treated volume was 22 cm(3) (range, 5-110) and median reference isodose rate was 0.4 Gy/h (range, 0.2-1.2). RESULTS: Median follow-up was 5.7 years (range, 0.5-29). The 10-year penile recurrence, inguinal lymph node recurrence, and inguinal nodal metastasis rates were: 20% (CI 95%, 11-29), 11% (CI 95%, 5-17), and 6% (CI 95%, 2-10), respectively. After salvage treatment, 86% patients with local failure were in a complete remission at last follow-up. The 10-year probability of avoiding penile surgery (for complication or local recurrence) was 72% (CI 95%, 62-82). The 10-year cancer-specific survival rate was 92% (CI 95%, 87-97). Diameter of tumor significantly increased the risk of recurrence (p = 0.02). The 10-year painful ulceration and stenosis risk rates were: 26% (CI 95%, 17-35) and 29% (CI 95%, 18-40), respectively. Seven patients required excision for necrosis. Treated volume and reference isodose rate significantly increased the risk of complications. CONCLUSION: BT is an effective conservative treatment for SCC confined to the glans. Salvage local treatment is effective. Dose rate should be limited to decrease toxicity.

Comparison of dose contribution to normal pelvic tissues among conventional, conformal and intensity-modulated radiotherapy techniques in prostate cancer.

High-energy external radiotherapy has become one of the most common treatment in localized prostate cancer. We compared the difference of dose distribution, mainly at the 5-30 Gy dose level, in the irradiated pelvic volume among three modalities of radiotherapy for patients with prostate cancer: conventional, conformal and intensity-modulated radiotherapy (IMRT). We selected six patients with prostate cancer treated by conformal radiotherapy at the doses of 46 Gy to PTVN (prostate and seminal vesicles), and 70 Gy to PTV-T (prostate). The conventional technique": an 8-field arrangement was used; the conformal technique 4 fields with a boost through 6 fields. For IMRT, a five-beam arrangement was used. Dose-volume histograms (DVH) were analyzed and compared among the three techniques. The IMRT technique significantly increased the pelvic volume covered by the isodose surfaces below 15 Gy as compared with the conventional and conformal techniques. The mean absolute increase for the pelvic volume included between 5-30 Gy for the IMRT technique, was about 2 900 ml as compared with the conventional technique. However, IMRT significantly reduced the irradiated volume of the rectum in the dose range of 5 to 40 Gy, also significantly reduced the irradiated volume of bladder and femoral heads, and obtained a similar or improved isodose distribution in the PTVs. In addition, the use of IMRT slightly increased the relative dose delivered to the body volume outside the pelvis, as estimated by the use of specific software. A long-term follow-up will be needed to evaluate potential late treatment complications related to the use of IMRT and the low or moderate irradiation dose level obtained in the pelvis and in the whole body.

[Management of locally advanced prostatic adenocarcinoma in France. OCTAVE observational survey]. / Prise en charge thérapeutique de l'adénocarcinome de la prostate localement avancé en France. Enquête Observationnelle OCTAVE.

OBJECTIVE: To describe the management of patients with locally advanced prostate cancer in France and the changes in this management between 2000 and 2003. MATERIAL AND METHODS: Observational survey on a sample of urologists and radiotherapists throughout France, comprising 2 aspects: a retrospective aspect (patients diagnosed and treated in 2000) and a prospective aspect (patients diagnosed in 2003 during the survey period). Eligible patients presented locally advanced prostate cancer (T3, biopsy pT3, T4, NO-N1-Nx, M0), not treated in the context of a therapeutic trial. Demographic data, prognostic factors and first-line treatments were collected. RESULTS: From September 2003 to January 2004, 1,076 patients with a mean age of 69.2 years were included in 188 centres. The percentage of most favourable stages, T3-pT3, N0-Nx, M0 was 84.6% in 2000 and 90.6% in 2003. The median PSA was 18 ng/ml and 21% of patients had a Gleason score > 7. Lymph node invasion was demonstrated in 9.4% of patients. Changing management practices between 2000 and 2003 were marked by an increased use of the radiotherapy/hormonal therapy combination (p<0.001) rather than exclusive radiotherapy (p< 0.001) and total prostatectomy either alone or combined with another modality (p=0.001). No other treatment was associated with prostatectomy in 70% of operated patients. One quarter of patients received exclusive hormonal therapy, and this rate remained stable between 2000 and 2003. CONCLUSION: Epidemiological data of the survey are concordant with those of the literature with a migration of TNM stages towards less advanced stages. In terms of treatment, there is a growing use of the radiotherapy-hormonal therapy combination, with a predominant place of hormonal therapy. The indication for prostatectomy appears to be optimized and constitutes the only therapeutic procedure in almost 70% of operated patients.

Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: a GORTEC trial.

PURPOSE: With the aim to increase the dose intensity of radiation therapy (RT), and subsequently the locoregional control rate, a very accelerated RT regimen was compared with conventional RT in a series of patients with head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Between 1994 and 1998, 268 patients with T3 or T4, N0 to N3 HNSCC (staged by 1997 International Union Against Cancer criteria) that was not eligible for surgery were randomly assigned to receive either conventional RT, delivering 70 Gy in 7 weeks to the primary tumor and 35 fractions of 2 Gy over 49 days, or to receive very accelerated RT, delivering 62 to 64 Gy in 31 to 32 fractions of 2 Gy over 22 to 23 days (2 Gy/fraction bid). RESULTS: The most common tumor site was the oropharynx and most of the patients (70%) had T4 and N1 to N3 tumors in 72% of patients. The main patient and tumor characteristics were well-balanced between the two arms. The median total doses were 63 Gy (accelerated) and 70 Gy (conventional), with a median overall time of 22 days and 48 days, respectively. Acute mucositis was markedly increased in the accelerated-RT arm (P < .001). The locoregional control rate was improved by 24% at 6 years with accelerated RT. In contrast, disease-free survival and overall survival were not significantly different between the two arms. There was no difference in late effects between the two arms. CONCLUSION: The very accelerated RT regimen was feasible and provided a major benefit in locoregional control but had a modest effect on survival.

