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Background

The literature supporting high-dose rate brachytherapy (HDR) in the treatment of cervical carcinoma derives primarily from retrospective series. However, controversy still persists regarding the efficacy and safety of HDR brachytherapy compared to low-dose rate (LDR) brachytherapy, in particular, due to inadequate tumor coverage for stage III patients. Whether LDR or HDR brachytherapy produces better results for these patients in terms of survival rate, local control rate and the treatment complications remain controversial.

Methods

A meta-analysis of RCT was performed comparing LDR to HDR brachytherapy for cervix cancer treated for radiotherapy alone. The MEDLINE, EMBASE, CANCERLIT and Cochrane Library databases, as well as abstracts published in the annual proceedings were systematically searched. We assessed methodological quality for each outcome by grading the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. We used "recommend" for strong recommendations, and "suggest" for weak recommendations.

Results

Pooled results from five randomized trials (2,065 patients) of HDR brachytherapy in cervix cancer showed no significant increase of mortality (p = 0.52), local recurrence (p = 0.68), or late complications (rectal; p = 0.7, bladder; p = 0.95 or small intestine; p = 0.06) rates as compared to LDR brachytherapy. In the subgroup analysis no difference was observed for overall mortality and local recurrence in patients with clinical stages I, II and III. The quality of evidence was low for mortality and local recurrence in patients with clinical stage I, and moderate for other clinical stages.

Conclusion

Our meta-analysis shows that there are no differences between HDR and LDR for overall survival, local recurrence and late complications for clinical stages I, II and III. By means of the GRADE system, we recommend the use of HDR for all clinical stages of cervix cancer.

The results of a phase I/II study on the use of vaginal testosterone to treat vaginal atrophy in women with breast cancer taking aromatase inhibitors are presented. A 4-week course improved signs and symptoms without increasing estradiol or testosterone levels.

Learning Objectives

After completing this course, the reader will be able to: Evaluate early data regarding the impact of daily vaginal testosterone on estradiol and testosterone levels in breast cancer patients receiving treatment with aromatase inhibitors.Explain the potential clinical benefits of vaginal testosterone therapy to treat vaginal atrophy in women with breast cancer receiving long-term aromatase inhibitor therapy.

This article is available for continuing medical education credit at CME.TheOncologist.com

Purpose.

Controversy exists about whether vaginal estrogens interfere with the efficacy of aromatase inhibitors (AIs) in breast cancer patients. With the greater incidence of vaginal atrophy in patients on AIs, a safe and effective nonestrogen therapy is necessary. We hypothesized that vaginal testosterone cream could safely treat vaginal atrophy in women on AIs.

Methods.

Twenty-one postmenopausal breast cancer patients on AIs with symptoms of vaginal atrophy were treated with testosterone cream applied to the vaginal epithelium daily for 28 days. Ten women received a dose of 300 μg, 10 received 150 μg, and one was not evaluable. Estradiol levels, testosterone levels, symptoms of vaginal atrophy, and gynecologic examinations with pH and vaginal cytology were compared before and after therapy.

Results.

Estradiol levels remained suppressed after treatment to <8 pg/mL. Mean total symptom scores improved from 2.0 to 0.7 after treatment (p < .001) and remained improved 1 month thereafter (p = .003). Dyspareunia (p = .0014) and vaginal dryness (p <.001) improved. The median vaginal pH decreased from 5.5 to 5.0 (p = .028). The median maturation index rose from 20% to 40% (p < .001). Although improvement in total symptom score was similar for both doses (−1.3 for 300 μg, −0.8 for 150 μg; p = .37), only the 300-μg dose was associated with improved pH and maturation values.

Conclusions.

A 4-week course of vaginal testosterone was associated with improved signs and symptoms of vaginal atrophy related to AI therapy without increasing estradiol or testosterone levels. Longer-term trials are warranted.

Brachytherapy results in better dose distribution compared with other treatments because of steep dose reduction in the surrounding normal tissues. Excellent local control rates and acceptable side effects have been demonstrated with brachytherapy as a sole treatment modality, a postoperative method, and a method of reirradiation. Low-dose-rate (LDR) brachytherapy has been employed worldwide for its superior outcome. With the advent of technology, high-dose-rate (HDR) brachytherapy has enabled health care providers to avoid radiation exposure. This therapy has been used for treating many types of cancer such as gynecological cancer, breast cancer, and prostate cancer. However, LDR and pulsed-dose-rate interstitial brachytherapies have been mainstays for head and neck cancer. HDR brachytherapy has not become widely used in the radiotherapy community for treating head and neck cancer because of lack of experience and biological concerns. On the other hand, because HDR brachytherapy is less time-consuming, treatment can occasionally be administered on an outpatient basis. For the convenience and safety of patients and medical staff, HDR brachytherapy should be explored. To enhance the role of this therapy in treatment of head and neck lesions, we have reviewed its outcomes with oral cancer, including Phase I/II to Phase III studies, evaluating this technique in terms of safety and efficacy. In particular, our studies have shown that superficial tumors can be treated using a non-invasive mold technique on an outpatient basis without adverse reactions. The next generation of image-guided brachytherapy using HDR has been discussed. In conclusion, although concrete evidence is yet to be produced with a sophisticated study in a reproducible manner, HDR brachytherapy remains an important option for treatment of oral cancer.

