Hyperthermia and radiation therapy in the treatment of recurrent Merkel cell tumors

A high incidence of local recurrence, spread to regional lymph nodes, and distant metastases has been reported after surgical excision of Merkel cell tumors (MCT). The use of postoperative radiation therapy and/or chemotherapy is reviewed from the literature. Despite adjuvant treatment, local tumor recurrences frequently develop. Two patients are presented with metastatic MCT recurrent in previously irradiated sites who had excellent clinical responses and local control following retreatment with local hyperthermia in conjunction with low to moderate dose radiation therapy. These patients represent the first reported use of hyperthermia in the management of MCT. The encouraging local responses described suggest a potential role for the use of hyperthermia and concomitant radiation therapy in the treatment of recurrent MCT.     

Evidence and interdisciplinary consensus-based German guidelines: surgical treatment and radiotherapy of melanoma

The primary treatment of a melanoma is surgical excision. An excisional biopsy is preferred, and safety margins of 1 cm for tumor thickness up to 2 mm and 2 cm for higher tumor thickness should be applied either at primary excision or in a two-step procedure. When dealing with facial, acral or anogenital melanomas, micrographic control of the surgical margins may be preferable to allow reduced safety margins and conservation of tissue. The sentinel lymph node biopsy should be performed in patients whose primary melanoma is thicker than 1.0 mm and this operation should be performed in centers where both the operative and nuclear medicine teams are experienced. In clinically identified lymph node metastases, radical lymph node dissection is considered standard therapy. If distant metastases involve just one internal organ and operative removal is feasible, then surgery should be seen as therapy of choice. Radiation therapy for the primary treatment of melanoma is indicated only in those cases in which surgery is impossible or not reasonable. In regional lymph nodes, radiation therapy is usually recommended when excision is not complete (R1 resection) or if the nodes are inoperable. In distant metastases, radiation therapy is particularly indicated in bone metastases, brain metastases and soft tissue metastases.     

Extraneural metastatic medulloblastoma in an adult

Summary Medulloblastoma is a rare malignancy in adults, accounting for approximately 1% of all primary brain tumors. Extraneural metastases have been reported in 10–30% of cases and most commonly involve bone; rarely lymph nodes, visceral organs and bone marrow may be involved with disease. We report here our experience with a 26 year-old woman with medulloblastoma treated with gross total resection followed by radiation therapy to her craniospinal axis. She subsequently developed widespread metastatic disease involving bone exclusive of the calvarium and spine for which multi-agent salvage chemotherapy was utilized with initial good clinical response. She␣later relapsed within the lymph nodes and soft tissues of the pelvis and eventually suffered a local recurrence within the posterior fossa. The treatment of medulloblastoma, particularly salvage therapy following disease recurrence, is reviewed.     

Radiotherapy for cutaneous malignant melanoma: rationale and indications

The use of radiation as adjuvant therapy for patients with cutaneous malignant melanoma has been hindered by the unsubstantiated belief that melanoma cells are radioresistant. An abundance of literature has now demonstrated that locoregional relapse of melanoma is common after surgery alone when certain clinicopathologic features are present. Features associated with a high risk of primary tumor recurrence include desmoplastic subtype, positive microscopic margins, recurrent disease, and thick primary lesions with ulceration or statellitosis. Features associated with a high risk of nodal relapse include extracapsular extension, involvement of four or more lymph nodes, lymph nodes measuring at least 3 cm, cervical lymph node location, and recurrent disease. Numerous studies support the efficacy of adjuvant irradiation in these clinical situations. Although data in the literature remain sparse, evidence also indicates that elective irradiation is effective in eradicating subclinical nodal metastases after removal of the primary melanoma. Consequently, there may be an opportunity to integrate radiotherapy into the multimodality treatment of patients at high risk of subclinical nodal disease, particularly those with an involved sentinel lymph node. Such patients are known to have a low rate of additional lymph node involvement, and thus in this group, a short course of radiotherapy may be an adequate substitute for regional lymph node dissection. This will be the topic of future research.     

Preliminary report of a cooperative randomized study for the treatment of localized small cell lung carcinoma.

