Aggressive surgical therapy and radiotherapy for patients with high-risk neuroblastoma treated with rapid sequence tandem transplant

Background/Purpose

The treatment approach for patients with high-risk neuroblastoma has been one of dose intensification chemotherapy and aggressive treatment of the primary tumor. Local tumor control is examined in high-risk patients treated with tandem stem cell transplant, aggressive surgery, and selected radiation therapy (XRT).

Methods

Seventy-six patients with high-risk stage III/IV neuroblastoma were treated on a standard protocol incorporating aggressive surgical resection with or without local XRT followed by tandem high-dose chemotherapy and stem cell rescue. Patients were evaluated for degree of surgical resection, site of progression, and outcome.

Results

Overall event-free survival for the series is 56%. Forty-eight had gross total resection, 12 had greater than 90% resection, 10 had 50% to 90% resection, and 6 had biopsy only or no surgery. Surgical complications occurred in 29% with no deaths. There were no isolated local failures. Two patients had local recurrence after gross total resection. Surgeon assessment of completeness of resection agreed with postoperative radiological findings 66% of the time.

Conclusion

Aggressive surgical treatment with local XRT and myeloablative chemotherapy with stem cell rescue provides excellent local control in high-risk neuroblastoma, although distant failures, particularly osseous, remain a problem. Poor correlation exists between the surgeon's perception of completeness of resection and findings on postoperative imaging studies.     

Local control, survival, and operative morbidity and mortality after re-resection, and intraoperative radiation therapy for recurrent or persistent primary high-risk neuroblastoma

Background/Purpose

Patients with locally recurrent or persistent high-risk neuroblastoma are difficult to treat. We describe our experience using intraoperative radiation therapy (IORT) after re-resection in this high-risk population.

Methods

We retrospectively reviewed 44 consecutive patients who received IORT at our institution between April 2000 and September 2009 after gross total resection of recurrent/persistent tumor. Specifically, we evaluated local recurrence rates, complications, and overall survival.

Results

The median age at diagnosis was 41.5 months. Median follow-up after IORT was 10.5 months. Each patient received prior chemotherapy and surgery, while 94.5% had previous external beam radiation therapy. MYCN was amplified in 34% of patients. There were no operative or postoperative deaths, and 18 patients (40.9%) had postoperative complications. There was a 50.4% probability of local control. MYCN amplification did not affect local control (local recurrence rate of 53.9% vs 52.4%, P = .89). Median overall survival was 18.7 months (95% confidence interval, 11.7-25.6 months). Mean survival for MYCN-amplified patients was 13.0 vs 39.2 months for those without MYCN amplification (P = .035).

Conclusions

Intraoperative radiation therapy after re-resection of locally recurrent/persistent neuroblastoma results in a reasonable rate of local control with acceptable morbidity and survival. This approach should be considered in this high-risk population.     

Bilateral Wilms' tumors with progressive or nonresponsive disease

Background

To provide guidelines for future cooperative group trials, we reviewed the outcomes of children with bilateral Wilms' tumors (BWTs) treated on National Wilms Tumor Study-4 (NWTS-4) who had progressive or nonresponsive disease (PNRD).

Methods

NWTS-4 enrolled 3335 patients from August 1986 to September 1994 including 188 patients with BWT (5.6%). Treatment and outcome data were collected on patients with BWT. Treatment guidelines were outlined in the protocol, but patients were not on study.

Results

Thirty-eight children with BWT had PNRD. Preoperative chemotherapy was given for a median of 7 months (range, 2-29 months) before definitive resection. After the initial chemotherapy regimen, 36 children went on to a second regimen, and of these, 21 children received a third regimen before resection. Eleven patients received irradiation to one or both kidneys. Pathology at resection revealed previously undiagnosed anaplasia in 3 patients (2 diffuse and 1 focal) treated for 14, 15, and 15 months before resection. A fourth patient developed a diffusely anaplastic tumor 13 months after therapy. Other pathological findings included rhabdomyomatous (4 patients) or differentiated stromal elements (10 patients) and complete necrosis (1 patient). Ten kidneys from 7 patients lacked biopsy at presentation or pathology review of those specimens.