The therapeutic impact of completion surgery (hysterectomy) after chemoradiotherapy was investigated in patients with stage IB or II cervical cancer. Hysterectomy had no therapeutic impact in patients with a clinical and radiological complete response after chemoradiotherapy, but this conclusion is limited by the lack of power.

Learning Objectives

After completing this course, the reader will be able to: Evaluate the therapeutic impact of hysterectomy after chemoradiation therapy in locally advanced cervical cancer.Evaluate the rate of histologic residual disease in patients with complete clinical and radiologic response after chemoradiation therapy.

This article is available for continuing medical education credit at CME.TheOncologist.com

Background.

Concomitant chemoradiation (CRT) (including brachytherapy) is considered the standard management for stage IB2 or II cervical cancer in many countries. Nevertheless, some of them discuss completion surgery (hysterectomy [HT]) after CRT. The aim of this study was to investigate the therapeutic impact of such surgery.

Methods.

A randomized trial was opened in France in 2003 to evaluate the interest in HT after CRT. Inclusion criteria were: (a) stage IB2 or II cervical cancer without extrapelvic disease on conventional imaging; (b) pelvic external radiation therapy (45 Gy with or without parametrial or nodal boost) with concomitant cisplatin chemotherapy (40 mg/m2 per week) followed by uterovaginal brachytherapy (15 Gy to the intermediate risk clinical target volume); and (c) complete clinical and radiological response 6–8 weeks after brachytherapy. Patients were randomized between HT (arm A) and no HT (arm B). Unfortunately this trial was closed because of poor accrual: 61 patients were enrolled (in 2003–2006) and are reported on here.

Results.

Thirty one and 30 patients were enrolled, respectively, in arm A and arm B. Twelve patients recurred (five of them died): respectively, eight and four in arm A and arm B. The 3-year event-free survival rates were 72% (standard error [SE], 9%) and 89% (SE, 6%) (not significant [NS]) in arm A and arm B, respectively. The 3-year overall survival rates were 86% (SE, 6%) and 97% (SE, 3%) (NS) in arm A and arm B, respectively.

Conclusions.

Results of the current trial seem to suggest that completion HT had no therapeutic impact in patients with clinical and radiological complete response after CRT (but this conclusion is limited by the lack of power).

Background

A crucial factor concerning the utility of Cancer Registries is the data quality with respect to comparability, completeness, validity and timeliness. However, the data quality of the registration of premalignant lesions has rarely been addressed. High grade vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VaIN) are premalignant lesions which may develop into cancer, and are often associated with infection with the human papillomarvirus (HPV). The aim was to evaluate the quality of registration of VIN and VaIN at the Cancer Registry of Norway (CRN).

Material and methods

We re-collected all notifications with high grade VIN and VaIN diagnoses during 2002 to 2007 from pathology laboratories, and compared these to the data in the CRN database so as to quantitatively measure the completeness, validity and timeliness of the data.

Results

Over the period 2002 to 2007 we estimated the completeness of the 1556 VIN and 297 VaIN notifications to be 95.0% and 92.9%, respectively. The original and reabstracted topography codes showed major discrepancies for 12 of 642 (1.9%) VIN and 7 of 128 (5.5%) VaIN notifications. The original and reabstracted morphology codes for VIN and VaIN were identical for 724 out of 814 notifications. Sixteen notifications had a major discrepancy. For the period 2002 to 2007 the median time elapsed between date of diagnosis and date of registration were 436 and 441 days for VTN and VaIN cases, respectively.

Discussion

Based on the present analysis of the comparability, completeness, validity and timeliness of premalignant lesions of vulva and vagina, we conclude that the Cancer Registry of Norway is able to monitor such premalignant lesions satisfactorily.

Background

To examine the role of brachytherapy for aged patients 80 or more in the trend of rapidly increasing number.

Methods

We examined the outcomes for elderly patients with node negative oral tongue cancer (T1-3N0M0) treated with brachytherapy. The 21 patients (2 T1, 14 T2, and 5 T3 cases) ranged in age from 80 to 89 years (median 81), and their cancer was pathologically confirmed. All patients underwent definitive radiation therapy, with low dose rate (LDR) Ra-226 brachytherapy (n = 4; median 70Gy), with Ir-192 (n = 12; 70Gy), with Au-198 (n = 1) or with high dose rate (HDR) Ir-192 brachytherapy (n = 4; 60 Gy). Eight patients also underwent external radiotherapy (median 30 Gy). The period of observation ranged from 13 months to 14 years (median 2.5 years). We selected 226 population matched younger counterpart from our medical chart.

Results

Definitive radiation therapy was completed for all 21 patients (100%), and acute grade 2-3 mucositis related to the therapy was tolerable. Local control (initial complete response) was attained in 19 of 21 patients (90%). The 2-year and 5-year local control rates were 91%, (100% for T1, 83% for T2 and 80% for T3 tumors after 2 years). These figures was not inferior to that of younger counterpart (82% at 5-year, n.s.). The cause-specific survival rate was 83% and the regional control rate 84% at the 2-years follow-up. However, 12 patients died because of intercurrent diseases or senility, resulting in overall survival rates of 55% at 2 years and 34% at 5 years.