An analysis of 171 of 222 entered patients with localized small cell lung cancer after randomization to four treatment arms has been carried out. All patients received radiation therapy (4500 rad to the primary tumor and draining lymph nodes). One group of patients received no other treatment; the second group received cyclophosphamide (CY) during radiation therapy and CY and CCNU following radiation therapy; the third group received prophylactic brain irradiation (3000 rad in 10 fractions); and the fourth group received both prophylactic CY and CCNU as well as brain irradiation. Patients who did not receive CY and CCNU initially were treated upon relapse with the same CY/CCNU regimen. There is a significant deference in the incidence of brain metastases between the arms containing prophylactic brain irradiation or treatment at time of recurrence. The difference in brain metastases following prophylactic chemotherapy or chemotherapy at time of recurrence is of borderline significance. All treatment arms remain coded, but 17–19% of patients in each treatment arm had local and 43–52% had distant relapse. Two percent of patients had severe esophagitis and pneumonids related to the radiation therapy regimen. Twenty to 24% of the patients in the chemotherapy groups have had severe bone marrow and GI toxicity. No patients have died of treatmentrelated toxicity. Patients with complete responses have a significantly longer median survival than those with partial or no responses.     

Intermediate- and high-risk melanoma

Opinion statement Intermediate and high risk for recurrence melanoma comprise a unique subset of patients with surgically treatable melanoma for whom cure is possible but relapse and distant metastases likely. Strategies to improve the prognosis for such patients with effective adjuvant therapies are critical. In recent randomized trials conducted by the cooperative groups in the United States of patients at high risk for recurrence (patients with thick primary melanomas and those with regional lymph node metastases) administered adjuvant therapy with high-dose interferon alfa-2b (HDI), relapse-free survival and overall survival rates improved significantly. Research efforts in this area continue to assess the role of intermediate-dose interferon, but there is no convincing evidence of success of the lower-dose regimens, despite the reduction in toxicity. For a subset of patients at highest risk (two or more involved lymph nodes), a regimen of therapy for metastatic stage IV melanoma (interleukin-2 based biochemotherapy) is being compared with HDI in an ongoing phase III trial. For intermediate-risk melanoma, no effective adjuvant therapy is available. For such patients, enrollment in ongoing clinical trials assessing the role of shorter courses of HDI or vaccines should be encouraged.     

Postmastectomy Radiation Therapy in Patients With Minimally Involved Lymph Nodes: A Review of the Current Data and Future Directions

Radiation therapy for patients with pN1mi or pN1 disease breast cancer undergoing mastectomy has been debated for a long time. Even in low metastatic burden in sentinel node biopsy, occult non-sentinel axillary nodal involvement can exist. Radiotherapy can sterilize axillary metastatic burden and seems to contribute a very low local recurrence rate in mastectomy patients with minimally involved lymph nodes. However, it should be considered that systemic therapy is evolving and the local recurrence difference between radiotherapy and no radiotherapy is relatively small. Regarding postmastectomy radiotherapy in patients pN1mi or pN1 cancer, published prospective clinical trial results should be considered; however, there are no such relevant results of clinical trials yet. Consideration of postmastectomy radiation therapy in pN1mi or pN1 patients should be based on identifying the high-risk group in terms of recurrence, stage, or tumor biology. When radiotherapy is determined, radiation oncologists should attempt individualized treatment approaches, such as irradiation field, and consider specific settings, such as neoadjuvant therapy. In this review, the role of radiotherapy in mastectomy patients with minimally involved lymph nodes and the relevant considerations are discussed.     

Strahlentherapie des kutanen Melanoms

Radiotherapy plays an important role in the multidisciplinary therapy of malignant cutaneous melanoma. Radiotherapy can provide long-term local control for patients with inoperable tumors or microscopic/macroscopic residual disease after surgical resection. In addition postoperative radiotherapy of regional lymph nodes reduces the risk of lymphatic recurrence. In palliative care radiotherapy decreases the symptoms caused by metastases and thus improves the quality of life of patients.     