Conclusions

BWT patients with PNRD received prolonged courses of chemotherapy. Early and sequential biopsies to establish the reason for failure to respond should be obtained. This will identify anaplastic tumors managed best by early nephrectomy and intensive chemotherapy and will also distinguish differentiated tumors that are best managed with early resection, but less intensive therapy after nephrectomy.     

Accuracy of ultrasonography and mammography in predicting pathologic response after neoadjuvant chemotherapy for breast cancer

Background

Neoadjuvant chemotherapy reduces tumor size before surgery in women with breast cancer. The aim of this study was to assess the ability of mammography and ultrasound to predict residual tumor size following neoadjuvant chemotherapy.

Methods

In a retrospective review of consecutive breast cancer patients treated with neoadjuvant chemotherapy, residual tumor size estimated by diagnostic imaging was compared with residual tumor size determined by surgical pathology.

Results

One hundred ninety-two patients with 196 primary breast cancers were studied. Of 104 tumors evaluated by both imaging modalities, ultrasound was able to size 91.3%, and mammography was able to size only 51.9% (χ²P < .001). Ultrasound also was more accurate than mammography in estimating residual tumor size (62 of 104 [59.6%] vs 33 of 104 [31.7%], P < .001). There was little difference in the ability of mammography and ultrasound to predict pathologic complete response (receiver operating characteristic, 0.741 vs 0.784).

Conclusions

Breast ultrasound was more accurate than mammography in predicting residual tumor size following neoadjuvant chemotherapy. The likelihood of a complete pathologic response was 80% when both imaging modalities demonstrated no residual disease.     

Excellent local tumor control regardless of extent of surgical resection after treatment on the Chicago Pilot II protocol for neuroblastoma

Background

Our aim was to investigate the impact of the extent of surgical resection on local recurrence and survival in high-risk patients treated with the Chicago Pilot II protocol.

Methods

Retrospective chart review was performed on 30 patients enrolled in the Chicago Pilot II protocol between 1995 and 2003. Variables studied were location of tumor, extent of resection, timing and location of recurrence, MYCN amplification, surgical complications, event-free survival, and overall survival (OS). Operative reports and postoperative meta-iodobenzylguanidine scans were used to assess extent of resection. Complete resection (CR) was defined as no gross residual tumor including primary and nodal disease.

Results

Three-year event-free survival and OS of this cohort of 30 patients was 58% and 82%, respectively. Only 1 patient developed a local recurrence, whereas metastatic recurrent disease was observed in 13 (43%) of the 30; and this subset had a significantly worse OS (23% vs 94%, P = .001). The most common relapse location was in bone. Patients with incomplete resection (IR) (11/30) and CR (19/30) had recurrence rates of 64% (7/11) and 32% (6/19, P = .12), respectively. Event-free survival was significantly better for patients with CR (68%) vs IR (27%; P = .05; odds ratio, 2.9). Overall survival rates for patients with CR vs IR were 68% vs 55%, respectively (P = .25).

Conclusions

Recurrence rate was the significant determinant of survival. Patients with CR had lower recurrence rates; however, they did not have improved local control. Final outcome of patients with unfavorable neuroblastoma will be determined by metastatic recurrence, not by extent of resection.     

Bacillus Calmette-Guérin without maintenance therapy for high-risk non-muscle-invasive bladder cancer

Background

Bacillus Calmette-Guérin (BCG) is the standard intravesical treatment of high-risk noninvasive (Ta, T1, Tis) bladder cancer. Maintenance BCG is recommended for maximum efficacy.

Objective

We compared our results in a large cohort of high-risk bladder cancer patients who received BCG without maintenance with published results from randomized maintenance BCG trials.

Design, setting, and participants

A cohort of 1021 patients underwent restaging transurethral resection for high-risk (Ta, T1, Tis) bladder cancer.

Intervention

Patients received a 6-wk induction course of BCG therapy. Responding patients did not receive maintenance BCG. Relapsing patients were eligible for retreatment with BCG. All patients were followed for a minimum of 5 yr.

Measurements

End points were 5-yr tumor- and progression-free survival rates.

Results and limitations

Of 816 complete responders to induction BCG, 2- and 5-yr recurrence-free survival rates were 73% and 46%, respectively. The progression-free survival rate was 89%. Progression-free survival time was 56 mo (95% confidence interval, 55-58 mo). Thirty-two percent of the patients required another course of BCG therapy. We cannot exclude that maintenance BCG may benefit patients beyond 5 yr over induction BCG alone and selective BCG retreatments.