Conclusion

Age is not a limiting factor for brachytherapy for appropriately selected elderly patients, and brachytherapy achieved good local control with acceptable morbidity.

This review discusses the indications for and the role of surgical interventions during the management of women with hydatidiform moles and malignant gestational trophoblastic neoplasia and reviews the use of radiation therapy in the treatment of women with malignant gestational trophoblastic neoplasia.

Learning Objectives

After completing this course, the reader will be able to: Describe the indications for surgical intervention in the management of patients with hydatidiform moles and malignant GTN in order to choose patients most likely to benefit from these interventions.Discuss the use of radiation in the management of patients with malignant GTN and consider its use as an adjunct to chemotherapy or surgery.

This article is available for continuing medical education credit at CME.TheOncologist.com

The primary management of hydatidiform moles remains surgical evacuation followed by human chorionic gonadotropin level monitoring. Although suction dilatation and evacuation is the most frequent technique for molar evacuation, hysterectomy is a viable option in older patients who do not wish to preserve fertility. Despite advances in chemotherapy regimens for treating malignant gestational trophoblastic neoplasia, hysterectomy and other extirpative procedures continue to play a role in the management of patients with both low-risk and high-risk gestational trophoblastic neoplasia. Primary hysterectomy can reduce the amount of chemotherapy required to treat low-risk disease, whereas surgical resections, including hysterectomy, pulmonary resections, and other extirpative procedures, can be invaluable for treating highly selected patients with persistent, drug-resistant disease. Radiation therapy is also often incorporated into the multimodality therapy of patients with high-risk metastatic disease. This review discusses the indications for and the role of surgical interventions during the management of women with hydatidiform moles and malignant gestational trophoblastic neoplasia and reviews the use of radiation therapy in the treatment of women with malignant gestational trophoblastic neoplasia.

Background

A modified form of high dose rate (HDR) brachytherapy has been developed called Axxent Electronic Brachytherapy (EBT). EBT uses a kilovolt X-ray source and does not require treatment in a shielded vault or a HDR afterloader unit. A multi-center clinical study was carried out to evaluate the success of treatment delivery, safety and toxicity of EBT in patients with endometrial cancer.

Methods

A total of 15 patients with stage I or II endometrial cancer were enrolled at 5 sites. Patients were treated with vaginal EBT alone or in combination with external beam radiation.

Results

The prescribed doses of EBT were successfully delivered in all 15 patients. From the first fraction through 3 months follow-up, there were 4 CTC Grade 1 adverse events and 2 CTC Grade II adverse events reported that were EBT related. The mild events reported were dysuria, vaginal dryness, mucosal atrophy, and rectal bleeding. The moderate treatment related adverse events included dysuria, and vaginal pain. No Grade III or IV adverse events were reported. The EBT system performed well and was associated with limited acute toxicities.

Conclusions

EBT shows acute results similar to HDR brachytherapy. Additional research is needed to further assess the clinical efficacy and safety of EBT in the treatment of endometrial cancer.

Brainstem gliomas are uncommon in adults and account for only 1%–2% of intracranial gliomas. In adults, a low-grade phenotype predominates, which is a feature that likely explains their better prognosis compared to that in children. A better understanding of the biology of these tumors is of primary importance for identifying homogeneous subgroups and for improving therapy options and outcomes.

Learning Objectives

After completing this course, the reader will be able to: Identify the different types of brainstem glioma in adults and their radiological features.Select the most accurate diagnostic test and propose options for treatment in patients suffering from brainstem gliomas.

This article is available for continuing medical education credit at CME.TheOncologist.com

Brainstem gliomas are uncommon in adults and account for only 1%–2% of intracranial gliomas. They represent a heterogeneous group of tumors that differ from those found in their pediatric counterparts. In adults, a low-grade phenotype predominates, which is a feature that likely explains their better prognosis compared to that in children. Because biopsies are rarely performed, classifications based on the radiological aspect of magnetic resonance imaging results have been proposed to establish treatment strategies and to determine outcomes: (a) diffuse intrinsic low-grade, (b) enhancing malignant glioma, (c) focal tectal gliomas, and (d) exophytic gliomas. Despite significant advances in neuroradiology techniques, a purely radiological classification remains imperfect in the absence of a histological diagnosis. Whereas a biopsy may often be reasonably avoided in the diffuse nonenhancing forms, obtaining histological proof seems necessary in many contrast-enhanced brainstem lesions because of the wide variety of differential diagnoses in adults. Conventional radiotherapy is the standard treatment for diffuse intrinsic low-grade brainstem gliomas in adults (the median survival is 5 years). In malignant brainstem gliomas, radiotherapy is the standard treatment. However, the possible benefit of combined radiotherapy and chemotherapy (temozolomide or other agents) has not been thoroughly evaluated in adults. The role of anti-angiogenic therapies in brainstem gliomas remains to be defined. A better understanding of the biology of these tumors is of primary importance for identifying homogeneous subgroups and for improving therapy options and outcomes.