Adjuvant irradiation for cervical lymph node metastases from melanoma

BACKGROUND: The risk of regional disease recurrence after surgery alone for lymph node metastases from melanoma is well documented. The role of adjuvant irradiation remains controversial. METHODS: The medical records of 160 patients with cervical lymph node metastases from melanoma were reviewed retrospectively. Of these, 148 (93%) presented with clinically palpable lymph node metastases. All patients underwent surgery and radiation to a median dose of 30 grays (Gy) at 6 Gy per fraction delivered twice weekly. Surgical resection was either a selective neck dissection in 90 patients or local excision of the lymph node metastasis in 35 patients. Only 35 patients underwent a radical, modified radical, or functional neck dissection. RESULTS: At a median follow-up of 78 months, the actuarial local, regional, and locoregional control rates at 10 years were 94%, 94%, and 91%, respectively. Univariate analysis of patient, tumor, and treatment characteristics failed to reveal any association with the subsequent rate of local or regional control. The actuarial disease-specific (DSS), disease-free, and distant metastasis-free survival (DMFS) rates at 10 years were 48%, 42%, and 43%, respectively. Univariate and multivariate analyses revealed that patients with four or more involved lymph nodes had a significantly worse DSS and DMFS. Nine patients developed a treatment-related complication requiring medical management, resulting in a 5-year actuarial complication-free survival rate of 90%. CONCLUSIONS: Adjuvant radiotherapy resulted in a 10-year regional control rate of 94%. Complications for all patients were rare and manageable when they did occur. The authors recommend adjuvant irradiation for patients with extracapsular extension, lymph nodes measuring 3 cm in size or larger, the involvement of multiple lymph nodes, recurrent disease, or any patient having undergone a selective therapeutic neck dissection.     

Brain metastasis in melanoma: clinical activity of CTLA-4 antibody therapy

Melanoma metastasizes frequently to the brain, and brain metastases generally drive the prognosis of melanoma patients. Surgical and radiation therapy improve the outcome of selected melanoma patients with brain metastasis, while systemic treatment using cytotoxic agents still plays a limited role. Temozolomide and fotemustine are preferentially used in melanoma patients with brain metastases in the United States and in Europe, respectively, with modest clinical activity. However, the results obtained with either agent are still limited, and efforts are needed to improve the outcome of these patients who are generally excluded from clinical trials. Among therapeutic agents in development, antibodies that block the interaction of cytotoxic T-lymphocyte-associated antigen (CTLA-4) with its ligands B7.1 and B7.2 and thus enhance antitumor immune responses have shown clinical benefit in patients with metastatic melanoma, including durable control of brain metastases. This chapter reviews the current data and the rationale for ongoing and future trials of combination cytotoxic plus immunomodulatory therapy by US and Italian multicenter trial groups.     

Treatment of melanoma brain metastases: a new paradigm

Brain metastases occur commonly in patients with metastatic melanoma, are associated with a poor prognosis, and cause significant morbidity. Both surgery and stereotactic radiosurgery are used to control brain metastases and, in selected patients, improve survival. In those with extensive brain involvement, whole-brain radiotherapy can alleviate symptoms. Historically, systemic therapy has had little role to play in the management of melanoma brain metastases; however, early clinical trials of BRAF inhibitors have shown promising activity. This review examines the evidence for local and systemic treatments in the management of patients with melanoma brain metastases. We present a new treatment algorithm for melanoma patients with brain metastases, which integrates the evolving evidence for the use of BRAF inhibitors.     

Metastasentherapie bei malignem Melanom mit unbekanntem Primärtumor

Malignant melanoma from unknown primary tumor is always a metastatic tumorous disease. The clinical presentation is often regional tumor manifestations in skin, subcutis, soft tissue or lymph nodes but may also show visceral metastases in lungs, liver, brain, bones, spleen or gastrointestinal manifestations. Diagnosis and treatment cannot always be separated. As multiple sites are frequently involved the individual treatment plan should be devised by an interdisciplinary tumor board after whole body staging. Documented local metastases in skin, soft tissue or lymph nodes are classified as stage III melanoma and treated accordingly. The prognosis has been shown to be equal to or even better than in cases with known primary tumor. Even after curative resection further recurrences are common but can often be re-resected with curative intent. Palliative treatment options, such as interventional procedures, radiotherapy, chemotherapy, novel kinase inhibitors and immunotherapy depend on tumor extent and the sites of the metastases.     