Conclusions

Our results with BCG treatment without maintenance of patients with high-risk non-muscle-invasive bladder cancer compare favorably with trials in which comparable patients received maintenance BCG.     

Sequential taxane and anthracycline-containing neoadjuvant regimens: The sequential order impact

Background

One can consider as a standard neoadjuvant treatment for breast cancer, the sequence of 4 cycles of anthracycline-based chemotherapy followed by 4 cycles of docetaxel. Based on the belief that the sequence order between anthracycline and taxane might be of interest, this study assessed the impact of the sequence order.

Methods

One hundred and twenty three patients with breast cancer were treated with neoadjuvant chemotherapy in 5 oncologic centers between 2003 and 2007. This study compared 65 patients treated with 4 cycles of docetaxel followed by 4 cycles of anthracycline-based chemotherapy (cohort T), versus another cohort of 58 patients treated with 4 cycles of anthracycline-based chemotherapy followed by 4 cycles of docetaxel (cohort A).

Results

The overall dose intensity of docetaxel and clinical complete responses were significantly higher in cohort T. No statistically significant differences were observed in terms of conservative surgeries or histological responses. The sequence of chemotherapy did not significantly influence other treatment-related toxicities. Mild neurotoxicity was higher in patients treated in cohort T. Anemias (≥Grade 1) were higher in cohort A (52% versus 81%; p = 0.0008).

Conclusion

The present study failed to identify an impact of the sequence of taxane administration on the efficacy. Nevertheless, starting neoadjuvant chemotherapy by taxane reduces the occurrence of anemia. These findings might allow a selection of the sequence order based on the toxicity profile.     

Resectability and operative morbidity after chemotherapy in neuroblastoma patients with encasement of major visceral arteries

Background/Purpose

Image-defined vessel encasement is a significant risk factor for surgical complications and incomplete resection for intermediate-risk tumors. We sought to examine the impact of vessel encasement on complications or resectability in intermediate-risk or high-risk patients after neoadjuvant chemotherapy.

Methods

We retrospectively reviewed 207 consecutive patients with circumferential encasement of the renal vessels, celiac axis, and/or superior mesenteric artery (SMA) who underwent resection between 1991 and 2009. Specifically, we evaluated resection rates, complications, and outcome.

Results

Median age at diagnosis was 3.0 years, and 79% of patients had stage 4 disease. Of known MYCN status, 23.4% had MYCN amplification. Vessel encasement included renal vessels, celiac axis, or SMA alone in 107, 7, and 4 patients, respectively. Both the renal vessels and celiac axis were encased in 5 patients, renal vessels and SMA in 7 patients, and celiac axis and SMA in 14 patients. Sixty-three patients had all 3 vessels encased. The gross total resection (GTR) rate was 94%. No operative or postoperative deaths occurred. The overall complication rate was 34.8% (n = 72). Overall 5-year survival (±SEM) was 67.4% (±7.4%).

Conclusion

Encasement of major visceral arteries in patients with neuroblastoma who have received chemotherapy does not preclude gross total resection.     

Stomal prolapse in children with chronic intestinal pseudoobstruction: a frequent complication?

Aim

The aim of the study was to evaluate the morbidity rate of stoma in children diagnosed with chronic intestinal pseudoobstruction (CIPO) and try to determine risk factors.

Material and Methods

Twenty-two children (65%) of 34 referred to our center between 1988 and 2008 had a stoma. They were compared with 22 other children referred for another pathology necessitating a stoma.

Results

The incidence of stomal prolapse in CIPO children was 45% vs 9% in non-CIPO children (P = .01). Prolapse occurred between the first postoperative day and the 10th postoperative month, with a median of 2 months. Surgical management was required in 60%, with an intestinal necrosis rate of 20% leading to intestinal resection. No mortality was noted. No risk factors favoring prolapse in CIPO children were identified.

Conclusion

Children with CIPO have a high rate of stomal prolapse with an increased risk of intestinal necrosis. Careful management of the stoma is necessary to avoid the risk of intestinal resection, which may aggravate the underlying intestinal disorder.     