Background

Brachytherapy, interstitial tumor bed irradiation, following conservative surgery has been shown to provide excellent local control and limb preservation in patients with soft tissue sarcomas (STS), whereas little is known about the tolerance of peripheral nerves to brachytherapy. In particular, nerve tolerance to high-dose-rate (HDR) brachytherapy has never been properly evaluated. In this study, we examined the efficacy and radiation neurotoxicity of HDR brachytherapy in patients with STS in contact with neurovascular structures.

Methods

Between 1995 and 2000, seven patients with STS involving the neurovascular bundle were treated in our institute with limb-preserving surgery, followed by fractionated HDR brachytherapy. Pathological examination demonstrated that 6 patients had high-grade lesions with five cases of negative margins and one case with positive margins, and one patient had a low-grade lesion with a negative margin. Afterloading catheters placed within the tumor bed directly upon the preserved neurovascular structures were postoperatively loaded with Iridium-192 with a total dose of 50 Gy in 6 patients. One patient received 30 Gy of HDR brachytherapy combined with 20 Gy of adjuvant external beam radiation.

Results

With a median follow-up of 4 years, the 5-year actuarial overall survival, disease-free survival, and local control rates were 83.3, 68.6, and 83.3%, respectively. None of the 7 patients developed HDR brachytherapy-induced peripheral neuropathy. Of 5 survivors, 3 evaluable patients had values of motor nerve conduction velocity of the preserved peripheral nerve in the normal range.

Conclusion

In this study, there were no practical and electrophysiological findings of neurotoxicity of HDR brachytherapy. Despite the small number of patients, our encouraging results are valuable for limb-preserving surgery of unmanageable STS involving critical neurovascular structures.

Treatment strategies, whether as follow-up or “total incisional biopsy” for gastric noninvasive intraepithelial neoplasia diagnosed by examination of an endoscopic forceps biopsy specimen, are controversial due to problems associated with the diagnostic accuracy of endoscopic forceps biopsy and questions about the safety and efficacy of endoscopic treatment. Based on the histological findings of the biopsy specimen, it is difficult to differentiate between reactive or regenerative changes, inflammation and neoplastic changes, intraepithelial and invasive tumors. Therefore, gastric neoplasia diagnosed as noninvasive intraepithelial often develop into invasive carcinoma during follow-up. Recent advances in endoscopic modalities and treatment devices, such as image-enhanced endoscopy and high-frequency generators, may make endoscopic treatment, such as endoscopic submucosal dissection (ESD), a therapeutic option for gastric intraepithelial neoplasia, including low-grade neoplasms. Future studies are required to evaluate whether ESD is a valid strategy for gastric intraepithelial neoplasm with regard to safety and cost effectiveness.

Purpose

To evaluate local control, survival and toxicity in patients with early-stage endometrioid adenocarcinoma of the uterus treated with adjuvant high-dose-rate (HDR) vaginal brachytherapy (VB) alone using a novel low dose regimen

Methods

We reviewed records of 414 patients with stage IA to stage II endometrial adenocarcinoma treated with VB alone from 2005 to 2011. Of these, 157 patients with endometrioid histology received 24 Gy in 6 fractions of HDR vaginal cylinder brachytherapy and constitute the study population. Dose was prescribed at the cylinder surface and delivered twice weekly in the post-operative setting. Local control and survival rates were calculated by the Kaplan-Meier method.

Results

All 157 patients completed the prescribed course of VB. Median follow-up time was 22.8 months (range, 1.5–76.5). Two patients developed vaginal recurrence, one in the periurethral region below the field and one in the fornix after treatment with a 2.5-cm cylinder. Three patients developed regional recurrence in the para-aortic region. Two patients developed distant metastasis (lung and carcinomatosis). The 2-year rate of vaginal control was 98.6%, locoregional control was 97.9% and disease-free survival was 96.8%. The 2-year overall survival rate was 98.7%. No Grade 2 or higher vaginal, gastrointestinal, genitourinary or skin long-term toxicity was reported for any patient.

Conclusion

Vaginal brachytherapy alone in early-stage endometrial cancer provides excellent results in terms of locoregional control and disease-free survival. The fractionation scheme of 24 Gy in 6 fractions prescribed to the cylinder surface was well-tolerated with minimal late toxicity.

Advances in treatment have not recently been reported in rare primary vaginal adenocarcinomas. A 56-year-old woman with a chronic vaginal cyst and possible in utero diethylstilbestrol exposure presented with postmenopausal bleeding. Biopsy of the vagina revealed high-grade papillary serous adenocarcinoma. MRI showed a 6-cm vaginal tumor and 3-cm left inguinal lymph node with metastasis. The patient initially received concurrent cisplatin and radiation. She then received high-dose-rate brachytherapy for further local control. Brachytherapy following external beam radiation with concurrent cisplatin led to clinically undetectable cancer at 24 months with minimal side effects.

A large proportion of vaginal and vulvar squamous cell carcinomas (SCCs) and intraepithelial neoplasias (VAIN and VIN) are associated with HPV infection, mainly type 16. The purpose of this study was to identify HPV genotypes, as well as E6/E7 mRNA expression of high-risk HPVs (16, 18, 31, 33, and 45) in 56 histology samples of VAIN, VIN, vaginal, and vulvar SCCs. HPV was identified in 56% of VAIN and 50% of vaginal SCCs, 71.4% of VIN and 50% of vulvar SCCs. E6/E7 mRNA expression was found in one-third of VAIN and in all vaginal SCCs, 42.9% of VIN and 83.3% of vulvar SCCs. Our data indicated that HPV 16 was the commonest genotype identified in VAIN and VIN and the only genotype found in SCCs of the vagina and vulva. These findings may suggest, in accordance with other studies, that mRNA assay might be useful in triaging lesions with increased risk of progression to cancer.