Merkel cell carcinoma

Opinion statement Merkel cell carcinoma is a rare cutaneous neoplasm most commonly affecting the head and neck of elderly white patients. Even with treatment, Merkel cell carcinoma has a strong propensity toward local recurrence, lymphatic spread, and distant metastasis. Because of its rarity and the subsequent lack of well-controlled clinical trials, no single standard of care exists for the treatment of this aggressive tumor. In our institution, primary lesions are excised with wide margins or by Mohs’ micrographic surgery. After local removal, the excision site is treated locally with external radiation therapy. Sentinel lymph node mapping and biopsy are performed. Patients with tumor within a sentinel lymph node undergo lymph node dissection and radiation to the lymphatic basin. Adjuvant chemotherapy is offered to high-risk patients with local disease and to patients with metastases. Patients with distant metastases are treated with a combination of salvage chemotherapy and radiation therapy.     

Analysis of treatment modalities and their failures in stage IB cancer of the cervix

This is a retrospective analysis of 240 patients who had clinical Stage IB cancer of the cervix treated with radiation between 1969 and 1980. Of these, 186 patients were treated with a combination of external and intracavitary radiation therapy, and 54 patients received adjuvant postoperative radiation therapy. The minimum follow-up was 5 years. In the group who received only radiation therapy, the overall recurrence in 170 patients (excluding 16 patients found at laparotomy to have unresectable disease) was 17% (29 of 170); pelvic recurrence was 9% and distant metastases alone was 6%. In the group who received the adjuvant postoperative radiation therapy, 16 patients had a simple hysterectomy followed by vaginal ovoid and/or external pelvic irradiation for an unexpected Stage IB cancer of the cervix. Their overall recurrence was 37.5% (6 of 16). Pelvic recurrence was the most common treatment failure with a recurrence of 31%. Significant prognostic factors were depth of stromal invasion and status of surgical margins. Thirty-eight patients had a radical hysterectomy followed by postoperative radiation therapy because of positive pelvic lymph nodes and/or close surgical margins. In patients with positive pelvic lymph nodes, the overall recurrence was 39% (9 of 23); pelvic recurrence was 13%. Distant metastases, the most common treatment failure, was 26%. In seven patients with close surgical margins, five recurred in the pelvis. There was no distant metastases without pelvic failure. Five of eight patients with close paracervical margins recurred in the pelvis. All five of these patients were treated with vaginal ovoid irradiation alone. Whole pelvic irradiation plus vaginal ovoid irradiation is necessary in those with close paracervical margins. The vaginal ovoid irradiation alone should be limited to very selected patients with positive vaginal margins only.     

Locally advanced melanoma: results of postoperative hypofractionated radiation therapy

BACKGROUND: High rates of locoregional recurrence have been reported from surgical series of locally advanced melanoma. In this study, the outcomes of patients treated with surgery and postoperative hypofractionated radiation therapy were reviewed to assess local recurrence and survival. METHODS: From 1989 to 1998, 174 patients with International Union Against Cancer Stage I-III melanoma received postoperative radiation therapy, either as a component of their initial management or following surgery for recurrence. Radiation was delivered to the primary site in 35 cases and involved regional lymph nodes in 139. The indications for irradiation included microscopically positive surgical margins or other adverse pathologic features. All patients received a hypofractionated schedule of 30-36 grays (Gy) in 5-7 fractions over 2.5 weeks. RESULTS: Recurrence within the radiation fields was identified in 20 patients (11%) at a median time of 6 months. There was no difference in recurrence rates for patients with microscopically positive margins compared with other indications for adjuvant treatment. The main complication of treatment was symptomatic arm lymphedema in 58% of patients following axillary dissection and postoperative irradiation. The median disease specific survival for the entire group was 25 months from radiation therapy, and the 5-year survival was 41%. The only factor that predicted significantly for decreased survival was infield recurrence (the median survival periods were 13 months and 35 months for those with and without infield recurrence, P < 0.0001). The median time to the development of distant metastasis was 19 months. CONCLUSIONS: Despite the high incidence of distant metastasis, locoregional control remains an important goal in the management of melanoma. Compared with published surgical data, postoperative adjuvant radiation therapy given according to a hypofractionated schedule was effective in reducing local recurrence in patients at high risk of locoregional failure.     