Surgical challenges associated with intensive treatment protocols for high-risk neuroblastoma

Background

High-risk neuroblastoma (NB; age, >1 year; INSS stage 4) is associated with a poor outcome. At our institution, the current dose-intensive high-risk Children's Oncology Group protocol for advanced NB appears to have a higher surgical complication rate as compared with previous protocols.

Methods

All stage 4 patients (n = 51) entered in high-risk protocols between 1995 and 2005 were analyzed. Patients in the current high-risk protocol, Children's Oncology Group A3973 (n = 22), were compared with those in the 2 previous protocols, CCG 3891 and POG 9341 (n = 29).

Results

Patients were comparable in their mean age and tumor markers, including Shimada histology, MYCN amplification, 1p deletion, tumor origin, and extent of metastasis. However, transfusion requirement (86% vs 45%; P = .0019), postoperative infection rate (32% vs 3%; P = .02), and other postoperative issues including nutritional support (45% vs 3%; P = .0001) were significantly higher with the current protocol. No perioperative mortality was noted in either group, and the extent of resectability and margins were similar. Importantly, with the current protocol, the survival rate was higher (P = .0022) and the recurrence rate was significantly lower (P = .0003).

Conclusions

Despite higher surgical morbidity associated with the current high-risk protocol (2.59 vs 0.86 complications/person; P < .01), the recurrence rate is lower and interim survival rate is improved for patients with high-risk NB. Therefore, the higher surgical complication rates associated with the current high-risk protocol are acceptable.     

Mortality and morbidity of patients with neuroblastoma who survived for more than 10 years after treatment—Niigata Tumor Board Study

Purpose

To evaluate the utility of treatment strategies in neuroblastoma (NB), the survival of the NB patients was retrospectively examined.

Methods

During the past 40 years from 1967 to 2006, 103 NB patients not detected by the mass screening program were treated. The patients were divided into 3 groups; the period of aggressive surgery (AS group: 43 patients) from 1967 to 1984, the period of aggressive chemotherapy (AC group: 40 patients), from 1985 to 1996, and the period of mega-chemotherapy with stem cell transplantation since 1997. The patients treated in the AC and the AS groups were examined.

Results

The survival curve reached a nadir within 3 years in the AS group, whereas the second major drop of the survival curve was found in the AC group, which was owing to late mortality of 7 patients more than 10 years after the initiation of treatment. As a result, the overall survival in the AS and the AC groups were approximately 30.2% and 30.0% at 20 years after treatment, respectively. A different kind of strategy-related morbidity was found in 46% of EFS in both the AS and the AC groups.

Conclusions

The effectiveness of a treatment strategy should therefore be assessed after several decades.     

The prognosis of gastric cardia cancer after R0 resection

Background

The aim of this study was to evaluate the prognosis of gastric cardia cancers in comparison with other gastric cancers.

Methods

The medical records of 251 patients with gastric cardia cancers and 6568 patients with other gastric cancers who underwent R0 resection were reviewed. Clinicopathologic characteristics and survival were analyzed.

Results

Gastric cardia cancer was associated with more advanced staging and less favorable clinicopathologic features at diagnosis compared with other gastric cancers. The overall 5-year survival rates were 79.7% and 84.6% in patients with cardia cancer and other cancers, respectively. There were no significant differences in survival curves between the groups at any stage. Lymph node metastasis was an independent prognostic factor for disease-free survival. The length of the proximal margin was not associated with locoregional tumor recurrence.

Conclusions

Although patients with gastric cardia cancers are diagnosed at an advanced stage, the long-term survival rates are similar to those with other gastric cancers. If curative resection with negative resection margin can be achieved, pN category is the only prognostic factor for survival.     

Prophylactic therapy with valganciclovir in high-risk (cytomegalovirus D+/R-) kidney transplant recipients: a single-center experience

Background

A prospective study was performed in kidney transplant patients at risk of developing cytomegalovirus (CMV) infection (CMV D⁺/R⁻). They were treated with valganciclovir (VGC) for 3 months as prophylactic therapy. The aim was to determine the safety and efficacy of prophylactic therapy with VGC.

Methods

Antigenemia and/or polymerase chain reaction CMV was routinely performed every 2 weeks up to month 3, monthly to month 6, and every other month until the end of the first year posttranplantation, as well as when clinically indicated.