Salvage surgery after failure of very accelerated radiotherapy in advanced head-and-neck squamous cell carcinoma.

PURPOSE: To assess the efficacy and toxicity of salvage surgery for local or cervical nodal recurrence after accelerated radiotherapy for locally advanced head-and-neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS: We reviewed the medical records of the 136 patients with HNSCC who had been treated in three consecutive clinical trials at the Institut Gustave-Roussy using a very accelerated radiotherapy regimen (62 to 64 Gy with 2 daily fractions of 1.8 to 2 Gy over 3.5 weeks). Sixty-nine patients of the 136 initial patients (51%) had local or neck lymph nodes relapse, or both. RESULTS: Sixteen of these 69 patients (23%) had undergone salvage surgery for recurrence locally (n = 8) or in the cervical nodes (n = 8). All 16 had initially been diagnosed with locally advanced oropharyngeal carcinoma (T4, 11 patients; T3, 5 patients), and 13 had initially had cervical node involvement. After salvage surgery, 6 patients had had a local recurrence; 7, cervical node recurrence; and 3, distant metastasis. Thus, salvage surgery had been successful only in 3 patients. The 3- and 5-year overall actuarial survival rates were 20% and 11%, respectively. Eight patients had major postoperative wound complications, including carotid rupture in three cases. CONCLUSION: Salvage surgery for relapse after very accelerated radiotherapy for advanced HNSCC is infrequently feasible and is of limited survival benefit. It should be used only in carefully selected cases.

Postoperative radiotherapy for primary mucosal melanoma of the head and neck.

BACKGROUND: Primary head and neck mucosal melanoma (HNMM) has a poor prognosis with a low local control rate and frequent distant metastases. The objective of the current study was to determine the impact of postoperative radiotherapy on local control and survival. METHODS: One hundred forty-two patients with primary HNMM treated between 1979 and 1997 were reviewed. Of these, 69 patients with confirmed primary mucosal melanoma, absence of metastatic disease, and definitive management by surgery with or without postoperative radiotherapy and follow-up at the Institut Gustave-Roussy (Villejuif) were selected. The site of primary HNMM was sinonasal in 46 patients, oral in 19 patients, and pharyngolaryngeal in 4 patients. Twenty-two patients (32%) had a locally advanced tumor (T3-T4) and 17 patients had regional lymph node metastases after pathologic examination (pN > 0). Thirty patients underwent surgery alone and 39 received postoperative radiotherapy. Patients with locally advanced tumors had received postoperative radiotherapy more frequently than those with small tumors (P = 0.02). RESULTS: Thirty-seven patients (54%) experienced local disease recurrence and 47 patients (68%) developed distant metastasis. The overall survival rates were 47% at 2 years and 20% at 5 years. In the Cox multivariate analysis, patients with early T-classification tumors who received postoperative radiotherapy had a better local disease-free survival (P = 0.004 and P = 0.05, respectively) compared with patients with late T-classification tumors who did not receive postoperative radiotherapy. Patients with advanced T-classification and pN > 0 stage had a shorter distant metastasis disease-free survival compared with patients with early T-classification and pN < 0 stage. Patients with advanced T-classification tumors had a shorter overall survival compared with patients with early T-classification tumors (P = 0.003). CONCLUSIONS: The prognosis of patients with HNMM was poor. Patients had a high rate of distant metastasis and a low rate of local control. The current study suggested that postoperative radiotherapy increased local control even for patients with small tumors.

Bladder-conserving surgery and interstitial brachytherapy for lymph node negative transitional cell carcinoma of the urinary bladder: results of a 28-year single institution experience.

BACKGROUND AND PURPOSE: We retrospectively analyzed results for lymph node negative transitional cell carcinoma of the bladder treated with brachytherapy. PATIENTS AND METHODS: From 1975-2002, 58 patients received preoperative external irradiation, partial cystectomy (in 69%), iliac node dissection, and iridium-192. Pathologic stage was: 10 pT1, 41 pT2, and 7 pT3. A median total brachytherapy dose of 60 Gy was delivered to the tumor bed. RESULTS: Mean follow-up was 76 months (range, 0.5-296). Tumor stage significantly impacted cause-specific and disease-free survival (P=0.02). Eight pT1 patients were free of disease and 2 died of other cause. For pT2 patients, 5-year cause-specific and overall survival rates were, respectively, 70% (CI 95%: 53-87) and 60% (CI 95%: 43-77). Three pT3 patients died of cancer. For the pT2 patients, the probability of 5-year local control was 65% (CI 95%: 47-83) and being alive without disease with a functional bladder, 50% (CI 95%: 33-67). Previous transurethral resection (TUR) increased the bladder relapse risk among pT2 patients (P=0.03). Twelve patients had severe acute complications and 5 had severe late effects. A high dose of external irradiation increased risk of late complications (P=0.01). Most complications occurred in patients treated before 1985. CONCLUSIONS: Highly select patients presenting with pT2 tumors less than 5 cm with no history of previous TUR may be successfully treated with low-dose external irradiation, limited partial cystectomy, and interstitial brachytherapy. High-risk pT1 patients may also benefit. Postoperative complications and late side effects are minimized with modern management. We recommend lifelong cystoscopic surveillance, with prompt surgical salvage for recurrence.