Subjective and objective assessments were used to describe the natural history of oxaliplatin-induced neuropathy. Findings establish the persistence of subjective and objective deficits in oxaliplatin-treated patients post-oxaliplatin, suggesting that sensory neuropathy is a long-term outcome, thereby challenging the literature on the reversibility of oxaliplatin-induced neuropathy.

Learning Objectives

After completing this course, the reader will be able to: Define the symptoms of sensory neurotoxicity in oxaliplatin-treated patients and identify the long-term natural history of nerve dysfunction as a long-lasting complication of treatment that does not necessarily resolve within 6 months.Use sensory excitability techniques to predict long-standing changes in sensory nerve function produced by oxaliplatin.

This article is available for continuing medical education credit at CME.TheOncologist.com

Objectives.

Oxaliplatin-induced neuropathy is a significant and dose-limiting toxicity that adversely affects quality of life. However, the long-term neurological sequelae have not been adequately described. The present study aimed to describe the natural history of oxaliplatin-induced neuropathy, using subjective and objective assessments.

Methods.

From a population of 108 oxaliplatin-treated patients referred for neurological assessment in 2002–2008, 52.2% of the surviving patient cohort (n = 24) was available for follow-up at a median of 25 months post-oxaliplatin. Patients underwent a protocol that incorporated clinical assessment scales, patient questionnaires, standard electrodiagnostic assessments, and novel nerve excitability studies to precisely assess nerve function.

Results.

At follow-up, 79.2% of patients reported residual neuropathic symptoms, with distal loss of pin-prick sensibility in 58.3% of patients and loss of vibration sensibility in 83.3% of patients. Symptom severity scores were significantly correlated with cumulative dose. There was no recovery of sensory action potential amplitudes in upper and lower limbs, consistent with persistent axonal sensory neuropathy. Sensory excitability parameters had not returned to baseline levels, suggesting persisting abnormalities in nerve function. The extent of excitability abnormalities during treatment was significantly correlated with clinical outcomes at follow-up.

Conclusions.

These findings establish the persistence of subjective and objective deficits in oxaliplatin-treated patients post-oxaliplatin, suggesting that sensory neuropathy is a long-term outcome, thereby challenging the literature on the reversibility of oxaliplatin-induced neuropathy.

This first part of a four-part series on pharmacogenetics describes the functional impact of genetic polymorphism and provides a general background to and insight into possible clinical consequences of pharmacogenetic variability.

Learning Objectives

After completing this course, the reader will be able to: Differentiate the candidate gene and genome-wide approaches to pharmacogenetic research and the impact of each on clinical study results.Describe the clinical implications of pharmacogenetic variability and its potential role in individualized treatment of patients with cancer.

This article is available for continuing medical education credit at CME.TheOncologist.com

Equivalent drug doses may lead to wide interpatient variability with regard to drug response, reflected by differences in drug activity and normal tissue toxicity. A major factor responsible for this variability is variation among patients in their genetic constitution. Genetic polymorphism may affect the activity of proteins encoded, which in turn may lead to changes in the pharmacokinetic and pharmacodynamic behavior of a drug, observed as differences in drug transport, drug metabolism, and pharmacodynamic drug effects. Recent insights into the functional effect of polymorphism in genes that are involved in the pharmacokinetics and pharmacodynamics of anticancer drugs have provided opportunities for patient-tailored therapy in oncology. Individualized pharmacotherapy based on genotype will help to increase treatment efficacy while reducing unnecessary toxicity, especially of drugs characterized by a narrow therapeutic window, such as anticancer drugs.

We provide a series of four reviews aimed at implementing pharmacogenetic-based drug and dose prescription in the daily clinical setting for the practicing oncologist. This first part in the series describes the functional impact of genetic polymorphism and provides a general background to and insight into possible clinical consequences of pharmacogenetic variability. It also discusses different methodologies for clinical pharmacogenetic studies and provides a concise overview about the different laboratory technologies for genetic mutation analysis that are currently widely applied. Subsequently, pharmacogenetic association studies in anticancer drug transport, phase I and II drug metabolism, and pharmacodynamic drug effects are discussed in the rest of the series. Opportunities for patient-tailored pharmacotherapy are highlighted.

Objectives To determine the effect of human papillomavirus (HPV) quadrivalent vaccine on the risk of developing subsequent disease after an excisional procedure for cervical intraepithelial neoplasia or diagnosis of genital warts, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia.

Design Retrospective analysis of data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)).

Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world.

Participants Among 17 622 women aged 15–26 years who underwent 1:1 randomisation to vaccine or placebo, 2054 received cervical surgery or were diagnosed with genital warts, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia.

Intervention Three doses of quadrivalent HPV vaccine or placebo at day 1, month 2, and month 6.

Main outcome measures Incidence of HPV related disease from 60 days after treatment or diagnosis, expressed as the number of women with an end point per 100 person years at risk.