Inefficacy of F-18 fluorodeoxy-D-glucose-positron emission tomography scans for initial evaluation in early-stage cutaneous melanoma

BACKGROUND: The purpose of the current study was to determine the sensitivity and specificity of initial F-18 fluorodeoxy-D-glucose-positron emission tomography (FDG-PET) scanning for detection of occult lymph node and distant metastases in patients with early-stage cutaneous melanoma. METHODS: The authors conducted a prospective nonrandomized clinical trial. Inclusion criteria were patients with cutaneous melanoma tumors > 1.0 mm Breslow thickness, local disease recurrence, or solitary intransit metastases without regional lymph or distant metastases by standard clinical evaluation. All patients underwent whole-body FDG-PET scanning before surgical therapy. Abnormal PET findings were studied by targeted conventional imaging and/or biopsy. FDG-PET scans were interpreted in a blinded fashion. Regional lymph node basins were staged by sentinel lymph node biopsy (SLNB). PET scan findings in regional lymph nodes were compared with histology of SLNB specimens. Abnormal distant PET scan findings were studied with repeat conventional scan imaging at 3-6 months and were correlated with the first site(s) of clinical disease recurrence. Blinded PET scan findings were correlated with all information to determine sensitivity and specificity. RESULTS: There were 144 assessable patients with a mean tumor depth of 2.8 mm. The median follow-up for these patients was 41.4 months. Blinded interpretations of FDG-PET scan images showed that 31 patients (21%) had signs of metastatic disease, 13 patients had probable regional lymph node metastases, and 18 patients had 23 sites of possible distant metastases. SLNB and/or follow-up demonstrated regional lymph node metastases in 43 of 184 lymph node basins in 40 patients (27.8%). Compared with all clinical information, FDG-PET scan sensitivity for detection of regional lymph node metastases was 0.21 (95% confidence [CI], 0.10-0.36) and specificity was 0.97 (95% CI, 0.93-0.99). No distant sites were confirmed to be true positive by targeted conventional imaging/biopsy at the time of presentation. Thirty-four patients (23.6%) presented with 54 foci of metastatic disease at initial disease recurrence. FDG-PET scan sensitivity for prediction of the first site(s) of clinical disease recurrence was 0.11 (95% CI, 0.04-0.23). Excluding patients with brain metastases, FDG-PET scan sensitivity for detection of occult Stage IV disease in patients was 0.04 (95% CI, 0.001-0.20) and specificity was 0.86 (95% CI, 0.79-0.92). CONCLUSIONS: FDG-PET scanning did not impact the care of patients with early-stage melanoma already staged by standard techniques. Routine FDG-PET scanning was not recommended for the initial staging evaluation in this population.     

Adjuvant postoperative radiation therapy following radical hysterectomy in stage IB CA of the cervix--analysis of treatment failure

Among 240 patients treated by radiation therapy for clinical Stage IB cancer of the cervix between 1969 and 1980, 38 patients received postoperative pelvic radiation therapy after radical hysterectomy because of positive pelvic lymph nodes and/or close surgical margins. The overall recurrence was 45% (17 of 38), and the major complication rate was 15% in minimum 5-year follow-up. In patients with positive pelvic lymph nodes, the pelvic recurrence was 13% (3 of 23). However, distant metastases alone was 26% (6 of 23), which was the most common treatment failure. In 11 patients with close surgical margins, eight patients had paracervical margins and three had vaginal margins. All five patients with paracervical margins treated with vaginal ovoid irradiation only had pelvic recurrence. No local failure occurred in the other three patients treated with whole pelvic irradiation. All patients with vaginal margin alone treated with vaginal ovoid or whole pelvic irradiation had no recurrence of cancer in the pelvis. On the basis of our data, whole pelvic irradiation with or without vaginal ovoid irradiation is necessary in those with a close paracervical margin. In patients with close vaginal margin, whole pelvic irradiation with or without vaginal ovoid irradiation is recommended. The vaginal ovoid irradiation alone should be limited to very selected cases.     