Results

From July 2007 to April 2010, 366 renal transplantations were performed at our center, including 34 (9%) high-risk patients for CMV infection. The median age was 47 years; 19 were males and 15 females. Twelve (35%) patients developed CMV infections: 10 (34%) gastrointestinal disease and 3 viral syndromes. The timing of the clinical manifestations was 16% (3/12) between months 1 and 3, 75% (8/12) between months 4 and 6, and 8% (1/12) in month 9 posttransplantation.

Conclusion

Treatment with intravenous ganciclovir followed by oral VGC was successful in all patients. No opportunistic infections or allograft rejection were observed; only 1 patient developed thrombocytopenia as an adverse event to VGC.     

Surgical treatment of pectus excavatum: 30 years 398 patients of experiences

Purpose

The aim of the study is to review the surgical experiences with pectus excavatum (PE) chest deformities at the Department of Pediatric Surgery, West China Hospital of Sichuan University (Sichuan, PR China), during a 30-year period.

Method

Records of 398 PE patients (396 congenital, 2 acquired) who underwent surgical repair between 1975 and 2005 were reviewed. Modified sternal elevation was applied in all patients. Repair was performed with subperiosteal resection of the abnormal cartilages, transverse wedge osteotomy of the anterior sternum, and internal support with a metal strut for 1 year. Five technical details were strictly followed for each case. Three hundred twelve patients (78.39%) were followed up from 1 to 16 years.

Result

There were no deaths. Normal contour of the costal cage was constructed postoperatively in 98.74% (393/398) of the patients. Exercise tolerance was improved, and cardiac function recovered to the healthy level of same age. But pulmonary function recovered slowly after surgery.

Conclusions

The 5 technical details are key principles for sternal elevation. Normal appearance of chest wall can be recovered; normal cardiopulmonary function can be restored by the modified sternal elevation with excellent long-term physiologic, cosmetic results and low rate of complications.     

Effect of postoperative chemotherapy on the serum alpha-fetoprotein level in hepatoblastoma

Purpose

It is generally accepted that postoperative chemotherapy does not affect the serum alpha-fetoprotein (AFP) level. The authors report on 3 patients who supposedly showed chemotherapy-related changes in their AFP levels after operation.

Methods

This study included 3 patients with hepatoblastoma (1 case of PRETEXT III and 2 cases of PRETEXT IV).

Results

One patient with PRETEXT III underwent a complete tumor resection, and the postoperative AFP level decreased until it reached the normal range. However, he consistently exhibited a transient, 2- to 3-fold increase in the AFP after each course of chemotherapy for 3 courses. The chemotherapy regimen had to be stopped because of drug-induced encephalopathy, but he has been followed up for 5 years without any evidence of recurrence, and his AFP level has also remained stable and in the normal range. Two patients with PRETEXT IV, who underwent a curative tumor resection, also showed similar chemotherapy-related changes in AFP levels. Both of these cases were observed only after the administration of routine postoperative chemotherapy instead of administering further high-dose chemotherapy. The AFP level remained stable for 17 months and 7 months after the cessation of chemotherapy in 2 cases, respectively.

Conclusions

Regarding the postoperative chemotherapy of hepatoblastoma, we have to pay close attention to both the AFP status during chemotherapy as well as the absolute AFP level.     

Diagnosis of neuroblastoma and ganglioneuroma using Raman spectroscopy

Background

Raman spectroscopy has proven to be useful in studying premalignant and malignant lesions in adults. This is the first report to evaluate Raman spectroscopy in the diagnosis and classification of neuroblastoma in children.

Methods

A biopsy or resection of fresh tissue samples from normal adrenal glands, neuroblastomas, ganglioneuromas, nerve sheath tumors, and pheochromocytoma at our hospital were equally divided between routine histology and spectroscopic studies. At least 12 spectra were collected from different regions of each sample using a Renishaw Raman microscope. Raw spectra were processed to remove noise, florescence, and shot noise, and then analyzed using principle component analysis and discriminant function analysis.

Results

We collected 698 spectra from 16 neuroblastomas, 5 ganglioneuromas, 3 normal adrenal glands, 6 nerve sheath tumors, and 1 pheochromocytoma. Raman spectroscopy differentiated between normal adrenal gland, and neuroblastoma and ganglioneuroma with 100% sensitivity and 100% specificity. It correlated well with the Shimada histologic classification system with 100% sensitivity and 100% specificity. It was also able to differentiate neuroblastoma from nerve sheath tumors and pheochromocytoma with high sensitivity and specificity.