Results A total of 587 vaccine and 763 placebo recipients underwent cervical surgery. The incidence of any subsequent HPV related disease was 6.6 and 12.2 in vaccine and placebo recipients respectively (46.2% reduction (95% confidence interval 22.5% to 63.2%) with vaccination). Vaccination was associated with a significant reduction in risk of any subsequent high grade disease of the cervix by 64.9% (20.1% to 86.3%). A total of 229 vaccine recipients and 475 placebo recipients were diagnosed with genital warts, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia, and the incidence of any subsequent HPV related disease was 20.1 and 31.0 in vaccine and placebo recipients respectively (35.2% reduction (13.8% to 51.8%)).

Conclusions Previous vaccination with quadrivalent HPV vaccine among women who had surgical treatment for HPV related disease significantly reduced the incidence of subsequent HPV related disease, including high grade disease.

Trial registrations NCT00092521 and NCT00092534

Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with or without radiotherapy was compared with CHOP with or without RT for the treatment of patients with primary mediastinal large B-cell lymphoma. R-CHOP was more effective than CHOP, with results comparable with those of more intensive regimens.

Learning Objectives

After completing this course, the reader will be able to: Describe the effect of the addition of rituximab to standard CHOP chemotherapy on the outcome of patients with primary mediastinal large B-cell lymphoma.Explain potential changes in the use of radiotherapy and aggressive chemotherapy in the rituximab era.

This article is available for continuing medical education credit at CME.TheOncologist.com

More aggressive treatment approaches (methotrexate, cytarabine, cyclophosphamide, vincristine, prednisone, and bleomycin [the MACOP-B regimen] or consolidation with high-dose therapy and autologous stem cell transplantation) have been considered to be superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with primary mediastinal large B-cell lymphoma (PMLBCL). Rituximab-CHOP (R-CHOP) is the standard of care for diffuse large B-cell lymphoma, whereas efficacy in PMLBCL has not been adequately confirmed.

Patient and Methods.

Seventy-six consecutive PMLBCL patients who received R-CHOP with or without radiotherapy (RT) were compared with 45 consecutive historical controls treated with CHOP with or without RT. Baseline characteristics of the two groups were balanced.

Results.

The rate of early treatment failure was much lower with R-CHOP with or without RT (9% versus 30%; p = .004). The 5-year freedom from progression rate after R-CHOP with or without RT was 81%, versus 48% for CHOP with or without RT (p < .0001). The 5-year event-free survival rates were 80% and 47% (p < .0001) and the 5-year overall and lymphoma-specific survival rates were 89% and 69% (p = .003) and 91% and 69% (p = .001), respectively, with only seven of 76 lymphoma-related deaths. Among R-CHOP responders, 52 of 68 received RT.

Conclusions.

Based on these results, most patients with PMLBCL appear to be cured by R-CHOP in 21-day cycles with or without RT, which could be the current standard of care. Therefore, the need for more aggressive treatment strategies is questionable unless high-risk patients are adequately defined. Further studies are required to establish the precise role of RT.

The pathologic complete response rate, delivered dose intensity, disease-free survival and overall survival rates, and toxicity of breast cancer patients treated with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus dose-intense FAC plus G-CSF in the neoadjuvant setting were compared.

Learning Objectives

After completing this course, the reader will be able to: Compare outcomes in patients treated with standard fluorouracil, doxorubicin, and cyclophosphamide (FAC) and those treated with dose-intense FAC.Describe toxicity profiles in patients treated with standard fluorouracil, doxorubicin, and cyclophosphamide (FAC) and those treated with dose-intense FAC.

This article is available for continuing medical education credit at CME.TheOncologist.com

Objective.

To compare the pathologic complete response (pCR) rate of patients treated with 5-fluorouracil (5-FU), doxorubicin, and cyclophosphamide (FAC) versus dose-intense FAC plus G-CSF in the neoadjuvant setting and to compare the delivered dose intensity, disease-free survival (DFS) and overall survival (OS) times, and toxicity between treatment arms in patients with breast cancer.

Methods.

Patients were randomized to receive preoperative FAC (5-FU, 500 mg/m2; doxorubicin, 50 mg/m2; cyclophosphamide, 500 mg/m2) every 21 days for four cycles or dose-intense FAC (5-FU, 600 mg/m2; doxorubicin, 60 mg/m2; cyclophosphamide, 1,000 mg/m2) plus G-CSF every 18 days for four cycles.

Results.

Two hundred two patients were randomly assigned. The median follow-up was 7.5 years. Patients randomized to FAC plus G-CSF had a higher pCR rate as well as clinical complete response rate; however, these differences were not statistically different from those with the FAC arm. Patients in the FAC + G-CSF arm had a higher delivered dose intensity of doxorubicin in the neoadjuvant and adjuvant settings than those in the standard FAC arm. DFS and OS times were not significantly different between the two groups. However, the OS and DFS rates were significantly higher for patients who achieved a pCR than for those who did not. Thrombocytopenia, febrile neutropenia, and infection rates were higher in the FAC + G-CSF arm.

Conclusions.