Vulvar melanoma: is there a role for sentinel lymph node biopsy?

BACKGROUND: The objective of this study was to evaluate the author's recent, preliminary experience with the sentinel lymph node procedure in patients with vulvar melanoma and to compare this experience with treatment and follow-up of patients with vulvar melanomas who were treated previously at their institution. METHODS: From 1997, sentinel lymph node procedure with the combined technique (99mTechnetium-labeled nanocolloid and Patente Blue-V) was performed as a standard staging procedure for patients with vulvar melanoma with a thickness > 1 mm and no clinically suspicious inguinofemoral lymph nodes. For the current study, clinicopathologic data from all 33 patients with vulvar melanoma who were treated between 1978 and 2000 at the University Hospital Groningen were reviewed and analyzed. RESULTS: From January 1997 until December 2000, identification of sentinel lymph nodes was successful in all nine patients who were referred for treatment of vulvar melanoma. Three patients underwent subsequent complete inguinofemoral lymphadenectomy because of metastatic sentinel lymph nodes. In follow-up, groin recurrences (in-transit metastases) occurred in two of nine patients, both 12 months after primary treatment. Both patients had melanomas with a thickness > 4 mm and previously had negative sentinel lymph nodes. There was a trend toward more frequent groin recurrences in patients after undergoing the sentinel lymph node procedure (2 of 9 patients) compared with 24 historic control patients (0 of 24 patients; P = 0.06). Five of 33 patients developed local recurrences: Two patients had groin recurrences, and 11 patients developed distant metastases. Twelve patients died of vulvar melanoma. Seventeen patients with a median follow-up of 66 months (range, 9-123 months) are currently alive (overall survival rate, 52%). CONCLUSIONS: Although the numbers were small, this study showed that the sentinel lymph node procedure is capable of identifying patients who have occult lymph node metastases and who may benefit from lymphadenectomy for locoregional control and prevention of distant metastases. However, the data also suggest that the sentinel lymph node procedure may increase the risk of locoregional recurrences (in-transit metastases), especially in patients with thick melanomas. The potential role of the sentinel lymph node procedure as an alternative method of lymph node staging in patients with vulvar melanoma needs further investigation only within the protection of clinical trials and probably should be restricted to patients with melanomas with intermediate thickness (1-4 mm).     

Management of metastatic melanoma patients with brain metastases

Brain metastases seem to be an almost inevitable complication in patients with metastatic melanoma. Except for the rare patients who can undergo successful surgical resection of brain metastases, current management strategies do not appear adequate and result in a poor outcome (median survival, 2–4 months). In recent small series, stereotactic radiosurgery or gamma-knife treatment has suggested improvement in local control compared with whole brain radiation therapy. We have recently shown prolonged survival (11.1 months) using a multimodality treatment approach in 44 sequential patients with melanoma brain metastases. A subsequent study demonstrated that the outcome of biochemotherapy for metastatic melanoma is not affected by the presence or absence of brain metastases. Our results suggest that the outcome of patients with melanoma brain metastases can be improved using a multidisciplinary management strategy.     

Radiation therapy following lymph node dissection in melanoma patients: treatment, outcome and complications

Adjuvant radiation treatment following lymph node dissection in the melanoma patient has been suggested and investigated in an attempt to gain regional control and improve survival. In this review we discussed the treatment, the loco-regional control, disease-free and survival rates and complications. Historically melanoma has been thought of as a relatively radioresistant tumour. Nowadays, radiation delivered according to the hypofractionated schedule is the most used, although there are no data to confirm that this schedule improves the therapeutic impact. Almost all the reviewed studies were retrospective, which could have led to an underestimation of the true incidence of the treatment toxicity and morbidity. Adjuvant radiotherapy after lymph node dissection for metastases of melanoma seems to improve loco-regional control without improving overall survival. The available data indicate the need for improved regional control rates in patients with extranodal extension, multiple involved nodes (more than three) and patients with large involved nodes (larger than 3 cm). The complications seem manageable and consist mainly of fibrosis and edema.