Conclusion

This technique can differentiate neuroblastoma from ganglioneuroma and other tumors. It has a potential as a noninvasive real-time diagnostic tool in classifying pediatric tumors.     

Extrapleural pneumonectomy in children

Background/Purpose

Extrapleural pneumonectomy (EPP) is an en bloc resection of the pleura, lung, diaphragm, and pericardium. EPP in the pediatric population has not been reported in the literature. We report our experience of using EPP in children to treat a variety of malignancies that involve the pleural surface.

Methods

We performed a retrospective review of all children treated through EPP at our institution. Data were obtained from patient charts and a pediatric database. All patients underwent en bloc resection of the pleura, lung, diaphragm, and pericardium and reconstruction.

Results

Four patients underwent EPP from 2000 to 2004 for inflammatory myofibroblastic tumor, spindle cell sarcoma, metastatic neuroblastoma, and malignant mesothelioma. The patients' ages were from 6 to 11 years. The patient with metastatic neuroblastoma had recurrent disease in the left chest 1 year after EPP and died of sepsis; the patient with mesothelioma died of disease extension into the abdomen 1.5 years later. The other 2 patients are free of disease.

Conclusions

EPP can be performed with curative intent in selected pediatric patients with pleural-based malignancies. EPP should be included in the armamentarium of the pediatric thoracic surgeon and evaluated in larger studies.     

Survival on Waiting List for Liver Transplantation Before and After Introduction of the Model for End-stage Liver Disease Score

Background

Since July 2006, the Model for End-stage Liver Disease (MELD) score has served as the national basis for allocation of donor livers for transplantation in Brazil. Patients with higher MELD scores receive greater priority for allocation regardless of the time on the waiting list.

Purpose

To investigate the impact of MELD score implementation on the survival of waiting list patients.

Methods

A retrospective study of patients registered at the national Organ Procurement Organization (OPO) for the liver transplantation waiting list between January 2004 and June 2006 (pre-MELD) and between July 2006 and December 2008 (post-MELD).

Results

We included listed patients awaiting liver transplantation in the pre-MELD era (n = 250, 48.4%) and in the post-MELD era (n = 266, 51.6%). The times awaiting transplant prior to and after the MELD system were 487.2 ± 384.8 days and 183.9 ± 157.2 days, respectively. Prior to the MELD score, waiting list survivals were greater when compared to rates in the current system. Early posttransplant patient survival rates were significantly reduced in the post-MELD era (83.4%) compared to the period before MELD implementation (93.2%).

Conclusions

MELD score provides a transparent, objective system to drive allocation policy; however, it presents several important limitations. Constant need of changes and reevaluation are needed as an evolutionary process. Future changes in the present system may be addressed by adjusting the MELD system.     

The impact of gross total resection on local control and survival in high-risk neuroblastoma

Background/purpose

Gross total resection of the primary tumor in treatment of high-risk neuroblastoma remains controversial. Furthermore, there are few reports of the effect of primary tumor resection on local control as opposed to overall survival. The authors reviewed their institutional experience to assess the effect of primary tumor resection on local control and overall survival.

Methods

A total of 141 patients were treated on protocol between November 1, 1979 and June 25, 2002 and are the subject of this report. Gross total resection was assessed by review of operative notes, postoperative computerized axial tomograms, and postoperative meta-iodobenzyl guanidine (MIBG)¹ scans when available.

Results

The median age was 3.3 years, and all patients were International Neuroblastoma Staging System (INSS) stage 4 with 79% having metastases to cortical bone. The primary site was the adrenal gland in 74%, the central abdominal compartment in 13%, the posterior mediastinum in 7%, and other sites in 6%. Gross total resection was accomplished in 103 (73%) but was more than 90% for the last 3 protocols. Five kidneys were lost overall. The probability of local progression was 50% in unresected patients compared with 10% in patients undergoing gross total resection (P < .01). Overall survival rate in resected patients was 50% compared with 11% in unresected patients (P < .01).

Conclusions

Our data indicate that local control and overall survival rate are correlated with gross total resection of the primary tumor in high-risk neuroblastoma. Gross total resection should be part of the management of stage 4 neuroblastoma in patients greater than 1 year of age.