A higher delivered dose intensity of doxorubicin with the FAC + G-CSF regimen did not result in a statistically significant higher pCR rate. However, patients who achieved a pCR experienced longer DFS and OS times.

The present study describes the results of a systematic review conducted to objectively assess the clinical effectiveness and toxicity of isolated limb perfusion for the treatment of patients with locally advanced melanoma of the limbs. The technique was found to be safe and efficacious in these patients.

Learning Objectives

After completing this course, the reader will be able to: Compare the response rate of ILP with melphalan and TNF to the response rate of ILP with single-agent melphalan in patients with unresectable locally advanced melanoma of the limbs.Compare the clinical response rates of repeated ILP after a recurrence or PR to a first ILP to clinical response rates after first ILP in patients with unresectable locally advanced melanoma of the limbs.In patients with unresectable malignant melanoma of the limbs, consider use of ILP to avoid amputation.

This article is available for continuing medical education credit at CME.TheOncologist.com

Background.

Isolated limb perfusion (ILP) involves the administration of chemotherapy drugs directly into a limb involved by locoregional metastases. Unresectable locally advanced melanoma of the limbs represents one of the clinical settings in which ILP has demonstrated benefits.

Methods.

A systematic review of the literature on ILP for patients with unresectable locally advanced melanoma of the limbs was conducted. MEDLINE, EMBASE, and Cochrane database searches were conducted to identify studies fulfilling the following inclusion criteria: hyper- or normothermic ILP with melphalan with or without tumor necrosis factor (TNF) or other drugs providing valid data on clinical response, survival, or toxicity. To allocate levels of evidence and grades of recommendation the Scottish Intercollegiate Guidelines Network system was used.

Results.

Twenty-two studies including 2,018 ILPs were selected with a clear predominance of observational studies (90.90%) against experimental studies (9.10%). The median complete response rate to ILP was of 58.20%, with a median overall response rate of 90.35%. ILP with melphalan yielded a median complete response rate of 46.50%, against a 68.90% median complete response rate for melphalan plus TNF ILP. The median 5-year overall-survival rate was 36.50%, with a median overall survival interval of 36.70 months. The Wieberdink IV and V regional toxicity rates were 2.00% and 0.65%, respectively.

Conclusions.

ILP is effective in achieving clinical responses in patients with unresectable locally advanced melanoma of the limbs. The disease-free and overall survival rates provided by ILP are acceptable. ILP is safe, with a low incidence of severe regional and systemic toxicity.

This study assesses the prevalence of taste alterations in cancer patients and their relation to sociodemographic and clinical variables, especially chemotherapy regimens. Furthermore the association between taste alterations and quality of life is investigated.

Learning Objectives

After completing this course, the reader will be able to: Evaluate the effect of various chemotherapy regimens on taste alterations.Investigate the effect of chemotherapy-induced taste alterations on patients and use available dietary approaches such as taste enhancement and substitution of proteins and nutrients of avoided food to improve quality of life.

This article is available for continuing medical education credit at CME.TheOncologist.com.

Background.

Taste alterations (TAs) are a frequent but under-recognized treatment side effect in cancer patients undergoing chemotherapy (CT). CT regimens with different toxicity profiles may vary in their impact on TAs, but research on this topic is lacking. This study assesses the prevalence of TAs and their relation to sociodemographic and clinical variables, especially CT regimens. Furthermore, the association between TAs and quality of life (QOL) is investigated.

Patients and Methods.

TAs and QOL data were collected longitudinally in 197 cancer patients (lung cancer, 54.3%; pancreatic cancer, 19.3%; colorectal cancer, 26.4%; age, 65.2 ±10.4 years; male, 57.4%) who were receiving CT at the Department of Internal Medicine at Kufstein County Hospital, giving rise to a total of 1,024 assessment times. Patients completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire and two additional questions taken from the EORTC item bank concerning TAs. Statistical analyses were performed using mixed-effect models.

Results.

The study showed that the prevalence of TAs in chemotherapy patients is alarmingly high (69.9%). There were clear differences in TA scores among treatment groups: patients receiving irinotecan reported significantly more TAs than patients in other treatment groups; patients receiving a combination of gemcitabine and a platinum agent reported the lowest TAs. Additionally, significant associations between TAs and several QOL dimensions were found, especially with appetite loss and fatigue.

Conclusion.

The high prevalence of TAs and their impact on QOL in CT patients underscore the urgent need for increased attention to this side effect, both in research and in clinical practice.

This paper reviews the adverse outcomes associated with polypharmacy and presents polypharmacy definitions offered by the geriatrics literature, examining the strengths and weaknesses of the various definitions, as well as exploring the relationships among these definitions and what is known about the prevalence and impact of polypharmacy in the geriatric-oncology population.

Learning Objectives

After completing this course, the reader will be able to: Differentiate the multiple definitions of polypharmacy in order to be able to recognize it in your patient population.Discuss the current data available in evaluating polypharmacy specifically in older adults with cancer and incorporate the data in your evaluation of older patients.Summarize the agents or drug classes that may be deemed inappropriate in older adults to avoid prescribing medications for older patients that may lead to adverse drug events.

This article is available for continuing medical education credit at CME.TheOncologist.com

The definition of “polypharmacy” ranges from the use of a large number of medications; the use of potentially inappropriate medications, which can increase the risk for adverse drug events; medication underuse despite instructions to the contrary; and medication duplication. Older adults are particularly at risk because they often present with several medical conditions requiring pharmacotherapy. Cancer-related therapy adds to this risk in older adults, but few studies have been conducted in this patient population. In this review, we outline the adverse outcomes associated with polypharmacy and present polypharmacy definitions offered by the geriatrics literature. We also examine the strengths and weaknesses of these definitions and explore the relationships among these definitions and what is known about the prevalence and impact of polypharmacy.

Background and Purpose

To evaluate the proximity, variance, predictors of dose, and complications to the sigmoid in cervical-cancer brachytherapy using 3D planning.

Materials and Methods

Over 36 months, 50 patients were treated for cervical cancer with either low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy. The distance from the central tandem to the sigmoid, the D0.1cc and the D2cc to the sigmoid, rectum and bladder doses, and toxicity were analyzed.

Results

The median sigmoid EQD2 D0.1cc and D2cc were 84 Gy and 68.3 Gy for HDR versus 71.1 Gy and 65.9 Gy for LDR (p=0.02 and 0.98, respectively). Twenty percent of the HDR fractions required manipulation of the superior dwell positions to decrease the sigmoid dose. The median distance from the sigmoid to the tandem was 1.7 cm (range [rg], 0.1 – 6.16 cm) for HDR and 2.7 cm (rg, 1.17 – 4.52 cm) for LDR; from the sigmoid to the 100% isodose region the median distances were – 0.1 cm (rg, -1.4 – 2.5 cm) and 0.44 cm (rg. -0.73 – 5.2 cm), respectively. The proximity of the sigmoid to the tandem is significantly related to sigmoid dose (p<0.0001). Within-patient (among-fraction) variation in sigmoid-to-tandem distance during HDR was substantial (coefficient of variation = 40%). No grade 3-4 sigmoid toxicity was seen after a median 31-month follow-up period.

Conclusions

3D imaging in cervical cancer brachytherapy shows the sigmoid in close proximity to the tandem. The sigmoid to tandem distance varies substantially between fractions, indicating the importance of sigmoid dose-volume evaluation with each fraction.

This review summarizes the current knowledge on parathyroid carcinoma and describes new information on parathyroid carcinoma gene expression and operative management using intraoperative parathyroid hormone monitoring.

Learning Objectives

After completing this course, the reader will be able to: Discuss the association of parathyroid cancers with severe hypercalcemia and markedly elevated parathyroid hormone levels.Describe the effect of the risk factors, clinical presentation, and gene expression on diagnosis of parathyroid cancers.Analyze the probability of cure for parathyroid cancers with treatment by aggressive surgery with en bloc resection and lymph node dissection.

This article is available for continuing medical education credit at CME.TheOncologist.com

Parathyroid carcinoma is an indolent but ultimately life-threatening malignancy. Due to the lack of definitive diagnostic markers and overlapping clinical features of benign primary hyperparathyroidism (PHPT), this disease is often misdiagnosed as parathyroid adenoma. Therefore, a high index of suspicion preoperatively and early intraoperative recognition with en bloc surgical resection are crucial for favorable outcome. Owing to the rarity of the disease, little is known about the molecular pathogenesis of parathyroid carcinoma. Here, we review the literature to present current understanding of the disease and provide new information on gene expression and use of intraoperative parathyroid hormone (PTH) monitoring in the surgical management of this rare malignancy. Specifically, using microarray transcriptome analysis of an unequivocal case of parathyroid carcinoma and a biopsy from the same patient's normal parathyroid gland, we identify APP, CDH1, KCNJ16, and UCHL1 as differentially expressed genes in parathyroid carcinoma. Further, using case records from four cases of unequivocal parathyroid carcinoma, we compared intraoperative PTH kinetics of these patients to 475 patients with benign PHPT, and show that intraoperative PTH monitoring is accurate in predicting postoperative normocalcemia in initial en bloc operations for parathyroid carcinoma.

The epidemiology, risk factors, pathogenesis, prognostic factors, and treatment of patients with meningioma are examined.

Learning Objectives

After completing this course, the reader will be able to: Evaluate patients with grade II and III meningiomas for possible implementation of adjuvant radiation therapy.Describe options of systemic treatment of refractory meningiomas with hydroxyurea, somatostatin analogues, or CAV multi-agent chemotherapy.

This article is available for continuing medical education credit at CME.TheOncologist.com

Although meningiomas are the most common tumor in the central nervous system, their incidence, epidemiology, and clinical outcomes have historically been poorly defined. This has been attributed to their benign course, difficulty obtaining histologic diagnosis, and lack of uniform database registration. Their clinical behavior can range from a silent incidentaloma to a lethal tumor. Projections of an aging population should raise medical awareness of an expectant rise in the incidence of meningiomas. This disease increases with advancing age, has a female predilection, and exposure to ionizing radiation is associated with a higher risk for disease development. There have been minimal advances in treatment, except in radiation therapy. Although no U.S. Food and Drug Administration–approved systemic therapy exists, there are treatment options that include hydroxyurea and sandostatin. Currently, no molecularly targeted therapy has provided clinical benefit, although recurring molecular alterations are present and novel therapies are being investigated.